Review ArticlePropolis A Complex Natural Product witha Plethora of Biological Activities That Can BeExplored for Drug Development
Ricardo Silva-Carvalho12 Faacutetima Baltazar12 and Cristina Almeida-Aguiar3
1Life and Health Sciences Research Institute (ICVS) School of Health Sciences University of Minho 4710-057 Braga Portugal2ICVS3Brsquos PT Government Associate Laboratory Guimaraes 4710-057 Braga Portugal3Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB) Biology DepartmentUniversity of Minho 4710-057 Braga Portugal
Correspondence should be addressed to Cristina Almeida-Aguiar cristinaaguiarbiouminhopt
Received 25 February 2015 Revised 10 May 2015 Accepted 12 May 2015
Academic Editor Jairo Kennup Bastos
Copyright copy 2015 Ricardo Silva-Carvalho et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited
The health industry has always used natural products as a rich promising and alternative source of drugs that are used in the healthsystem Propolis a natural resinous product known for centuries is a complex product obtained by honey bees from substancescollected from parts of different plants buds and exudates in different geographic areas Propolis has been attracting scientificattention since it has many biological and pharmacological properties which are related to its chemical composition Several invitro and in vivo studies have been performed to characterize and understand the diverse bioactivities of propolis and its isolatedcompounds as well as to evaluate and validate its potential Yet there is a lack of information concerning clinical effectivenessThegoal of this review is to discuss the potential of propolis for the development of new drugs by presenting published data concerningthe chemical composition and the biological properties of this natural compound from different geographic origins
1 Introduction
Over the years nature is continually surprising with diver-sified natural compounds that can be promising sources forthe discovery of new drugs important in medicine [1] Infact approximately half of the currently available drugs wereobtained from natural compounds or related [2] The use ofnatural products as an essential route to new pharmaceuticalleads is continually growing and is a research field of enor-mous interest because the different structural range of naturalcompounds can provide lead compounds for therapeuticimprovement based on rationalized molecular modifications[3 4] It is well known that scientists have curiosity in herbsand other natural plant products for research however onlyin the last years the interest in modified plant productsby animals which normally have been largely ignored andwasted has been increased [5 6]
Propolis a complex mixture of compounds also calledbee glue is a natural resinous product that honeybees collectfrom several plants and mix it with beeswax and salivaryenzymes (120573-glucosidase) [7ndash11] As inferred for the meaningof the Greek word propolismdashpro- for or in defence andpolis the city [10]mdashbees use propolis on their hives asprotection against predators and microorganisms to repairdamage as a thermal isolator and to build aseptic localsto prevent microbial infection of larvae [7 9 10 12] Sinceancient times propolis has been used by humans to meetthe needs of health and food preservation [5] but only inthe last years the interest in this complex natural producthas increased due to its broad spectrum of biological andpharmacological properties [12ndash14] Propolis is a lipophilicmaterial that is hard and breakable when cold but softflexible and very sticky when warm it possesses an enjoyablearomatic smell and different coloration including brown
Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2015 Article ID 206439 29 pageshttpdxdoiorg1011552015206439
2 Evidence-Based Complementary and Alternative Medicine
green and red among others [5 7 12] In terms of chemicalcomposition it is generally composed of 50 resin 30wax 10 essential oils 5 pollen and 5 other substanceswhich includeminerals and organic compounds like phenolicacids (cinnamic and caffeic acid) or their esters flavonoids(flavones flavanones flavonols and dihydroflavonols chal-cones) terpenes aromatic aldehydes and alcohols fatty acidsstilbenes and 120573-steroids [8 9] Analysis of different samplesrevealed that propolis chemical composition is difficult tostandardize because it depends on different phytogeographiccharacteristics like vegetation season and environmentalconditions of the site of collection as bees select differentplants in different habitats for propolis production [6 8 9]
Several in vitro and in vivo studies have been describingthe plethora of biological activities and chemical profilesof propolis from different geographic origins This reviewhighlights published data about such works focusing on theantimicrobial anti-inflammatory antioxidant immunomod-ulatory and antitumor activities of different propolis types inorder to unravel the potential of this natural compound forthe development of new drugs
2 Use of Propolis in Ancientand Current Times
Propolis is not a new discovery Since beersquos domesticationmen explore its products to their own benefit and propolisone of the most important chemical weapons of bees is noexception having been employed extensively since almostimmemorial times [6 13 15ndash17] It is stated that propolis usedates back to ancient times at least to 300 BC where it wasused in folk medicine and other activities in many parts ofthe world [16] It was familiar to the Egyptians in particularby the priests who controlled medicine and chemistry andknew very well propolis antiputrefactive properties Theylearned from the bees the embalming capacity of propolis asthis natural product is used to perform the mummificationof corpses and prevent spread of infections The Greekand the Roman physicians also acknowledged the potentialof propolis by employing it in wound treatment as anantiseptic and cicatrizing agent and as mouth disinfectantThe Persians described propolis as a drug capable of actingagainst eczemas myalgia and rheumatism Populations ofthe new world like Incas also used propolis as an antipyreticagent
Between the 17th and 20th century this natural productbecame very popular in Europe In 1969 in the former Unionof Soviet Socialist Republics (USSR) the use of propolis wasaccepted in human and veterinary medicine with severalapplications including the treatment of tuberculosis wherethe regression of lung problems and recovery of appetitewere observed Also it was believed to cure some diseases infolk Georgian medicine During World War II (1939ndash1945)doctors used propolis to treat wounds [15ndash17] but only in1985 in Japan propolis was considered as very promising inpharmacology Before that propolis was considered a prod-uct without market value especially because its productionis low and affects honey production Nowadays propolisis an important product in alternative medicine in Japan
being widely imported from Brazil [18] In the 17th centurythe Italian Antonio Stradivari who is considered the mostsignificant and the greatest crafter of string instruments likeviolins used propolis as an ingredient in the varnish of hisinstruments Curiously such as in the 17th century propolisis currently used in rosin for stringed instruments and in therepair of accordions [16]
Propolis is one of the few natural products that main-tained popularity for a long time although it is not considereda therapeutic agent in conventional medicine Actually it iswidely used as a component in pharmaceutical and cosmeticproducts such as antiacne creams facial and body creamsointments and lotions and several formulations for oralhygiene [15 16] It is also used in some foods and beveragesor simply as food supplement or healthy drinks This namewas attributed to the drinks because it is thought that propolisimproves human health and prevents diseases such as heartdisease or diabetes among others [19]
3 Origin and Composition of Propolis
Propolis knowledge has registered an important evolutionover time due to exhaustive studies regarding its chem-ical composition and biological activities In the 60s itwas thought that despite its complexity propolis chemicalcomposition was more or less constant Nevertheless inthe following years analysis of a large number of samplesfrom different geographic origins revealed that chemicalcomposition of propolis is highly variable and also difficultto standardize because it depends on factors such as thevegetation season and environmental conditions of the siteof collection [6 8 9] Marcucci [7] and Bankova et al [10]registered more than 300 substances in propolis and recentreports showed the presence of compounds never mentionedbefore [12 17 20 21]
Generally the main constituents of propolis are resin andvolatiles which are substances obtained from a variety ofbotanical processes in different parts of plants and beeswaxsecreted by the bees [9] Typical compounds are summarizedin Table 1 As can be seen plant sources vary among thedifferent parts of the globe leading to panoply of compoundsIn a review on propolis standardization different resin typeswere proposed poplar propolis birch green red ldquoPacificrdquoand ldquoCanarianrdquo [9 12] Samples of poplar propolis (egfrom Europe North America New Zealand and temperatezones of Asia) are mainly composed of flavonoids phenolicacids and their esters [10 20 22] clearly different fromother propolis types (Table 1) Portuguese propolis despitesimilar to the ones found in European samples also containsnew methylated esterified and hydroxylated derivatives offlavonoids and pinocembrinpinobanksin derivatives con-taining a phenylpropanoic acid derivative moiety in theirstructure [20 21] Our group recently showed that propolisfrom Pereiro (district of Guarda Beira Alta) (Figure 1) has ahigh concentration of phenolic components [23]
Poplar-type propolis is undoubtedly themost studied onebut there are many other propolis types Recent studies haverevealed a new type of European propolis Mediterraneanpropolis This type of propolis is distinguished by the high
Evidence-Based Complementary and Alternative Medicine 3
Figure 1 Crude sample of propolis from Pereiro obtained in thecentral region of Portugal (Guarda)The sample was kindly suppliedby Engineer Pedro Fernandes (Mel do Abel)
concentration of diterpenoids and is found in many regionslike Greece [24 25] Switzerland [26]Malta [27] Turkey [28ndash30] or Algeria [28 31]
Propolis from tropic regions like Brazil CubaVenezuelaand Chile has been attracting much attention in thelast years due to its particular chemical profiles Preny-lated phenylpropanoids prenylated p-coumaric acids ace-tophenones diterpenic acids and caffeoylquinic acids wereshown to be very common and abundant in propolis fromBrazil mainly from the south-eastern region [9 10 21]The flavonoids kaempferide and isosakuranetin and someamounts of kaempferol were also found in Brazilian samples[32] Additionally red propolis from the northeast regionsof Brazil presents high concentrations of phenolic acids andthe flavonoids formononetin isoliquiritigenin liquiritigeninmedicarpin and biochanin A [33ndash35] Cuban propolis hasa peculiar enrichment in polyisoprenylated benzophenonesmore specifically nemorosone and a minor content of amixture of xanthochymol and guttiferone E [9 36] makingthis type of sample chemically distinct from both Europeanand Brazilian propolis Propolis from Venezuela is alsocomposed of polyisoprenylated benzophenones in additionto the usual constituents found in samples of tropical regions[9 37 38]
Information about the chemical composition of Aus-tralian propolis is very limited despite the great biodiversityof the island Propolis from Kangaroo Island is mainlycomposed of stilbenes some of them being prenylated Ad-ditionally it has also some prenylated cinnamic acids andflavonoids [39] like 210158403101584041015840-trimethoxychalcone 21015840-hy-droxy-3101584041015840-dimethoxychalcone 2101584041015840-dihydroxy-31015840-metho-xychalcone 57-dihydroxy-23-dihydroflavonol 3-acetate (pi-nobanksin 3-acetate) and 57-dihydroxy-6-methoxy-23-dihydroflavonol 3-acetate [40] Western Australian propolisis composed of Xanthorrhoeol pterostilbene sakuranetinand pinostrobin [41] Propolis of Australian stingless bees(Tetragonula carbonaria) is composed of C-methylatedflavanones [42]
ldquoPacificrdquo propolis (eg Okinawa Taiwan Hawaii Indo-nesia and Myanmar) is another particular type of propolisA new family of compounds the prenylflavonoids morespecifically isonymphaeol-B was identified in Okinawapropolis although three already known compoundsmdashnym-phaeol-A nymphaeol-B and nymphaeol-Cmdashhave also
been isolated in three samples [43] As Okinawan propolisHawaiian propolis is also composed of nine prenylflavonoids[44] Taiwanese propolis is composed of eight prenylfla-vanones nymphaeol-A nymphaeol-B and nymphaeol-Cpropolins A B and E isonymphaeol B and 31015840-geranyl-naringenin [45] In another sample of the Pacific regionthe Indonesian propolis an inseparable mixture of fouralk(en)ylresorcinols (5-pentadecylresorcinol 5-(81015840Z111015840Z-heptadecadienyl)-resorcinol 5-(111015840Z-heptadecenyl)-resor-cinol and 5-heptadecylresorcinol) along with four prenylfla-vanones propolins D C F and G and three cycloartane-type triterpenes mangiferolic acid isomangiferolic acidand 27-hydroxyisomangiferolic acid was identified [46]Additionally fractioning of propolis extracts from Myanmarled to the isolation of two new cycloartane-type triterpenestogether with 13 cycloartanes and four known prenylatedflavanones [47] Thailand propolis which might bepossibly obtained from Styrax trees comprises not onlythe typical compounds of temperate regions but also thetwo new phenylallylflavanones (710158401015840S)-8-[1-(41015840-hydroxy-31015840-methoxyphenyl)prop-2-en-1-yl]-(2S)-pinocembrin and (E)-cinnamyl-(E)-cinnamylidenate [48] In propolis fromCanaryIslands a different phenolic profile was found furofuranlignans being the main compounds Six furofuran lignanswere isolated and characterized as sesamin episesaminmethyl xanthoxylol aschantin sesartenin and yangambinPropolis also contains sugars and sugar alcohols [10 49]Many studies with African propolis from different regionslike Kenya Cameroon Congo Oman and Ethiopia showedthat triterpenoids are major chemical components [50ndash53]Southern Nigeria propolis is uncommon since it presentsprenylated isoflavonoids like Brazilian red propolis and ahigh abundance of stilbenoid compounds [54]
Propolis additionally contains minerals such as mag-nesium calcium iodine potassium sodium copper zincmanganese and iron some vitamins like B1 B2 B6 CE and D as well as provitamin A a few fatty acids andalso some enzymes derived from bee glandular secretion orpossibly from pollen like succinic dehydrogenase adenosinetriphosphatase glucose-6-phosphatase acid phosphatase120572-amylase 120573-amylase 120572-lactamase 120573-lactamase maltaseesterase and transhydrogenase [17 55] Polysaccharides likestarch and the di- and monosaccharaides glucose fructoseribose rhamnose talose gulose and saccharose are com-monly present in propolis too [55]
4 Biological Properties and TherapeuticActivity of Propolis
Despite propolis popularity over time it is not consid-ered as a therapeutic agent in conventional medicine asthe standardization of chemical composition and biologicalactivity is lacking Such standardization is indispensablefor acceptance in the health system Thus characterizationof different types of propolis according to its plant originand corresponding chemical profile is mandatory Studiesabout propolis bioactivity must start with chemical profilingof the extracts since that information is essential to havedetailed and consistent comparative data between each type
4 Evidence-Based Complementary and Alternative Medicine
Table1Ch
aracteris
ticcompo
unds
ofprop
olisfro
mdifferent
geograph
icoriginsa
ndrespectiv
eplant
source
Geographico
rigin
Plantsou
rce
Typicalcon
stituents(m
aincompo
nents)
References
EuropeN
orth
AmericaNew
Zealandand
temperatezoneso
fAsia
Popu
lusspp
morep
redo
minantly
Pnigra
Pino
cembrinpinob
anksinchrysingalangin
caffeicacidferulicacidcinnamicacidand
their
esters
[102022]
Brazil
Green
prop
olis
Baccharis
spppredo
minantly
Bdracun
culifolia
Prenylated
phenylprop
anoidspheno
licacidsprenylated
p-coum
aricacidsacetop
heno
nes
diterpenicacidscaffeoylquinica
cidskaempferideiso
saku
ranetin
and
kaem
pferol
[9103233]
Redprop
olis
Dalbergiaecastaphyllum
Form
onon
etinisoliq
uiritigeninliquiritigeninm
edicarpin
andbiochaninA
[323435]
Russia
Betulasppm
ores
pecificallyB
verrucosaB
pend
ulaandB
pubescens
Cinn
amicacidsph
enylprop
anoidsesquiterpenolsacacetinapigenin
ermaninrhamno
citrin
kaem
pferide120572-acetoxybetuleno
l[10180]
CubaV
enezuela
Clusiasppm
ores
pecificallyC
rosea
andC
minor
Polyiso
prenylated
benzop
heno
nesmores
pecificallynemoroson
exantho
chym
oland
guttiferone
E[936]
Mediterranean
Greece
Prob
ablyCo
nifer
spp
Flavon
oidsditerpenicacidssuchas
isocupressic
pim
aricand
commun
icacidsiso
agatho
lal
agathadiolferrugino
l8-elem
eneandtotarol
[2425]
Switzerland
Ptre
mula
Benzylp-coum
aratebenzylferulateandph
enolicglycerides
liked
icou
maroylacetylglycerol
diferuloylacetylglycerolferuloylcou
maroylacetylglycerolandcaffeoylcou
maroylacetylglycerol
[26]
Malta
Ferulaspp m
ostp
robablyFerula
commun
isDiterpenicacidssuchas
isocupressic
com
mun
icpim
aricand
imbricatoloica
cidtogether
with
totaroland
13-epitorulosal
[27]
Turkey
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativa
Pino
cembrinpinob
anksin
andits
acetateprenylestersof
caffeicacidferulicacidsditerpenicacids
likep
imaricisopimaricabieticdihydroabietic
acidscinn
amylcinn
amateandethyloleate
arom
aticacid
esterssuch
asbenzylcinn
amatebenzenedicarbo
xylic
acid
andflavano
lssuch
asbenzop
yran
andchrysin
[28ndash30]
Algeria
Popu
lusspp
Cistu
sspp
Pino
cembrinpinob
anksin
andits
acetatechrysin
apigenin
pectolinarigeninpilo
sinladanein
galang
inn
aringenin
tectochrysinm
etho
xychrysin
prenyleste
rsof
caffeicacidsferulic
acids
diterpenicacidslikeh
ydroxyditerpenicacidlabdaneand
clerod
ane
[2831]
Austr
alia
Apismellifera
Acaciaparadoxa
Xantho
rrho
eolpterostilbenesakuranetinpinostro
bin
stilbenesprenylatedtetrahydroxystilbenes
prenylated
cinn
amicacidsflavano
nesflavono
lschalcones
[39ndash
42181]
Stinglessb
eeTetra
gonu
lacarbonaria
Ctorellianatre
es(fr
uitresins)
Africa
Nigeria
Prob
ablyMschwe
infurthii
Isofl
avon
oidsprenylatediso
flavono
idsandstilbenoids
[54]
Kenya
Triterpenesarylnaphtalenelignans
such
astetrahydrojusticidinBand6-metho
xydiph
yllin
geranyl
stilbenesand
geranylflavon
macarangin
[50]
Cameroo
nCon
goTriterpenesderivatives
ofam
yrin
andlupeolanddiprenylflavono
ids
[53]
Oman
Azadira
chta
indicaA
cacia
sppand
Mangifer
aindica
Triterpenesprenylatedflavano
nessuchas
7-O-m
ethyl-8
-prenylnaringenin
310158408-diprenylnaringenin
and8-prenyl-57-dihydroxy-31015840-(3-hydroxy-3-methylbutyl)-41015840-m
etho
xyflavano
nechalco
nes
cardanolcardo
lsandanacardica
cids
[51]
Ethiop
iaProb
ablyAc
aciaspp
Triterpenoids
such
as120572-a
nd120573-amyrins120572-a
nd120573-amyrylacetateslup
eoland120572-a
nd120573-lu
peyl
acetates
[52]
Thailand
Styrax
trees
Phenylallylflavanon
e(E)-cinn
amyl-(E)-cinnamylidenate
[48]
TheP
acificr
egion
OkinawaHaw
aiiandTaiwan
Macaranga
tanariu
sPrenylflavono
idsmores
pecificallyiso
nymph
aeol-Bnym
phaeol-Anym
phaeol-Bnym
phaeol-C
prop
olins31015840-geranyl-naringenin
[43ndash45]
Indo
nesia
Myanm
arMangifer
aindica
Alk(en)ylresorcinolscyclo
artane-ty
petriterpenescycloartanesandprenylated
flavano
nes
[4647]
Canary
Island
sUn
know
nFu
rofuranlignans
[49182]
Evidence-Based Complementary and Alternative Medicine 5
of biological activity and chemical data This informationallows extrapolating the possible activity and mechanism ofaction of new propolis under study and provides substantialclues for the development of new drug candidates [6 9]
In the last decades several studies have demonstrated thebiological and pharmacological actions of different world-wide propolis samplesThe following sections summarize therecent published information about antibacterial and anti-fungal [6 7 56ndash59] antiviral [7 59 60] anti-inflammatory[61] antioxidant [62ndash64] immunomodulatory [6 65 66]and antitumor activities [8 17 23 64 66 67] revealing theinterest of researchers in this bee product and its potentialfor the development of new drugs as well
41 Antioxidant Activity It is well known that an endogenousstimuli like cellular metabolism and exogenous agents likeUV toxins and drugs among others generate reactiveoxygen species (ROS) such as hydrogen peroxide (H
2O2) the
superoxide anion (O2minus) and hydroxyl ion (HOminus) as well as
reactive nitrogen species (RNS) especially nitric oxide (NO)Carbohydrates proteins lipids and nucleic acids amongother biomolecules when exposed to the reactive speciessuffer oxidative modifications that modify the cell and leadto its death [68ndash70] Oxidative stress is responsible for theoccurrence of a wide variety of human diseases such asneurodegenerative [71] or cardiovascular diseases [72 73]cancer [68 74] diabetes [6] and atherosclerosis [75]
In the last years several studies have been performedto evaluate the antioxidant capacity of natural productsPropolis extracts composed of different polyphenols havebeen reported to possess a potent antioxidant activity [7076 77] Additionally the chemical varieties in differentpropolis samples from different regions have an influenceon the antioxidant activity Recently Fabris et al showedthat a sample of Italian and Russian propolis ethanol extract(PEE) which have a similar polyphenolic composition havea similar antioxidant activity while Brazilian PEE whichhave low polyphenolic composition have a weak antioxidantactivity [78] Another study also showed using differentsamples of Transylvania PEE a positive correlation betweenhigh polyphenolic composition and high antioxidant activity[79] Phenolic acids and flavonoids are characterized bya powerful antioxidant activity which is closely related tothe chemical structure of the compounds [80] Briefly theantioxidant activity is exerted by inhibiting the activity ofsome enzymes (eg xanthine oxidase protein kinase Cascorbic acid oxidase cyclooxygenase lipoxygenase Na+K+ATPase and cAMP phosphodiesterase) which inhibit theproduction of ROS species by scavenging interrupting thereactions that lead to the lipid peroxidation by chelatingmetal ions mainly iron and copper that are involved in theprocess of free radical creation or by potentiating the actionof other antioxidants [55] Table 2 summarizes some of thestudies addressing the antioxidant activity of propolis
Moreira et al [62] and Miguel et al [63] proposed thatPortuguese propolis an important source of total phenolsflavones and flavonols could be beneficial for human healthdue to its antioxidant properties Portuguese propolis alsoprotects human erythrocytes from free radicals damaging
by decreasing lipid peroxidation [64] These studies suggestthat Portuguese propolis is a powerful antioxidant agentthat can be used against oxidative stress thus maintainingthe structural and functional integrity of the cells Cuesta-Rubio et al [36] demonstrated that nemorosone the mostabundant polyisoprenylated benzophenone present in Cubanpropolis exhibits antioxidant capacity However when thiscompound suffers methylation a process that facilitates theseparation of the compound from the propolis sample theantioxidant property is abolished Ethyl acetate extract ofKangaroo Island propolis which is rich in stilbenes showeda stronger scavenging activity [39] Yang et al showed thatethyl acetate of propolis collected in Anhui China hasstrong scavenging activity and ferric reducing activity thoseactivities being influenced by caffeic acid phenethyl caffeatecinnamyl caffeate and benzyl caffeate [81] Another studyshowed that samples of methanolic extracts of Algerianpropolis that contains high amounts of caffeic acid estersand flavanones kaempferol and galangin possess strongscavenging activity and ferric reducing activity [31] Uruguaypropolis with high polyphenolic composition inhibits low-density lipoprotein (LDL) peroxidation and protein nitra-tion in vitro Moreover it induces the expression of nitricoxide synthase (eNOS) and inhibits NADPH oxidase inbovine aortic endothelial cells [82] In another study thetopical administration of Romanian PEE in mouse eitherprior to or after UVB exposure significantly attenuated themalondialdehyde (MDA) formation and restored glutathioneperoxidase (GSH-Px) activity [83] Talas et al [84] showedthat Turkish PEE has antioxidant properties in the livertissue of NOS inhibited rats In fact NOS inhibition causedan increase in CAT activity and MDA levels effect thatwas significantly decreased when the rats were treated withPEE It is well known that propolis composition is variablenevertheless one of itsmajor components CAPE (caffeic acidphenethyl ester) plays an important role in the antioxidantactivity [85ndash87]
Antioxidant activity is one of the most studied andimportant activities of propolis though there are no studieswith data on the safe dose to be used in humansThus clinicalstudies using propolis and its active compounds are needed
42 Anti-Inflammatory Activity Inflammation is an eventthat normally occurs in response to the constant exposureto environmental and endogenous stimuli as well as toaccidental damage [61] A complex cascade of chemicalsignals initiates after tissue injury and maintains a hostresponse to repair the injured tissue There are two stagesof inflammation acute and chronic Acute inflammation ismediated through the activation of the immune system cellswhich migrate to the site of damage and release growthfactors cytokines and ROSRNS species Chronic inflamma-tion occurs when the acute inflammation is not successfullyresolved This inflammatory condition plays a critical role inthe pathogenesis of many diseases including atherosclerosiscancer asthma Alzheimerrsquos and Parkinsonism [88 89]
Several studies have associated different types of propolisand its various constituents with anti-inflammatory activ-ity [61 90ndash95] Table 3 summarizes the anti-inflammatory
6 Evidence-Based Complementary and Alternative Medicine
Table2Antioxidant
activ
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Portug
al(Serra
deBo
rnes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Hum
anerythrocytes
Decreaseinlip
idperoxidatio
n[64]
Free
radicalscaveng
ing
[62]
Brazil
Prop
olisfro
mthes
tinglessb
eeMelipona
orbignyi
prob
ablypo
plar
tree
PEE
Hum
anerythrocytes
Free
radicalscaveng
inginhibitio
nof
hemolysisandlip
idperoxidatio
n[183]
Portugal(C
entral
Algarve)
European
prop
olisPopu
lus
nigra
PEE
PWE
andmethano
licextracts
Free
radicalsscavenging
chelatio
nof
metalions
[63]
Cuba
Redprop
olisC
rosea
Methano
licextract
Nem
oroson
eFree
radicalsscavenging
[36]
Slovenia
European
prop
olisPopu
lus
nigra
PEE
Strong
redu
cing
power
andabilityto
scavenge
freer
adicals
andmetalions
[184]
Romania
European
prop
olisPopu
lus
nigra
PEE
FemaleS
wiss
mice(UVB
expo
sure)
Decreaseinmalon
dialdehyde
levels
resto
ratio
nof
glutathion
eperoxidase
activ
ity[83]
Kang
aroo
Island
Austr
alianprop
olisAc
acia
paradoxa
Ethylacetateextractstilbenes
Free
radicalscaveng
ing
[39]
China
European
prop
olisPopu
lus
nigra
Ethylacetateextract
Free
radicalscaveng
ingandferricredu
cing
activ
ity[81]
Algeria
Mediterranean
prop
olisPopu
lusspp
andCistu
sspp
Methano
licextract
Free
radicalscaveng
ingandferricredu
cing
activ
ity[31]
Urugu
ayEu
ropean
andgreen
prop
olisPopu
lusn
igra
andB
dracun
culifolia
PEE
Bovine
aorticendo
thelialcells
Inhibitio
nof
low-densitylip
oprotein
peroxidatio
nand
NADPH
oxidasea
ndincrease
innitricoxides
ynthase
[82]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
C57B
L6mice(acutelun
ginflammationcaused
bycigarette
smoke)
Normalizationof
nitritem
yeloperoxidase
levels
superoxide
dism
utasecatalaseand
glutathion
eperoxidasea
ctivity
and
redu
ctionof
glutathion
eoxidized
glutathion
eratio
and
malon
dialdehyde
levels
[185]
Turkey
Mediterranean
prop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
nea
sativa
PEE
Fibrob
lastcells
Decreaseo
fDNAdamageind
uced
byH
2O2
[186]
MaleW
istar
rats
DecreaseinCA
Tactiv
ityandMDAlevelsin
NOSinhibited
rats
[84]
Carps
(Cyprin
uscarpio)
Decreaseinmalon
dialdehyde
levels
superoxide
dism
utase
activ
ityandincrease
ofcatalase
andglutathion
eperoxidase
activ
ity[187]
Purchasedfro
mSigm
aAldric
hCo
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Free
radicalscaveng
inginhibitio
nof
xanthine
oxidasea
ctivity
andlip
idperoxidatio
n[85]
MaleW
istar
albino
rats
Maintenance
ofsuperoxide
dism
utasea
ctivitydecreaseo
fxanthine
oxidasea
ctivity
andmalon
dialdehyde
andnitric
oxidaselevels
[86]
Perip
heralblood
mon
onuclear
cells
from
cyclists
Redu
ctionof
hypertherm
ia-in
ducedsurvivalinhibitio
nnecrosis
superoxide
prod
uctio
nglutathion
edepletio
nand
intracellularsup
eroxide
[87]
Evidence-Based Complementary and Alternative Medicine 7
Table3Anti-infl
ammatorymechanism
sinvestig
ated
with
prop
olis
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
PurchasedSigm
aAldric
hCo
Synthesiz
ed
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacidquercetin
narin
genin
CAPE
Periton
ealm
acroph
ages
Supp
ressionof
lipoxygenasep
athw
ayof
arachido
nica
cid
metabolism
CAPE
beingthem
ostp
otentm
odulator
ofthea
rachidon
icacid
cascade
[90]
Croatia
European
prop
olisPopu
lusn
igra
Water-solub
lederiv
atives
Swiss
albino
mice
Redu
ctionof
DNAdamageinperip
herallym
phocytes
[188]
PEE
MaleS
wiss
albino
mice
Supp
ressionof
functio
nalactivity
ofmacroph
ages
[104]
PurchasedSigm
aAldric
hCo
J774
macroph
agesM
ale
Wistar
rats
Invitro
andin
vivo
inhibitio
nof
cyclo
oxygenase1
and
cyclo
oxygenase2
activ
ity[91189]
MaleW
istar
albino
rats
Decreaseo
fpolym
orph
onuclear
neutroph
ilicleuko
cyte
infiltra
tionin
thelun
gstissues
[190]
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Gastricepith
elialcelllin
e(A
GS)H
pylori(str
ainNCT
C116
38)
Inhibitio
nof
Hpylori-ind
uced
NF-kB
andactiv
ator
protein
1-DNA-
bind
ingactiv
itypreventionof
IkB120572
degradationin
AGSandsupp
ressionof
TNF-120572andinterle
ukin
8prod
uctio
n[191]
PurchasedWakoPu
reCh
emicalIndu
stries
Ltd
RAW2647macroph
ages
Decreaseo
fthe
prod
uctio
nof
interle
ukin-1120573m
onocyte
chem
oattractant
protein1andthep
rodu
ctionandexpressio
nof
tumor
necrosisfactor120572(TNF-120572)
[98]
MaleS
wiss
inbred
strainmice
Decreaseo
fcyclooxygenase2
expressio
nNF-120581Bactiv
ity
c-Jun-N-te
rminalkinaseinh
ibito
rofN
F-120581Bkinase
(IKK
)andinhibitoro
fNF-120581B(IkB
)pho
spho
rylatio
n[97]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
RAW2647macroph
ages
Dow
nregulationof
NF-120581B
p38mito
gen-activ
ated
protein
kinaseand
c-Jun-N-te
rminalkinase
[101]
PurchasedAc
ros
Organics
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacid
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Sprague-Daw
leyrats
Inhibitio
nof
carrageenan-indu
cedrath
indpawse
demaa
ndthec
hemotaxisof
human
polymorph
onuclear
leuk
ocytes
(PMNs)
[95]
Synthesiz
edCh
aracteristic
ofEu
ropean
type
prop
olis
CAPE
Polymorph
onuclear
leuk
ocytes
obtained
from
Hum
anbloo
dInhibitio
nof
5-lip
oxygenasea
ctivity
andarachido
nica
cid
release
[103]
Chile
European
prop
olispo
plar
trees
PEE
MaleC
F-1m
ice
Inhibitio
nof
NOreleaseb
ythem
acroph
ages
[102]
China
European
prop
olisPopu
lusn
igra
PEEandPW
EMaleICR
micea
ndmale
Wistar
rats
Inhibitio
nof
thea
ctivationanddifferentiatio
nof
mon
onuclear
macroph
agesdecreasep
rosta
glandin-E2
(PGE2)
andnitric
oxide(NO)levels
[61]
Brazil
Green
prop
olisB
dracun
culifolia
PWE
Swiss
andBA
LBcmice
Decreaseinthen
umbero
fmacroph
ages
andneutroph
ils
inhibitio
nof
proinfl
ammatorycytokinesa
ndincrease
ofanti-inflammatorycytokines
[99]
Redprop
olisDalbergia
ecastaphyllum
PEE
MaleW
istar
rats
Decreaseinrenalm
acroph
ageinfi
ltrationin
ratswith
chronic
kidn
eydisease
[100]
Nepal
Nepalesep
ropo
lisprobablyShorea
robu
staD
albergiasissooAc
acia
catechuandBo
mbaxcie
ba
PEE
3101584041015840-dihydroxy-4-
metho
xydalbergion
e4-etho
xydalbergion
cearoin
andchrysin
Bone
marrow-derived
mast
cells
(BMMC)
from
C57B
L6
mice
Inhibitin
gIL-6T
NF-120572and
IL-13gene
expressio
nin
BMMC
andalso
inhibitin
gthea
ctivationof
IKKleadingto
NF-120581B
inactiv
ation
[96]
8 Evidence-Based Complementary and Alternative Medicine
mechanisms investigated with propolis and its chemicalconstituents Recently the role of the flavonoids quercetinflavonols and flavones in modulating inflammatory cellfunction was studied [92] Funakoshi-Tago et al [96] inves-tigated the anti-inflammatory effects of flavonoids isolatedfrom Nepalese PEE on the IL-33 signaling pathway Theisolated flavonoids 3101584041015840-dihydroxy-4-methoxydalbergione4-methoxydalbergion cearoin and chrysin inhibited theexpression of inflammatory genes including IL-6 TNF-120572and IL-13 in bone marrow-derived mast cells (BMMC) andalso inhibited the activation of IKK which leads to thedegradation of I120581B120572 and inhibits the activation of nuclearfactor 120581B (NF-120581B)
The release and oxygenation of arachidonic acid are acritical event in inflammation Mirzoeva and Calder [90]demonstrated that propolis components such as CAPE caf-feic acid quercetin andnaringenin among others inhibit theproduction of eicosanoids In fact these components signif-icantly suppressed the lipoxygenase pathway of arachidonicacid metabolism CAPE being the most potent modulatorAnother study indicated that CAPE treatment improveshepatic steatosis induced by high-fat diet in a mouse modelThis effect was attributed to the reduction of c-Jun-N-terminal kinase (JNK12) andNF-120581B activationwith decreasein COX-2 expression [97] Recently it was reported thatCAPE exhibits inhibitory effects on the production of proin-flammatory cytokines (interleukin-1120573 (IL-1120573)) tumor necro-sis factor-120572 (TNF-120572) and monocyte chemoattractant pro-tein 1 (MCP-1) from lipopolysaccharide- (LPS-) stimulatedRAW2647 macrophages [98] Machado et al [99] showedthat Brazilian green propolis water extracts (PWE) modulatean anti-inflammatory cellular response in the model of LPS-induced pulmonary inflammation by decreasing the numberof macrophages and neutrophils Additionally it induced areduction in the secretion of IL-6 and TNF-120572 and an increasein TGF-120573 and IL-10 Another study showed that Brazilianred PEE promotes a significant decrease in renal macrophageinfiltration in rats with chronic kidney disease [100] Bufaloet al [101] demonstrated that Brazilian PEE and caffeicacid inhibited LPS-induced NO production by RAW2647macrophages acting at the transcriptional level and sug-gesting that their anti-inflammatory effects were mediatedby downregulating NF-120581B p38 MAP kinase and JNK12According to Naito et al [95] topical application of BrazilianPEE is effective in inhibiting carrageenan-induced rat hindpaw edemaThis sample appears to inhibit the chemotaxis ofhuman polymorphonuclear leukocytes (PMNs) which alsocontributes to its anti-inflammatory effects Another studyshowed the topical anti-inflammatory activity of propolisfrom Chile in mice ear with induced-edema In fact PEEfrom Buin Chile was the most active against the inflamma-tion induced by 12-O-tetradeca-noylphorbol-13-acetate andarachidonic acid and also inhibits significantly NO releaseby the macrophages [102] More recently Boudreau et al[103] indicated that CAPE is a potent leukotriene biosynthesisinhibitor in PMNs that blocks 5-lipoxygenase (5-LO) activityand arachidonic acid release A Croatian PEE may improvepsoriatic-like skin lesions whichwere induced in the study byirritant agents like n-hexyl salicylate or di-n-propyl disulfide
by reducing the lipid peroxidation in the skin and totalnumber of inflammatory cells in the skin and peritonealcavity more specially by suppressing functional activity ofmacrophages [104]
43 Immunomodulatory Activity Natural substances areconsidered alternative adjuvant therapies in the treatment ofdifferent diseases due to their immunomodulatory effectsInformation about this type of activity was scarce for propolisuntil the 1990s but published work in the last years has pro-vided information about the influence of different propolissamples on the immune system [65 105ndash112] (Table 4)
In a study using Brazilian green propolis it was seenthat the administration for 3 days of a PEE to male BALBcmice modulated the activation of the initial steps of theimmune response by upregulating toll-like receptor- (TLR-)2 and toll-like receptor-4 expression and proinflammatorycytokines (IL-1 and IL-6) production by macrophages andspleen cells [105] Another study demonstrated that BraziliangreenPEEupregulates TLR-4 andCD80 expression in humanmonocytes as well as TNF-120572 and IL-10 production [113] Itwas also shown that caffeic acid stimulates the activity ofmonocytes againstC albicans but it inhibits TLR-2 andHLA-DR expression as well as TNF-120572 and IL-10 production [114]
Additionally Missima et al [115] showed that Braziliangreen PEE administered to stressed mice reduces the proin-flammatory cytokines IL-1120573 and IL-6 When administered tomelanoma-bearing mice submitted or not to chronic stressit induces high levels of IL-1120573 and IL-6 and also stimu-lates Th1 cytokines production indicating the activation ofantitumour cell-mediated immunity Bachiega et al [116]investigated the immunomodulatory effect of propolis andcinnamic and coumaric acids on cytokines IL-1120573 IL-6 andIL-10 production Peritonealmacrophages fromBALBcmicewere incubated with different concentrations of propolis(5 50 and 100mgwell) and coumaric and cinnamic acid(50 and 100mgwell) Propolis and the acids stimulated IL-1120573 production and significantly inhibited IL-6 productionThen after LPS incubation the inhibitory concentrations ofcinnamic and coumaric acids prevented efficiently its effectson IL-6 production whereas propolis inhibited LPS effectsboth before and after its addition Additionally propolis andcoumaric and cinnamic acids inhibited IL-10 production Astudy which evaluated the effect of Brazilian green propolison macrophage activation by H
2O2and NO metabolite
determination [107] showed that propolis increased H2O2
generation and decreased NO generation which favoursthe microbicidal activity Recently the immunomodulatoryeffect of propolis collected in Brazil was evaluated in Leish-mania (Viannia) braziliensis experimental infection Datashows that macrophages incubated with propolis showed asignificant increase in interiorization and further killing ofparasites Also an increased TNF-120572 production was seen inpropolis-pretreated mice whereas IL-12 was downregulatedduring the infection [117]
The immunomodulatory action of propolis does notoccur only at the macrophage level In fact some studiesshow that this action has also an effect on lymphocyte pro-liferation [106 108] Sa-Nunes et al [108] showed inhibitory
Evidence-Based Complementary and Alternative Medicine 9
Table4Im
mun
omod
ulatoryactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
MaleB
ALB
cmice
Upregulationof
toll-lik
ereceptor-2andreceptor-4
expressio
nand
increasesininterle
ukin-1andinterle
ukin-6
prod
uctio
n[105]
Upregulationof
toll-lik
ereceptor-2andreceptor-4
mRN
Aexpressio
n[111]
MaleC
57BL
6miceB16F
10cell
line
Stim
ulationof
thee
xpressionandprod
uctio
nof
interle
ukin-2
and
interle
ukin-10andTh
1cytokine(interle
ukin-2
andIFN-120574)p
rodu
ction
[192]
MaleB
ALB
cmice
Inhibitio
nof
Th1cellsgeneratio
nredu
ctionof
thefrequ
ency
ofIFN-120574-produ
cing
CD4+
Tcells
underTh
1-polarizingcond
ition
s[118]
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecreasesintheN
Ogeneratio
nin
periton
ealm
acroph
ages
[109]
MaleB
ALB
cmice
Increase
intheinterioriz
ationandkilling
ofthep
arasitesL
eishm
ania
(Viann
ia)b
raziliensisby
macroph
agesincreaseinTN
F-120572prod
uctio
nanddecrease
ininterle
ukin-12prod
uctio
n[117]
Mon
ocytes
from
human
bloo
dTL
R-4andCD
80expressio
nin
human
mon
ocytes
aswellasT
NF-120572
andIL-10prod
uctio
n[113]
Mela
nomac
ells(B16F10)m
ale
C57B
L6mice
Redu
ctionof
IL-1120573andIL-6
inLP
S-str
essedmiceindu
ctionof
IL-1120573
andIL-6
andTh
1cytok
ines
inmela
noma-bearingmices
ubmitted
orno
ttochronics
tress
[115]
Brazil
PurchasedAc
rosO
rganics
Green
prop
olisB
dracun
culifolia
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
PEE
cinn
amicandcoum
aricacids
MaleB
ALB
cmice
Stim
ulationof
interle
ukin-1120573prod
uctio
nandinhibitio
nof
interle
ukin-6
andinterle
ukin-10prod
uctio
ns[116]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
and
Mediterraneanprop
olis
Caffeicacid
Mon
ocytes
from
human
bloo
dStim
ulationof
mon
ocytes
activ
ityagainstC
albica
nsdow
nregulation
ofTL
R-2andHLA
-DRexpressio
nandinhibitio
nof
cytokine
prod
uctio
n[114]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
Cinn
amicacid
Mon
ocytes
from
human
bloo
dDow
nregulationof
toll-lik
ereceptor-2HLA
-DRmolecules
from
human
antig
en-presentingcellsand
CD80upregulationof
toll-lik
ereceptor-4inh
ibition
ofTN
F-120572andinterle
ukin-10prod
uctio
n[19
3]
PurchasedSigm
aAldric
hCo
Cinn
amicacid
FemaleIRC
mice
Increase
oflymph
ocytep
roliferationandreleaseo
fcytok
ines
interle
ukin-1andinterle
ukin-2
[106]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Hydroalcoho
lic(H
PE)solution
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecrease
ofNOgeneratio
n[107]
MaleB
ALB
cmice
Decreaseo
fsplenocytep
roliferationandincrease
ofIFN-120574
prod
uctio
nby
spleen
cells
[108]
Indo
nesia
TheP
acificr
egionprop
olisMacaranga
tanariu
sand
Mind
icaHPE
MaleB
ALB
cmice
Increase
ofIgGgeneratio
nandmacroph
agep
hagocytosis
activ
ityand
capacity
[110]
Turkey
Mediterraneanprop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
neasativa
PEE
Perip
heralblood
mon
onuclear
cells
from
healthyhu
mans
Supp
ressionof
neop
terin
releasea
ndtryptoph
andegradation
downregulationof
thee
nzym
eind
oleamine2
3-dioxygenase
(IDO)and
decrease
ofIFN-120574
andTN
F-120572levels
[194]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
CAPE
Hum
anmon
ocyte-deriv
eddend
riticcells
(MoD
Cs)g
enerated
from
perip
heralm
onocytes
Inhibitio
nof
IL-12p4
0IL-12p70IL-10IFN-120574-in
duciblep
rotein-(IP-)
10levels
inhibitio
nof
I120581B120572
phosph
orylationandNF-120581Bactiv
ation
[112]
FemaleB
ALB
cmice
Increase
ofIgM
antib
odyprod
uctio
nTlymph
ocytep
roliferation
interle
ukin-4
andinterle
ukin-2
prod
uctio
nby
spleno
cytesandIFN-120574
prod
uctio
n[195]
Hum
anperip
heralblood
mon
onuclear
cellsjurkatcells
Inhibitio
nof
transcrip
tionfactorsN
F-120581BandNFA
Tinhibitio
nof
interle
ukin-2
gene
transcrip
tion
interle
ukin-2
receptor
expressio
nand
proliferatio
nof
human
Tcells
[94]
10 Evidence-Based Complementary and Alternative Medicine
effects of Brazilian green propolis on splenocyte proliferationeffect that was attributed to flavonoids and enhancementeffects on interferon- (IFN-) 120574 production by spleen cellsCAPE displays inhibitory effects on transcription factors NF-120581B and NFAT and as a consequence inhibits IL-2 genetranscription IL-2 receptor expression and proliferation ofhuman T cells [94] This provides new information into themolecular mechanisms involved in the anti-inflammatoryand immunomodulatory activities of propolis CAPE hasvarious biological activities but its effect on the immunomod-ulatory activity remains little studied According to Wanget al [112] CAPE can be useful in the treatment of asthmaand other allergic diseases because it can inhibit cytokinesand chemokines production by human monocyte-deriveddendritic cells (MoDCs) which might be related to theNF-120581B signalling pathway Another study demonstrated forthe first time that Brazilian propolis significantly inhibitedthe generation of Th1 cells Furthermore the effects ofpropolis were investigated on 246-trinitrobenzene sulfonicacid- (TNBS-) induced colitis in a mouse model Propolisreduced the frequency of IFN-120574-producing CD4 T cellsin a dose-dependent way under Th1-polarizing conditionsThe inhibitory effect of propolis on Th1 differentiation wasdemonstrated in vivo too and the severity of colitis inpropolis-fed mice was significantly lower than that of micefed with the control diet [118]
44 Antiviral Activity Propolis comprises a complexity ofcompounds which play a role in antiviral protection Despitethe few data available regarding this activity it was shown thatpropolis from different geographic regions has considerableantiviral activity by acting at different levels and interferingwith the replication of some viruses [12] like herpes simplextypes 1 and 2 adenovirus type 2 influenza virus or humanimmunodeficiency virus (HIV) among others [7 60 119ndash124] Table 5 summarizes the antiviral activity of propolis andits chemical constituents
Schnitzler et al [123] analysed the antiviral effect ofPWE and PEE from Czech Republic as well as that ofthe constituents caffeic acid p-coumaric acid benzoic acidgalangin pinocembrin and chrysin against herpes simplexvirus type 1 (HSV-1) in cell culture Both extracts exhibitedhigh anti-HSV-1 activity when cells were treated prior toviral infection galangin and chrysin being the main bioac-tive compounds Amoros et al [60] showed the antiviralactivity of the major flavonoids of propolis more specificallyflavonols and flavones the first being more active againstHSV-1 Additionally they analysed the effect of propolis onseveral DNA and RNA viruses (HSV-1 HSV-2 adenovirustype 2 vesicular stomatitis virus (VSV) and poliovirus type2) Propolis at a concentration of 30120583gmL reduced thetiter of herpes virus however vesicular stomatitis virusand adenovirus were less susceptible In addition propo-lis appears to exert a virucidal action on the envelopedviruses HSV and VSV [120] Recently it was shown thathydromethanolic extract of geopropolis from the stinglessbee Scaptotrigona postica (Brazil) inhibits theHSV replicationand also the entry of the virus into cells effect that wasattributed to the C-glycosyl flavones catechin-3-O-gallate
and 34-dicaffeoylquinic acid [125] According to Tait etal [126] natural and synthetic flavonoids might interferewith picornavirus replication preventing the decapsidationof viral particles and RNA release within cells or blockingviral RNA synthesis These authors also showed that differ-ent homoisoflavonoids have good antiviral activity againstthe coxsackie viruses B3 B4 and A9 and echovirus 30Shvarzbeyn and Huleihel [127] tried to determine whichstep of Tax oncoprotein-induced NF-120581B activation is blockedby propolis and CAPE and showed that both substantiallyinhibited the activation of NF-120581B-dependent promoter byTax Also they strongly prevented both Tax binding to I120581B120572and its induced degradation by Tax Ma et al [128] showedthat nanometer propolis flavones could significantly inhibitin vitro porcine parvovirus (PPV) infecting PK-15 cells andin vivo they restrain the PPV copy in lung gonad and blooddecrease the impact of PPV on weight of guinea pigs andincrease hemagglutination inhibition of PPV in serum as wellas improving the contents of IL-2 IL-6 and 120574-IFN
Over recent years therapeutic benefits of propolis andorits isolated compounds have been described in HIV treat-ment Ito et al [129] tested the anti-HIV activity in H9lymphocytes of triterpenoids melliferone moronic acidanwuweizonic acid and betulonic acid and four knownaromatic compounds isolated from Brazilian propolis andshowed that moronic acid had significant anti-HIV activityGekker et al [119] assessed the anti-HIV-1 activity of propolisin CD4+ lymphocytes and microglial cell cultures observ-ing the inhibition of viral expression in a concentration-dependent wayThe possible mechanism of propolis antiviralproperty was suggested to involve inhibition of viral entry
45 Antimicrobial Activity Antimicrobial activity one ofthe most studied propolis biological properties is very welldocumented This bioactivity has been largely investigatedin the last years due to the need of new treatments againstinfectious diseases especially with the increase of resistantpathogens to current antibiotics Tables 6 and 7 summarisethe antibacterial and antifungal activities found in propolisfrom different geographic origin andor its chemical con-stituents
451 Antibacterial Activity Propolis effect against severalbacterial strains has evaluated [7 56ndash59 130] and supportedthe fact that propolis is more active against Gram-positivebacteria than Gram-negative bacteria [12 59] Briefly datafrom different studies showed that propolis inhibits bac-terial motility and enzyme activity exhibits bacteriostaticactivity against different bacterial genera can be bactericidalin high concentrations and affects cytoplasmic membrane[130]
Mirzoeva et al [130] investigated the effect of PEEon the physiology of Bacillus subtilis Escherichia coli andRhodobacter sphaeroides proposing that propolis and someof its components like cinnamic acid and flavonoids affectthe ion permeability of the inner bacterial membrane causingthe dissipation of the membrane potential and inhibitingbacterial motility A recent study [131] provided valuableinformation for understanding the potential anti-H pylori
Evidence-Based Complementary and Alternative Medicine 11
Table5Antivira
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescellsviru
ses
Effect
References
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
Caffeicacidp-cou
maricacid
benzoica
cidgalang
in
pino
cembrinand
chrysin
RC-37cellsherpessim
plex
virustype1
(HSV
-1)
strainKO
SHighanti-HSV
-1activ
ityforb
othextractswhencells
weretreated
prior
toviralinfectio
n[123]
CzechRe
public
European
prop
olisPopu
lusn
igra
PEEandPW
ERC
-37cellsherpessim
plex
virustype2
(HSV
-2)
Highantih
erpetic
activ
ityforb
othextractswhenvirusesw
ere
pretreated
priortoinfection
[196]
Brazil
Brow
nprop
olisB
dracun
culifolia
HPE
HSV
-2str
ainprop
agated
inVe
rocellsfem
aleB
ALB
cmice
Effectiv
eagainstHSV
-2infectionandin
redu
cing
extravaginallesio
nsby
actin
gon
inflammatoryandoxidativep
rocessesreducingreactiv
especiestyrosin
enitration
ascorbicacid
levels
andmyeloperoxidase
activ
ityandprotectin
gagainstinh
ibition
ofcatalase
activ
ity
[124]
Characteris
ticof
Brazilian
prop
olis
Isop
entylferulate(
isolatedfro
man
PEE)
Influ
enza
virusesA
PR834
(H1N
1)
AKrasnod
ar10
159(H
2N2)and
AH
ongKo
ng168
(H3N
2)Supp
ressionof
influ
enza
virusA
Hon
gKo
ngreprod
uctio
nin
vitro
[121]
Green
prop
olisB
dracun
culifolia
Beriocla
daM
yrceugeniaeuosma
PEE
Influ
enza
APR834
(H1N
1)virusp
ropagated
Madin-D
arby
canine
kidn
ey(M
DCK
)cells
female
DBA
2Cr
mice
Redu
ctionof
body
weightlosso
finfectedmicea
ndvirusy
ieldsinthe
bron
choalveolarlavagefl
uids
oflung
s[122]
France
European
prop
olisPopu
lusn
igra
PEE
RC-37cellsH
SV-1str
ainH29Sacyclovirresistant
mutantH
SV1-R
strainH29R
HSV
-2adeno
virustype
2po
liovirustype2
and
vesic
ular
stomatitisv
irus
(VSV
)
Redu
ctionof
titre
ofherpes
virusbeingvesic
ular
stomatitisv
irusa
ndadenoviru
slesssusceptibleviru
cidalactionon
thee
nvelo
pedviruses
HSV
andVS
V[120]
Brazil
Geoprop
olisfro
mthes
tinglessb
eeScaptotrigona
postica
Hydromethano
licextract
African
greenmon
keykidn
eycells
(ATC
CCC
L-81)
herpes
simplex
virusstrain(M
cIntyre)
Inhibitio
nof
HSV
replicationandentryinto
cells
[125]
Synthesiz
edCh
aracteris
ticof
Brazilian
redand
greenprop
olis
Hom
oisoflavono
idsspecially
3-benzyl-4-chrom
ones
BGM
(Buff
aloGreen
Mon
key)
cellscoxsackieviruses
B3B
4andA9andecho
virus3
0Goo
dantiv
iralactivity
againstthe
coxsackiev
irusesB
3B4
and
A9and
echo
virus3
0[126]
Canada
European
prop
olisPtrichocarpa
andPtre
muloides
PEE
HSV
-1andHSV
-2virusreplicated
inMDBK
(mon
olayer
cultu
reso
fMadin-D
arby
bovine
kidn
ey)
cells
Impairing
thea
bilityof
thev
irustoadsorb
orto
penetratethe
hostcells
[197]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Water
extracts
FemaleB
ALB
cmiceInflu
enza
Avirusstrain
AW
SN33(H
1N1)
Extensionof
thelifetim
eofm
ice34-dicaffeoylquinica
cidwhich
increasesm
RNAlevelsof
tumor
necrosisfactor-related
apop
tosis
-indu
cing
anddecreasesH
1N1h
emagglutinin
mRN
A[19
8]Ch
aracteris
ticof
Brazilian
green
prop
olis
34-dicaffeoylquinica
cid
(Isolated
from
Brazilian
prop
olis)
Brazil
Characteris
ticof
Brazilian
green
prop
olis
Melliferon
emoron
icacid
anwuw
eizonica
cidand
betulonica
cid(isolated
from
Brazilian
prop
olis)
H9lymph
ocytesH
IV-1
Moron
icacid
inhibitin
ganti-HIV
replication
[129]
Israel
Mediterraneanprop
olisPopu
lus
sppE
ucalyptusspp
andCa
stanea
sativa
PWE
Jurkatuninfectedhu
man
T-celllin
esand
MT2
(HTL
V-1infectedhu
man
Tcells)cells
Inhibitio
nof
thea
ctivationof
NF-120581B-depend
entp
romoter
byTaxand
preventio
nof
Taxbind
ingto
I120581B120572
andits
degradation
[127]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Provided
byBinzho
uAnimal
Sciencea
ndVe
terin
ary
MedicineA
cademyof
Shando
ngProvince
Nanom
eter
prop
olisFlavon
eKidn
eycells
(PK-
15)
Porcinep
arvovirus(PP
V)
Britain
Whiteguinea
pigs
Inhibitio
nof
PPVinfectingpo
rcinek
idney-
(PK-
)15cells
Restr
aining
ofPP
Vcopy
inlung
gon
adand
bloo
ddecrease
ofthe
impactof
PPVon
weighto
fguineap
igsandincrease
ofhemagglutinationinhibitio
nof
PPVin
serum
aswellasimprovingthe
contentsof
IL-2IL-6and120574-IFN
[128]
USA
andCh
ina
European
prop
olisPopu
lusn
igra
PEE
Perip
heralblood
mon
onuclear
cells
obtained
from
bloo
dof
healthyd
onorsmicroglialcellsiso
latedfro
mhu
man
fetalbrain
tissueHIV-1ATH
IV-1SF162
Inhibitio
nof
HIV-1varia
ntse
xpression
[119]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
12 Evidence-Based Complementary and Alternative Medicine
Table6Antibacteria
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
PurchasedBe
eHealth
Ltd
(Scarborou
ghYorkshire
UK)
Eu
ropean
prop
olisPopu
lusn
igra
PEE
BsubtilisS
G38E
coliandR
sphaeroides
Influ
encing
theion
perm
eabilityof
theinn
erbacterial
mem
brane
Inhibitio
nof
bacterialm
otility
[130]
PurchasedSigm
aCh
emicalCo(Poo
leDorsetUK)
Characteris
ticof
EuropeanB
razilian
andMediterraneanprop
olis
CaffeicacidC
APE
qu
ercetin
and
narin
genin
Greece
Mediterraneanprop
olisprob
ablyCo
nifer
spp
Terpenes
(isolated
from
Cretan
prop
olis)
Saureus
(ATC
C25923)Sepiderm
idis(ATC
C12228)E
coli
(ATC
C25922)E
cloacae
(ATC
C13047)K
pneumoniae
(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Influ
encing
theG
ram-positive
andGram-negativeb
acteria
viability
[199]
France
European
prop
olisPopu
lusn
igra
Dichlorom
ethane
extract
Gram-negative7Ac
inetobacterb
aumannii(RC
HSAN00812
AYE
CIP7
034107292and
5377)2Escherich
iacoli(ATC
C25922andac
linicaliso
late)3
Pseudomonas
aeruginosa
(ATC
C27853andtwoclinicalisolates)and4clinicalisolates
ofEn
terobacterclo
acaeE
aerogenesK
lebsiella
oxytocaand
Salm
onellaenteritidis(phage
type
4)Gram-negative13
Staphylococcus
aureus
(ATC
C25923six
methicillin-susceptib
leclinicalisolatesandsix
methicillin-resistant
clinicalisolates)2
clinicalisolates
ofS
epidermidis(m
ethiSandmethiR)3
clinicalisolates
ofEn
terococcus
faecalisand1E
faeciu
mand
1clin
icaliso
lateof
Corynebacterium
striatum
Influ
encing
theG
ram-positive
bacteriaviabilityspecially
Saureus
andseveralofitsmethicillin-resistant
and
methicillin-susceptib
le[133]
Bulgaria
Mediterraneanprop
olis
PEE
Saureus
209E
coliWF+
Decreaseo
fSaureusg
rowth
andweakor
lack
ofactiv
ityagainstE
coli
[28]
Greece
Popu
lusspp
Tu
rkey
Conifer
spp
Algeria
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativaPopu
lusspp
Cistu
sspp
Austr
alia
Austr
alianprop
olisfro
msting
lessbee
Tetra
gonu
lacarbonariaCtorelliana
trees
(fruitresins)
PEE
Saureus
(ATC
C25923)
Paeruginosa
(ATC
C27853)
Inhibitio
nof
Saureus
grow
th[42]
Cameroo
nandCon
goAfrican
prop
olisprob
ablyM
schw
einfurthii
PEE
Saureus
(ATC
C25923)Sepiderm
is(ATC
C13047)E
coli
(ATC
C25922)K
lebsiella
pneumonia(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Inhibitio
nof
Saureus
grow
th[53]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Saureus
2979
andSaureus
4118
isolated
from
mastiticcows
Saureus
(ATC
C29213)
Decreaseo
fSaureusg
rowth
incomplex
mediaandkilling
ofSaureus
cells
resuspendedin
milk
promotionof
changesin
morph
olog
yandcellsiz
e[200]
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsu
lfoxide
extract
Saureus
(CAPM
5970)E
faecalis(C
APM
5613
(EBF
3039))
Ecoli(C
AMP3101
T(U
541))and
Lmonocytogenes(C
CM5580)
Differentcon
centratio
nsaffectthe
grow
thofthetestedbacteria
[201]
Italy
Mediterraneanprop
olisCrup
essusspp
PE
E
Staphylococcus
sppstr
ains
(35Saureus63Sepidermidis
7S
hominis
18Shaem
olyticu
s10
Swa
rneri4Scapitisand
3S
auric
ularis)
andStreptococcusspp
strains
(59Sfaecalis
30S
virid
ans15
S120573-haemolyticu
sand19
Spn
eumoniae)
Com
pletes
uppressio
nof
thefactorc
oagu
lasereductio
nof
lipasea
ndpreventio
nof
biofi
lmform
ationof
Staphylococcus
increase
ofthee
ffectof
ampicillingentam
ycinand
streptomycin
andmod
eratingthea
ctionof
chloramph
enicol
ceftriaxoneand
vancom
ycin
[56]
Brazil
Redprop
olisDecasto
phyllum
Green
prop
olisB
dracun
culifolia
PEE
Saureus
(ATC
C25923)
NanoH
Amatrix
with
redandgreenprop
oliswhich
redu
ces
bacterialgrowth
andbiofi
lmform
ation
then
anoH
Awith
red
prop
olisbeingthem
ostefficient
[136]
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
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[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
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[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
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[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
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[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
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[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
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[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
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24 Evidence-Based Complementary and Alternative Medicine
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[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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ObesityJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
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Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
2 Evidence-Based Complementary and Alternative Medicine
green and red among others [5 7 12] In terms of chemicalcomposition it is generally composed of 50 resin 30wax 10 essential oils 5 pollen and 5 other substanceswhich includeminerals and organic compounds like phenolicacids (cinnamic and caffeic acid) or their esters flavonoids(flavones flavanones flavonols and dihydroflavonols chal-cones) terpenes aromatic aldehydes and alcohols fatty acidsstilbenes and 120573-steroids [8 9] Analysis of different samplesrevealed that propolis chemical composition is difficult tostandardize because it depends on different phytogeographiccharacteristics like vegetation season and environmentalconditions of the site of collection as bees select differentplants in different habitats for propolis production [6 8 9]
Several in vitro and in vivo studies have been describingthe plethora of biological activities and chemical profilesof propolis from different geographic origins This reviewhighlights published data about such works focusing on theantimicrobial anti-inflammatory antioxidant immunomod-ulatory and antitumor activities of different propolis types inorder to unravel the potential of this natural compound forthe development of new drugs
2 Use of Propolis in Ancientand Current Times
Propolis is not a new discovery Since beersquos domesticationmen explore its products to their own benefit and propolisone of the most important chemical weapons of bees is noexception having been employed extensively since almostimmemorial times [6 13 15ndash17] It is stated that propolis usedates back to ancient times at least to 300 BC where it wasused in folk medicine and other activities in many parts ofthe world [16] It was familiar to the Egyptians in particularby the priests who controlled medicine and chemistry andknew very well propolis antiputrefactive properties Theylearned from the bees the embalming capacity of propolis asthis natural product is used to perform the mummificationof corpses and prevent spread of infections The Greekand the Roman physicians also acknowledged the potentialof propolis by employing it in wound treatment as anantiseptic and cicatrizing agent and as mouth disinfectantThe Persians described propolis as a drug capable of actingagainst eczemas myalgia and rheumatism Populations ofthe new world like Incas also used propolis as an antipyreticagent
Between the 17th and 20th century this natural productbecame very popular in Europe In 1969 in the former Unionof Soviet Socialist Republics (USSR) the use of propolis wasaccepted in human and veterinary medicine with severalapplications including the treatment of tuberculosis wherethe regression of lung problems and recovery of appetitewere observed Also it was believed to cure some diseases infolk Georgian medicine During World War II (1939ndash1945)doctors used propolis to treat wounds [15ndash17] but only in1985 in Japan propolis was considered as very promising inpharmacology Before that propolis was considered a prod-uct without market value especially because its productionis low and affects honey production Nowadays propolisis an important product in alternative medicine in Japan
being widely imported from Brazil [18] In the 17th centurythe Italian Antonio Stradivari who is considered the mostsignificant and the greatest crafter of string instruments likeviolins used propolis as an ingredient in the varnish of hisinstruments Curiously such as in the 17th century propolisis currently used in rosin for stringed instruments and in therepair of accordions [16]
Propolis is one of the few natural products that main-tained popularity for a long time although it is not considereda therapeutic agent in conventional medicine Actually it iswidely used as a component in pharmaceutical and cosmeticproducts such as antiacne creams facial and body creamsointments and lotions and several formulations for oralhygiene [15 16] It is also used in some foods and beveragesor simply as food supplement or healthy drinks This namewas attributed to the drinks because it is thought that propolisimproves human health and prevents diseases such as heartdisease or diabetes among others [19]
3 Origin and Composition of Propolis
Propolis knowledge has registered an important evolutionover time due to exhaustive studies regarding its chem-ical composition and biological activities In the 60s itwas thought that despite its complexity propolis chemicalcomposition was more or less constant Nevertheless inthe following years analysis of a large number of samplesfrom different geographic origins revealed that chemicalcomposition of propolis is highly variable and also difficultto standardize because it depends on factors such as thevegetation season and environmental conditions of the siteof collection [6 8 9] Marcucci [7] and Bankova et al [10]registered more than 300 substances in propolis and recentreports showed the presence of compounds never mentionedbefore [12 17 20 21]
Generally the main constituents of propolis are resin andvolatiles which are substances obtained from a variety ofbotanical processes in different parts of plants and beeswaxsecreted by the bees [9] Typical compounds are summarizedin Table 1 As can be seen plant sources vary among thedifferent parts of the globe leading to panoply of compoundsIn a review on propolis standardization different resin typeswere proposed poplar propolis birch green red ldquoPacificrdquoand ldquoCanarianrdquo [9 12] Samples of poplar propolis (egfrom Europe North America New Zealand and temperatezones of Asia) are mainly composed of flavonoids phenolicacids and their esters [10 20 22] clearly different fromother propolis types (Table 1) Portuguese propolis despitesimilar to the ones found in European samples also containsnew methylated esterified and hydroxylated derivatives offlavonoids and pinocembrinpinobanksin derivatives con-taining a phenylpropanoic acid derivative moiety in theirstructure [20 21] Our group recently showed that propolisfrom Pereiro (district of Guarda Beira Alta) (Figure 1) has ahigh concentration of phenolic components [23]
Poplar-type propolis is undoubtedly themost studied onebut there are many other propolis types Recent studies haverevealed a new type of European propolis Mediterraneanpropolis This type of propolis is distinguished by the high
Evidence-Based Complementary and Alternative Medicine 3
Figure 1 Crude sample of propolis from Pereiro obtained in thecentral region of Portugal (Guarda)The sample was kindly suppliedby Engineer Pedro Fernandes (Mel do Abel)
concentration of diterpenoids and is found in many regionslike Greece [24 25] Switzerland [26]Malta [27] Turkey [28ndash30] or Algeria [28 31]
Propolis from tropic regions like Brazil CubaVenezuelaand Chile has been attracting much attention in thelast years due to its particular chemical profiles Preny-lated phenylpropanoids prenylated p-coumaric acids ace-tophenones diterpenic acids and caffeoylquinic acids wereshown to be very common and abundant in propolis fromBrazil mainly from the south-eastern region [9 10 21]The flavonoids kaempferide and isosakuranetin and someamounts of kaempferol were also found in Brazilian samples[32] Additionally red propolis from the northeast regionsof Brazil presents high concentrations of phenolic acids andthe flavonoids formononetin isoliquiritigenin liquiritigeninmedicarpin and biochanin A [33ndash35] Cuban propolis hasa peculiar enrichment in polyisoprenylated benzophenonesmore specifically nemorosone and a minor content of amixture of xanthochymol and guttiferone E [9 36] makingthis type of sample chemically distinct from both Europeanand Brazilian propolis Propolis from Venezuela is alsocomposed of polyisoprenylated benzophenones in additionto the usual constituents found in samples of tropical regions[9 37 38]
Information about the chemical composition of Aus-tralian propolis is very limited despite the great biodiversityof the island Propolis from Kangaroo Island is mainlycomposed of stilbenes some of them being prenylated Ad-ditionally it has also some prenylated cinnamic acids andflavonoids [39] like 210158403101584041015840-trimethoxychalcone 21015840-hy-droxy-3101584041015840-dimethoxychalcone 2101584041015840-dihydroxy-31015840-metho-xychalcone 57-dihydroxy-23-dihydroflavonol 3-acetate (pi-nobanksin 3-acetate) and 57-dihydroxy-6-methoxy-23-dihydroflavonol 3-acetate [40] Western Australian propolisis composed of Xanthorrhoeol pterostilbene sakuranetinand pinostrobin [41] Propolis of Australian stingless bees(Tetragonula carbonaria) is composed of C-methylatedflavanones [42]
ldquoPacificrdquo propolis (eg Okinawa Taiwan Hawaii Indo-nesia and Myanmar) is another particular type of propolisA new family of compounds the prenylflavonoids morespecifically isonymphaeol-B was identified in Okinawapropolis although three already known compoundsmdashnym-phaeol-A nymphaeol-B and nymphaeol-Cmdashhave also
been isolated in three samples [43] As Okinawan propolisHawaiian propolis is also composed of nine prenylflavonoids[44] Taiwanese propolis is composed of eight prenylfla-vanones nymphaeol-A nymphaeol-B and nymphaeol-Cpropolins A B and E isonymphaeol B and 31015840-geranyl-naringenin [45] In another sample of the Pacific regionthe Indonesian propolis an inseparable mixture of fouralk(en)ylresorcinols (5-pentadecylresorcinol 5-(81015840Z111015840Z-heptadecadienyl)-resorcinol 5-(111015840Z-heptadecenyl)-resor-cinol and 5-heptadecylresorcinol) along with four prenylfla-vanones propolins D C F and G and three cycloartane-type triterpenes mangiferolic acid isomangiferolic acidand 27-hydroxyisomangiferolic acid was identified [46]Additionally fractioning of propolis extracts from Myanmarled to the isolation of two new cycloartane-type triterpenestogether with 13 cycloartanes and four known prenylatedflavanones [47] Thailand propolis which might bepossibly obtained from Styrax trees comprises not onlythe typical compounds of temperate regions but also thetwo new phenylallylflavanones (710158401015840S)-8-[1-(41015840-hydroxy-31015840-methoxyphenyl)prop-2-en-1-yl]-(2S)-pinocembrin and (E)-cinnamyl-(E)-cinnamylidenate [48] In propolis fromCanaryIslands a different phenolic profile was found furofuranlignans being the main compounds Six furofuran lignanswere isolated and characterized as sesamin episesaminmethyl xanthoxylol aschantin sesartenin and yangambinPropolis also contains sugars and sugar alcohols [10 49]Many studies with African propolis from different regionslike Kenya Cameroon Congo Oman and Ethiopia showedthat triterpenoids are major chemical components [50ndash53]Southern Nigeria propolis is uncommon since it presentsprenylated isoflavonoids like Brazilian red propolis and ahigh abundance of stilbenoid compounds [54]
Propolis additionally contains minerals such as mag-nesium calcium iodine potassium sodium copper zincmanganese and iron some vitamins like B1 B2 B6 CE and D as well as provitamin A a few fatty acids andalso some enzymes derived from bee glandular secretion orpossibly from pollen like succinic dehydrogenase adenosinetriphosphatase glucose-6-phosphatase acid phosphatase120572-amylase 120573-amylase 120572-lactamase 120573-lactamase maltaseesterase and transhydrogenase [17 55] Polysaccharides likestarch and the di- and monosaccharaides glucose fructoseribose rhamnose talose gulose and saccharose are com-monly present in propolis too [55]
4 Biological Properties and TherapeuticActivity of Propolis
Despite propolis popularity over time it is not consid-ered as a therapeutic agent in conventional medicine asthe standardization of chemical composition and biologicalactivity is lacking Such standardization is indispensablefor acceptance in the health system Thus characterizationof different types of propolis according to its plant originand corresponding chemical profile is mandatory Studiesabout propolis bioactivity must start with chemical profilingof the extracts since that information is essential to havedetailed and consistent comparative data between each type
4 Evidence-Based Complementary and Alternative Medicine
Table1Ch
aracteris
ticcompo
unds
ofprop
olisfro
mdifferent
geograph
icoriginsa
ndrespectiv
eplant
source
Geographico
rigin
Plantsou
rce
Typicalcon
stituents(m
aincompo
nents)
References
EuropeN
orth
AmericaNew
Zealandand
temperatezoneso
fAsia
Popu
lusspp
morep
redo
minantly
Pnigra
Pino
cembrinpinob
anksinchrysingalangin
caffeicacidferulicacidcinnamicacidand
their
esters
[102022]
Brazil
Green
prop
olis
Baccharis
spppredo
minantly
Bdracun
culifolia
Prenylated
phenylprop
anoidspheno
licacidsprenylated
p-coum
aricacidsacetop
heno
nes
diterpenicacidscaffeoylquinica
cidskaempferideiso
saku
ranetin
and
kaem
pferol
[9103233]
Redprop
olis
Dalbergiaecastaphyllum
Form
onon
etinisoliq
uiritigeninliquiritigeninm
edicarpin
andbiochaninA
[323435]
Russia
Betulasppm
ores
pecificallyB
verrucosaB
pend
ulaandB
pubescens
Cinn
amicacidsph
enylprop
anoidsesquiterpenolsacacetinapigenin
ermaninrhamno
citrin
kaem
pferide120572-acetoxybetuleno
l[10180]
CubaV
enezuela
Clusiasppm
ores
pecificallyC
rosea
andC
minor
Polyiso
prenylated
benzop
heno
nesmores
pecificallynemoroson
exantho
chym
oland
guttiferone
E[936]
Mediterranean
Greece
Prob
ablyCo
nifer
spp
Flavon
oidsditerpenicacidssuchas
isocupressic
pim
aricand
commun
icacidsiso
agatho
lal
agathadiolferrugino
l8-elem
eneandtotarol
[2425]
Switzerland
Ptre
mula
Benzylp-coum
aratebenzylferulateandph
enolicglycerides
liked
icou
maroylacetylglycerol
diferuloylacetylglycerolferuloylcou
maroylacetylglycerolandcaffeoylcou
maroylacetylglycerol
[26]
Malta
Ferulaspp m
ostp
robablyFerula
commun
isDiterpenicacidssuchas
isocupressic
com
mun
icpim
aricand
imbricatoloica
cidtogether
with
totaroland
13-epitorulosal
[27]
Turkey
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativa
Pino
cembrinpinob
anksin
andits
acetateprenylestersof
caffeicacidferulicacidsditerpenicacids
likep
imaricisopimaricabieticdihydroabietic
acidscinn
amylcinn
amateandethyloleate
arom
aticacid
esterssuch
asbenzylcinn
amatebenzenedicarbo
xylic
acid
andflavano
lssuch
asbenzop
yran
andchrysin
[28ndash30]
Algeria
Popu
lusspp
Cistu
sspp
Pino
cembrinpinob
anksin
andits
acetatechrysin
apigenin
pectolinarigeninpilo
sinladanein
galang
inn
aringenin
tectochrysinm
etho
xychrysin
prenyleste
rsof
caffeicacidsferulic
acids
diterpenicacidslikeh
ydroxyditerpenicacidlabdaneand
clerod
ane
[2831]
Austr
alia
Apismellifera
Acaciaparadoxa
Xantho
rrho
eolpterostilbenesakuranetinpinostro
bin
stilbenesprenylatedtetrahydroxystilbenes
prenylated
cinn
amicacidsflavano
nesflavono
lschalcones
[39ndash
42181]
Stinglessb
eeTetra
gonu
lacarbonaria
Ctorellianatre
es(fr
uitresins)
Africa
Nigeria
Prob
ablyMschwe
infurthii
Isofl
avon
oidsprenylatediso
flavono
idsandstilbenoids
[54]
Kenya
Triterpenesarylnaphtalenelignans
such
astetrahydrojusticidinBand6-metho
xydiph
yllin
geranyl
stilbenesand
geranylflavon
macarangin
[50]
Cameroo
nCon
goTriterpenesderivatives
ofam
yrin
andlupeolanddiprenylflavono
ids
[53]
Oman
Azadira
chta
indicaA
cacia
sppand
Mangifer
aindica
Triterpenesprenylatedflavano
nessuchas
7-O-m
ethyl-8
-prenylnaringenin
310158408-diprenylnaringenin
and8-prenyl-57-dihydroxy-31015840-(3-hydroxy-3-methylbutyl)-41015840-m
etho
xyflavano
nechalco
nes
cardanolcardo
lsandanacardica
cids
[51]
Ethiop
iaProb
ablyAc
aciaspp
Triterpenoids
such
as120572-a
nd120573-amyrins120572-a
nd120573-amyrylacetateslup
eoland120572-a
nd120573-lu
peyl
acetates
[52]
Thailand
Styrax
trees
Phenylallylflavanon
e(E)-cinn
amyl-(E)-cinnamylidenate
[48]
TheP
acificr
egion
OkinawaHaw
aiiandTaiwan
Macaranga
tanariu
sPrenylflavono
idsmores
pecificallyiso
nymph
aeol-Bnym
phaeol-Anym
phaeol-Bnym
phaeol-C
prop
olins31015840-geranyl-naringenin
[43ndash45]
Indo
nesia
Myanm
arMangifer
aindica
Alk(en)ylresorcinolscyclo
artane-ty
petriterpenescycloartanesandprenylated
flavano
nes
[4647]
Canary
Island
sUn
know
nFu
rofuranlignans
[49182]
Evidence-Based Complementary and Alternative Medicine 5
of biological activity and chemical data This informationallows extrapolating the possible activity and mechanism ofaction of new propolis under study and provides substantialclues for the development of new drug candidates [6 9]
In the last decades several studies have demonstrated thebiological and pharmacological actions of different world-wide propolis samplesThe following sections summarize therecent published information about antibacterial and anti-fungal [6 7 56ndash59] antiviral [7 59 60] anti-inflammatory[61] antioxidant [62ndash64] immunomodulatory [6 65 66]and antitumor activities [8 17 23 64 66 67] revealing theinterest of researchers in this bee product and its potentialfor the development of new drugs as well
41 Antioxidant Activity It is well known that an endogenousstimuli like cellular metabolism and exogenous agents likeUV toxins and drugs among others generate reactiveoxygen species (ROS) such as hydrogen peroxide (H
2O2) the
superoxide anion (O2minus) and hydroxyl ion (HOminus) as well as
reactive nitrogen species (RNS) especially nitric oxide (NO)Carbohydrates proteins lipids and nucleic acids amongother biomolecules when exposed to the reactive speciessuffer oxidative modifications that modify the cell and leadto its death [68ndash70] Oxidative stress is responsible for theoccurrence of a wide variety of human diseases such asneurodegenerative [71] or cardiovascular diseases [72 73]cancer [68 74] diabetes [6] and atherosclerosis [75]
In the last years several studies have been performedto evaluate the antioxidant capacity of natural productsPropolis extracts composed of different polyphenols havebeen reported to possess a potent antioxidant activity [7076 77] Additionally the chemical varieties in differentpropolis samples from different regions have an influenceon the antioxidant activity Recently Fabris et al showedthat a sample of Italian and Russian propolis ethanol extract(PEE) which have a similar polyphenolic composition havea similar antioxidant activity while Brazilian PEE whichhave low polyphenolic composition have a weak antioxidantactivity [78] Another study also showed using differentsamples of Transylvania PEE a positive correlation betweenhigh polyphenolic composition and high antioxidant activity[79] Phenolic acids and flavonoids are characterized bya powerful antioxidant activity which is closely related tothe chemical structure of the compounds [80] Briefly theantioxidant activity is exerted by inhibiting the activity ofsome enzymes (eg xanthine oxidase protein kinase Cascorbic acid oxidase cyclooxygenase lipoxygenase Na+K+ATPase and cAMP phosphodiesterase) which inhibit theproduction of ROS species by scavenging interrupting thereactions that lead to the lipid peroxidation by chelatingmetal ions mainly iron and copper that are involved in theprocess of free radical creation or by potentiating the actionof other antioxidants [55] Table 2 summarizes some of thestudies addressing the antioxidant activity of propolis
Moreira et al [62] and Miguel et al [63] proposed thatPortuguese propolis an important source of total phenolsflavones and flavonols could be beneficial for human healthdue to its antioxidant properties Portuguese propolis alsoprotects human erythrocytes from free radicals damaging
by decreasing lipid peroxidation [64] These studies suggestthat Portuguese propolis is a powerful antioxidant agentthat can be used against oxidative stress thus maintainingthe structural and functional integrity of the cells Cuesta-Rubio et al [36] demonstrated that nemorosone the mostabundant polyisoprenylated benzophenone present in Cubanpropolis exhibits antioxidant capacity However when thiscompound suffers methylation a process that facilitates theseparation of the compound from the propolis sample theantioxidant property is abolished Ethyl acetate extract ofKangaroo Island propolis which is rich in stilbenes showeda stronger scavenging activity [39] Yang et al showed thatethyl acetate of propolis collected in Anhui China hasstrong scavenging activity and ferric reducing activity thoseactivities being influenced by caffeic acid phenethyl caffeatecinnamyl caffeate and benzyl caffeate [81] Another studyshowed that samples of methanolic extracts of Algerianpropolis that contains high amounts of caffeic acid estersand flavanones kaempferol and galangin possess strongscavenging activity and ferric reducing activity [31] Uruguaypropolis with high polyphenolic composition inhibits low-density lipoprotein (LDL) peroxidation and protein nitra-tion in vitro Moreover it induces the expression of nitricoxide synthase (eNOS) and inhibits NADPH oxidase inbovine aortic endothelial cells [82] In another study thetopical administration of Romanian PEE in mouse eitherprior to or after UVB exposure significantly attenuated themalondialdehyde (MDA) formation and restored glutathioneperoxidase (GSH-Px) activity [83] Talas et al [84] showedthat Turkish PEE has antioxidant properties in the livertissue of NOS inhibited rats In fact NOS inhibition causedan increase in CAT activity and MDA levels effect thatwas significantly decreased when the rats were treated withPEE It is well known that propolis composition is variablenevertheless one of itsmajor components CAPE (caffeic acidphenethyl ester) plays an important role in the antioxidantactivity [85ndash87]
Antioxidant activity is one of the most studied andimportant activities of propolis though there are no studieswith data on the safe dose to be used in humansThus clinicalstudies using propolis and its active compounds are needed
42 Anti-Inflammatory Activity Inflammation is an eventthat normally occurs in response to the constant exposureto environmental and endogenous stimuli as well as toaccidental damage [61] A complex cascade of chemicalsignals initiates after tissue injury and maintains a hostresponse to repair the injured tissue There are two stagesof inflammation acute and chronic Acute inflammation ismediated through the activation of the immune system cellswhich migrate to the site of damage and release growthfactors cytokines and ROSRNS species Chronic inflamma-tion occurs when the acute inflammation is not successfullyresolved This inflammatory condition plays a critical role inthe pathogenesis of many diseases including atherosclerosiscancer asthma Alzheimerrsquos and Parkinsonism [88 89]
Several studies have associated different types of propolisand its various constituents with anti-inflammatory activ-ity [61 90ndash95] Table 3 summarizes the anti-inflammatory
6 Evidence-Based Complementary and Alternative Medicine
Table2Antioxidant
activ
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Portug
al(Serra
deBo
rnes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Hum
anerythrocytes
Decreaseinlip
idperoxidatio
n[64]
Free
radicalscaveng
ing
[62]
Brazil
Prop
olisfro
mthes
tinglessb
eeMelipona
orbignyi
prob
ablypo
plar
tree
PEE
Hum
anerythrocytes
Free
radicalscaveng
inginhibitio
nof
hemolysisandlip
idperoxidatio
n[183]
Portugal(C
entral
Algarve)
European
prop
olisPopu
lus
nigra
PEE
PWE
andmethano
licextracts
Free
radicalsscavenging
chelatio
nof
metalions
[63]
Cuba
Redprop
olisC
rosea
Methano
licextract
Nem
oroson
eFree
radicalsscavenging
[36]
Slovenia
European
prop
olisPopu
lus
nigra
PEE
Strong
redu
cing
power
andabilityto
scavenge
freer
adicals
andmetalions
[184]
Romania
European
prop
olisPopu
lus
nigra
PEE
FemaleS
wiss
mice(UVB
expo
sure)
Decreaseinmalon
dialdehyde
levels
resto
ratio
nof
glutathion
eperoxidase
activ
ity[83]
Kang
aroo
Island
Austr
alianprop
olisAc
acia
paradoxa
Ethylacetateextractstilbenes
Free
radicalscaveng
ing
[39]
China
European
prop
olisPopu
lus
nigra
Ethylacetateextract
Free
radicalscaveng
ingandferricredu
cing
activ
ity[81]
Algeria
Mediterranean
prop
olisPopu
lusspp
andCistu
sspp
Methano
licextract
Free
radicalscaveng
ingandferricredu
cing
activ
ity[31]
Urugu
ayEu
ropean
andgreen
prop
olisPopu
lusn
igra
andB
dracun
culifolia
PEE
Bovine
aorticendo
thelialcells
Inhibitio
nof
low-densitylip
oprotein
peroxidatio
nand
NADPH
oxidasea
ndincrease
innitricoxides
ynthase
[82]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
C57B
L6mice(acutelun
ginflammationcaused
bycigarette
smoke)
Normalizationof
nitritem
yeloperoxidase
levels
superoxide
dism
utasecatalaseand
glutathion
eperoxidasea
ctivity
and
redu
ctionof
glutathion
eoxidized
glutathion
eratio
and
malon
dialdehyde
levels
[185]
Turkey
Mediterranean
prop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
nea
sativa
PEE
Fibrob
lastcells
Decreaseo
fDNAdamageind
uced
byH
2O2
[186]
MaleW
istar
rats
DecreaseinCA
Tactiv
ityandMDAlevelsin
NOSinhibited
rats
[84]
Carps
(Cyprin
uscarpio)
Decreaseinmalon
dialdehyde
levels
superoxide
dism
utase
activ
ityandincrease
ofcatalase
andglutathion
eperoxidase
activ
ity[187]
Purchasedfro
mSigm
aAldric
hCo
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Free
radicalscaveng
inginhibitio
nof
xanthine
oxidasea
ctivity
andlip
idperoxidatio
n[85]
MaleW
istar
albino
rats
Maintenance
ofsuperoxide
dism
utasea
ctivitydecreaseo
fxanthine
oxidasea
ctivity
andmalon
dialdehyde
andnitric
oxidaselevels
[86]
Perip
heralblood
mon
onuclear
cells
from
cyclists
Redu
ctionof
hypertherm
ia-in
ducedsurvivalinhibitio
nnecrosis
superoxide
prod
uctio
nglutathion
edepletio
nand
intracellularsup
eroxide
[87]
Evidence-Based Complementary and Alternative Medicine 7
Table3Anti-infl
ammatorymechanism
sinvestig
ated
with
prop
olis
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
PurchasedSigm
aAldric
hCo
Synthesiz
ed
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacidquercetin
narin
genin
CAPE
Periton
ealm
acroph
ages
Supp
ressionof
lipoxygenasep
athw
ayof
arachido
nica
cid
metabolism
CAPE
beingthem
ostp
otentm
odulator
ofthea
rachidon
icacid
cascade
[90]
Croatia
European
prop
olisPopu
lusn
igra
Water-solub
lederiv
atives
Swiss
albino
mice
Redu
ctionof
DNAdamageinperip
herallym
phocytes
[188]
PEE
MaleS
wiss
albino
mice
Supp
ressionof
functio
nalactivity
ofmacroph
ages
[104]
PurchasedSigm
aAldric
hCo
J774
macroph
agesM
ale
Wistar
rats
Invitro
andin
vivo
inhibitio
nof
cyclo
oxygenase1
and
cyclo
oxygenase2
activ
ity[91189]
MaleW
istar
albino
rats
Decreaseo
fpolym
orph
onuclear
neutroph
ilicleuko
cyte
infiltra
tionin
thelun
gstissues
[190]
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Gastricepith
elialcelllin
e(A
GS)H
pylori(str
ainNCT
C116
38)
Inhibitio
nof
Hpylori-ind
uced
NF-kB
andactiv
ator
protein
1-DNA-
bind
ingactiv
itypreventionof
IkB120572
degradationin
AGSandsupp
ressionof
TNF-120572andinterle
ukin
8prod
uctio
n[191]
PurchasedWakoPu
reCh
emicalIndu
stries
Ltd
RAW2647macroph
ages
Decreaseo
fthe
prod
uctio
nof
interle
ukin-1120573m
onocyte
chem
oattractant
protein1andthep
rodu
ctionandexpressio
nof
tumor
necrosisfactor120572(TNF-120572)
[98]
MaleS
wiss
inbred
strainmice
Decreaseo
fcyclooxygenase2
expressio
nNF-120581Bactiv
ity
c-Jun-N-te
rminalkinaseinh
ibito
rofN
F-120581Bkinase
(IKK
)andinhibitoro
fNF-120581B(IkB
)pho
spho
rylatio
n[97]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
RAW2647macroph
ages
Dow
nregulationof
NF-120581B
p38mito
gen-activ
ated
protein
kinaseand
c-Jun-N-te
rminalkinase
[101]
PurchasedAc
ros
Organics
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacid
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Sprague-Daw
leyrats
Inhibitio
nof
carrageenan-indu
cedrath
indpawse
demaa
ndthec
hemotaxisof
human
polymorph
onuclear
leuk
ocytes
(PMNs)
[95]
Synthesiz
edCh
aracteristic
ofEu
ropean
type
prop
olis
CAPE
Polymorph
onuclear
leuk
ocytes
obtained
from
Hum
anbloo
dInhibitio
nof
5-lip
oxygenasea
ctivity
andarachido
nica
cid
release
[103]
Chile
European
prop
olispo
plar
trees
PEE
MaleC
F-1m
ice
Inhibitio
nof
NOreleaseb
ythem
acroph
ages
[102]
China
European
prop
olisPopu
lusn
igra
PEEandPW
EMaleICR
micea
ndmale
Wistar
rats
Inhibitio
nof
thea
ctivationanddifferentiatio
nof
mon
onuclear
macroph
agesdecreasep
rosta
glandin-E2
(PGE2)
andnitric
oxide(NO)levels
[61]
Brazil
Green
prop
olisB
dracun
culifolia
PWE
Swiss
andBA
LBcmice
Decreaseinthen
umbero
fmacroph
ages
andneutroph
ils
inhibitio
nof
proinfl
ammatorycytokinesa
ndincrease
ofanti-inflammatorycytokines
[99]
Redprop
olisDalbergia
ecastaphyllum
PEE
MaleW
istar
rats
Decreaseinrenalm
acroph
ageinfi
ltrationin
ratswith
chronic
kidn
eydisease
[100]
Nepal
Nepalesep
ropo
lisprobablyShorea
robu
staD
albergiasissooAc
acia
catechuandBo
mbaxcie
ba
PEE
3101584041015840-dihydroxy-4-
metho
xydalbergion
e4-etho
xydalbergion
cearoin
andchrysin
Bone
marrow-derived
mast
cells
(BMMC)
from
C57B
L6
mice
Inhibitin
gIL-6T
NF-120572and
IL-13gene
expressio
nin
BMMC
andalso
inhibitin
gthea
ctivationof
IKKleadingto
NF-120581B
inactiv
ation
[96]
8 Evidence-Based Complementary and Alternative Medicine
mechanisms investigated with propolis and its chemicalconstituents Recently the role of the flavonoids quercetinflavonols and flavones in modulating inflammatory cellfunction was studied [92] Funakoshi-Tago et al [96] inves-tigated the anti-inflammatory effects of flavonoids isolatedfrom Nepalese PEE on the IL-33 signaling pathway Theisolated flavonoids 3101584041015840-dihydroxy-4-methoxydalbergione4-methoxydalbergion cearoin and chrysin inhibited theexpression of inflammatory genes including IL-6 TNF-120572and IL-13 in bone marrow-derived mast cells (BMMC) andalso inhibited the activation of IKK which leads to thedegradation of I120581B120572 and inhibits the activation of nuclearfactor 120581B (NF-120581B)
The release and oxygenation of arachidonic acid are acritical event in inflammation Mirzoeva and Calder [90]demonstrated that propolis components such as CAPE caf-feic acid quercetin andnaringenin among others inhibit theproduction of eicosanoids In fact these components signif-icantly suppressed the lipoxygenase pathway of arachidonicacid metabolism CAPE being the most potent modulatorAnother study indicated that CAPE treatment improveshepatic steatosis induced by high-fat diet in a mouse modelThis effect was attributed to the reduction of c-Jun-N-terminal kinase (JNK12) andNF-120581B activationwith decreasein COX-2 expression [97] Recently it was reported thatCAPE exhibits inhibitory effects on the production of proin-flammatory cytokines (interleukin-1120573 (IL-1120573)) tumor necro-sis factor-120572 (TNF-120572) and monocyte chemoattractant pro-tein 1 (MCP-1) from lipopolysaccharide- (LPS-) stimulatedRAW2647 macrophages [98] Machado et al [99] showedthat Brazilian green propolis water extracts (PWE) modulatean anti-inflammatory cellular response in the model of LPS-induced pulmonary inflammation by decreasing the numberof macrophages and neutrophils Additionally it induced areduction in the secretion of IL-6 and TNF-120572 and an increasein TGF-120573 and IL-10 Another study showed that Brazilianred PEE promotes a significant decrease in renal macrophageinfiltration in rats with chronic kidney disease [100] Bufaloet al [101] demonstrated that Brazilian PEE and caffeicacid inhibited LPS-induced NO production by RAW2647macrophages acting at the transcriptional level and sug-gesting that their anti-inflammatory effects were mediatedby downregulating NF-120581B p38 MAP kinase and JNK12According to Naito et al [95] topical application of BrazilianPEE is effective in inhibiting carrageenan-induced rat hindpaw edemaThis sample appears to inhibit the chemotaxis ofhuman polymorphonuclear leukocytes (PMNs) which alsocontributes to its anti-inflammatory effects Another studyshowed the topical anti-inflammatory activity of propolisfrom Chile in mice ear with induced-edema In fact PEEfrom Buin Chile was the most active against the inflamma-tion induced by 12-O-tetradeca-noylphorbol-13-acetate andarachidonic acid and also inhibits significantly NO releaseby the macrophages [102] More recently Boudreau et al[103] indicated that CAPE is a potent leukotriene biosynthesisinhibitor in PMNs that blocks 5-lipoxygenase (5-LO) activityand arachidonic acid release A Croatian PEE may improvepsoriatic-like skin lesions whichwere induced in the study byirritant agents like n-hexyl salicylate or di-n-propyl disulfide
by reducing the lipid peroxidation in the skin and totalnumber of inflammatory cells in the skin and peritonealcavity more specially by suppressing functional activity ofmacrophages [104]
43 Immunomodulatory Activity Natural substances areconsidered alternative adjuvant therapies in the treatment ofdifferent diseases due to their immunomodulatory effectsInformation about this type of activity was scarce for propolisuntil the 1990s but published work in the last years has pro-vided information about the influence of different propolissamples on the immune system [65 105ndash112] (Table 4)
In a study using Brazilian green propolis it was seenthat the administration for 3 days of a PEE to male BALBcmice modulated the activation of the initial steps of theimmune response by upregulating toll-like receptor- (TLR-)2 and toll-like receptor-4 expression and proinflammatorycytokines (IL-1 and IL-6) production by macrophages andspleen cells [105] Another study demonstrated that BraziliangreenPEEupregulates TLR-4 andCD80 expression in humanmonocytes as well as TNF-120572 and IL-10 production [113] Itwas also shown that caffeic acid stimulates the activity ofmonocytes againstC albicans but it inhibits TLR-2 andHLA-DR expression as well as TNF-120572 and IL-10 production [114]
Additionally Missima et al [115] showed that Braziliangreen PEE administered to stressed mice reduces the proin-flammatory cytokines IL-1120573 and IL-6 When administered tomelanoma-bearing mice submitted or not to chronic stressit induces high levels of IL-1120573 and IL-6 and also stimu-lates Th1 cytokines production indicating the activation ofantitumour cell-mediated immunity Bachiega et al [116]investigated the immunomodulatory effect of propolis andcinnamic and coumaric acids on cytokines IL-1120573 IL-6 andIL-10 production Peritonealmacrophages fromBALBcmicewere incubated with different concentrations of propolis(5 50 and 100mgwell) and coumaric and cinnamic acid(50 and 100mgwell) Propolis and the acids stimulated IL-1120573 production and significantly inhibited IL-6 productionThen after LPS incubation the inhibitory concentrations ofcinnamic and coumaric acids prevented efficiently its effectson IL-6 production whereas propolis inhibited LPS effectsboth before and after its addition Additionally propolis andcoumaric and cinnamic acids inhibited IL-10 production Astudy which evaluated the effect of Brazilian green propolison macrophage activation by H
2O2and NO metabolite
determination [107] showed that propolis increased H2O2
generation and decreased NO generation which favoursthe microbicidal activity Recently the immunomodulatoryeffect of propolis collected in Brazil was evaluated in Leish-mania (Viannia) braziliensis experimental infection Datashows that macrophages incubated with propolis showed asignificant increase in interiorization and further killing ofparasites Also an increased TNF-120572 production was seen inpropolis-pretreated mice whereas IL-12 was downregulatedduring the infection [117]
The immunomodulatory action of propolis does notoccur only at the macrophage level In fact some studiesshow that this action has also an effect on lymphocyte pro-liferation [106 108] Sa-Nunes et al [108] showed inhibitory
Evidence-Based Complementary and Alternative Medicine 9
Table4Im
mun
omod
ulatoryactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
MaleB
ALB
cmice
Upregulationof
toll-lik
ereceptor-2andreceptor-4
expressio
nand
increasesininterle
ukin-1andinterle
ukin-6
prod
uctio
n[105]
Upregulationof
toll-lik
ereceptor-2andreceptor-4
mRN
Aexpressio
n[111]
MaleC
57BL
6miceB16F
10cell
line
Stim
ulationof
thee
xpressionandprod
uctio
nof
interle
ukin-2
and
interle
ukin-10andTh
1cytokine(interle
ukin-2
andIFN-120574)p
rodu
ction
[192]
MaleB
ALB
cmice
Inhibitio
nof
Th1cellsgeneratio
nredu
ctionof
thefrequ
ency
ofIFN-120574-produ
cing
CD4+
Tcells
underTh
1-polarizingcond
ition
s[118]
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecreasesintheN
Ogeneratio
nin
periton
ealm
acroph
ages
[109]
MaleB
ALB
cmice
Increase
intheinterioriz
ationandkilling
ofthep
arasitesL
eishm
ania
(Viann
ia)b
raziliensisby
macroph
agesincreaseinTN
F-120572prod
uctio
nanddecrease
ininterle
ukin-12prod
uctio
n[117]
Mon
ocytes
from
human
bloo
dTL
R-4andCD
80expressio
nin
human
mon
ocytes
aswellasT
NF-120572
andIL-10prod
uctio
n[113]
Mela
nomac
ells(B16F10)m
ale
C57B
L6mice
Redu
ctionof
IL-1120573andIL-6
inLP
S-str
essedmiceindu
ctionof
IL-1120573
andIL-6
andTh
1cytok
ines
inmela
noma-bearingmices
ubmitted
orno
ttochronics
tress
[115]
Brazil
PurchasedAc
rosO
rganics
Green
prop
olisB
dracun
culifolia
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
PEE
cinn
amicandcoum
aricacids
MaleB
ALB
cmice
Stim
ulationof
interle
ukin-1120573prod
uctio
nandinhibitio
nof
interle
ukin-6
andinterle
ukin-10prod
uctio
ns[116]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
and
Mediterraneanprop
olis
Caffeicacid
Mon
ocytes
from
human
bloo
dStim
ulationof
mon
ocytes
activ
ityagainstC
albica
nsdow
nregulation
ofTL
R-2andHLA
-DRexpressio
nandinhibitio
nof
cytokine
prod
uctio
n[114]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
Cinn
amicacid
Mon
ocytes
from
human
bloo
dDow
nregulationof
toll-lik
ereceptor-2HLA
-DRmolecules
from
human
antig
en-presentingcellsand
CD80upregulationof
toll-lik
ereceptor-4inh
ibition
ofTN
F-120572andinterle
ukin-10prod
uctio
n[19
3]
PurchasedSigm
aAldric
hCo
Cinn
amicacid
FemaleIRC
mice
Increase
oflymph
ocytep
roliferationandreleaseo
fcytok
ines
interle
ukin-1andinterle
ukin-2
[106]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Hydroalcoho
lic(H
PE)solution
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecrease
ofNOgeneratio
n[107]
MaleB
ALB
cmice
Decreaseo
fsplenocytep
roliferationandincrease
ofIFN-120574
prod
uctio
nby
spleen
cells
[108]
Indo
nesia
TheP
acificr
egionprop
olisMacaranga
tanariu
sand
Mind
icaHPE
MaleB
ALB
cmice
Increase
ofIgGgeneratio
nandmacroph
agep
hagocytosis
activ
ityand
capacity
[110]
Turkey
Mediterraneanprop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
neasativa
PEE
Perip
heralblood
mon
onuclear
cells
from
healthyhu
mans
Supp
ressionof
neop
terin
releasea
ndtryptoph
andegradation
downregulationof
thee
nzym
eind
oleamine2
3-dioxygenase
(IDO)and
decrease
ofIFN-120574
andTN
F-120572levels
[194]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
CAPE
Hum
anmon
ocyte-deriv
eddend
riticcells
(MoD
Cs)g
enerated
from
perip
heralm
onocytes
Inhibitio
nof
IL-12p4
0IL-12p70IL-10IFN-120574-in
duciblep
rotein-(IP-)
10levels
inhibitio
nof
I120581B120572
phosph
orylationandNF-120581Bactiv
ation
[112]
FemaleB
ALB
cmice
Increase
ofIgM
antib
odyprod
uctio
nTlymph
ocytep
roliferation
interle
ukin-4
andinterle
ukin-2
prod
uctio
nby
spleno
cytesandIFN-120574
prod
uctio
n[195]
Hum
anperip
heralblood
mon
onuclear
cellsjurkatcells
Inhibitio
nof
transcrip
tionfactorsN
F-120581BandNFA
Tinhibitio
nof
interle
ukin-2
gene
transcrip
tion
interle
ukin-2
receptor
expressio
nand
proliferatio
nof
human
Tcells
[94]
10 Evidence-Based Complementary and Alternative Medicine
effects of Brazilian green propolis on splenocyte proliferationeffect that was attributed to flavonoids and enhancementeffects on interferon- (IFN-) 120574 production by spleen cellsCAPE displays inhibitory effects on transcription factors NF-120581B and NFAT and as a consequence inhibits IL-2 genetranscription IL-2 receptor expression and proliferation ofhuman T cells [94] This provides new information into themolecular mechanisms involved in the anti-inflammatoryand immunomodulatory activities of propolis CAPE hasvarious biological activities but its effect on the immunomod-ulatory activity remains little studied According to Wanget al [112] CAPE can be useful in the treatment of asthmaand other allergic diseases because it can inhibit cytokinesand chemokines production by human monocyte-deriveddendritic cells (MoDCs) which might be related to theNF-120581B signalling pathway Another study demonstrated forthe first time that Brazilian propolis significantly inhibitedthe generation of Th1 cells Furthermore the effects ofpropolis were investigated on 246-trinitrobenzene sulfonicacid- (TNBS-) induced colitis in a mouse model Propolisreduced the frequency of IFN-120574-producing CD4 T cellsin a dose-dependent way under Th1-polarizing conditionsThe inhibitory effect of propolis on Th1 differentiation wasdemonstrated in vivo too and the severity of colitis inpropolis-fed mice was significantly lower than that of micefed with the control diet [118]
44 Antiviral Activity Propolis comprises a complexity ofcompounds which play a role in antiviral protection Despitethe few data available regarding this activity it was shown thatpropolis from different geographic regions has considerableantiviral activity by acting at different levels and interferingwith the replication of some viruses [12] like herpes simplextypes 1 and 2 adenovirus type 2 influenza virus or humanimmunodeficiency virus (HIV) among others [7 60 119ndash124] Table 5 summarizes the antiviral activity of propolis andits chemical constituents
Schnitzler et al [123] analysed the antiviral effect ofPWE and PEE from Czech Republic as well as that ofthe constituents caffeic acid p-coumaric acid benzoic acidgalangin pinocembrin and chrysin against herpes simplexvirus type 1 (HSV-1) in cell culture Both extracts exhibitedhigh anti-HSV-1 activity when cells were treated prior toviral infection galangin and chrysin being the main bioac-tive compounds Amoros et al [60] showed the antiviralactivity of the major flavonoids of propolis more specificallyflavonols and flavones the first being more active againstHSV-1 Additionally they analysed the effect of propolis onseveral DNA and RNA viruses (HSV-1 HSV-2 adenovirustype 2 vesicular stomatitis virus (VSV) and poliovirus type2) Propolis at a concentration of 30120583gmL reduced thetiter of herpes virus however vesicular stomatitis virusand adenovirus were less susceptible In addition propo-lis appears to exert a virucidal action on the envelopedviruses HSV and VSV [120] Recently it was shown thathydromethanolic extract of geopropolis from the stinglessbee Scaptotrigona postica (Brazil) inhibits theHSV replicationand also the entry of the virus into cells effect that wasattributed to the C-glycosyl flavones catechin-3-O-gallate
and 34-dicaffeoylquinic acid [125] According to Tait etal [126] natural and synthetic flavonoids might interferewith picornavirus replication preventing the decapsidationof viral particles and RNA release within cells or blockingviral RNA synthesis These authors also showed that differ-ent homoisoflavonoids have good antiviral activity againstthe coxsackie viruses B3 B4 and A9 and echovirus 30Shvarzbeyn and Huleihel [127] tried to determine whichstep of Tax oncoprotein-induced NF-120581B activation is blockedby propolis and CAPE and showed that both substantiallyinhibited the activation of NF-120581B-dependent promoter byTax Also they strongly prevented both Tax binding to I120581B120572and its induced degradation by Tax Ma et al [128] showedthat nanometer propolis flavones could significantly inhibitin vitro porcine parvovirus (PPV) infecting PK-15 cells andin vivo they restrain the PPV copy in lung gonad and blooddecrease the impact of PPV on weight of guinea pigs andincrease hemagglutination inhibition of PPV in serum as wellas improving the contents of IL-2 IL-6 and 120574-IFN
Over recent years therapeutic benefits of propolis andorits isolated compounds have been described in HIV treat-ment Ito et al [129] tested the anti-HIV activity in H9lymphocytes of triterpenoids melliferone moronic acidanwuweizonic acid and betulonic acid and four knownaromatic compounds isolated from Brazilian propolis andshowed that moronic acid had significant anti-HIV activityGekker et al [119] assessed the anti-HIV-1 activity of propolisin CD4+ lymphocytes and microglial cell cultures observ-ing the inhibition of viral expression in a concentration-dependent wayThe possible mechanism of propolis antiviralproperty was suggested to involve inhibition of viral entry
45 Antimicrobial Activity Antimicrobial activity one ofthe most studied propolis biological properties is very welldocumented This bioactivity has been largely investigatedin the last years due to the need of new treatments againstinfectious diseases especially with the increase of resistantpathogens to current antibiotics Tables 6 and 7 summarisethe antibacterial and antifungal activities found in propolisfrom different geographic origin andor its chemical con-stituents
451 Antibacterial Activity Propolis effect against severalbacterial strains has evaluated [7 56ndash59 130] and supportedthe fact that propolis is more active against Gram-positivebacteria than Gram-negative bacteria [12 59] Briefly datafrom different studies showed that propolis inhibits bac-terial motility and enzyme activity exhibits bacteriostaticactivity against different bacterial genera can be bactericidalin high concentrations and affects cytoplasmic membrane[130]
Mirzoeva et al [130] investigated the effect of PEEon the physiology of Bacillus subtilis Escherichia coli andRhodobacter sphaeroides proposing that propolis and someof its components like cinnamic acid and flavonoids affectthe ion permeability of the inner bacterial membrane causingthe dissipation of the membrane potential and inhibitingbacterial motility A recent study [131] provided valuableinformation for understanding the potential anti-H pylori
Evidence-Based Complementary and Alternative Medicine 11
Table5Antivira
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescellsviru
ses
Effect
References
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
Caffeicacidp-cou
maricacid
benzoica
cidgalang
in
pino
cembrinand
chrysin
RC-37cellsherpessim
plex
virustype1
(HSV
-1)
strainKO
SHighanti-HSV
-1activ
ityforb
othextractswhencells
weretreated
prior
toviralinfectio
n[123]
CzechRe
public
European
prop
olisPopu
lusn
igra
PEEandPW
ERC
-37cellsherpessim
plex
virustype2
(HSV
-2)
Highantih
erpetic
activ
ityforb
othextractswhenvirusesw
ere
pretreated
priortoinfection
[196]
Brazil
Brow
nprop
olisB
dracun
culifolia
HPE
HSV
-2str
ainprop
agated
inVe
rocellsfem
aleB
ALB
cmice
Effectiv
eagainstHSV
-2infectionandin
redu
cing
extravaginallesio
nsby
actin
gon
inflammatoryandoxidativep
rocessesreducingreactiv
especiestyrosin
enitration
ascorbicacid
levels
andmyeloperoxidase
activ
ityandprotectin
gagainstinh
ibition
ofcatalase
activ
ity
[124]
Characteris
ticof
Brazilian
prop
olis
Isop
entylferulate(
isolatedfro
man
PEE)
Influ
enza
virusesA
PR834
(H1N
1)
AKrasnod
ar10
159(H
2N2)and
AH
ongKo
ng168
(H3N
2)Supp
ressionof
influ
enza
virusA
Hon
gKo
ngreprod
uctio
nin
vitro
[121]
Green
prop
olisB
dracun
culifolia
Beriocla
daM
yrceugeniaeuosma
PEE
Influ
enza
APR834
(H1N
1)virusp
ropagated
Madin-D
arby
canine
kidn
ey(M
DCK
)cells
female
DBA
2Cr
mice
Redu
ctionof
body
weightlosso
finfectedmicea
ndvirusy
ieldsinthe
bron
choalveolarlavagefl
uids
oflung
s[122]
France
European
prop
olisPopu
lusn
igra
PEE
RC-37cellsH
SV-1str
ainH29Sacyclovirresistant
mutantH
SV1-R
strainH29R
HSV
-2adeno
virustype
2po
liovirustype2
and
vesic
ular
stomatitisv
irus
(VSV
)
Redu
ctionof
titre
ofherpes
virusbeingvesic
ular
stomatitisv
irusa
ndadenoviru
slesssusceptibleviru
cidalactionon
thee
nvelo
pedviruses
HSV
andVS
V[120]
Brazil
Geoprop
olisfro
mthes
tinglessb
eeScaptotrigona
postica
Hydromethano
licextract
African
greenmon
keykidn
eycells
(ATC
CCC
L-81)
herpes
simplex
virusstrain(M
cIntyre)
Inhibitio
nof
HSV
replicationandentryinto
cells
[125]
Synthesiz
edCh
aracteris
ticof
Brazilian
redand
greenprop
olis
Hom
oisoflavono
idsspecially
3-benzyl-4-chrom
ones
BGM
(Buff
aloGreen
Mon
key)
cellscoxsackieviruses
B3B
4andA9andecho
virus3
0Goo
dantiv
iralactivity
againstthe
coxsackiev
irusesB
3B4
and
A9and
echo
virus3
0[126]
Canada
European
prop
olisPtrichocarpa
andPtre
muloides
PEE
HSV
-1andHSV
-2virusreplicated
inMDBK
(mon
olayer
cultu
reso
fMadin-D
arby
bovine
kidn
ey)
cells
Impairing
thea
bilityof
thev
irustoadsorb
orto
penetratethe
hostcells
[197]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Water
extracts
FemaleB
ALB
cmiceInflu
enza
Avirusstrain
AW
SN33(H
1N1)
Extensionof
thelifetim
eofm
ice34-dicaffeoylquinica
cidwhich
increasesm
RNAlevelsof
tumor
necrosisfactor-related
apop
tosis
-indu
cing
anddecreasesH
1N1h
emagglutinin
mRN
A[19
8]Ch
aracteris
ticof
Brazilian
green
prop
olis
34-dicaffeoylquinica
cid
(Isolated
from
Brazilian
prop
olis)
Brazil
Characteris
ticof
Brazilian
green
prop
olis
Melliferon
emoron
icacid
anwuw
eizonica
cidand
betulonica
cid(isolated
from
Brazilian
prop
olis)
H9lymph
ocytesH
IV-1
Moron
icacid
inhibitin
ganti-HIV
replication
[129]
Israel
Mediterraneanprop
olisPopu
lus
sppE
ucalyptusspp
andCa
stanea
sativa
PWE
Jurkatuninfectedhu
man
T-celllin
esand
MT2
(HTL
V-1infectedhu
man
Tcells)cells
Inhibitio
nof
thea
ctivationof
NF-120581B-depend
entp
romoter
byTaxand
preventio
nof
Taxbind
ingto
I120581B120572
andits
degradation
[127]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Provided
byBinzho
uAnimal
Sciencea
ndVe
terin
ary
MedicineA
cademyof
Shando
ngProvince
Nanom
eter
prop
olisFlavon
eKidn
eycells
(PK-
15)
Porcinep
arvovirus(PP
V)
Britain
Whiteguinea
pigs
Inhibitio
nof
PPVinfectingpo
rcinek
idney-
(PK-
)15cells
Restr
aining
ofPP
Vcopy
inlung
gon
adand
bloo
ddecrease
ofthe
impactof
PPVon
weighto
fguineap
igsandincrease
ofhemagglutinationinhibitio
nof
PPVin
serum
aswellasimprovingthe
contentsof
IL-2IL-6and120574-IFN
[128]
USA
andCh
ina
European
prop
olisPopu
lusn
igra
PEE
Perip
heralblood
mon
onuclear
cells
obtained
from
bloo
dof
healthyd
onorsmicroglialcellsiso
latedfro
mhu
man
fetalbrain
tissueHIV-1ATH
IV-1SF162
Inhibitio
nof
HIV-1varia
ntse
xpression
[119]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
12 Evidence-Based Complementary and Alternative Medicine
Table6Antibacteria
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
PurchasedBe
eHealth
Ltd
(Scarborou
ghYorkshire
UK)
Eu
ropean
prop
olisPopu
lusn
igra
PEE
BsubtilisS
G38E
coliandR
sphaeroides
Influ
encing
theion
perm
eabilityof
theinn
erbacterial
mem
brane
Inhibitio
nof
bacterialm
otility
[130]
PurchasedSigm
aCh
emicalCo(Poo
leDorsetUK)
Characteris
ticof
EuropeanB
razilian
andMediterraneanprop
olis
CaffeicacidC
APE
qu
ercetin
and
narin
genin
Greece
Mediterraneanprop
olisprob
ablyCo
nifer
spp
Terpenes
(isolated
from
Cretan
prop
olis)
Saureus
(ATC
C25923)Sepiderm
idis(ATC
C12228)E
coli
(ATC
C25922)E
cloacae
(ATC
C13047)K
pneumoniae
(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Influ
encing
theG
ram-positive
andGram-negativeb
acteria
viability
[199]
France
European
prop
olisPopu
lusn
igra
Dichlorom
ethane
extract
Gram-negative7Ac
inetobacterb
aumannii(RC
HSAN00812
AYE
CIP7
034107292and
5377)2Escherich
iacoli(ATC
C25922andac
linicaliso
late)3
Pseudomonas
aeruginosa
(ATC
C27853andtwoclinicalisolates)and4clinicalisolates
ofEn
terobacterclo
acaeE
aerogenesK
lebsiella
oxytocaand
Salm
onellaenteritidis(phage
type
4)Gram-negative13
Staphylococcus
aureus
(ATC
C25923six
methicillin-susceptib
leclinicalisolatesandsix
methicillin-resistant
clinicalisolates)2
clinicalisolates
ofS
epidermidis(m
ethiSandmethiR)3
clinicalisolates
ofEn
terococcus
faecalisand1E
faeciu
mand
1clin
icaliso
lateof
Corynebacterium
striatum
Influ
encing
theG
ram-positive
bacteriaviabilityspecially
Saureus
andseveralofitsmethicillin-resistant
and
methicillin-susceptib
le[133]
Bulgaria
Mediterraneanprop
olis
PEE
Saureus
209E
coliWF+
Decreaseo
fSaureusg
rowth
andweakor
lack
ofactiv
ityagainstE
coli
[28]
Greece
Popu
lusspp
Tu
rkey
Conifer
spp
Algeria
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativaPopu
lusspp
Cistu
sspp
Austr
alia
Austr
alianprop
olisfro
msting
lessbee
Tetra
gonu
lacarbonariaCtorelliana
trees
(fruitresins)
PEE
Saureus
(ATC
C25923)
Paeruginosa
(ATC
C27853)
Inhibitio
nof
Saureus
grow
th[42]
Cameroo
nandCon
goAfrican
prop
olisprob
ablyM
schw
einfurthii
PEE
Saureus
(ATC
C25923)Sepiderm
is(ATC
C13047)E
coli
(ATC
C25922)K
lebsiella
pneumonia(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Inhibitio
nof
Saureus
grow
th[53]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Saureus
2979
andSaureus
4118
isolated
from
mastiticcows
Saureus
(ATC
C29213)
Decreaseo
fSaureusg
rowth
incomplex
mediaandkilling
ofSaureus
cells
resuspendedin
milk
promotionof
changesin
morph
olog
yandcellsiz
e[200]
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsu
lfoxide
extract
Saureus
(CAPM
5970)E
faecalis(C
APM
5613
(EBF
3039))
Ecoli(C
AMP3101
T(U
541))and
Lmonocytogenes(C
CM5580)
Differentcon
centratio
nsaffectthe
grow
thofthetestedbacteria
[201]
Italy
Mediterraneanprop
olisCrup
essusspp
PE
E
Staphylococcus
sppstr
ains
(35Saureus63Sepidermidis
7S
hominis
18Shaem
olyticu
s10
Swa
rneri4Scapitisand
3S
auric
ularis)
andStreptococcusspp
strains
(59Sfaecalis
30S
virid
ans15
S120573-haemolyticu
sand19
Spn
eumoniae)
Com
pletes
uppressio
nof
thefactorc
oagu
lasereductio
nof
lipasea
ndpreventio
nof
biofi
lmform
ationof
Staphylococcus
increase
ofthee
ffectof
ampicillingentam
ycinand
streptomycin
andmod
eratingthea
ctionof
chloramph
enicol
ceftriaxoneand
vancom
ycin
[56]
Brazil
Redprop
olisDecasto
phyllum
Green
prop
olisB
dracun
culifolia
PEE
Saureus
(ATC
C25923)
NanoH
Amatrix
with
redandgreenprop
oliswhich
redu
ces
bacterialgrowth
andbiofi
lmform
ation
then
anoH
Awith
red
prop
olisbeingthem
ostefficient
[136]
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
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[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
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[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
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[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
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[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
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Evidence-Based Complementary and Alternative Medicine 23
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24 Evidence-Based Complementary and Alternative Medicine
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[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
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[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
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[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
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[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 3
Figure 1 Crude sample of propolis from Pereiro obtained in thecentral region of Portugal (Guarda)The sample was kindly suppliedby Engineer Pedro Fernandes (Mel do Abel)
concentration of diterpenoids and is found in many regionslike Greece [24 25] Switzerland [26]Malta [27] Turkey [28ndash30] or Algeria [28 31]
Propolis from tropic regions like Brazil CubaVenezuelaand Chile has been attracting much attention in thelast years due to its particular chemical profiles Preny-lated phenylpropanoids prenylated p-coumaric acids ace-tophenones diterpenic acids and caffeoylquinic acids wereshown to be very common and abundant in propolis fromBrazil mainly from the south-eastern region [9 10 21]The flavonoids kaempferide and isosakuranetin and someamounts of kaempferol were also found in Brazilian samples[32] Additionally red propolis from the northeast regionsof Brazil presents high concentrations of phenolic acids andthe flavonoids formononetin isoliquiritigenin liquiritigeninmedicarpin and biochanin A [33ndash35] Cuban propolis hasa peculiar enrichment in polyisoprenylated benzophenonesmore specifically nemorosone and a minor content of amixture of xanthochymol and guttiferone E [9 36] makingthis type of sample chemically distinct from both Europeanand Brazilian propolis Propolis from Venezuela is alsocomposed of polyisoprenylated benzophenones in additionto the usual constituents found in samples of tropical regions[9 37 38]
Information about the chemical composition of Aus-tralian propolis is very limited despite the great biodiversityof the island Propolis from Kangaroo Island is mainlycomposed of stilbenes some of them being prenylated Ad-ditionally it has also some prenylated cinnamic acids andflavonoids [39] like 210158403101584041015840-trimethoxychalcone 21015840-hy-droxy-3101584041015840-dimethoxychalcone 2101584041015840-dihydroxy-31015840-metho-xychalcone 57-dihydroxy-23-dihydroflavonol 3-acetate (pi-nobanksin 3-acetate) and 57-dihydroxy-6-methoxy-23-dihydroflavonol 3-acetate [40] Western Australian propolisis composed of Xanthorrhoeol pterostilbene sakuranetinand pinostrobin [41] Propolis of Australian stingless bees(Tetragonula carbonaria) is composed of C-methylatedflavanones [42]
ldquoPacificrdquo propolis (eg Okinawa Taiwan Hawaii Indo-nesia and Myanmar) is another particular type of propolisA new family of compounds the prenylflavonoids morespecifically isonymphaeol-B was identified in Okinawapropolis although three already known compoundsmdashnym-phaeol-A nymphaeol-B and nymphaeol-Cmdashhave also
been isolated in three samples [43] As Okinawan propolisHawaiian propolis is also composed of nine prenylflavonoids[44] Taiwanese propolis is composed of eight prenylfla-vanones nymphaeol-A nymphaeol-B and nymphaeol-Cpropolins A B and E isonymphaeol B and 31015840-geranyl-naringenin [45] In another sample of the Pacific regionthe Indonesian propolis an inseparable mixture of fouralk(en)ylresorcinols (5-pentadecylresorcinol 5-(81015840Z111015840Z-heptadecadienyl)-resorcinol 5-(111015840Z-heptadecenyl)-resor-cinol and 5-heptadecylresorcinol) along with four prenylfla-vanones propolins D C F and G and three cycloartane-type triterpenes mangiferolic acid isomangiferolic acidand 27-hydroxyisomangiferolic acid was identified [46]Additionally fractioning of propolis extracts from Myanmarled to the isolation of two new cycloartane-type triterpenestogether with 13 cycloartanes and four known prenylatedflavanones [47] Thailand propolis which might bepossibly obtained from Styrax trees comprises not onlythe typical compounds of temperate regions but also thetwo new phenylallylflavanones (710158401015840S)-8-[1-(41015840-hydroxy-31015840-methoxyphenyl)prop-2-en-1-yl]-(2S)-pinocembrin and (E)-cinnamyl-(E)-cinnamylidenate [48] In propolis fromCanaryIslands a different phenolic profile was found furofuranlignans being the main compounds Six furofuran lignanswere isolated and characterized as sesamin episesaminmethyl xanthoxylol aschantin sesartenin and yangambinPropolis also contains sugars and sugar alcohols [10 49]Many studies with African propolis from different regionslike Kenya Cameroon Congo Oman and Ethiopia showedthat triterpenoids are major chemical components [50ndash53]Southern Nigeria propolis is uncommon since it presentsprenylated isoflavonoids like Brazilian red propolis and ahigh abundance of stilbenoid compounds [54]
Propolis additionally contains minerals such as mag-nesium calcium iodine potassium sodium copper zincmanganese and iron some vitamins like B1 B2 B6 CE and D as well as provitamin A a few fatty acids andalso some enzymes derived from bee glandular secretion orpossibly from pollen like succinic dehydrogenase adenosinetriphosphatase glucose-6-phosphatase acid phosphatase120572-amylase 120573-amylase 120572-lactamase 120573-lactamase maltaseesterase and transhydrogenase [17 55] Polysaccharides likestarch and the di- and monosaccharaides glucose fructoseribose rhamnose talose gulose and saccharose are com-monly present in propolis too [55]
4 Biological Properties and TherapeuticActivity of Propolis
Despite propolis popularity over time it is not consid-ered as a therapeutic agent in conventional medicine asthe standardization of chemical composition and biologicalactivity is lacking Such standardization is indispensablefor acceptance in the health system Thus characterizationof different types of propolis according to its plant originand corresponding chemical profile is mandatory Studiesabout propolis bioactivity must start with chemical profilingof the extracts since that information is essential to havedetailed and consistent comparative data between each type
4 Evidence-Based Complementary and Alternative Medicine
Table1Ch
aracteris
ticcompo
unds
ofprop
olisfro
mdifferent
geograph
icoriginsa
ndrespectiv
eplant
source
Geographico
rigin
Plantsou
rce
Typicalcon
stituents(m
aincompo
nents)
References
EuropeN
orth
AmericaNew
Zealandand
temperatezoneso
fAsia
Popu
lusspp
morep
redo
minantly
Pnigra
Pino
cembrinpinob
anksinchrysingalangin
caffeicacidferulicacidcinnamicacidand
their
esters
[102022]
Brazil
Green
prop
olis
Baccharis
spppredo
minantly
Bdracun
culifolia
Prenylated
phenylprop
anoidspheno
licacidsprenylated
p-coum
aricacidsacetop
heno
nes
diterpenicacidscaffeoylquinica
cidskaempferideiso
saku
ranetin
and
kaem
pferol
[9103233]
Redprop
olis
Dalbergiaecastaphyllum
Form
onon
etinisoliq
uiritigeninliquiritigeninm
edicarpin
andbiochaninA
[323435]
Russia
Betulasppm
ores
pecificallyB
verrucosaB
pend
ulaandB
pubescens
Cinn
amicacidsph
enylprop
anoidsesquiterpenolsacacetinapigenin
ermaninrhamno
citrin
kaem
pferide120572-acetoxybetuleno
l[10180]
CubaV
enezuela
Clusiasppm
ores
pecificallyC
rosea
andC
minor
Polyiso
prenylated
benzop
heno
nesmores
pecificallynemoroson
exantho
chym
oland
guttiferone
E[936]
Mediterranean
Greece
Prob
ablyCo
nifer
spp
Flavon
oidsditerpenicacidssuchas
isocupressic
pim
aricand
commun
icacidsiso
agatho
lal
agathadiolferrugino
l8-elem
eneandtotarol
[2425]
Switzerland
Ptre
mula
Benzylp-coum
aratebenzylferulateandph
enolicglycerides
liked
icou
maroylacetylglycerol
diferuloylacetylglycerolferuloylcou
maroylacetylglycerolandcaffeoylcou
maroylacetylglycerol
[26]
Malta
Ferulaspp m
ostp
robablyFerula
commun
isDiterpenicacidssuchas
isocupressic
com
mun
icpim
aricand
imbricatoloica
cidtogether
with
totaroland
13-epitorulosal
[27]
Turkey
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativa
Pino
cembrinpinob
anksin
andits
acetateprenylestersof
caffeicacidferulicacidsditerpenicacids
likep
imaricisopimaricabieticdihydroabietic
acidscinn
amylcinn
amateandethyloleate
arom
aticacid
esterssuch
asbenzylcinn
amatebenzenedicarbo
xylic
acid
andflavano
lssuch
asbenzop
yran
andchrysin
[28ndash30]
Algeria
Popu
lusspp
Cistu
sspp
Pino
cembrinpinob
anksin
andits
acetatechrysin
apigenin
pectolinarigeninpilo
sinladanein
galang
inn
aringenin
tectochrysinm
etho
xychrysin
prenyleste
rsof
caffeicacidsferulic
acids
diterpenicacidslikeh
ydroxyditerpenicacidlabdaneand
clerod
ane
[2831]
Austr
alia
Apismellifera
Acaciaparadoxa
Xantho
rrho
eolpterostilbenesakuranetinpinostro
bin
stilbenesprenylatedtetrahydroxystilbenes
prenylated
cinn
amicacidsflavano
nesflavono
lschalcones
[39ndash
42181]
Stinglessb
eeTetra
gonu
lacarbonaria
Ctorellianatre
es(fr
uitresins)
Africa
Nigeria
Prob
ablyMschwe
infurthii
Isofl
avon
oidsprenylatediso
flavono
idsandstilbenoids
[54]
Kenya
Triterpenesarylnaphtalenelignans
such
astetrahydrojusticidinBand6-metho
xydiph
yllin
geranyl
stilbenesand
geranylflavon
macarangin
[50]
Cameroo
nCon
goTriterpenesderivatives
ofam
yrin
andlupeolanddiprenylflavono
ids
[53]
Oman
Azadira
chta
indicaA
cacia
sppand
Mangifer
aindica
Triterpenesprenylatedflavano
nessuchas
7-O-m
ethyl-8
-prenylnaringenin
310158408-diprenylnaringenin
and8-prenyl-57-dihydroxy-31015840-(3-hydroxy-3-methylbutyl)-41015840-m
etho
xyflavano
nechalco
nes
cardanolcardo
lsandanacardica
cids
[51]
Ethiop
iaProb
ablyAc
aciaspp
Triterpenoids
such
as120572-a
nd120573-amyrins120572-a
nd120573-amyrylacetateslup
eoland120572-a
nd120573-lu
peyl
acetates
[52]
Thailand
Styrax
trees
Phenylallylflavanon
e(E)-cinn
amyl-(E)-cinnamylidenate
[48]
TheP
acificr
egion
OkinawaHaw
aiiandTaiwan
Macaranga
tanariu
sPrenylflavono
idsmores
pecificallyiso
nymph
aeol-Bnym
phaeol-Anym
phaeol-Bnym
phaeol-C
prop
olins31015840-geranyl-naringenin
[43ndash45]
Indo
nesia
Myanm
arMangifer
aindica
Alk(en)ylresorcinolscyclo
artane-ty
petriterpenescycloartanesandprenylated
flavano
nes
[4647]
Canary
Island
sUn
know
nFu
rofuranlignans
[49182]
Evidence-Based Complementary and Alternative Medicine 5
of biological activity and chemical data This informationallows extrapolating the possible activity and mechanism ofaction of new propolis under study and provides substantialclues for the development of new drug candidates [6 9]
In the last decades several studies have demonstrated thebiological and pharmacological actions of different world-wide propolis samplesThe following sections summarize therecent published information about antibacterial and anti-fungal [6 7 56ndash59] antiviral [7 59 60] anti-inflammatory[61] antioxidant [62ndash64] immunomodulatory [6 65 66]and antitumor activities [8 17 23 64 66 67] revealing theinterest of researchers in this bee product and its potentialfor the development of new drugs as well
41 Antioxidant Activity It is well known that an endogenousstimuli like cellular metabolism and exogenous agents likeUV toxins and drugs among others generate reactiveoxygen species (ROS) such as hydrogen peroxide (H
2O2) the
superoxide anion (O2minus) and hydroxyl ion (HOminus) as well as
reactive nitrogen species (RNS) especially nitric oxide (NO)Carbohydrates proteins lipids and nucleic acids amongother biomolecules when exposed to the reactive speciessuffer oxidative modifications that modify the cell and leadto its death [68ndash70] Oxidative stress is responsible for theoccurrence of a wide variety of human diseases such asneurodegenerative [71] or cardiovascular diseases [72 73]cancer [68 74] diabetes [6] and atherosclerosis [75]
In the last years several studies have been performedto evaluate the antioxidant capacity of natural productsPropolis extracts composed of different polyphenols havebeen reported to possess a potent antioxidant activity [7076 77] Additionally the chemical varieties in differentpropolis samples from different regions have an influenceon the antioxidant activity Recently Fabris et al showedthat a sample of Italian and Russian propolis ethanol extract(PEE) which have a similar polyphenolic composition havea similar antioxidant activity while Brazilian PEE whichhave low polyphenolic composition have a weak antioxidantactivity [78] Another study also showed using differentsamples of Transylvania PEE a positive correlation betweenhigh polyphenolic composition and high antioxidant activity[79] Phenolic acids and flavonoids are characterized bya powerful antioxidant activity which is closely related tothe chemical structure of the compounds [80] Briefly theantioxidant activity is exerted by inhibiting the activity ofsome enzymes (eg xanthine oxidase protein kinase Cascorbic acid oxidase cyclooxygenase lipoxygenase Na+K+ATPase and cAMP phosphodiesterase) which inhibit theproduction of ROS species by scavenging interrupting thereactions that lead to the lipid peroxidation by chelatingmetal ions mainly iron and copper that are involved in theprocess of free radical creation or by potentiating the actionof other antioxidants [55] Table 2 summarizes some of thestudies addressing the antioxidant activity of propolis
Moreira et al [62] and Miguel et al [63] proposed thatPortuguese propolis an important source of total phenolsflavones and flavonols could be beneficial for human healthdue to its antioxidant properties Portuguese propolis alsoprotects human erythrocytes from free radicals damaging
by decreasing lipid peroxidation [64] These studies suggestthat Portuguese propolis is a powerful antioxidant agentthat can be used against oxidative stress thus maintainingthe structural and functional integrity of the cells Cuesta-Rubio et al [36] demonstrated that nemorosone the mostabundant polyisoprenylated benzophenone present in Cubanpropolis exhibits antioxidant capacity However when thiscompound suffers methylation a process that facilitates theseparation of the compound from the propolis sample theantioxidant property is abolished Ethyl acetate extract ofKangaroo Island propolis which is rich in stilbenes showeda stronger scavenging activity [39] Yang et al showed thatethyl acetate of propolis collected in Anhui China hasstrong scavenging activity and ferric reducing activity thoseactivities being influenced by caffeic acid phenethyl caffeatecinnamyl caffeate and benzyl caffeate [81] Another studyshowed that samples of methanolic extracts of Algerianpropolis that contains high amounts of caffeic acid estersand flavanones kaempferol and galangin possess strongscavenging activity and ferric reducing activity [31] Uruguaypropolis with high polyphenolic composition inhibits low-density lipoprotein (LDL) peroxidation and protein nitra-tion in vitro Moreover it induces the expression of nitricoxide synthase (eNOS) and inhibits NADPH oxidase inbovine aortic endothelial cells [82] In another study thetopical administration of Romanian PEE in mouse eitherprior to or after UVB exposure significantly attenuated themalondialdehyde (MDA) formation and restored glutathioneperoxidase (GSH-Px) activity [83] Talas et al [84] showedthat Turkish PEE has antioxidant properties in the livertissue of NOS inhibited rats In fact NOS inhibition causedan increase in CAT activity and MDA levels effect thatwas significantly decreased when the rats were treated withPEE It is well known that propolis composition is variablenevertheless one of itsmajor components CAPE (caffeic acidphenethyl ester) plays an important role in the antioxidantactivity [85ndash87]
Antioxidant activity is one of the most studied andimportant activities of propolis though there are no studieswith data on the safe dose to be used in humansThus clinicalstudies using propolis and its active compounds are needed
42 Anti-Inflammatory Activity Inflammation is an eventthat normally occurs in response to the constant exposureto environmental and endogenous stimuli as well as toaccidental damage [61] A complex cascade of chemicalsignals initiates after tissue injury and maintains a hostresponse to repair the injured tissue There are two stagesof inflammation acute and chronic Acute inflammation ismediated through the activation of the immune system cellswhich migrate to the site of damage and release growthfactors cytokines and ROSRNS species Chronic inflamma-tion occurs when the acute inflammation is not successfullyresolved This inflammatory condition plays a critical role inthe pathogenesis of many diseases including atherosclerosiscancer asthma Alzheimerrsquos and Parkinsonism [88 89]
Several studies have associated different types of propolisand its various constituents with anti-inflammatory activ-ity [61 90ndash95] Table 3 summarizes the anti-inflammatory
6 Evidence-Based Complementary and Alternative Medicine
Table2Antioxidant
activ
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Portug
al(Serra
deBo
rnes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Hum
anerythrocytes
Decreaseinlip
idperoxidatio
n[64]
Free
radicalscaveng
ing
[62]
Brazil
Prop
olisfro
mthes
tinglessb
eeMelipona
orbignyi
prob
ablypo
plar
tree
PEE
Hum
anerythrocytes
Free
radicalscaveng
inginhibitio
nof
hemolysisandlip
idperoxidatio
n[183]
Portugal(C
entral
Algarve)
European
prop
olisPopu
lus
nigra
PEE
PWE
andmethano
licextracts
Free
radicalsscavenging
chelatio
nof
metalions
[63]
Cuba
Redprop
olisC
rosea
Methano
licextract
Nem
oroson
eFree
radicalsscavenging
[36]
Slovenia
European
prop
olisPopu
lus
nigra
PEE
Strong
redu
cing
power
andabilityto
scavenge
freer
adicals
andmetalions
[184]
Romania
European
prop
olisPopu
lus
nigra
PEE
FemaleS
wiss
mice(UVB
expo
sure)
Decreaseinmalon
dialdehyde
levels
resto
ratio
nof
glutathion
eperoxidase
activ
ity[83]
Kang
aroo
Island
Austr
alianprop
olisAc
acia
paradoxa
Ethylacetateextractstilbenes
Free
radicalscaveng
ing
[39]
China
European
prop
olisPopu
lus
nigra
Ethylacetateextract
Free
radicalscaveng
ingandferricredu
cing
activ
ity[81]
Algeria
Mediterranean
prop
olisPopu
lusspp
andCistu
sspp
Methano
licextract
Free
radicalscaveng
ingandferricredu
cing
activ
ity[31]
Urugu
ayEu
ropean
andgreen
prop
olisPopu
lusn
igra
andB
dracun
culifolia
PEE
Bovine
aorticendo
thelialcells
Inhibitio
nof
low-densitylip
oprotein
peroxidatio
nand
NADPH
oxidasea
ndincrease
innitricoxides
ynthase
[82]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
C57B
L6mice(acutelun
ginflammationcaused
bycigarette
smoke)
Normalizationof
nitritem
yeloperoxidase
levels
superoxide
dism
utasecatalaseand
glutathion
eperoxidasea
ctivity
and
redu
ctionof
glutathion
eoxidized
glutathion
eratio
and
malon
dialdehyde
levels
[185]
Turkey
Mediterranean
prop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
nea
sativa
PEE
Fibrob
lastcells
Decreaseo
fDNAdamageind
uced
byH
2O2
[186]
MaleW
istar
rats
DecreaseinCA
Tactiv
ityandMDAlevelsin
NOSinhibited
rats
[84]
Carps
(Cyprin
uscarpio)
Decreaseinmalon
dialdehyde
levels
superoxide
dism
utase
activ
ityandincrease
ofcatalase
andglutathion
eperoxidase
activ
ity[187]
Purchasedfro
mSigm
aAldric
hCo
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Free
radicalscaveng
inginhibitio
nof
xanthine
oxidasea
ctivity
andlip
idperoxidatio
n[85]
MaleW
istar
albino
rats
Maintenance
ofsuperoxide
dism
utasea
ctivitydecreaseo
fxanthine
oxidasea
ctivity
andmalon
dialdehyde
andnitric
oxidaselevels
[86]
Perip
heralblood
mon
onuclear
cells
from
cyclists
Redu
ctionof
hypertherm
ia-in
ducedsurvivalinhibitio
nnecrosis
superoxide
prod
uctio
nglutathion
edepletio
nand
intracellularsup
eroxide
[87]
Evidence-Based Complementary and Alternative Medicine 7
Table3Anti-infl
ammatorymechanism
sinvestig
ated
with
prop
olis
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
PurchasedSigm
aAldric
hCo
Synthesiz
ed
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacidquercetin
narin
genin
CAPE
Periton
ealm
acroph
ages
Supp
ressionof
lipoxygenasep
athw
ayof
arachido
nica
cid
metabolism
CAPE
beingthem
ostp
otentm
odulator
ofthea
rachidon
icacid
cascade
[90]
Croatia
European
prop
olisPopu
lusn
igra
Water-solub
lederiv
atives
Swiss
albino
mice
Redu
ctionof
DNAdamageinperip
herallym
phocytes
[188]
PEE
MaleS
wiss
albino
mice
Supp
ressionof
functio
nalactivity
ofmacroph
ages
[104]
PurchasedSigm
aAldric
hCo
J774
macroph
agesM
ale
Wistar
rats
Invitro
andin
vivo
inhibitio
nof
cyclo
oxygenase1
and
cyclo
oxygenase2
activ
ity[91189]
MaleW
istar
albino
rats
Decreaseo
fpolym
orph
onuclear
neutroph
ilicleuko
cyte
infiltra
tionin
thelun
gstissues
[190]
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Gastricepith
elialcelllin
e(A
GS)H
pylori(str
ainNCT
C116
38)
Inhibitio
nof
Hpylori-ind
uced
NF-kB
andactiv
ator
protein
1-DNA-
bind
ingactiv
itypreventionof
IkB120572
degradationin
AGSandsupp
ressionof
TNF-120572andinterle
ukin
8prod
uctio
n[191]
PurchasedWakoPu
reCh
emicalIndu
stries
Ltd
RAW2647macroph
ages
Decreaseo
fthe
prod
uctio
nof
interle
ukin-1120573m
onocyte
chem
oattractant
protein1andthep
rodu
ctionandexpressio
nof
tumor
necrosisfactor120572(TNF-120572)
[98]
MaleS
wiss
inbred
strainmice
Decreaseo
fcyclooxygenase2
expressio
nNF-120581Bactiv
ity
c-Jun-N-te
rminalkinaseinh
ibito
rofN
F-120581Bkinase
(IKK
)andinhibitoro
fNF-120581B(IkB
)pho
spho
rylatio
n[97]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
RAW2647macroph
ages
Dow
nregulationof
NF-120581B
p38mito
gen-activ
ated
protein
kinaseand
c-Jun-N-te
rminalkinase
[101]
PurchasedAc
ros
Organics
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacid
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Sprague-Daw
leyrats
Inhibitio
nof
carrageenan-indu
cedrath
indpawse
demaa
ndthec
hemotaxisof
human
polymorph
onuclear
leuk
ocytes
(PMNs)
[95]
Synthesiz
edCh
aracteristic
ofEu
ropean
type
prop
olis
CAPE
Polymorph
onuclear
leuk
ocytes
obtained
from
Hum
anbloo
dInhibitio
nof
5-lip
oxygenasea
ctivity
andarachido
nica
cid
release
[103]
Chile
European
prop
olispo
plar
trees
PEE
MaleC
F-1m
ice
Inhibitio
nof
NOreleaseb
ythem
acroph
ages
[102]
China
European
prop
olisPopu
lusn
igra
PEEandPW
EMaleICR
micea
ndmale
Wistar
rats
Inhibitio
nof
thea
ctivationanddifferentiatio
nof
mon
onuclear
macroph
agesdecreasep
rosta
glandin-E2
(PGE2)
andnitric
oxide(NO)levels
[61]
Brazil
Green
prop
olisB
dracun
culifolia
PWE
Swiss
andBA
LBcmice
Decreaseinthen
umbero
fmacroph
ages
andneutroph
ils
inhibitio
nof
proinfl
ammatorycytokinesa
ndincrease
ofanti-inflammatorycytokines
[99]
Redprop
olisDalbergia
ecastaphyllum
PEE
MaleW
istar
rats
Decreaseinrenalm
acroph
ageinfi
ltrationin
ratswith
chronic
kidn
eydisease
[100]
Nepal
Nepalesep
ropo
lisprobablyShorea
robu
staD
albergiasissooAc
acia
catechuandBo
mbaxcie
ba
PEE
3101584041015840-dihydroxy-4-
metho
xydalbergion
e4-etho
xydalbergion
cearoin
andchrysin
Bone
marrow-derived
mast
cells
(BMMC)
from
C57B
L6
mice
Inhibitin
gIL-6T
NF-120572and
IL-13gene
expressio
nin
BMMC
andalso
inhibitin
gthea
ctivationof
IKKleadingto
NF-120581B
inactiv
ation
[96]
8 Evidence-Based Complementary and Alternative Medicine
mechanisms investigated with propolis and its chemicalconstituents Recently the role of the flavonoids quercetinflavonols and flavones in modulating inflammatory cellfunction was studied [92] Funakoshi-Tago et al [96] inves-tigated the anti-inflammatory effects of flavonoids isolatedfrom Nepalese PEE on the IL-33 signaling pathway Theisolated flavonoids 3101584041015840-dihydroxy-4-methoxydalbergione4-methoxydalbergion cearoin and chrysin inhibited theexpression of inflammatory genes including IL-6 TNF-120572and IL-13 in bone marrow-derived mast cells (BMMC) andalso inhibited the activation of IKK which leads to thedegradation of I120581B120572 and inhibits the activation of nuclearfactor 120581B (NF-120581B)
The release and oxygenation of arachidonic acid are acritical event in inflammation Mirzoeva and Calder [90]demonstrated that propolis components such as CAPE caf-feic acid quercetin andnaringenin among others inhibit theproduction of eicosanoids In fact these components signif-icantly suppressed the lipoxygenase pathway of arachidonicacid metabolism CAPE being the most potent modulatorAnother study indicated that CAPE treatment improveshepatic steatosis induced by high-fat diet in a mouse modelThis effect was attributed to the reduction of c-Jun-N-terminal kinase (JNK12) andNF-120581B activationwith decreasein COX-2 expression [97] Recently it was reported thatCAPE exhibits inhibitory effects on the production of proin-flammatory cytokines (interleukin-1120573 (IL-1120573)) tumor necro-sis factor-120572 (TNF-120572) and monocyte chemoattractant pro-tein 1 (MCP-1) from lipopolysaccharide- (LPS-) stimulatedRAW2647 macrophages [98] Machado et al [99] showedthat Brazilian green propolis water extracts (PWE) modulatean anti-inflammatory cellular response in the model of LPS-induced pulmonary inflammation by decreasing the numberof macrophages and neutrophils Additionally it induced areduction in the secretion of IL-6 and TNF-120572 and an increasein TGF-120573 and IL-10 Another study showed that Brazilianred PEE promotes a significant decrease in renal macrophageinfiltration in rats with chronic kidney disease [100] Bufaloet al [101] demonstrated that Brazilian PEE and caffeicacid inhibited LPS-induced NO production by RAW2647macrophages acting at the transcriptional level and sug-gesting that their anti-inflammatory effects were mediatedby downregulating NF-120581B p38 MAP kinase and JNK12According to Naito et al [95] topical application of BrazilianPEE is effective in inhibiting carrageenan-induced rat hindpaw edemaThis sample appears to inhibit the chemotaxis ofhuman polymorphonuclear leukocytes (PMNs) which alsocontributes to its anti-inflammatory effects Another studyshowed the topical anti-inflammatory activity of propolisfrom Chile in mice ear with induced-edema In fact PEEfrom Buin Chile was the most active against the inflamma-tion induced by 12-O-tetradeca-noylphorbol-13-acetate andarachidonic acid and also inhibits significantly NO releaseby the macrophages [102] More recently Boudreau et al[103] indicated that CAPE is a potent leukotriene biosynthesisinhibitor in PMNs that blocks 5-lipoxygenase (5-LO) activityand arachidonic acid release A Croatian PEE may improvepsoriatic-like skin lesions whichwere induced in the study byirritant agents like n-hexyl salicylate or di-n-propyl disulfide
by reducing the lipid peroxidation in the skin and totalnumber of inflammatory cells in the skin and peritonealcavity more specially by suppressing functional activity ofmacrophages [104]
43 Immunomodulatory Activity Natural substances areconsidered alternative adjuvant therapies in the treatment ofdifferent diseases due to their immunomodulatory effectsInformation about this type of activity was scarce for propolisuntil the 1990s but published work in the last years has pro-vided information about the influence of different propolissamples on the immune system [65 105ndash112] (Table 4)
In a study using Brazilian green propolis it was seenthat the administration for 3 days of a PEE to male BALBcmice modulated the activation of the initial steps of theimmune response by upregulating toll-like receptor- (TLR-)2 and toll-like receptor-4 expression and proinflammatorycytokines (IL-1 and IL-6) production by macrophages andspleen cells [105] Another study demonstrated that BraziliangreenPEEupregulates TLR-4 andCD80 expression in humanmonocytes as well as TNF-120572 and IL-10 production [113] Itwas also shown that caffeic acid stimulates the activity ofmonocytes againstC albicans but it inhibits TLR-2 andHLA-DR expression as well as TNF-120572 and IL-10 production [114]
Additionally Missima et al [115] showed that Braziliangreen PEE administered to stressed mice reduces the proin-flammatory cytokines IL-1120573 and IL-6 When administered tomelanoma-bearing mice submitted or not to chronic stressit induces high levels of IL-1120573 and IL-6 and also stimu-lates Th1 cytokines production indicating the activation ofantitumour cell-mediated immunity Bachiega et al [116]investigated the immunomodulatory effect of propolis andcinnamic and coumaric acids on cytokines IL-1120573 IL-6 andIL-10 production Peritonealmacrophages fromBALBcmicewere incubated with different concentrations of propolis(5 50 and 100mgwell) and coumaric and cinnamic acid(50 and 100mgwell) Propolis and the acids stimulated IL-1120573 production and significantly inhibited IL-6 productionThen after LPS incubation the inhibitory concentrations ofcinnamic and coumaric acids prevented efficiently its effectson IL-6 production whereas propolis inhibited LPS effectsboth before and after its addition Additionally propolis andcoumaric and cinnamic acids inhibited IL-10 production Astudy which evaluated the effect of Brazilian green propolison macrophage activation by H
2O2and NO metabolite
determination [107] showed that propolis increased H2O2
generation and decreased NO generation which favoursthe microbicidal activity Recently the immunomodulatoryeffect of propolis collected in Brazil was evaluated in Leish-mania (Viannia) braziliensis experimental infection Datashows that macrophages incubated with propolis showed asignificant increase in interiorization and further killing ofparasites Also an increased TNF-120572 production was seen inpropolis-pretreated mice whereas IL-12 was downregulatedduring the infection [117]
The immunomodulatory action of propolis does notoccur only at the macrophage level In fact some studiesshow that this action has also an effect on lymphocyte pro-liferation [106 108] Sa-Nunes et al [108] showed inhibitory
Evidence-Based Complementary and Alternative Medicine 9
Table4Im
mun
omod
ulatoryactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
MaleB
ALB
cmice
Upregulationof
toll-lik
ereceptor-2andreceptor-4
expressio
nand
increasesininterle
ukin-1andinterle
ukin-6
prod
uctio
n[105]
Upregulationof
toll-lik
ereceptor-2andreceptor-4
mRN
Aexpressio
n[111]
MaleC
57BL
6miceB16F
10cell
line
Stim
ulationof
thee
xpressionandprod
uctio
nof
interle
ukin-2
and
interle
ukin-10andTh
1cytokine(interle
ukin-2
andIFN-120574)p
rodu
ction
[192]
MaleB
ALB
cmice
Inhibitio
nof
Th1cellsgeneratio
nredu
ctionof
thefrequ
ency
ofIFN-120574-produ
cing
CD4+
Tcells
underTh
1-polarizingcond
ition
s[118]
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecreasesintheN
Ogeneratio
nin
periton
ealm
acroph
ages
[109]
MaleB
ALB
cmice
Increase
intheinterioriz
ationandkilling
ofthep
arasitesL
eishm
ania
(Viann
ia)b
raziliensisby
macroph
agesincreaseinTN
F-120572prod
uctio
nanddecrease
ininterle
ukin-12prod
uctio
n[117]
Mon
ocytes
from
human
bloo
dTL
R-4andCD
80expressio
nin
human
mon
ocytes
aswellasT
NF-120572
andIL-10prod
uctio
n[113]
Mela
nomac
ells(B16F10)m
ale
C57B
L6mice
Redu
ctionof
IL-1120573andIL-6
inLP
S-str
essedmiceindu
ctionof
IL-1120573
andIL-6
andTh
1cytok
ines
inmela
noma-bearingmices
ubmitted
orno
ttochronics
tress
[115]
Brazil
PurchasedAc
rosO
rganics
Green
prop
olisB
dracun
culifolia
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
PEE
cinn
amicandcoum
aricacids
MaleB
ALB
cmice
Stim
ulationof
interle
ukin-1120573prod
uctio
nandinhibitio
nof
interle
ukin-6
andinterle
ukin-10prod
uctio
ns[116]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
and
Mediterraneanprop
olis
Caffeicacid
Mon
ocytes
from
human
bloo
dStim
ulationof
mon
ocytes
activ
ityagainstC
albica
nsdow
nregulation
ofTL
R-2andHLA
-DRexpressio
nandinhibitio
nof
cytokine
prod
uctio
n[114]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
Cinn
amicacid
Mon
ocytes
from
human
bloo
dDow
nregulationof
toll-lik
ereceptor-2HLA
-DRmolecules
from
human
antig
en-presentingcellsand
CD80upregulationof
toll-lik
ereceptor-4inh
ibition
ofTN
F-120572andinterle
ukin-10prod
uctio
n[19
3]
PurchasedSigm
aAldric
hCo
Cinn
amicacid
FemaleIRC
mice
Increase
oflymph
ocytep
roliferationandreleaseo
fcytok
ines
interle
ukin-1andinterle
ukin-2
[106]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Hydroalcoho
lic(H
PE)solution
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecrease
ofNOgeneratio
n[107]
MaleB
ALB
cmice
Decreaseo
fsplenocytep
roliferationandincrease
ofIFN-120574
prod
uctio
nby
spleen
cells
[108]
Indo
nesia
TheP
acificr
egionprop
olisMacaranga
tanariu
sand
Mind
icaHPE
MaleB
ALB
cmice
Increase
ofIgGgeneratio
nandmacroph
agep
hagocytosis
activ
ityand
capacity
[110]
Turkey
Mediterraneanprop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
neasativa
PEE
Perip
heralblood
mon
onuclear
cells
from
healthyhu
mans
Supp
ressionof
neop
terin
releasea
ndtryptoph
andegradation
downregulationof
thee
nzym
eind
oleamine2
3-dioxygenase
(IDO)and
decrease
ofIFN-120574
andTN
F-120572levels
[194]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
CAPE
Hum
anmon
ocyte-deriv
eddend
riticcells
(MoD
Cs)g
enerated
from
perip
heralm
onocytes
Inhibitio
nof
IL-12p4
0IL-12p70IL-10IFN-120574-in
duciblep
rotein-(IP-)
10levels
inhibitio
nof
I120581B120572
phosph
orylationandNF-120581Bactiv
ation
[112]
FemaleB
ALB
cmice
Increase
ofIgM
antib
odyprod
uctio
nTlymph
ocytep
roliferation
interle
ukin-4
andinterle
ukin-2
prod
uctio
nby
spleno
cytesandIFN-120574
prod
uctio
n[195]
Hum
anperip
heralblood
mon
onuclear
cellsjurkatcells
Inhibitio
nof
transcrip
tionfactorsN
F-120581BandNFA
Tinhibitio
nof
interle
ukin-2
gene
transcrip
tion
interle
ukin-2
receptor
expressio
nand
proliferatio
nof
human
Tcells
[94]
10 Evidence-Based Complementary and Alternative Medicine
effects of Brazilian green propolis on splenocyte proliferationeffect that was attributed to flavonoids and enhancementeffects on interferon- (IFN-) 120574 production by spleen cellsCAPE displays inhibitory effects on transcription factors NF-120581B and NFAT and as a consequence inhibits IL-2 genetranscription IL-2 receptor expression and proliferation ofhuman T cells [94] This provides new information into themolecular mechanisms involved in the anti-inflammatoryand immunomodulatory activities of propolis CAPE hasvarious biological activities but its effect on the immunomod-ulatory activity remains little studied According to Wanget al [112] CAPE can be useful in the treatment of asthmaand other allergic diseases because it can inhibit cytokinesand chemokines production by human monocyte-deriveddendritic cells (MoDCs) which might be related to theNF-120581B signalling pathway Another study demonstrated forthe first time that Brazilian propolis significantly inhibitedthe generation of Th1 cells Furthermore the effects ofpropolis were investigated on 246-trinitrobenzene sulfonicacid- (TNBS-) induced colitis in a mouse model Propolisreduced the frequency of IFN-120574-producing CD4 T cellsin a dose-dependent way under Th1-polarizing conditionsThe inhibitory effect of propolis on Th1 differentiation wasdemonstrated in vivo too and the severity of colitis inpropolis-fed mice was significantly lower than that of micefed with the control diet [118]
44 Antiviral Activity Propolis comprises a complexity ofcompounds which play a role in antiviral protection Despitethe few data available regarding this activity it was shown thatpropolis from different geographic regions has considerableantiviral activity by acting at different levels and interferingwith the replication of some viruses [12] like herpes simplextypes 1 and 2 adenovirus type 2 influenza virus or humanimmunodeficiency virus (HIV) among others [7 60 119ndash124] Table 5 summarizes the antiviral activity of propolis andits chemical constituents
Schnitzler et al [123] analysed the antiviral effect ofPWE and PEE from Czech Republic as well as that ofthe constituents caffeic acid p-coumaric acid benzoic acidgalangin pinocembrin and chrysin against herpes simplexvirus type 1 (HSV-1) in cell culture Both extracts exhibitedhigh anti-HSV-1 activity when cells were treated prior toviral infection galangin and chrysin being the main bioac-tive compounds Amoros et al [60] showed the antiviralactivity of the major flavonoids of propolis more specificallyflavonols and flavones the first being more active againstHSV-1 Additionally they analysed the effect of propolis onseveral DNA and RNA viruses (HSV-1 HSV-2 adenovirustype 2 vesicular stomatitis virus (VSV) and poliovirus type2) Propolis at a concentration of 30120583gmL reduced thetiter of herpes virus however vesicular stomatitis virusand adenovirus were less susceptible In addition propo-lis appears to exert a virucidal action on the envelopedviruses HSV and VSV [120] Recently it was shown thathydromethanolic extract of geopropolis from the stinglessbee Scaptotrigona postica (Brazil) inhibits theHSV replicationand also the entry of the virus into cells effect that wasattributed to the C-glycosyl flavones catechin-3-O-gallate
and 34-dicaffeoylquinic acid [125] According to Tait etal [126] natural and synthetic flavonoids might interferewith picornavirus replication preventing the decapsidationof viral particles and RNA release within cells or blockingviral RNA synthesis These authors also showed that differ-ent homoisoflavonoids have good antiviral activity againstthe coxsackie viruses B3 B4 and A9 and echovirus 30Shvarzbeyn and Huleihel [127] tried to determine whichstep of Tax oncoprotein-induced NF-120581B activation is blockedby propolis and CAPE and showed that both substantiallyinhibited the activation of NF-120581B-dependent promoter byTax Also they strongly prevented both Tax binding to I120581B120572and its induced degradation by Tax Ma et al [128] showedthat nanometer propolis flavones could significantly inhibitin vitro porcine parvovirus (PPV) infecting PK-15 cells andin vivo they restrain the PPV copy in lung gonad and blooddecrease the impact of PPV on weight of guinea pigs andincrease hemagglutination inhibition of PPV in serum as wellas improving the contents of IL-2 IL-6 and 120574-IFN
Over recent years therapeutic benefits of propolis andorits isolated compounds have been described in HIV treat-ment Ito et al [129] tested the anti-HIV activity in H9lymphocytes of triterpenoids melliferone moronic acidanwuweizonic acid and betulonic acid and four knownaromatic compounds isolated from Brazilian propolis andshowed that moronic acid had significant anti-HIV activityGekker et al [119] assessed the anti-HIV-1 activity of propolisin CD4+ lymphocytes and microglial cell cultures observ-ing the inhibition of viral expression in a concentration-dependent wayThe possible mechanism of propolis antiviralproperty was suggested to involve inhibition of viral entry
45 Antimicrobial Activity Antimicrobial activity one ofthe most studied propolis biological properties is very welldocumented This bioactivity has been largely investigatedin the last years due to the need of new treatments againstinfectious diseases especially with the increase of resistantpathogens to current antibiotics Tables 6 and 7 summarisethe antibacterial and antifungal activities found in propolisfrom different geographic origin andor its chemical con-stituents
451 Antibacterial Activity Propolis effect against severalbacterial strains has evaluated [7 56ndash59 130] and supportedthe fact that propolis is more active against Gram-positivebacteria than Gram-negative bacteria [12 59] Briefly datafrom different studies showed that propolis inhibits bac-terial motility and enzyme activity exhibits bacteriostaticactivity against different bacterial genera can be bactericidalin high concentrations and affects cytoplasmic membrane[130]
Mirzoeva et al [130] investigated the effect of PEEon the physiology of Bacillus subtilis Escherichia coli andRhodobacter sphaeroides proposing that propolis and someof its components like cinnamic acid and flavonoids affectthe ion permeability of the inner bacterial membrane causingthe dissipation of the membrane potential and inhibitingbacterial motility A recent study [131] provided valuableinformation for understanding the potential anti-H pylori
Evidence-Based Complementary and Alternative Medicine 11
Table5Antivira
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescellsviru
ses
Effect
References
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
Caffeicacidp-cou
maricacid
benzoica
cidgalang
in
pino
cembrinand
chrysin
RC-37cellsherpessim
plex
virustype1
(HSV
-1)
strainKO
SHighanti-HSV
-1activ
ityforb
othextractswhencells
weretreated
prior
toviralinfectio
n[123]
CzechRe
public
European
prop
olisPopu
lusn
igra
PEEandPW
ERC
-37cellsherpessim
plex
virustype2
(HSV
-2)
Highantih
erpetic
activ
ityforb
othextractswhenvirusesw
ere
pretreated
priortoinfection
[196]
Brazil
Brow
nprop
olisB
dracun
culifolia
HPE
HSV
-2str
ainprop
agated
inVe
rocellsfem
aleB
ALB
cmice
Effectiv
eagainstHSV
-2infectionandin
redu
cing
extravaginallesio
nsby
actin
gon
inflammatoryandoxidativep
rocessesreducingreactiv
especiestyrosin
enitration
ascorbicacid
levels
andmyeloperoxidase
activ
ityandprotectin
gagainstinh
ibition
ofcatalase
activ
ity
[124]
Characteris
ticof
Brazilian
prop
olis
Isop
entylferulate(
isolatedfro
man
PEE)
Influ
enza
virusesA
PR834
(H1N
1)
AKrasnod
ar10
159(H
2N2)and
AH
ongKo
ng168
(H3N
2)Supp
ressionof
influ
enza
virusA
Hon
gKo
ngreprod
uctio
nin
vitro
[121]
Green
prop
olisB
dracun
culifolia
Beriocla
daM
yrceugeniaeuosma
PEE
Influ
enza
APR834
(H1N
1)virusp
ropagated
Madin-D
arby
canine
kidn
ey(M
DCK
)cells
female
DBA
2Cr
mice
Redu
ctionof
body
weightlosso
finfectedmicea
ndvirusy
ieldsinthe
bron
choalveolarlavagefl
uids
oflung
s[122]
France
European
prop
olisPopu
lusn
igra
PEE
RC-37cellsH
SV-1str
ainH29Sacyclovirresistant
mutantH
SV1-R
strainH29R
HSV
-2adeno
virustype
2po
liovirustype2
and
vesic
ular
stomatitisv
irus
(VSV
)
Redu
ctionof
titre
ofherpes
virusbeingvesic
ular
stomatitisv
irusa
ndadenoviru
slesssusceptibleviru
cidalactionon
thee
nvelo
pedviruses
HSV
andVS
V[120]
Brazil
Geoprop
olisfro
mthes
tinglessb
eeScaptotrigona
postica
Hydromethano
licextract
African
greenmon
keykidn
eycells
(ATC
CCC
L-81)
herpes
simplex
virusstrain(M
cIntyre)
Inhibitio
nof
HSV
replicationandentryinto
cells
[125]
Synthesiz
edCh
aracteris
ticof
Brazilian
redand
greenprop
olis
Hom
oisoflavono
idsspecially
3-benzyl-4-chrom
ones
BGM
(Buff
aloGreen
Mon
key)
cellscoxsackieviruses
B3B
4andA9andecho
virus3
0Goo
dantiv
iralactivity
againstthe
coxsackiev
irusesB
3B4
and
A9and
echo
virus3
0[126]
Canada
European
prop
olisPtrichocarpa
andPtre
muloides
PEE
HSV
-1andHSV
-2virusreplicated
inMDBK
(mon
olayer
cultu
reso
fMadin-D
arby
bovine
kidn
ey)
cells
Impairing
thea
bilityof
thev
irustoadsorb
orto
penetratethe
hostcells
[197]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Water
extracts
FemaleB
ALB
cmiceInflu
enza
Avirusstrain
AW
SN33(H
1N1)
Extensionof
thelifetim
eofm
ice34-dicaffeoylquinica
cidwhich
increasesm
RNAlevelsof
tumor
necrosisfactor-related
apop
tosis
-indu
cing
anddecreasesH
1N1h
emagglutinin
mRN
A[19
8]Ch
aracteris
ticof
Brazilian
green
prop
olis
34-dicaffeoylquinica
cid
(Isolated
from
Brazilian
prop
olis)
Brazil
Characteris
ticof
Brazilian
green
prop
olis
Melliferon
emoron
icacid
anwuw
eizonica
cidand
betulonica
cid(isolated
from
Brazilian
prop
olis)
H9lymph
ocytesH
IV-1
Moron
icacid
inhibitin
ganti-HIV
replication
[129]
Israel
Mediterraneanprop
olisPopu
lus
sppE
ucalyptusspp
andCa
stanea
sativa
PWE
Jurkatuninfectedhu
man
T-celllin
esand
MT2
(HTL
V-1infectedhu
man
Tcells)cells
Inhibitio
nof
thea
ctivationof
NF-120581B-depend
entp
romoter
byTaxand
preventio
nof
Taxbind
ingto
I120581B120572
andits
degradation
[127]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Provided
byBinzho
uAnimal
Sciencea
ndVe
terin
ary
MedicineA
cademyof
Shando
ngProvince
Nanom
eter
prop
olisFlavon
eKidn
eycells
(PK-
15)
Porcinep
arvovirus(PP
V)
Britain
Whiteguinea
pigs
Inhibitio
nof
PPVinfectingpo
rcinek
idney-
(PK-
)15cells
Restr
aining
ofPP
Vcopy
inlung
gon
adand
bloo
ddecrease
ofthe
impactof
PPVon
weighto
fguineap
igsandincrease
ofhemagglutinationinhibitio
nof
PPVin
serum
aswellasimprovingthe
contentsof
IL-2IL-6and120574-IFN
[128]
USA
andCh
ina
European
prop
olisPopu
lusn
igra
PEE
Perip
heralblood
mon
onuclear
cells
obtained
from
bloo
dof
healthyd
onorsmicroglialcellsiso
latedfro
mhu
man
fetalbrain
tissueHIV-1ATH
IV-1SF162
Inhibitio
nof
HIV-1varia
ntse
xpression
[119]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
12 Evidence-Based Complementary and Alternative Medicine
Table6Antibacteria
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
PurchasedBe
eHealth
Ltd
(Scarborou
ghYorkshire
UK)
Eu
ropean
prop
olisPopu
lusn
igra
PEE
BsubtilisS
G38E
coliandR
sphaeroides
Influ
encing
theion
perm
eabilityof
theinn
erbacterial
mem
brane
Inhibitio
nof
bacterialm
otility
[130]
PurchasedSigm
aCh
emicalCo(Poo
leDorsetUK)
Characteris
ticof
EuropeanB
razilian
andMediterraneanprop
olis
CaffeicacidC
APE
qu
ercetin
and
narin
genin
Greece
Mediterraneanprop
olisprob
ablyCo
nifer
spp
Terpenes
(isolated
from
Cretan
prop
olis)
Saureus
(ATC
C25923)Sepiderm
idis(ATC
C12228)E
coli
(ATC
C25922)E
cloacae
(ATC
C13047)K
pneumoniae
(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Influ
encing
theG
ram-positive
andGram-negativeb
acteria
viability
[199]
France
European
prop
olisPopu
lusn
igra
Dichlorom
ethane
extract
Gram-negative7Ac
inetobacterb
aumannii(RC
HSAN00812
AYE
CIP7
034107292and
5377)2Escherich
iacoli(ATC
C25922andac
linicaliso
late)3
Pseudomonas
aeruginosa
(ATC
C27853andtwoclinicalisolates)and4clinicalisolates
ofEn
terobacterclo
acaeE
aerogenesK
lebsiella
oxytocaand
Salm
onellaenteritidis(phage
type
4)Gram-negative13
Staphylococcus
aureus
(ATC
C25923six
methicillin-susceptib
leclinicalisolatesandsix
methicillin-resistant
clinicalisolates)2
clinicalisolates
ofS
epidermidis(m
ethiSandmethiR)3
clinicalisolates
ofEn
terococcus
faecalisand1E
faeciu
mand
1clin
icaliso
lateof
Corynebacterium
striatum
Influ
encing
theG
ram-positive
bacteriaviabilityspecially
Saureus
andseveralofitsmethicillin-resistant
and
methicillin-susceptib
le[133]
Bulgaria
Mediterraneanprop
olis
PEE
Saureus
209E
coliWF+
Decreaseo
fSaureusg
rowth
andweakor
lack
ofactiv
ityagainstE
coli
[28]
Greece
Popu
lusspp
Tu
rkey
Conifer
spp
Algeria
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativaPopu
lusspp
Cistu
sspp
Austr
alia
Austr
alianprop
olisfro
msting
lessbee
Tetra
gonu
lacarbonariaCtorelliana
trees
(fruitresins)
PEE
Saureus
(ATC
C25923)
Paeruginosa
(ATC
C27853)
Inhibitio
nof
Saureus
grow
th[42]
Cameroo
nandCon
goAfrican
prop
olisprob
ablyM
schw
einfurthii
PEE
Saureus
(ATC
C25923)Sepiderm
is(ATC
C13047)E
coli
(ATC
C25922)K
lebsiella
pneumonia(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Inhibitio
nof
Saureus
grow
th[53]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Saureus
2979
andSaureus
4118
isolated
from
mastiticcows
Saureus
(ATC
C29213)
Decreaseo
fSaureusg
rowth
incomplex
mediaandkilling
ofSaureus
cells
resuspendedin
milk
promotionof
changesin
morph
olog
yandcellsiz
e[200]
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsu
lfoxide
extract
Saureus
(CAPM
5970)E
faecalis(C
APM
5613
(EBF
3039))
Ecoli(C
AMP3101
T(U
541))and
Lmonocytogenes(C
CM5580)
Differentcon
centratio
nsaffectthe
grow
thofthetestedbacteria
[201]
Italy
Mediterraneanprop
olisCrup
essusspp
PE
E
Staphylococcus
sppstr
ains
(35Saureus63Sepidermidis
7S
hominis
18Shaem
olyticu
s10
Swa
rneri4Scapitisand
3S
auric
ularis)
andStreptococcusspp
strains
(59Sfaecalis
30S
virid
ans15
S120573-haemolyticu
sand19
Spn
eumoniae)
Com
pletes
uppressio
nof
thefactorc
oagu
lasereductio
nof
lipasea
ndpreventio
nof
biofi
lmform
ationof
Staphylococcus
increase
ofthee
ffectof
ampicillingentam
ycinand
streptomycin
andmod
eratingthea
ctionof
chloramph
enicol
ceftriaxoneand
vancom
ycin
[56]
Brazil
Redprop
olisDecasto
phyllum
Green
prop
olisB
dracun
culifolia
PEE
Saureus
(ATC
C25923)
NanoH
Amatrix
with
redandgreenprop
oliswhich
redu
ces
bacterialgrowth
andbiofi
lmform
ation
then
anoH
Awith
red
prop
olisbeingthem
ostefficient
[136]
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
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[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
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[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
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[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
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[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
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[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
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[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
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[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
4 Evidence-Based Complementary and Alternative Medicine
Table1Ch
aracteris
ticcompo
unds
ofprop
olisfro
mdifferent
geograph
icoriginsa
ndrespectiv
eplant
source
Geographico
rigin
Plantsou
rce
Typicalcon
stituents(m
aincompo
nents)
References
EuropeN
orth
AmericaNew
Zealandand
temperatezoneso
fAsia
Popu
lusspp
morep
redo
minantly
Pnigra
Pino
cembrinpinob
anksinchrysingalangin
caffeicacidferulicacidcinnamicacidand
their
esters
[102022]
Brazil
Green
prop
olis
Baccharis
spppredo
minantly
Bdracun
culifolia
Prenylated
phenylprop
anoidspheno
licacidsprenylated
p-coum
aricacidsacetop
heno
nes
diterpenicacidscaffeoylquinica
cidskaempferideiso
saku
ranetin
and
kaem
pferol
[9103233]
Redprop
olis
Dalbergiaecastaphyllum
Form
onon
etinisoliq
uiritigeninliquiritigeninm
edicarpin
andbiochaninA
[323435]
Russia
Betulasppm
ores
pecificallyB
verrucosaB
pend
ulaandB
pubescens
Cinn
amicacidsph
enylprop
anoidsesquiterpenolsacacetinapigenin
ermaninrhamno
citrin
kaem
pferide120572-acetoxybetuleno
l[10180]
CubaV
enezuela
Clusiasppm
ores
pecificallyC
rosea
andC
minor
Polyiso
prenylated
benzop
heno
nesmores
pecificallynemoroson
exantho
chym
oland
guttiferone
E[936]
Mediterranean
Greece
Prob
ablyCo
nifer
spp
Flavon
oidsditerpenicacidssuchas
isocupressic
pim
aricand
commun
icacidsiso
agatho
lal
agathadiolferrugino
l8-elem
eneandtotarol
[2425]
Switzerland
Ptre
mula
Benzylp-coum
aratebenzylferulateandph
enolicglycerides
liked
icou
maroylacetylglycerol
diferuloylacetylglycerolferuloylcou
maroylacetylglycerolandcaffeoylcou
maroylacetylglycerol
[26]
Malta
Ferulaspp m
ostp
robablyFerula
commun
isDiterpenicacidssuchas
isocupressic
com
mun
icpim
aricand
imbricatoloica
cidtogether
with
totaroland
13-epitorulosal
[27]
Turkey
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativa
Pino
cembrinpinob
anksin
andits
acetateprenylestersof
caffeicacidferulicacidsditerpenicacids
likep
imaricisopimaricabieticdihydroabietic
acidscinn
amylcinn
amateandethyloleate
arom
aticacid
esterssuch
asbenzylcinn
amatebenzenedicarbo
xylic
acid
andflavano
lssuch
asbenzop
yran
andchrysin
[28ndash30]
Algeria
Popu
lusspp
Cistu
sspp
Pino
cembrinpinob
anksin
andits
acetatechrysin
apigenin
pectolinarigeninpilo
sinladanein
galang
inn
aringenin
tectochrysinm
etho
xychrysin
prenyleste
rsof
caffeicacidsferulic
acids
diterpenicacidslikeh
ydroxyditerpenicacidlabdaneand
clerod
ane
[2831]
Austr
alia
Apismellifera
Acaciaparadoxa
Xantho
rrho
eolpterostilbenesakuranetinpinostro
bin
stilbenesprenylatedtetrahydroxystilbenes
prenylated
cinn
amicacidsflavano
nesflavono
lschalcones
[39ndash
42181]
Stinglessb
eeTetra
gonu
lacarbonaria
Ctorellianatre
es(fr
uitresins)
Africa
Nigeria
Prob
ablyMschwe
infurthii
Isofl
avon
oidsprenylatediso
flavono
idsandstilbenoids
[54]
Kenya
Triterpenesarylnaphtalenelignans
such
astetrahydrojusticidinBand6-metho
xydiph
yllin
geranyl
stilbenesand
geranylflavon
macarangin
[50]
Cameroo
nCon
goTriterpenesderivatives
ofam
yrin
andlupeolanddiprenylflavono
ids
[53]
Oman
Azadira
chta
indicaA
cacia
sppand
Mangifer
aindica
Triterpenesprenylatedflavano
nessuchas
7-O-m
ethyl-8
-prenylnaringenin
310158408-diprenylnaringenin
and8-prenyl-57-dihydroxy-31015840-(3-hydroxy-3-methylbutyl)-41015840-m
etho
xyflavano
nechalco
nes
cardanolcardo
lsandanacardica
cids
[51]
Ethiop
iaProb
ablyAc
aciaspp
Triterpenoids
such
as120572-a
nd120573-amyrins120572-a
nd120573-amyrylacetateslup
eoland120572-a
nd120573-lu
peyl
acetates
[52]
Thailand
Styrax
trees
Phenylallylflavanon
e(E)-cinn
amyl-(E)-cinnamylidenate
[48]
TheP
acificr
egion
OkinawaHaw
aiiandTaiwan
Macaranga
tanariu
sPrenylflavono
idsmores
pecificallyiso
nymph
aeol-Bnym
phaeol-Anym
phaeol-Bnym
phaeol-C
prop
olins31015840-geranyl-naringenin
[43ndash45]
Indo
nesia
Myanm
arMangifer
aindica
Alk(en)ylresorcinolscyclo
artane-ty
petriterpenescycloartanesandprenylated
flavano
nes
[4647]
Canary
Island
sUn
know
nFu
rofuranlignans
[49182]
Evidence-Based Complementary and Alternative Medicine 5
of biological activity and chemical data This informationallows extrapolating the possible activity and mechanism ofaction of new propolis under study and provides substantialclues for the development of new drug candidates [6 9]
In the last decades several studies have demonstrated thebiological and pharmacological actions of different world-wide propolis samplesThe following sections summarize therecent published information about antibacterial and anti-fungal [6 7 56ndash59] antiviral [7 59 60] anti-inflammatory[61] antioxidant [62ndash64] immunomodulatory [6 65 66]and antitumor activities [8 17 23 64 66 67] revealing theinterest of researchers in this bee product and its potentialfor the development of new drugs as well
41 Antioxidant Activity It is well known that an endogenousstimuli like cellular metabolism and exogenous agents likeUV toxins and drugs among others generate reactiveoxygen species (ROS) such as hydrogen peroxide (H
2O2) the
superoxide anion (O2minus) and hydroxyl ion (HOminus) as well as
reactive nitrogen species (RNS) especially nitric oxide (NO)Carbohydrates proteins lipids and nucleic acids amongother biomolecules when exposed to the reactive speciessuffer oxidative modifications that modify the cell and leadto its death [68ndash70] Oxidative stress is responsible for theoccurrence of a wide variety of human diseases such asneurodegenerative [71] or cardiovascular diseases [72 73]cancer [68 74] diabetes [6] and atherosclerosis [75]
In the last years several studies have been performedto evaluate the antioxidant capacity of natural productsPropolis extracts composed of different polyphenols havebeen reported to possess a potent antioxidant activity [7076 77] Additionally the chemical varieties in differentpropolis samples from different regions have an influenceon the antioxidant activity Recently Fabris et al showedthat a sample of Italian and Russian propolis ethanol extract(PEE) which have a similar polyphenolic composition havea similar antioxidant activity while Brazilian PEE whichhave low polyphenolic composition have a weak antioxidantactivity [78] Another study also showed using differentsamples of Transylvania PEE a positive correlation betweenhigh polyphenolic composition and high antioxidant activity[79] Phenolic acids and flavonoids are characterized bya powerful antioxidant activity which is closely related tothe chemical structure of the compounds [80] Briefly theantioxidant activity is exerted by inhibiting the activity ofsome enzymes (eg xanthine oxidase protein kinase Cascorbic acid oxidase cyclooxygenase lipoxygenase Na+K+ATPase and cAMP phosphodiesterase) which inhibit theproduction of ROS species by scavenging interrupting thereactions that lead to the lipid peroxidation by chelatingmetal ions mainly iron and copper that are involved in theprocess of free radical creation or by potentiating the actionof other antioxidants [55] Table 2 summarizes some of thestudies addressing the antioxidant activity of propolis
Moreira et al [62] and Miguel et al [63] proposed thatPortuguese propolis an important source of total phenolsflavones and flavonols could be beneficial for human healthdue to its antioxidant properties Portuguese propolis alsoprotects human erythrocytes from free radicals damaging
by decreasing lipid peroxidation [64] These studies suggestthat Portuguese propolis is a powerful antioxidant agentthat can be used against oxidative stress thus maintainingthe structural and functional integrity of the cells Cuesta-Rubio et al [36] demonstrated that nemorosone the mostabundant polyisoprenylated benzophenone present in Cubanpropolis exhibits antioxidant capacity However when thiscompound suffers methylation a process that facilitates theseparation of the compound from the propolis sample theantioxidant property is abolished Ethyl acetate extract ofKangaroo Island propolis which is rich in stilbenes showeda stronger scavenging activity [39] Yang et al showed thatethyl acetate of propolis collected in Anhui China hasstrong scavenging activity and ferric reducing activity thoseactivities being influenced by caffeic acid phenethyl caffeatecinnamyl caffeate and benzyl caffeate [81] Another studyshowed that samples of methanolic extracts of Algerianpropolis that contains high amounts of caffeic acid estersand flavanones kaempferol and galangin possess strongscavenging activity and ferric reducing activity [31] Uruguaypropolis with high polyphenolic composition inhibits low-density lipoprotein (LDL) peroxidation and protein nitra-tion in vitro Moreover it induces the expression of nitricoxide synthase (eNOS) and inhibits NADPH oxidase inbovine aortic endothelial cells [82] In another study thetopical administration of Romanian PEE in mouse eitherprior to or after UVB exposure significantly attenuated themalondialdehyde (MDA) formation and restored glutathioneperoxidase (GSH-Px) activity [83] Talas et al [84] showedthat Turkish PEE has antioxidant properties in the livertissue of NOS inhibited rats In fact NOS inhibition causedan increase in CAT activity and MDA levels effect thatwas significantly decreased when the rats were treated withPEE It is well known that propolis composition is variablenevertheless one of itsmajor components CAPE (caffeic acidphenethyl ester) plays an important role in the antioxidantactivity [85ndash87]
Antioxidant activity is one of the most studied andimportant activities of propolis though there are no studieswith data on the safe dose to be used in humansThus clinicalstudies using propolis and its active compounds are needed
42 Anti-Inflammatory Activity Inflammation is an eventthat normally occurs in response to the constant exposureto environmental and endogenous stimuli as well as toaccidental damage [61] A complex cascade of chemicalsignals initiates after tissue injury and maintains a hostresponse to repair the injured tissue There are two stagesof inflammation acute and chronic Acute inflammation ismediated through the activation of the immune system cellswhich migrate to the site of damage and release growthfactors cytokines and ROSRNS species Chronic inflamma-tion occurs when the acute inflammation is not successfullyresolved This inflammatory condition plays a critical role inthe pathogenesis of many diseases including atherosclerosiscancer asthma Alzheimerrsquos and Parkinsonism [88 89]
Several studies have associated different types of propolisand its various constituents with anti-inflammatory activ-ity [61 90ndash95] Table 3 summarizes the anti-inflammatory
6 Evidence-Based Complementary and Alternative Medicine
Table2Antioxidant
activ
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Portug
al(Serra
deBo
rnes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Hum
anerythrocytes
Decreaseinlip
idperoxidatio
n[64]
Free
radicalscaveng
ing
[62]
Brazil
Prop
olisfro
mthes
tinglessb
eeMelipona
orbignyi
prob
ablypo
plar
tree
PEE
Hum
anerythrocytes
Free
radicalscaveng
inginhibitio
nof
hemolysisandlip
idperoxidatio
n[183]
Portugal(C
entral
Algarve)
European
prop
olisPopu
lus
nigra
PEE
PWE
andmethano
licextracts
Free
radicalsscavenging
chelatio
nof
metalions
[63]
Cuba
Redprop
olisC
rosea
Methano
licextract
Nem
oroson
eFree
radicalsscavenging
[36]
Slovenia
European
prop
olisPopu
lus
nigra
PEE
Strong
redu
cing
power
andabilityto
scavenge
freer
adicals
andmetalions
[184]
Romania
European
prop
olisPopu
lus
nigra
PEE
FemaleS
wiss
mice(UVB
expo
sure)
Decreaseinmalon
dialdehyde
levels
resto
ratio
nof
glutathion
eperoxidase
activ
ity[83]
Kang
aroo
Island
Austr
alianprop
olisAc
acia
paradoxa
Ethylacetateextractstilbenes
Free
radicalscaveng
ing
[39]
China
European
prop
olisPopu
lus
nigra
Ethylacetateextract
Free
radicalscaveng
ingandferricredu
cing
activ
ity[81]
Algeria
Mediterranean
prop
olisPopu
lusspp
andCistu
sspp
Methano
licextract
Free
radicalscaveng
ingandferricredu
cing
activ
ity[31]
Urugu
ayEu
ropean
andgreen
prop
olisPopu
lusn
igra
andB
dracun
culifolia
PEE
Bovine
aorticendo
thelialcells
Inhibitio
nof
low-densitylip
oprotein
peroxidatio
nand
NADPH
oxidasea
ndincrease
innitricoxides
ynthase
[82]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
C57B
L6mice(acutelun
ginflammationcaused
bycigarette
smoke)
Normalizationof
nitritem
yeloperoxidase
levels
superoxide
dism
utasecatalaseand
glutathion
eperoxidasea
ctivity
and
redu
ctionof
glutathion
eoxidized
glutathion
eratio
and
malon
dialdehyde
levels
[185]
Turkey
Mediterranean
prop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
nea
sativa
PEE
Fibrob
lastcells
Decreaseo
fDNAdamageind
uced
byH
2O2
[186]
MaleW
istar
rats
DecreaseinCA
Tactiv
ityandMDAlevelsin
NOSinhibited
rats
[84]
Carps
(Cyprin
uscarpio)
Decreaseinmalon
dialdehyde
levels
superoxide
dism
utase
activ
ityandincrease
ofcatalase
andglutathion
eperoxidase
activ
ity[187]
Purchasedfro
mSigm
aAldric
hCo
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Free
radicalscaveng
inginhibitio
nof
xanthine
oxidasea
ctivity
andlip
idperoxidatio
n[85]
MaleW
istar
albino
rats
Maintenance
ofsuperoxide
dism
utasea
ctivitydecreaseo
fxanthine
oxidasea
ctivity
andmalon
dialdehyde
andnitric
oxidaselevels
[86]
Perip
heralblood
mon
onuclear
cells
from
cyclists
Redu
ctionof
hypertherm
ia-in
ducedsurvivalinhibitio
nnecrosis
superoxide
prod
uctio
nglutathion
edepletio
nand
intracellularsup
eroxide
[87]
Evidence-Based Complementary and Alternative Medicine 7
Table3Anti-infl
ammatorymechanism
sinvestig
ated
with
prop
olis
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
PurchasedSigm
aAldric
hCo
Synthesiz
ed
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacidquercetin
narin
genin
CAPE
Periton
ealm
acroph
ages
Supp
ressionof
lipoxygenasep
athw
ayof
arachido
nica
cid
metabolism
CAPE
beingthem
ostp
otentm
odulator
ofthea
rachidon
icacid
cascade
[90]
Croatia
European
prop
olisPopu
lusn
igra
Water-solub
lederiv
atives
Swiss
albino
mice
Redu
ctionof
DNAdamageinperip
herallym
phocytes
[188]
PEE
MaleS
wiss
albino
mice
Supp
ressionof
functio
nalactivity
ofmacroph
ages
[104]
PurchasedSigm
aAldric
hCo
J774
macroph
agesM
ale
Wistar
rats
Invitro
andin
vivo
inhibitio
nof
cyclo
oxygenase1
and
cyclo
oxygenase2
activ
ity[91189]
MaleW
istar
albino
rats
Decreaseo
fpolym
orph
onuclear
neutroph
ilicleuko
cyte
infiltra
tionin
thelun
gstissues
[190]
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Gastricepith
elialcelllin
e(A
GS)H
pylori(str
ainNCT
C116
38)
Inhibitio
nof
Hpylori-ind
uced
NF-kB
andactiv
ator
protein
1-DNA-
bind
ingactiv
itypreventionof
IkB120572
degradationin
AGSandsupp
ressionof
TNF-120572andinterle
ukin
8prod
uctio
n[191]
PurchasedWakoPu
reCh
emicalIndu
stries
Ltd
RAW2647macroph
ages
Decreaseo
fthe
prod
uctio
nof
interle
ukin-1120573m
onocyte
chem
oattractant
protein1andthep
rodu
ctionandexpressio
nof
tumor
necrosisfactor120572(TNF-120572)
[98]
MaleS
wiss
inbred
strainmice
Decreaseo
fcyclooxygenase2
expressio
nNF-120581Bactiv
ity
c-Jun-N-te
rminalkinaseinh
ibito
rofN
F-120581Bkinase
(IKK
)andinhibitoro
fNF-120581B(IkB
)pho
spho
rylatio
n[97]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
RAW2647macroph
ages
Dow
nregulationof
NF-120581B
p38mito
gen-activ
ated
protein
kinaseand
c-Jun-N-te
rminalkinase
[101]
PurchasedAc
ros
Organics
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacid
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Sprague-Daw
leyrats
Inhibitio
nof
carrageenan-indu
cedrath
indpawse
demaa
ndthec
hemotaxisof
human
polymorph
onuclear
leuk
ocytes
(PMNs)
[95]
Synthesiz
edCh
aracteristic
ofEu
ropean
type
prop
olis
CAPE
Polymorph
onuclear
leuk
ocytes
obtained
from
Hum
anbloo
dInhibitio
nof
5-lip
oxygenasea
ctivity
andarachido
nica
cid
release
[103]
Chile
European
prop
olispo
plar
trees
PEE
MaleC
F-1m
ice
Inhibitio
nof
NOreleaseb
ythem
acroph
ages
[102]
China
European
prop
olisPopu
lusn
igra
PEEandPW
EMaleICR
micea
ndmale
Wistar
rats
Inhibitio
nof
thea
ctivationanddifferentiatio
nof
mon
onuclear
macroph
agesdecreasep
rosta
glandin-E2
(PGE2)
andnitric
oxide(NO)levels
[61]
Brazil
Green
prop
olisB
dracun
culifolia
PWE
Swiss
andBA
LBcmice
Decreaseinthen
umbero
fmacroph
ages
andneutroph
ils
inhibitio
nof
proinfl
ammatorycytokinesa
ndincrease
ofanti-inflammatorycytokines
[99]
Redprop
olisDalbergia
ecastaphyllum
PEE
MaleW
istar
rats
Decreaseinrenalm
acroph
ageinfi
ltrationin
ratswith
chronic
kidn
eydisease
[100]
Nepal
Nepalesep
ropo
lisprobablyShorea
robu
staD
albergiasissooAc
acia
catechuandBo
mbaxcie
ba
PEE
3101584041015840-dihydroxy-4-
metho
xydalbergion
e4-etho
xydalbergion
cearoin
andchrysin
Bone
marrow-derived
mast
cells
(BMMC)
from
C57B
L6
mice
Inhibitin
gIL-6T
NF-120572and
IL-13gene
expressio
nin
BMMC
andalso
inhibitin
gthea
ctivationof
IKKleadingto
NF-120581B
inactiv
ation
[96]
8 Evidence-Based Complementary and Alternative Medicine
mechanisms investigated with propolis and its chemicalconstituents Recently the role of the flavonoids quercetinflavonols and flavones in modulating inflammatory cellfunction was studied [92] Funakoshi-Tago et al [96] inves-tigated the anti-inflammatory effects of flavonoids isolatedfrom Nepalese PEE on the IL-33 signaling pathway Theisolated flavonoids 3101584041015840-dihydroxy-4-methoxydalbergione4-methoxydalbergion cearoin and chrysin inhibited theexpression of inflammatory genes including IL-6 TNF-120572and IL-13 in bone marrow-derived mast cells (BMMC) andalso inhibited the activation of IKK which leads to thedegradation of I120581B120572 and inhibits the activation of nuclearfactor 120581B (NF-120581B)
The release and oxygenation of arachidonic acid are acritical event in inflammation Mirzoeva and Calder [90]demonstrated that propolis components such as CAPE caf-feic acid quercetin andnaringenin among others inhibit theproduction of eicosanoids In fact these components signif-icantly suppressed the lipoxygenase pathway of arachidonicacid metabolism CAPE being the most potent modulatorAnother study indicated that CAPE treatment improveshepatic steatosis induced by high-fat diet in a mouse modelThis effect was attributed to the reduction of c-Jun-N-terminal kinase (JNK12) andNF-120581B activationwith decreasein COX-2 expression [97] Recently it was reported thatCAPE exhibits inhibitory effects on the production of proin-flammatory cytokines (interleukin-1120573 (IL-1120573)) tumor necro-sis factor-120572 (TNF-120572) and monocyte chemoattractant pro-tein 1 (MCP-1) from lipopolysaccharide- (LPS-) stimulatedRAW2647 macrophages [98] Machado et al [99] showedthat Brazilian green propolis water extracts (PWE) modulatean anti-inflammatory cellular response in the model of LPS-induced pulmonary inflammation by decreasing the numberof macrophages and neutrophils Additionally it induced areduction in the secretion of IL-6 and TNF-120572 and an increasein TGF-120573 and IL-10 Another study showed that Brazilianred PEE promotes a significant decrease in renal macrophageinfiltration in rats with chronic kidney disease [100] Bufaloet al [101] demonstrated that Brazilian PEE and caffeicacid inhibited LPS-induced NO production by RAW2647macrophages acting at the transcriptional level and sug-gesting that their anti-inflammatory effects were mediatedby downregulating NF-120581B p38 MAP kinase and JNK12According to Naito et al [95] topical application of BrazilianPEE is effective in inhibiting carrageenan-induced rat hindpaw edemaThis sample appears to inhibit the chemotaxis ofhuman polymorphonuclear leukocytes (PMNs) which alsocontributes to its anti-inflammatory effects Another studyshowed the topical anti-inflammatory activity of propolisfrom Chile in mice ear with induced-edema In fact PEEfrom Buin Chile was the most active against the inflamma-tion induced by 12-O-tetradeca-noylphorbol-13-acetate andarachidonic acid and also inhibits significantly NO releaseby the macrophages [102] More recently Boudreau et al[103] indicated that CAPE is a potent leukotriene biosynthesisinhibitor in PMNs that blocks 5-lipoxygenase (5-LO) activityand arachidonic acid release A Croatian PEE may improvepsoriatic-like skin lesions whichwere induced in the study byirritant agents like n-hexyl salicylate or di-n-propyl disulfide
by reducing the lipid peroxidation in the skin and totalnumber of inflammatory cells in the skin and peritonealcavity more specially by suppressing functional activity ofmacrophages [104]
43 Immunomodulatory Activity Natural substances areconsidered alternative adjuvant therapies in the treatment ofdifferent diseases due to their immunomodulatory effectsInformation about this type of activity was scarce for propolisuntil the 1990s but published work in the last years has pro-vided information about the influence of different propolissamples on the immune system [65 105ndash112] (Table 4)
In a study using Brazilian green propolis it was seenthat the administration for 3 days of a PEE to male BALBcmice modulated the activation of the initial steps of theimmune response by upregulating toll-like receptor- (TLR-)2 and toll-like receptor-4 expression and proinflammatorycytokines (IL-1 and IL-6) production by macrophages andspleen cells [105] Another study demonstrated that BraziliangreenPEEupregulates TLR-4 andCD80 expression in humanmonocytes as well as TNF-120572 and IL-10 production [113] Itwas also shown that caffeic acid stimulates the activity ofmonocytes againstC albicans but it inhibits TLR-2 andHLA-DR expression as well as TNF-120572 and IL-10 production [114]
Additionally Missima et al [115] showed that Braziliangreen PEE administered to stressed mice reduces the proin-flammatory cytokines IL-1120573 and IL-6 When administered tomelanoma-bearing mice submitted or not to chronic stressit induces high levels of IL-1120573 and IL-6 and also stimu-lates Th1 cytokines production indicating the activation ofantitumour cell-mediated immunity Bachiega et al [116]investigated the immunomodulatory effect of propolis andcinnamic and coumaric acids on cytokines IL-1120573 IL-6 andIL-10 production Peritonealmacrophages fromBALBcmicewere incubated with different concentrations of propolis(5 50 and 100mgwell) and coumaric and cinnamic acid(50 and 100mgwell) Propolis and the acids stimulated IL-1120573 production and significantly inhibited IL-6 productionThen after LPS incubation the inhibitory concentrations ofcinnamic and coumaric acids prevented efficiently its effectson IL-6 production whereas propolis inhibited LPS effectsboth before and after its addition Additionally propolis andcoumaric and cinnamic acids inhibited IL-10 production Astudy which evaluated the effect of Brazilian green propolison macrophage activation by H
2O2and NO metabolite
determination [107] showed that propolis increased H2O2
generation and decreased NO generation which favoursthe microbicidal activity Recently the immunomodulatoryeffect of propolis collected in Brazil was evaluated in Leish-mania (Viannia) braziliensis experimental infection Datashows that macrophages incubated with propolis showed asignificant increase in interiorization and further killing ofparasites Also an increased TNF-120572 production was seen inpropolis-pretreated mice whereas IL-12 was downregulatedduring the infection [117]
The immunomodulatory action of propolis does notoccur only at the macrophage level In fact some studiesshow that this action has also an effect on lymphocyte pro-liferation [106 108] Sa-Nunes et al [108] showed inhibitory
Evidence-Based Complementary and Alternative Medicine 9
Table4Im
mun
omod
ulatoryactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
MaleB
ALB
cmice
Upregulationof
toll-lik
ereceptor-2andreceptor-4
expressio
nand
increasesininterle
ukin-1andinterle
ukin-6
prod
uctio
n[105]
Upregulationof
toll-lik
ereceptor-2andreceptor-4
mRN
Aexpressio
n[111]
MaleC
57BL
6miceB16F
10cell
line
Stim
ulationof
thee
xpressionandprod
uctio
nof
interle
ukin-2
and
interle
ukin-10andTh
1cytokine(interle
ukin-2
andIFN-120574)p
rodu
ction
[192]
MaleB
ALB
cmice
Inhibitio
nof
Th1cellsgeneratio
nredu
ctionof
thefrequ
ency
ofIFN-120574-produ
cing
CD4+
Tcells
underTh
1-polarizingcond
ition
s[118]
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecreasesintheN
Ogeneratio
nin
periton
ealm
acroph
ages
[109]
MaleB
ALB
cmice
Increase
intheinterioriz
ationandkilling
ofthep
arasitesL
eishm
ania
(Viann
ia)b
raziliensisby
macroph
agesincreaseinTN
F-120572prod
uctio
nanddecrease
ininterle
ukin-12prod
uctio
n[117]
Mon
ocytes
from
human
bloo
dTL
R-4andCD
80expressio
nin
human
mon
ocytes
aswellasT
NF-120572
andIL-10prod
uctio
n[113]
Mela
nomac
ells(B16F10)m
ale
C57B
L6mice
Redu
ctionof
IL-1120573andIL-6
inLP
S-str
essedmiceindu
ctionof
IL-1120573
andIL-6
andTh
1cytok
ines
inmela
noma-bearingmices
ubmitted
orno
ttochronics
tress
[115]
Brazil
PurchasedAc
rosO
rganics
Green
prop
olisB
dracun
culifolia
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
PEE
cinn
amicandcoum
aricacids
MaleB
ALB
cmice
Stim
ulationof
interle
ukin-1120573prod
uctio
nandinhibitio
nof
interle
ukin-6
andinterle
ukin-10prod
uctio
ns[116]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
and
Mediterraneanprop
olis
Caffeicacid
Mon
ocytes
from
human
bloo
dStim
ulationof
mon
ocytes
activ
ityagainstC
albica
nsdow
nregulation
ofTL
R-2andHLA
-DRexpressio
nandinhibitio
nof
cytokine
prod
uctio
n[114]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
Cinn
amicacid
Mon
ocytes
from
human
bloo
dDow
nregulationof
toll-lik
ereceptor-2HLA
-DRmolecules
from
human
antig
en-presentingcellsand
CD80upregulationof
toll-lik
ereceptor-4inh
ibition
ofTN
F-120572andinterle
ukin-10prod
uctio
n[19
3]
PurchasedSigm
aAldric
hCo
Cinn
amicacid
FemaleIRC
mice
Increase
oflymph
ocytep
roliferationandreleaseo
fcytok
ines
interle
ukin-1andinterle
ukin-2
[106]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Hydroalcoho
lic(H
PE)solution
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecrease
ofNOgeneratio
n[107]
MaleB
ALB
cmice
Decreaseo
fsplenocytep
roliferationandincrease
ofIFN-120574
prod
uctio
nby
spleen
cells
[108]
Indo
nesia
TheP
acificr
egionprop
olisMacaranga
tanariu
sand
Mind
icaHPE
MaleB
ALB
cmice
Increase
ofIgGgeneratio
nandmacroph
agep
hagocytosis
activ
ityand
capacity
[110]
Turkey
Mediterraneanprop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
neasativa
PEE
Perip
heralblood
mon
onuclear
cells
from
healthyhu
mans
Supp
ressionof
neop
terin
releasea
ndtryptoph
andegradation
downregulationof
thee
nzym
eind
oleamine2
3-dioxygenase
(IDO)and
decrease
ofIFN-120574
andTN
F-120572levels
[194]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
CAPE
Hum
anmon
ocyte-deriv
eddend
riticcells
(MoD
Cs)g
enerated
from
perip
heralm
onocytes
Inhibitio
nof
IL-12p4
0IL-12p70IL-10IFN-120574-in
duciblep
rotein-(IP-)
10levels
inhibitio
nof
I120581B120572
phosph
orylationandNF-120581Bactiv
ation
[112]
FemaleB
ALB
cmice
Increase
ofIgM
antib
odyprod
uctio
nTlymph
ocytep
roliferation
interle
ukin-4
andinterle
ukin-2
prod
uctio
nby
spleno
cytesandIFN-120574
prod
uctio
n[195]
Hum
anperip
heralblood
mon
onuclear
cellsjurkatcells
Inhibitio
nof
transcrip
tionfactorsN
F-120581BandNFA
Tinhibitio
nof
interle
ukin-2
gene
transcrip
tion
interle
ukin-2
receptor
expressio
nand
proliferatio
nof
human
Tcells
[94]
10 Evidence-Based Complementary and Alternative Medicine
effects of Brazilian green propolis on splenocyte proliferationeffect that was attributed to flavonoids and enhancementeffects on interferon- (IFN-) 120574 production by spleen cellsCAPE displays inhibitory effects on transcription factors NF-120581B and NFAT and as a consequence inhibits IL-2 genetranscription IL-2 receptor expression and proliferation ofhuman T cells [94] This provides new information into themolecular mechanisms involved in the anti-inflammatoryand immunomodulatory activities of propolis CAPE hasvarious biological activities but its effect on the immunomod-ulatory activity remains little studied According to Wanget al [112] CAPE can be useful in the treatment of asthmaand other allergic diseases because it can inhibit cytokinesand chemokines production by human monocyte-deriveddendritic cells (MoDCs) which might be related to theNF-120581B signalling pathway Another study demonstrated forthe first time that Brazilian propolis significantly inhibitedthe generation of Th1 cells Furthermore the effects ofpropolis were investigated on 246-trinitrobenzene sulfonicacid- (TNBS-) induced colitis in a mouse model Propolisreduced the frequency of IFN-120574-producing CD4 T cellsin a dose-dependent way under Th1-polarizing conditionsThe inhibitory effect of propolis on Th1 differentiation wasdemonstrated in vivo too and the severity of colitis inpropolis-fed mice was significantly lower than that of micefed with the control diet [118]
44 Antiviral Activity Propolis comprises a complexity ofcompounds which play a role in antiviral protection Despitethe few data available regarding this activity it was shown thatpropolis from different geographic regions has considerableantiviral activity by acting at different levels and interferingwith the replication of some viruses [12] like herpes simplextypes 1 and 2 adenovirus type 2 influenza virus or humanimmunodeficiency virus (HIV) among others [7 60 119ndash124] Table 5 summarizes the antiviral activity of propolis andits chemical constituents
Schnitzler et al [123] analysed the antiviral effect ofPWE and PEE from Czech Republic as well as that ofthe constituents caffeic acid p-coumaric acid benzoic acidgalangin pinocembrin and chrysin against herpes simplexvirus type 1 (HSV-1) in cell culture Both extracts exhibitedhigh anti-HSV-1 activity when cells were treated prior toviral infection galangin and chrysin being the main bioac-tive compounds Amoros et al [60] showed the antiviralactivity of the major flavonoids of propolis more specificallyflavonols and flavones the first being more active againstHSV-1 Additionally they analysed the effect of propolis onseveral DNA and RNA viruses (HSV-1 HSV-2 adenovirustype 2 vesicular stomatitis virus (VSV) and poliovirus type2) Propolis at a concentration of 30120583gmL reduced thetiter of herpes virus however vesicular stomatitis virusand adenovirus were less susceptible In addition propo-lis appears to exert a virucidal action on the envelopedviruses HSV and VSV [120] Recently it was shown thathydromethanolic extract of geopropolis from the stinglessbee Scaptotrigona postica (Brazil) inhibits theHSV replicationand also the entry of the virus into cells effect that wasattributed to the C-glycosyl flavones catechin-3-O-gallate
and 34-dicaffeoylquinic acid [125] According to Tait etal [126] natural and synthetic flavonoids might interferewith picornavirus replication preventing the decapsidationof viral particles and RNA release within cells or blockingviral RNA synthesis These authors also showed that differ-ent homoisoflavonoids have good antiviral activity againstthe coxsackie viruses B3 B4 and A9 and echovirus 30Shvarzbeyn and Huleihel [127] tried to determine whichstep of Tax oncoprotein-induced NF-120581B activation is blockedby propolis and CAPE and showed that both substantiallyinhibited the activation of NF-120581B-dependent promoter byTax Also they strongly prevented both Tax binding to I120581B120572and its induced degradation by Tax Ma et al [128] showedthat nanometer propolis flavones could significantly inhibitin vitro porcine parvovirus (PPV) infecting PK-15 cells andin vivo they restrain the PPV copy in lung gonad and blooddecrease the impact of PPV on weight of guinea pigs andincrease hemagglutination inhibition of PPV in serum as wellas improving the contents of IL-2 IL-6 and 120574-IFN
Over recent years therapeutic benefits of propolis andorits isolated compounds have been described in HIV treat-ment Ito et al [129] tested the anti-HIV activity in H9lymphocytes of triterpenoids melliferone moronic acidanwuweizonic acid and betulonic acid and four knownaromatic compounds isolated from Brazilian propolis andshowed that moronic acid had significant anti-HIV activityGekker et al [119] assessed the anti-HIV-1 activity of propolisin CD4+ lymphocytes and microglial cell cultures observ-ing the inhibition of viral expression in a concentration-dependent wayThe possible mechanism of propolis antiviralproperty was suggested to involve inhibition of viral entry
45 Antimicrobial Activity Antimicrobial activity one ofthe most studied propolis biological properties is very welldocumented This bioactivity has been largely investigatedin the last years due to the need of new treatments againstinfectious diseases especially with the increase of resistantpathogens to current antibiotics Tables 6 and 7 summarisethe antibacterial and antifungal activities found in propolisfrom different geographic origin andor its chemical con-stituents
451 Antibacterial Activity Propolis effect against severalbacterial strains has evaluated [7 56ndash59 130] and supportedthe fact that propolis is more active against Gram-positivebacteria than Gram-negative bacteria [12 59] Briefly datafrom different studies showed that propolis inhibits bac-terial motility and enzyme activity exhibits bacteriostaticactivity against different bacterial genera can be bactericidalin high concentrations and affects cytoplasmic membrane[130]
Mirzoeva et al [130] investigated the effect of PEEon the physiology of Bacillus subtilis Escherichia coli andRhodobacter sphaeroides proposing that propolis and someof its components like cinnamic acid and flavonoids affectthe ion permeability of the inner bacterial membrane causingthe dissipation of the membrane potential and inhibitingbacterial motility A recent study [131] provided valuableinformation for understanding the potential anti-H pylori
Evidence-Based Complementary and Alternative Medicine 11
Table5Antivira
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescellsviru
ses
Effect
References
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
Caffeicacidp-cou
maricacid
benzoica
cidgalang
in
pino
cembrinand
chrysin
RC-37cellsherpessim
plex
virustype1
(HSV
-1)
strainKO
SHighanti-HSV
-1activ
ityforb
othextractswhencells
weretreated
prior
toviralinfectio
n[123]
CzechRe
public
European
prop
olisPopu
lusn
igra
PEEandPW
ERC
-37cellsherpessim
plex
virustype2
(HSV
-2)
Highantih
erpetic
activ
ityforb
othextractswhenvirusesw
ere
pretreated
priortoinfection
[196]
Brazil
Brow
nprop
olisB
dracun
culifolia
HPE
HSV
-2str
ainprop
agated
inVe
rocellsfem
aleB
ALB
cmice
Effectiv
eagainstHSV
-2infectionandin
redu
cing
extravaginallesio
nsby
actin
gon
inflammatoryandoxidativep
rocessesreducingreactiv
especiestyrosin
enitration
ascorbicacid
levels
andmyeloperoxidase
activ
ityandprotectin
gagainstinh
ibition
ofcatalase
activ
ity
[124]
Characteris
ticof
Brazilian
prop
olis
Isop
entylferulate(
isolatedfro
man
PEE)
Influ
enza
virusesA
PR834
(H1N
1)
AKrasnod
ar10
159(H
2N2)and
AH
ongKo
ng168
(H3N
2)Supp
ressionof
influ
enza
virusA
Hon
gKo
ngreprod
uctio
nin
vitro
[121]
Green
prop
olisB
dracun
culifolia
Beriocla
daM
yrceugeniaeuosma
PEE
Influ
enza
APR834
(H1N
1)virusp
ropagated
Madin-D
arby
canine
kidn
ey(M
DCK
)cells
female
DBA
2Cr
mice
Redu
ctionof
body
weightlosso
finfectedmicea
ndvirusy
ieldsinthe
bron
choalveolarlavagefl
uids
oflung
s[122]
France
European
prop
olisPopu
lusn
igra
PEE
RC-37cellsH
SV-1str
ainH29Sacyclovirresistant
mutantH
SV1-R
strainH29R
HSV
-2adeno
virustype
2po
liovirustype2
and
vesic
ular
stomatitisv
irus
(VSV
)
Redu
ctionof
titre
ofherpes
virusbeingvesic
ular
stomatitisv
irusa
ndadenoviru
slesssusceptibleviru
cidalactionon
thee
nvelo
pedviruses
HSV
andVS
V[120]
Brazil
Geoprop
olisfro
mthes
tinglessb
eeScaptotrigona
postica
Hydromethano
licextract
African
greenmon
keykidn
eycells
(ATC
CCC
L-81)
herpes
simplex
virusstrain(M
cIntyre)
Inhibitio
nof
HSV
replicationandentryinto
cells
[125]
Synthesiz
edCh
aracteris
ticof
Brazilian
redand
greenprop
olis
Hom
oisoflavono
idsspecially
3-benzyl-4-chrom
ones
BGM
(Buff
aloGreen
Mon
key)
cellscoxsackieviruses
B3B
4andA9andecho
virus3
0Goo
dantiv
iralactivity
againstthe
coxsackiev
irusesB
3B4
and
A9and
echo
virus3
0[126]
Canada
European
prop
olisPtrichocarpa
andPtre
muloides
PEE
HSV
-1andHSV
-2virusreplicated
inMDBK
(mon
olayer
cultu
reso
fMadin-D
arby
bovine
kidn
ey)
cells
Impairing
thea
bilityof
thev
irustoadsorb
orto
penetratethe
hostcells
[197]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Water
extracts
FemaleB
ALB
cmiceInflu
enza
Avirusstrain
AW
SN33(H
1N1)
Extensionof
thelifetim
eofm
ice34-dicaffeoylquinica
cidwhich
increasesm
RNAlevelsof
tumor
necrosisfactor-related
apop
tosis
-indu
cing
anddecreasesH
1N1h
emagglutinin
mRN
A[19
8]Ch
aracteris
ticof
Brazilian
green
prop
olis
34-dicaffeoylquinica
cid
(Isolated
from
Brazilian
prop
olis)
Brazil
Characteris
ticof
Brazilian
green
prop
olis
Melliferon
emoron
icacid
anwuw
eizonica
cidand
betulonica
cid(isolated
from
Brazilian
prop
olis)
H9lymph
ocytesH
IV-1
Moron
icacid
inhibitin
ganti-HIV
replication
[129]
Israel
Mediterraneanprop
olisPopu
lus
sppE
ucalyptusspp
andCa
stanea
sativa
PWE
Jurkatuninfectedhu
man
T-celllin
esand
MT2
(HTL
V-1infectedhu
man
Tcells)cells
Inhibitio
nof
thea
ctivationof
NF-120581B-depend
entp
romoter
byTaxand
preventio
nof
Taxbind
ingto
I120581B120572
andits
degradation
[127]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Provided
byBinzho
uAnimal
Sciencea
ndVe
terin
ary
MedicineA
cademyof
Shando
ngProvince
Nanom
eter
prop
olisFlavon
eKidn
eycells
(PK-
15)
Porcinep
arvovirus(PP
V)
Britain
Whiteguinea
pigs
Inhibitio
nof
PPVinfectingpo
rcinek
idney-
(PK-
)15cells
Restr
aining
ofPP
Vcopy
inlung
gon
adand
bloo
ddecrease
ofthe
impactof
PPVon
weighto
fguineap
igsandincrease
ofhemagglutinationinhibitio
nof
PPVin
serum
aswellasimprovingthe
contentsof
IL-2IL-6and120574-IFN
[128]
USA
andCh
ina
European
prop
olisPopu
lusn
igra
PEE
Perip
heralblood
mon
onuclear
cells
obtained
from
bloo
dof
healthyd
onorsmicroglialcellsiso
latedfro
mhu
man
fetalbrain
tissueHIV-1ATH
IV-1SF162
Inhibitio
nof
HIV-1varia
ntse
xpression
[119]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
12 Evidence-Based Complementary and Alternative Medicine
Table6Antibacteria
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
PurchasedBe
eHealth
Ltd
(Scarborou
ghYorkshire
UK)
Eu
ropean
prop
olisPopu
lusn
igra
PEE
BsubtilisS
G38E
coliandR
sphaeroides
Influ
encing
theion
perm
eabilityof
theinn
erbacterial
mem
brane
Inhibitio
nof
bacterialm
otility
[130]
PurchasedSigm
aCh
emicalCo(Poo
leDorsetUK)
Characteris
ticof
EuropeanB
razilian
andMediterraneanprop
olis
CaffeicacidC
APE
qu
ercetin
and
narin
genin
Greece
Mediterraneanprop
olisprob
ablyCo
nifer
spp
Terpenes
(isolated
from
Cretan
prop
olis)
Saureus
(ATC
C25923)Sepiderm
idis(ATC
C12228)E
coli
(ATC
C25922)E
cloacae
(ATC
C13047)K
pneumoniae
(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Influ
encing
theG
ram-positive
andGram-negativeb
acteria
viability
[199]
France
European
prop
olisPopu
lusn
igra
Dichlorom
ethane
extract
Gram-negative7Ac
inetobacterb
aumannii(RC
HSAN00812
AYE
CIP7
034107292and
5377)2Escherich
iacoli(ATC
C25922andac
linicaliso
late)3
Pseudomonas
aeruginosa
(ATC
C27853andtwoclinicalisolates)and4clinicalisolates
ofEn
terobacterclo
acaeE
aerogenesK
lebsiella
oxytocaand
Salm
onellaenteritidis(phage
type
4)Gram-negative13
Staphylococcus
aureus
(ATC
C25923six
methicillin-susceptib
leclinicalisolatesandsix
methicillin-resistant
clinicalisolates)2
clinicalisolates
ofS
epidermidis(m
ethiSandmethiR)3
clinicalisolates
ofEn
terococcus
faecalisand1E
faeciu
mand
1clin
icaliso
lateof
Corynebacterium
striatum
Influ
encing
theG
ram-positive
bacteriaviabilityspecially
Saureus
andseveralofitsmethicillin-resistant
and
methicillin-susceptib
le[133]
Bulgaria
Mediterraneanprop
olis
PEE
Saureus
209E
coliWF+
Decreaseo
fSaureusg
rowth
andweakor
lack
ofactiv
ityagainstE
coli
[28]
Greece
Popu
lusspp
Tu
rkey
Conifer
spp
Algeria
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativaPopu
lusspp
Cistu
sspp
Austr
alia
Austr
alianprop
olisfro
msting
lessbee
Tetra
gonu
lacarbonariaCtorelliana
trees
(fruitresins)
PEE
Saureus
(ATC
C25923)
Paeruginosa
(ATC
C27853)
Inhibitio
nof
Saureus
grow
th[42]
Cameroo
nandCon
goAfrican
prop
olisprob
ablyM
schw
einfurthii
PEE
Saureus
(ATC
C25923)Sepiderm
is(ATC
C13047)E
coli
(ATC
C25922)K
lebsiella
pneumonia(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Inhibitio
nof
Saureus
grow
th[53]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Saureus
2979
andSaureus
4118
isolated
from
mastiticcows
Saureus
(ATC
C29213)
Decreaseo
fSaureusg
rowth
incomplex
mediaandkilling
ofSaureus
cells
resuspendedin
milk
promotionof
changesin
morph
olog
yandcellsiz
e[200]
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsu
lfoxide
extract
Saureus
(CAPM
5970)E
faecalis(C
APM
5613
(EBF
3039))
Ecoli(C
AMP3101
T(U
541))and
Lmonocytogenes(C
CM5580)
Differentcon
centratio
nsaffectthe
grow
thofthetestedbacteria
[201]
Italy
Mediterraneanprop
olisCrup
essusspp
PE
E
Staphylococcus
sppstr
ains
(35Saureus63Sepidermidis
7S
hominis
18Shaem
olyticu
s10
Swa
rneri4Scapitisand
3S
auric
ularis)
andStreptococcusspp
strains
(59Sfaecalis
30S
virid
ans15
S120573-haemolyticu
sand19
Spn
eumoniae)
Com
pletes
uppressio
nof
thefactorc
oagu
lasereductio
nof
lipasea
ndpreventio
nof
biofi
lmform
ationof
Staphylococcus
increase
ofthee
ffectof
ampicillingentam
ycinand
streptomycin
andmod
eratingthea
ctionof
chloramph
enicol
ceftriaxoneand
vancom
ycin
[56]
Brazil
Redprop
olisDecasto
phyllum
Green
prop
olisB
dracun
culifolia
PEE
Saureus
(ATC
C25923)
NanoH
Amatrix
with
redandgreenprop
oliswhich
redu
ces
bacterialgrowth
andbiofi
lmform
ation
then
anoH
Awith
red
prop
olisbeingthem
ostefficient
[136]
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
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Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 5
of biological activity and chemical data This informationallows extrapolating the possible activity and mechanism ofaction of new propolis under study and provides substantialclues for the development of new drug candidates [6 9]
In the last decades several studies have demonstrated thebiological and pharmacological actions of different world-wide propolis samplesThe following sections summarize therecent published information about antibacterial and anti-fungal [6 7 56ndash59] antiviral [7 59 60] anti-inflammatory[61] antioxidant [62ndash64] immunomodulatory [6 65 66]and antitumor activities [8 17 23 64 66 67] revealing theinterest of researchers in this bee product and its potentialfor the development of new drugs as well
41 Antioxidant Activity It is well known that an endogenousstimuli like cellular metabolism and exogenous agents likeUV toxins and drugs among others generate reactiveoxygen species (ROS) such as hydrogen peroxide (H
2O2) the
superoxide anion (O2minus) and hydroxyl ion (HOminus) as well as
reactive nitrogen species (RNS) especially nitric oxide (NO)Carbohydrates proteins lipids and nucleic acids amongother biomolecules when exposed to the reactive speciessuffer oxidative modifications that modify the cell and leadto its death [68ndash70] Oxidative stress is responsible for theoccurrence of a wide variety of human diseases such asneurodegenerative [71] or cardiovascular diseases [72 73]cancer [68 74] diabetes [6] and atherosclerosis [75]
In the last years several studies have been performedto evaluate the antioxidant capacity of natural productsPropolis extracts composed of different polyphenols havebeen reported to possess a potent antioxidant activity [7076 77] Additionally the chemical varieties in differentpropolis samples from different regions have an influenceon the antioxidant activity Recently Fabris et al showedthat a sample of Italian and Russian propolis ethanol extract(PEE) which have a similar polyphenolic composition havea similar antioxidant activity while Brazilian PEE whichhave low polyphenolic composition have a weak antioxidantactivity [78] Another study also showed using differentsamples of Transylvania PEE a positive correlation betweenhigh polyphenolic composition and high antioxidant activity[79] Phenolic acids and flavonoids are characterized bya powerful antioxidant activity which is closely related tothe chemical structure of the compounds [80] Briefly theantioxidant activity is exerted by inhibiting the activity ofsome enzymes (eg xanthine oxidase protein kinase Cascorbic acid oxidase cyclooxygenase lipoxygenase Na+K+ATPase and cAMP phosphodiesterase) which inhibit theproduction of ROS species by scavenging interrupting thereactions that lead to the lipid peroxidation by chelatingmetal ions mainly iron and copper that are involved in theprocess of free radical creation or by potentiating the actionof other antioxidants [55] Table 2 summarizes some of thestudies addressing the antioxidant activity of propolis
Moreira et al [62] and Miguel et al [63] proposed thatPortuguese propolis an important source of total phenolsflavones and flavonols could be beneficial for human healthdue to its antioxidant properties Portuguese propolis alsoprotects human erythrocytes from free radicals damaging
by decreasing lipid peroxidation [64] These studies suggestthat Portuguese propolis is a powerful antioxidant agentthat can be used against oxidative stress thus maintainingthe structural and functional integrity of the cells Cuesta-Rubio et al [36] demonstrated that nemorosone the mostabundant polyisoprenylated benzophenone present in Cubanpropolis exhibits antioxidant capacity However when thiscompound suffers methylation a process that facilitates theseparation of the compound from the propolis sample theantioxidant property is abolished Ethyl acetate extract ofKangaroo Island propolis which is rich in stilbenes showeda stronger scavenging activity [39] Yang et al showed thatethyl acetate of propolis collected in Anhui China hasstrong scavenging activity and ferric reducing activity thoseactivities being influenced by caffeic acid phenethyl caffeatecinnamyl caffeate and benzyl caffeate [81] Another studyshowed that samples of methanolic extracts of Algerianpropolis that contains high amounts of caffeic acid estersand flavanones kaempferol and galangin possess strongscavenging activity and ferric reducing activity [31] Uruguaypropolis with high polyphenolic composition inhibits low-density lipoprotein (LDL) peroxidation and protein nitra-tion in vitro Moreover it induces the expression of nitricoxide synthase (eNOS) and inhibits NADPH oxidase inbovine aortic endothelial cells [82] In another study thetopical administration of Romanian PEE in mouse eitherprior to or after UVB exposure significantly attenuated themalondialdehyde (MDA) formation and restored glutathioneperoxidase (GSH-Px) activity [83] Talas et al [84] showedthat Turkish PEE has antioxidant properties in the livertissue of NOS inhibited rats In fact NOS inhibition causedan increase in CAT activity and MDA levels effect thatwas significantly decreased when the rats were treated withPEE It is well known that propolis composition is variablenevertheless one of itsmajor components CAPE (caffeic acidphenethyl ester) plays an important role in the antioxidantactivity [85ndash87]
Antioxidant activity is one of the most studied andimportant activities of propolis though there are no studieswith data on the safe dose to be used in humansThus clinicalstudies using propolis and its active compounds are needed
42 Anti-Inflammatory Activity Inflammation is an eventthat normally occurs in response to the constant exposureto environmental and endogenous stimuli as well as toaccidental damage [61] A complex cascade of chemicalsignals initiates after tissue injury and maintains a hostresponse to repair the injured tissue There are two stagesof inflammation acute and chronic Acute inflammation ismediated through the activation of the immune system cellswhich migrate to the site of damage and release growthfactors cytokines and ROSRNS species Chronic inflamma-tion occurs when the acute inflammation is not successfullyresolved This inflammatory condition plays a critical role inthe pathogenesis of many diseases including atherosclerosiscancer asthma Alzheimerrsquos and Parkinsonism [88 89]
Several studies have associated different types of propolisand its various constituents with anti-inflammatory activ-ity [61 90ndash95] Table 3 summarizes the anti-inflammatory
6 Evidence-Based Complementary and Alternative Medicine
Table2Antioxidant
activ
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Portug
al(Serra
deBo
rnes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Hum
anerythrocytes
Decreaseinlip
idperoxidatio
n[64]
Free
radicalscaveng
ing
[62]
Brazil
Prop
olisfro
mthes
tinglessb
eeMelipona
orbignyi
prob
ablypo
plar
tree
PEE
Hum
anerythrocytes
Free
radicalscaveng
inginhibitio
nof
hemolysisandlip
idperoxidatio
n[183]
Portugal(C
entral
Algarve)
European
prop
olisPopu
lus
nigra
PEE
PWE
andmethano
licextracts
Free
radicalsscavenging
chelatio
nof
metalions
[63]
Cuba
Redprop
olisC
rosea
Methano
licextract
Nem
oroson
eFree
radicalsscavenging
[36]
Slovenia
European
prop
olisPopu
lus
nigra
PEE
Strong
redu
cing
power
andabilityto
scavenge
freer
adicals
andmetalions
[184]
Romania
European
prop
olisPopu
lus
nigra
PEE
FemaleS
wiss
mice(UVB
expo
sure)
Decreaseinmalon
dialdehyde
levels
resto
ratio
nof
glutathion
eperoxidase
activ
ity[83]
Kang
aroo
Island
Austr
alianprop
olisAc
acia
paradoxa
Ethylacetateextractstilbenes
Free
radicalscaveng
ing
[39]
China
European
prop
olisPopu
lus
nigra
Ethylacetateextract
Free
radicalscaveng
ingandferricredu
cing
activ
ity[81]
Algeria
Mediterranean
prop
olisPopu
lusspp
andCistu
sspp
Methano
licextract
Free
radicalscaveng
ingandferricredu
cing
activ
ity[31]
Urugu
ayEu
ropean
andgreen
prop
olisPopu
lusn
igra
andB
dracun
culifolia
PEE
Bovine
aorticendo
thelialcells
Inhibitio
nof
low-densitylip
oprotein
peroxidatio
nand
NADPH
oxidasea
ndincrease
innitricoxides
ynthase
[82]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
C57B
L6mice(acutelun
ginflammationcaused
bycigarette
smoke)
Normalizationof
nitritem
yeloperoxidase
levels
superoxide
dism
utasecatalaseand
glutathion
eperoxidasea
ctivity
and
redu
ctionof
glutathion
eoxidized
glutathion
eratio
and
malon
dialdehyde
levels
[185]
Turkey
Mediterranean
prop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
nea
sativa
PEE
Fibrob
lastcells
Decreaseo
fDNAdamageind
uced
byH
2O2
[186]
MaleW
istar
rats
DecreaseinCA
Tactiv
ityandMDAlevelsin
NOSinhibited
rats
[84]
Carps
(Cyprin
uscarpio)
Decreaseinmalon
dialdehyde
levels
superoxide
dism
utase
activ
ityandincrease
ofcatalase
andglutathion
eperoxidase
activ
ity[187]
Purchasedfro
mSigm
aAldric
hCo
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Free
radicalscaveng
inginhibitio
nof
xanthine
oxidasea
ctivity
andlip
idperoxidatio
n[85]
MaleW
istar
albino
rats
Maintenance
ofsuperoxide
dism
utasea
ctivitydecreaseo
fxanthine
oxidasea
ctivity
andmalon
dialdehyde
andnitric
oxidaselevels
[86]
Perip
heralblood
mon
onuclear
cells
from
cyclists
Redu
ctionof
hypertherm
ia-in
ducedsurvivalinhibitio
nnecrosis
superoxide
prod
uctio
nglutathion
edepletio
nand
intracellularsup
eroxide
[87]
Evidence-Based Complementary and Alternative Medicine 7
Table3Anti-infl
ammatorymechanism
sinvestig
ated
with
prop
olis
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
PurchasedSigm
aAldric
hCo
Synthesiz
ed
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacidquercetin
narin
genin
CAPE
Periton
ealm
acroph
ages
Supp
ressionof
lipoxygenasep
athw
ayof
arachido
nica
cid
metabolism
CAPE
beingthem
ostp
otentm
odulator
ofthea
rachidon
icacid
cascade
[90]
Croatia
European
prop
olisPopu
lusn
igra
Water-solub
lederiv
atives
Swiss
albino
mice
Redu
ctionof
DNAdamageinperip
herallym
phocytes
[188]
PEE
MaleS
wiss
albino
mice
Supp
ressionof
functio
nalactivity
ofmacroph
ages
[104]
PurchasedSigm
aAldric
hCo
J774
macroph
agesM
ale
Wistar
rats
Invitro
andin
vivo
inhibitio
nof
cyclo
oxygenase1
and
cyclo
oxygenase2
activ
ity[91189]
MaleW
istar
albino
rats
Decreaseo
fpolym
orph
onuclear
neutroph
ilicleuko
cyte
infiltra
tionin
thelun
gstissues
[190]
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Gastricepith
elialcelllin
e(A
GS)H
pylori(str
ainNCT
C116
38)
Inhibitio
nof
Hpylori-ind
uced
NF-kB
andactiv
ator
protein
1-DNA-
bind
ingactiv
itypreventionof
IkB120572
degradationin
AGSandsupp
ressionof
TNF-120572andinterle
ukin
8prod
uctio
n[191]
PurchasedWakoPu
reCh
emicalIndu
stries
Ltd
RAW2647macroph
ages
Decreaseo
fthe
prod
uctio
nof
interle
ukin-1120573m
onocyte
chem
oattractant
protein1andthep
rodu
ctionandexpressio
nof
tumor
necrosisfactor120572(TNF-120572)
[98]
MaleS
wiss
inbred
strainmice
Decreaseo
fcyclooxygenase2
expressio
nNF-120581Bactiv
ity
c-Jun-N-te
rminalkinaseinh
ibito
rofN
F-120581Bkinase
(IKK
)andinhibitoro
fNF-120581B(IkB
)pho
spho
rylatio
n[97]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
RAW2647macroph
ages
Dow
nregulationof
NF-120581B
p38mito
gen-activ
ated
protein
kinaseand
c-Jun-N-te
rminalkinase
[101]
PurchasedAc
ros
Organics
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacid
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Sprague-Daw
leyrats
Inhibitio
nof
carrageenan-indu
cedrath
indpawse
demaa
ndthec
hemotaxisof
human
polymorph
onuclear
leuk
ocytes
(PMNs)
[95]
Synthesiz
edCh
aracteristic
ofEu
ropean
type
prop
olis
CAPE
Polymorph
onuclear
leuk
ocytes
obtained
from
Hum
anbloo
dInhibitio
nof
5-lip
oxygenasea
ctivity
andarachido
nica
cid
release
[103]
Chile
European
prop
olispo
plar
trees
PEE
MaleC
F-1m
ice
Inhibitio
nof
NOreleaseb
ythem
acroph
ages
[102]
China
European
prop
olisPopu
lusn
igra
PEEandPW
EMaleICR
micea
ndmale
Wistar
rats
Inhibitio
nof
thea
ctivationanddifferentiatio
nof
mon
onuclear
macroph
agesdecreasep
rosta
glandin-E2
(PGE2)
andnitric
oxide(NO)levels
[61]
Brazil
Green
prop
olisB
dracun
culifolia
PWE
Swiss
andBA
LBcmice
Decreaseinthen
umbero
fmacroph
ages
andneutroph
ils
inhibitio
nof
proinfl
ammatorycytokinesa
ndincrease
ofanti-inflammatorycytokines
[99]
Redprop
olisDalbergia
ecastaphyllum
PEE
MaleW
istar
rats
Decreaseinrenalm
acroph
ageinfi
ltrationin
ratswith
chronic
kidn
eydisease
[100]
Nepal
Nepalesep
ropo
lisprobablyShorea
robu
staD
albergiasissooAc
acia
catechuandBo
mbaxcie
ba
PEE
3101584041015840-dihydroxy-4-
metho
xydalbergion
e4-etho
xydalbergion
cearoin
andchrysin
Bone
marrow-derived
mast
cells
(BMMC)
from
C57B
L6
mice
Inhibitin
gIL-6T
NF-120572and
IL-13gene
expressio
nin
BMMC
andalso
inhibitin
gthea
ctivationof
IKKleadingto
NF-120581B
inactiv
ation
[96]
8 Evidence-Based Complementary and Alternative Medicine
mechanisms investigated with propolis and its chemicalconstituents Recently the role of the flavonoids quercetinflavonols and flavones in modulating inflammatory cellfunction was studied [92] Funakoshi-Tago et al [96] inves-tigated the anti-inflammatory effects of flavonoids isolatedfrom Nepalese PEE on the IL-33 signaling pathway Theisolated flavonoids 3101584041015840-dihydroxy-4-methoxydalbergione4-methoxydalbergion cearoin and chrysin inhibited theexpression of inflammatory genes including IL-6 TNF-120572and IL-13 in bone marrow-derived mast cells (BMMC) andalso inhibited the activation of IKK which leads to thedegradation of I120581B120572 and inhibits the activation of nuclearfactor 120581B (NF-120581B)
The release and oxygenation of arachidonic acid are acritical event in inflammation Mirzoeva and Calder [90]demonstrated that propolis components such as CAPE caf-feic acid quercetin andnaringenin among others inhibit theproduction of eicosanoids In fact these components signif-icantly suppressed the lipoxygenase pathway of arachidonicacid metabolism CAPE being the most potent modulatorAnother study indicated that CAPE treatment improveshepatic steatosis induced by high-fat diet in a mouse modelThis effect was attributed to the reduction of c-Jun-N-terminal kinase (JNK12) andNF-120581B activationwith decreasein COX-2 expression [97] Recently it was reported thatCAPE exhibits inhibitory effects on the production of proin-flammatory cytokines (interleukin-1120573 (IL-1120573)) tumor necro-sis factor-120572 (TNF-120572) and monocyte chemoattractant pro-tein 1 (MCP-1) from lipopolysaccharide- (LPS-) stimulatedRAW2647 macrophages [98] Machado et al [99] showedthat Brazilian green propolis water extracts (PWE) modulatean anti-inflammatory cellular response in the model of LPS-induced pulmonary inflammation by decreasing the numberof macrophages and neutrophils Additionally it induced areduction in the secretion of IL-6 and TNF-120572 and an increasein TGF-120573 and IL-10 Another study showed that Brazilianred PEE promotes a significant decrease in renal macrophageinfiltration in rats with chronic kidney disease [100] Bufaloet al [101] demonstrated that Brazilian PEE and caffeicacid inhibited LPS-induced NO production by RAW2647macrophages acting at the transcriptional level and sug-gesting that their anti-inflammatory effects were mediatedby downregulating NF-120581B p38 MAP kinase and JNK12According to Naito et al [95] topical application of BrazilianPEE is effective in inhibiting carrageenan-induced rat hindpaw edemaThis sample appears to inhibit the chemotaxis ofhuman polymorphonuclear leukocytes (PMNs) which alsocontributes to its anti-inflammatory effects Another studyshowed the topical anti-inflammatory activity of propolisfrom Chile in mice ear with induced-edema In fact PEEfrom Buin Chile was the most active against the inflamma-tion induced by 12-O-tetradeca-noylphorbol-13-acetate andarachidonic acid and also inhibits significantly NO releaseby the macrophages [102] More recently Boudreau et al[103] indicated that CAPE is a potent leukotriene biosynthesisinhibitor in PMNs that blocks 5-lipoxygenase (5-LO) activityand arachidonic acid release A Croatian PEE may improvepsoriatic-like skin lesions whichwere induced in the study byirritant agents like n-hexyl salicylate or di-n-propyl disulfide
by reducing the lipid peroxidation in the skin and totalnumber of inflammatory cells in the skin and peritonealcavity more specially by suppressing functional activity ofmacrophages [104]
43 Immunomodulatory Activity Natural substances areconsidered alternative adjuvant therapies in the treatment ofdifferent diseases due to their immunomodulatory effectsInformation about this type of activity was scarce for propolisuntil the 1990s but published work in the last years has pro-vided information about the influence of different propolissamples on the immune system [65 105ndash112] (Table 4)
In a study using Brazilian green propolis it was seenthat the administration for 3 days of a PEE to male BALBcmice modulated the activation of the initial steps of theimmune response by upregulating toll-like receptor- (TLR-)2 and toll-like receptor-4 expression and proinflammatorycytokines (IL-1 and IL-6) production by macrophages andspleen cells [105] Another study demonstrated that BraziliangreenPEEupregulates TLR-4 andCD80 expression in humanmonocytes as well as TNF-120572 and IL-10 production [113] Itwas also shown that caffeic acid stimulates the activity ofmonocytes againstC albicans but it inhibits TLR-2 andHLA-DR expression as well as TNF-120572 and IL-10 production [114]
Additionally Missima et al [115] showed that Braziliangreen PEE administered to stressed mice reduces the proin-flammatory cytokines IL-1120573 and IL-6 When administered tomelanoma-bearing mice submitted or not to chronic stressit induces high levels of IL-1120573 and IL-6 and also stimu-lates Th1 cytokines production indicating the activation ofantitumour cell-mediated immunity Bachiega et al [116]investigated the immunomodulatory effect of propolis andcinnamic and coumaric acids on cytokines IL-1120573 IL-6 andIL-10 production Peritonealmacrophages fromBALBcmicewere incubated with different concentrations of propolis(5 50 and 100mgwell) and coumaric and cinnamic acid(50 and 100mgwell) Propolis and the acids stimulated IL-1120573 production and significantly inhibited IL-6 productionThen after LPS incubation the inhibitory concentrations ofcinnamic and coumaric acids prevented efficiently its effectson IL-6 production whereas propolis inhibited LPS effectsboth before and after its addition Additionally propolis andcoumaric and cinnamic acids inhibited IL-10 production Astudy which evaluated the effect of Brazilian green propolison macrophage activation by H
2O2and NO metabolite
determination [107] showed that propolis increased H2O2
generation and decreased NO generation which favoursthe microbicidal activity Recently the immunomodulatoryeffect of propolis collected in Brazil was evaluated in Leish-mania (Viannia) braziliensis experimental infection Datashows that macrophages incubated with propolis showed asignificant increase in interiorization and further killing ofparasites Also an increased TNF-120572 production was seen inpropolis-pretreated mice whereas IL-12 was downregulatedduring the infection [117]
The immunomodulatory action of propolis does notoccur only at the macrophage level In fact some studiesshow that this action has also an effect on lymphocyte pro-liferation [106 108] Sa-Nunes et al [108] showed inhibitory
Evidence-Based Complementary and Alternative Medicine 9
Table4Im
mun
omod
ulatoryactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
MaleB
ALB
cmice
Upregulationof
toll-lik
ereceptor-2andreceptor-4
expressio
nand
increasesininterle
ukin-1andinterle
ukin-6
prod
uctio
n[105]
Upregulationof
toll-lik
ereceptor-2andreceptor-4
mRN
Aexpressio
n[111]
MaleC
57BL
6miceB16F
10cell
line
Stim
ulationof
thee
xpressionandprod
uctio
nof
interle
ukin-2
and
interle
ukin-10andTh
1cytokine(interle
ukin-2
andIFN-120574)p
rodu
ction
[192]
MaleB
ALB
cmice
Inhibitio
nof
Th1cellsgeneratio
nredu
ctionof
thefrequ
ency
ofIFN-120574-produ
cing
CD4+
Tcells
underTh
1-polarizingcond
ition
s[118]
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecreasesintheN
Ogeneratio
nin
periton
ealm
acroph
ages
[109]
MaleB
ALB
cmice
Increase
intheinterioriz
ationandkilling
ofthep
arasitesL
eishm
ania
(Viann
ia)b
raziliensisby
macroph
agesincreaseinTN
F-120572prod
uctio
nanddecrease
ininterle
ukin-12prod
uctio
n[117]
Mon
ocytes
from
human
bloo
dTL
R-4andCD
80expressio
nin
human
mon
ocytes
aswellasT
NF-120572
andIL-10prod
uctio
n[113]
Mela
nomac
ells(B16F10)m
ale
C57B
L6mice
Redu
ctionof
IL-1120573andIL-6
inLP
S-str
essedmiceindu
ctionof
IL-1120573
andIL-6
andTh
1cytok
ines
inmela
noma-bearingmices
ubmitted
orno
ttochronics
tress
[115]
Brazil
PurchasedAc
rosO
rganics
Green
prop
olisB
dracun
culifolia
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
PEE
cinn
amicandcoum
aricacids
MaleB
ALB
cmice
Stim
ulationof
interle
ukin-1120573prod
uctio
nandinhibitio
nof
interle
ukin-6
andinterle
ukin-10prod
uctio
ns[116]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
and
Mediterraneanprop
olis
Caffeicacid
Mon
ocytes
from
human
bloo
dStim
ulationof
mon
ocytes
activ
ityagainstC
albica
nsdow
nregulation
ofTL
R-2andHLA
-DRexpressio
nandinhibitio
nof
cytokine
prod
uctio
n[114]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
Cinn
amicacid
Mon
ocytes
from
human
bloo
dDow
nregulationof
toll-lik
ereceptor-2HLA
-DRmolecules
from
human
antig
en-presentingcellsand
CD80upregulationof
toll-lik
ereceptor-4inh
ibition
ofTN
F-120572andinterle
ukin-10prod
uctio
n[19
3]
PurchasedSigm
aAldric
hCo
Cinn
amicacid
FemaleIRC
mice
Increase
oflymph
ocytep
roliferationandreleaseo
fcytok
ines
interle
ukin-1andinterle
ukin-2
[106]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Hydroalcoho
lic(H
PE)solution
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecrease
ofNOgeneratio
n[107]
MaleB
ALB
cmice
Decreaseo
fsplenocytep
roliferationandincrease
ofIFN-120574
prod
uctio
nby
spleen
cells
[108]
Indo
nesia
TheP
acificr
egionprop
olisMacaranga
tanariu
sand
Mind
icaHPE
MaleB
ALB
cmice
Increase
ofIgGgeneratio
nandmacroph
agep
hagocytosis
activ
ityand
capacity
[110]
Turkey
Mediterraneanprop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
neasativa
PEE
Perip
heralblood
mon
onuclear
cells
from
healthyhu
mans
Supp
ressionof
neop
terin
releasea
ndtryptoph
andegradation
downregulationof
thee
nzym
eind
oleamine2
3-dioxygenase
(IDO)and
decrease
ofIFN-120574
andTN
F-120572levels
[194]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
CAPE
Hum
anmon
ocyte-deriv
eddend
riticcells
(MoD
Cs)g
enerated
from
perip
heralm
onocytes
Inhibitio
nof
IL-12p4
0IL-12p70IL-10IFN-120574-in
duciblep
rotein-(IP-)
10levels
inhibitio
nof
I120581B120572
phosph
orylationandNF-120581Bactiv
ation
[112]
FemaleB
ALB
cmice
Increase
ofIgM
antib
odyprod
uctio
nTlymph
ocytep
roliferation
interle
ukin-4
andinterle
ukin-2
prod
uctio
nby
spleno
cytesandIFN-120574
prod
uctio
n[195]
Hum
anperip
heralblood
mon
onuclear
cellsjurkatcells
Inhibitio
nof
transcrip
tionfactorsN
F-120581BandNFA
Tinhibitio
nof
interle
ukin-2
gene
transcrip
tion
interle
ukin-2
receptor
expressio
nand
proliferatio
nof
human
Tcells
[94]
10 Evidence-Based Complementary and Alternative Medicine
effects of Brazilian green propolis on splenocyte proliferationeffect that was attributed to flavonoids and enhancementeffects on interferon- (IFN-) 120574 production by spleen cellsCAPE displays inhibitory effects on transcription factors NF-120581B and NFAT and as a consequence inhibits IL-2 genetranscription IL-2 receptor expression and proliferation ofhuman T cells [94] This provides new information into themolecular mechanisms involved in the anti-inflammatoryand immunomodulatory activities of propolis CAPE hasvarious biological activities but its effect on the immunomod-ulatory activity remains little studied According to Wanget al [112] CAPE can be useful in the treatment of asthmaand other allergic diseases because it can inhibit cytokinesand chemokines production by human monocyte-deriveddendritic cells (MoDCs) which might be related to theNF-120581B signalling pathway Another study demonstrated forthe first time that Brazilian propolis significantly inhibitedthe generation of Th1 cells Furthermore the effects ofpropolis were investigated on 246-trinitrobenzene sulfonicacid- (TNBS-) induced colitis in a mouse model Propolisreduced the frequency of IFN-120574-producing CD4 T cellsin a dose-dependent way under Th1-polarizing conditionsThe inhibitory effect of propolis on Th1 differentiation wasdemonstrated in vivo too and the severity of colitis inpropolis-fed mice was significantly lower than that of micefed with the control diet [118]
44 Antiviral Activity Propolis comprises a complexity ofcompounds which play a role in antiviral protection Despitethe few data available regarding this activity it was shown thatpropolis from different geographic regions has considerableantiviral activity by acting at different levels and interferingwith the replication of some viruses [12] like herpes simplextypes 1 and 2 adenovirus type 2 influenza virus or humanimmunodeficiency virus (HIV) among others [7 60 119ndash124] Table 5 summarizes the antiviral activity of propolis andits chemical constituents
Schnitzler et al [123] analysed the antiviral effect ofPWE and PEE from Czech Republic as well as that ofthe constituents caffeic acid p-coumaric acid benzoic acidgalangin pinocembrin and chrysin against herpes simplexvirus type 1 (HSV-1) in cell culture Both extracts exhibitedhigh anti-HSV-1 activity when cells were treated prior toviral infection galangin and chrysin being the main bioac-tive compounds Amoros et al [60] showed the antiviralactivity of the major flavonoids of propolis more specificallyflavonols and flavones the first being more active againstHSV-1 Additionally they analysed the effect of propolis onseveral DNA and RNA viruses (HSV-1 HSV-2 adenovirustype 2 vesicular stomatitis virus (VSV) and poliovirus type2) Propolis at a concentration of 30120583gmL reduced thetiter of herpes virus however vesicular stomatitis virusand adenovirus were less susceptible In addition propo-lis appears to exert a virucidal action on the envelopedviruses HSV and VSV [120] Recently it was shown thathydromethanolic extract of geopropolis from the stinglessbee Scaptotrigona postica (Brazil) inhibits theHSV replicationand also the entry of the virus into cells effect that wasattributed to the C-glycosyl flavones catechin-3-O-gallate
and 34-dicaffeoylquinic acid [125] According to Tait etal [126] natural and synthetic flavonoids might interferewith picornavirus replication preventing the decapsidationof viral particles and RNA release within cells or blockingviral RNA synthesis These authors also showed that differ-ent homoisoflavonoids have good antiviral activity againstthe coxsackie viruses B3 B4 and A9 and echovirus 30Shvarzbeyn and Huleihel [127] tried to determine whichstep of Tax oncoprotein-induced NF-120581B activation is blockedby propolis and CAPE and showed that both substantiallyinhibited the activation of NF-120581B-dependent promoter byTax Also they strongly prevented both Tax binding to I120581B120572and its induced degradation by Tax Ma et al [128] showedthat nanometer propolis flavones could significantly inhibitin vitro porcine parvovirus (PPV) infecting PK-15 cells andin vivo they restrain the PPV copy in lung gonad and blooddecrease the impact of PPV on weight of guinea pigs andincrease hemagglutination inhibition of PPV in serum as wellas improving the contents of IL-2 IL-6 and 120574-IFN
Over recent years therapeutic benefits of propolis andorits isolated compounds have been described in HIV treat-ment Ito et al [129] tested the anti-HIV activity in H9lymphocytes of triterpenoids melliferone moronic acidanwuweizonic acid and betulonic acid and four knownaromatic compounds isolated from Brazilian propolis andshowed that moronic acid had significant anti-HIV activityGekker et al [119] assessed the anti-HIV-1 activity of propolisin CD4+ lymphocytes and microglial cell cultures observ-ing the inhibition of viral expression in a concentration-dependent wayThe possible mechanism of propolis antiviralproperty was suggested to involve inhibition of viral entry
45 Antimicrobial Activity Antimicrobial activity one ofthe most studied propolis biological properties is very welldocumented This bioactivity has been largely investigatedin the last years due to the need of new treatments againstinfectious diseases especially with the increase of resistantpathogens to current antibiotics Tables 6 and 7 summarisethe antibacterial and antifungal activities found in propolisfrom different geographic origin andor its chemical con-stituents
451 Antibacterial Activity Propolis effect against severalbacterial strains has evaluated [7 56ndash59 130] and supportedthe fact that propolis is more active against Gram-positivebacteria than Gram-negative bacteria [12 59] Briefly datafrom different studies showed that propolis inhibits bac-terial motility and enzyme activity exhibits bacteriostaticactivity against different bacterial genera can be bactericidalin high concentrations and affects cytoplasmic membrane[130]
Mirzoeva et al [130] investigated the effect of PEEon the physiology of Bacillus subtilis Escherichia coli andRhodobacter sphaeroides proposing that propolis and someof its components like cinnamic acid and flavonoids affectthe ion permeability of the inner bacterial membrane causingthe dissipation of the membrane potential and inhibitingbacterial motility A recent study [131] provided valuableinformation for understanding the potential anti-H pylori
Evidence-Based Complementary and Alternative Medicine 11
Table5Antivira
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescellsviru
ses
Effect
References
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
Caffeicacidp-cou
maricacid
benzoica
cidgalang
in
pino
cembrinand
chrysin
RC-37cellsherpessim
plex
virustype1
(HSV
-1)
strainKO
SHighanti-HSV
-1activ
ityforb
othextractswhencells
weretreated
prior
toviralinfectio
n[123]
CzechRe
public
European
prop
olisPopu
lusn
igra
PEEandPW
ERC
-37cellsherpessim
plex
virustype2
(HSV
-2)
Highantih
erpetic
activ
ityforb
othextractswhenvirusesw
ere
pretreated
priortoinfection
[196]
Brazil
Brow
nprop
olisB
dracun
culifolia
HPE
HSV
-2str
ainprop
agated
inVe
rocellsfem
aleB
ALB
cmice
Effectiv
eagainstHSV
-2infectionandin
redu
cing
extravaginallesio
nsby
actin
gon
inflammatoryandoxidativep
rocessesreducingreactiv
especiestyrosin
enitration
ascorbicacid
levels
andmyeloperoxidase
activ
ityandprotectin
gagainstinh
ibition
ofcatalase
activ
ity
[124]
Characteris
ticof
Brazilian
prop
olis
Isop
entylferulate(
isolatedfro
man
PEE)
Influ
enza
virusesA
PR834
(H1N
1)
AKrasnod
ar10
159(H
2N2)and
AH
ongKo
ng168
(H3N
2)Supp
ressionof
influ
enza
virusA
Hon
gKo
ngreprod
uctio
nin
vitro
[121]
Green
prop
olisB
dracun
culifolia
Beriocla
daM
yrceugeniaeuosma
PEE
Influ
enza
APR834
(H1N
1)virusp
ropagated
Madin-D
arby
canine
kidn
ey(M
DCK
)cells
female
DBA
2Cr
mice
Redu
ctionof
body
weightlosso
finfectedmicea
ndvirusy
ieldsinthe
bron
choalveolarlavagefl
uids
oflung
s[122]
France
European
prop
olisPopu
lusn
igra
PEE
RC-37cellsH
SV-1str
ainH29Sacyclovirresistant
mutantH
SV1-R
strainH29R
HSV
-2adeno
virustype
2po
liovirustype2
and
vesic
ular
stomatitisv
irus
(VSV
)
Redu
ctionof
titre
ofherpes
virusbeingvesic
ular
stomatitisv
irusa
ndadenoviru
slesssusceptibleviru
cidalactionon
thee
nvelo
pedviruses
HSV
andVS
V[120]
Brazil
Geoprop
olisfro
mthes
tinglessb
eeScaptotrigona
postica
Hydromethano
licextract
African
greenmon
keykidn
eycells
(ATC
CCC
L-81)
herpes
simplex
virusstrain(M
cIntyre)
Inhibitio
nof
HSV
replicationandentryinto
cells
[125]
Synthesiz
edCh
aracteris
ticof
Brazilian
redand
greenprop
olis
Hom
oisoflavono
idsspecially
3-benzyl-4-chrom
ones
BGM
(Buff
aloGreen
Mon
key)
cellscoxsackieviruses
B3B
4andA9andecho
virus3
0Goo
dantiv
iralactivity
againstthe
coxsackiev
irusesB
3B4
and
A9and
echo
virus3
0[126]
Canada
European
prop
olisPtrichocarpa
andPtre
muloides
PEE
HSV
-1andHSV
-2virusreplicated
inMDBK
(mon
olayer
cultu
reso
fMadin-D
arby
bovine
kidn
ey)
cells
Impairing
thea
bilityof
thev
irustoadsorb
orto
penetratethe
hostcells
[197]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Water
extracts
FemaleB
ALB
cmiceInflu
enza
Avirusstrain
AW
SN33(H
1N1)
Extensionof
thelifetim
eofm
ice34-dicaffeoylquinica
cidwhich
increasesm
RNAlevelsof
tumor
necrosisfactor-related
apop
tosis
-indu
cing
anddecreasesH
1N1h
emagglutinin
mRN
A[19
8]Ch
aracteris
ticof
Brazilian
green
prop
olis
34-dicaffeoylquinica
cid
(Isolated
from
Brazilian
prop
olis)
Brazil
Characteris
ticof
Brazilian
green
prop
olis
Melliferon
emoron
icacid
anwuw
eizonica
cidand
betulonica
cid(isolated
from
Brazilian
prop
olis)
H9lymph
ocytesH
IV-1
Moron
icacid
inhibitin
ganti-HIV
replication
[129]
Israel
Mediterraneanprop
olisPopu
lus
sppE
ucalyptusspp
andCa
stanea
sativa
PWE
Jurkatuninfectedhu
man
T-celllin
esand
MT2
(HTL
V-1infectedhu
man
Tcells)cells
Inhibitio
nof
thea
ctivationof
NF-120581B-depend
entp
romoter
byTaxand
preventio
nof
Taxbind
ingto
I120581B120572
andits
degradation
[127]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Provided
byBinzho
uAnimal
Sciencea
ndVe
terin
ary
MedicineA
cademyof
Shando
ngProvince
Nanom
eter
prop
olisFlavon
eKidn
eycells
(PK-
15)
Porcinep
arvovirus(PP
V)
Britain
Whiteguinea
pigs
Inhibitio
nof
PPVinfectingpo
rcinek
idney-
(PK-
)15cells
Restr
aining
ofPP
Vcopy
inlung
gon
adand
bloo
ddecrease
ofthe
impactof
PPVon
weighto
fguineap
igsandincrease
ofhemagglutinationinhibitio
nof
PPVin
serum
aswellasimprovingthe
contentsof
IL-2IL-6and120574-IFN
[128]
USA
andCh
ina
European
prop
olisPopu
lusn
igra
PEE
Perip
heralblood
mon
onuclear
cells
obtained
from
bloo
dof
healthyd
onorsmicroglialcellsiso
latedfro
mhu
man
fetalbrain
tissueHIV-1ATH
IV-1SF162
Inhibitio
nof
HIV-1varia
ntse
xpression
[119]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
12 Evidence-Based Complementary and Alternative Medicine
Table6Antibacteria
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
PurchasedBe
eHealth
Ltd
(Scarborou
ghYorkshire
UK)
Eu
ropean
prop
olisPopu
lusn
igra
PEE
BsubtilisS
G38E
coliandR
sphaeroides
Influ
encing
theion
perm
eabilityof
theinn
erbacterial
mem
brane
Inhibitio
nof
bacterialm
otility
[130]
PurchasedSigm
aCh
emicalCo(Poo
leDorsetUK)
Characteris
ticof
EuropeanB
razilian
andMediterraneanprop
olis
CaffeicacidC
APE
qu
ercetin
and
narin
genin
Greece
Mediterraneanprop
olisprob
ablyCo
nifer
spp
Terpenes
(isolated
from
Cretan
prop
olis)
Saureus
(ATC
C25923)Sepiderm
idis(ATC
C12228)E
coli
(ATC
C25922)E
cloacae
(ATC
C13047)K
pneumoniae
(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Influ
encing
theG
ram-positive
andGram-negativeb
acteria
viability
[199]
France
European
prop
olisPopu
lusn
igra
Dichlorom
ethane
extract
Gram-negative7Ac
inetobacterb
aumannii(RC
HSAN00812
AYE
CIP7
034107292and
5377)2Escherich
iacoli(ATC
C25922andac
linicaliso
late)3
Pseudomonas
aeruginosa
(ATC
C27853andtwoclinicalisolates)and4clinicalisolates
ofEn
terobacterclo
acaeE
aerogenesK
lebsiella
oxytocaand
Salm
onellaenteritidis(phage
type
4)Gram-negative13
Staphylococcus
aureus
(ATC
C25923six
methicillin-susceptib
leclinicalisolatesandsix
methicillin-resistant
clinicalisolates)2
clinicalisolates
ofS
epidermidis(m
ethiSandmethiR)3
clinicalisolates
ofEn
terococcus
faecalisand1E
faeciu
mand
1clin
icaliso
lateof
Corynebacterium
striatum
Influ
encing
theG
ram-positive
bacteriaviabilityspecially
Saureus
andseveralofitsmethicillin-resistant
and
methicillin-susceptib
le[133]
Bulgaria
Mediterraneanprop
olis
PEE
Saureus
209E
coliWF+
Decreaseo
fSaureusg
rowth
andweakor
lack
ofactiv
ityagainstE
coli
[28]
Greece
Popu
lusspp
Tu
rkey
Conifer
spp
Algeria
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativaPopu
lusspp
Cistu
sspp
Austr
alia
Austr
alianprop
olisfro
msting
lessbee
Tetra
gonu
lacarbonariaCtorelliana
trees
(fruitresins)
PEE
Saureus
(ATC
C25923)
Paeruginosa
(ATC
C27853)
Inhibitio
nof
Saureus
grow
th[42]
Cameroo
nandCon
goAfrican
prop
olisprob
ablyM
schw
einfurthii
PEE
Saureus
(ATC
C25923)Sepiderm
is(ATC
C13047)E
coli
(ATC
C25922)K
lebsiella
pneumonia(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Inhibitio
nof
Saureus
grow
th[53]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Saureus
2979
andSaureus
4118
isolated
from
mastiticcows
Saureus
(ATC
C29213)
Decreaseo
fSaureusg
rowth
incomplex
mediaandkilling
ofSaureus
cells
resuspendedin
milk
promotionof
changesin
morph
olog
yandcellsiz
e[200]
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsu
lfoxide
extract
Saureus
(CAPM
5970)E
faecalis(C
APM
5613
(EBF
3039))
Ecoli(C
AMP3101
T(U
541))and
Lmonocytogenes(C
CM5580)
Differentcon
centratio
nsaffectthe
grow
thofthetestedbacteria
[201]
Italy
Mediterraneanprop
olisCrup
essusspp
PE
E
Staphylococcus
sppstr
ains
(35Saureus63Sepidermidis
7S
hominis
18Shaem
olyticu
s10
Swa
rneri4Scapitisand
3S
auric
ularis)
andStreptococcusspp
strains
(59Sfaecalis
30S
virid
ans15
S120573-haemolyticu
sand19
Spn
eumoniae)
Com
pletes
uppressio
nof
thefactorc
oagu
lasereductio
nof
lipasea
ndpreventio
nof
biofi
lmform
ationof
Staphylococcus
increase
ofthee
ffectof
ampicillingentam
ycinand
streptomycin
andmod
eratingthea
ctionof
chloramph
enicol
ceftriaxoneand
vancom
ycin
[56]
Brazil
Redprop
olisDecasto
phyllum
Green
prop
olisB
dracun
culifolia
PEE
Saureus
(ATC
C25923)
NanoH
Amatrix
with
redandgreenprop
oliswhich
redu
ces
bacterialgrowth
andbiofi
lmform
ation
then
anoH
Awith
red
prop
olisbeingthem
ostefficient
[136]
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
6 Evidence-Based Complementary and Alternative Medicine
Table2Antioxidant
activ
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Portug
al(Serra
deBo
rnes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Hum
anerythrocytes
Decreaseinlip
idperoxidatio
n[64]
Free
radicalscaveng
ing
[62]
Brazil
Prop
olisfro
mthes
tinglessb
eeMelipona
orbignyi
prob
ablypo
plar
tree
PEE
Hum
anerythrocytes
Free
radicalscaveng
inginhibitio
nof
hemolysisandlip
idperoxidatio
n[183]
Portugal(C
entral
Algarve)
European
prop
olisPopu
lus
nigra
PEE
PWE
andmethano
licextracts
Free
radicalsscavenging
chelatio
nof
metalions
[63]
Cuba
Redprop
olisC
rosea
Methano
licextract
Nem
oroson
eFree
radicalsscavenging
[36]
Slovenia
European
prop
olisPopu
lus
nigra
PEE
Strong
redu
cing
power
andabilityto
scavenge
freer
adicals
andmetalions
[184]
Romania
European
prop
olisPopu
lus
nigra
PEE
FemaleS
wiss
mice(UVB
expo
sure)
Decreaseinmalon
dialdehyde
levels
resto
ratio
nof
glutathion
eperoxidase
activ
ity[83]
Kang
aroo
Island
Austr
alianprop
olisAc
acia
paradoxa
Ethylacetateextractstilbenes
Free
radicalscaveng
ing
[39]
China
European
prop
olisPopu
lus
nigra
Ethylacetateextract
Free
radicalscaveng
ingandferricredu
cing
activ
ity[81]
Algeria
Mediterranean
prop
olisPopu
lusspp
andCistu
sspp
Methano
licextract
Free
radicalscaveng
ingandferricredu
cing
activ
ity[31]
Urugu
ayEu
ropean
andgreen
prop
olisPopu
lusn
igra
andB
dracun
culifolia
PEE
Bovine
aorticendo
thelialcells
Inhibitio
nof
low-densitylip
oprotein
peroxidatio
nand
NADPH
oxidasea
ndincrease
innitricoxides
ynthase
[82]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
C57B
L6mice(acutelun
ginflammationcaused
bycigarette
smoke)
Normalizationof
nitritem
yeloperoxidase
levels
superoxide
dism
utasecatalaseand
glutathion
eperoxidasea
ctivity
and
redu
ctionof
glutathion
eoxidized
glutathion
eratio
and
malon
dialdehyde
levels
[185]
Turkey
Mediterranean
prop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
nea
sativa
PEE
Fibrob
lastcells
Decreaseo
fDNAdamageind
uced
byH
2O2
[186]
MaleW
istar
rats
DecreaseinCA
Tactiv
ityandMDAlevelsin
NOSinhibited
rats
[84]
Carps
(Cyprin
uscarpio)
Decreaseinmalon
dialdehyde
levels
superoxide
dism
utase
activ
ityandincrease
ofcatalase
andglutathion
eperoxidase
activ
ity[187]
Purchasedfro
mSigm
aAldric
hCo
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Free
radicalscaveng
inginhibitio
nof
xanthine
oxidasea
ctivity
andlip
idperoxidatio
n[85]
MaleW
istar
albino
rats
Maintenance
ofsuperoxide
dism
utasea
ctivitydecreaseo
fxanthine
oxidasea
ctivity
andmalon
dialdehyde
andnitric
oxidaselevels
[86]
Perip
heralblood
mon
onuclear
cells
from
cyclists
Redu
ctionof
hypertherm
ia-in
ducedsurvivalinhibitio
nnecrosis
superoxide
prod
uctio
nglutathion
edepletio
nand
intracellularsup
eroxide
[87]
Evidence-Based Complementary and Alternative Medicine 7
Table3Anti-infl
ammatorymechanism
sinvestig
ated
with
prop
olis
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
PurchasedSigm
aAldric
hCo
Synthesiz
ed
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacidquercetin
narin
genin
CAPE
Periton
ealm
acroph
ages
Supp
ressionof
lipoxygenasep
athw
ayof
arachido
nica
cid
metabolism
CAPE
beingthem
ostp
otentm
odulator
ofthea
rachidon
icacid
cascade
[90]
Croatia
European
prop
olisPopu
lusn
igra
Water-solub
lederiv
atives
Swiss
albino
mice
Redu
ctionof
DNAdamageinperip
herallym
phocytes
[188]
PEE
MaleS
wiss
albino
mice
Supp
ressionof
functio
nalactivity
ofmacroph
ages
[104]
PurchasedSigm
aAldric
hCo
J774
macroph
agesM
ale
Wistar
rats
Invitro
andin
vivo
inhibitio
nof
cyclo
oxygenase1
and
cyclo
oxygenase2
activ
ity[91189]
MaleW
istar
albino
rats
Decreaseo
fpolym
orph
onuclear
neutroph
ilicleuko
cyte
infiltra
tionin
thelun
gstissues
[190]
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Gastricepith
elialcelllin
e(A
GS)H
pylori(str
ainNCT
C116
38)
Inhibitio
nof
Hpylori-ind
uced
NF-kB
andactiv
ator
protein
1-DNA-
bind
ingactiv
itypreventionof
IkB120572
degradationin
AGSandsupp
ressionof
TNF-120572andinterle
ukin
8prod
uctio
n[191]
PurchasedWakoPu
reCh
emicalIndu
stries
Ltd
RAW2647macroph
ages
Decreaseo
fthe
prod
uctio
nof
interle
ukin-1120573m
onocyte
chem
oattractant
protein1andthep
rodu
ctionandexpressio
nof
tumor
necrosisfactor120572(TNF-120572)
[98]
MaleS
wiss
inbred
strainmice
Decreaseo
fcyclooxygenase2
expressio
nNF-120581Bactiv
ity
c-Jun-N-te
rminalkinaseinh
ibito
rofN
F-120581Bkinase
(IKK
)andinhibitoro
fNF-120581B(IkB
)pho
spho
rylatio
n[97]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
RAW2647macroph
ages
Dow
nregulationof
NF-120581B
p38mito
gen-activ
ated
protein
kinaseand
c-Jun-N-te
rminalkinase
[101]
PurchasedAc
ros
Organics
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacid
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Sprague-Daw
leyrats
Inhibitio
nof
carrageenan-indu
cedrath
indpawse
demaa
ndthec
hemotaxisof
human
polymorph
onuclear
leuk
ocytes
(PMNs)
[95]
Synthesiz
edCh
aracteristic
ofEu
ropean
type
prop
olis
CAPE
Polymorph
onuclear
leuk
ocytes
obtained
from
Hum
anbloo
dInhibitio
nof
5-lip
oxygenasea
ctivity
andarachido
nica
cid
release
[103]
Chile
European
prop
olispo
plar
trees
PEE
MaleC
F-1m
ice
Inhibitio
nof
NOreleaseb
ythem
acroph
ages
[102]
China
European
prop
olisPopu
lusn
igra
PEEandPW
EMaleICR
micea
ndmale
Wistar
rats
Inhibitio
nof
thea
ctivationanddifferentiatio
nof
mon
onuclear
macroph
agesdecreasep
rosta
glandin-E2
(PGE2)
andnitric
oxide(NO)levels
[61]
Brazil
Green
prop
olisB
dracun
culifolia
PWE
Swiss
andBA
LBcmice
Decreaseinthen
umbero
fmacroph
ages
andneutroph
ils
inhibitio
nof
proinfl
ammatorycytokinesa
ndincrease
ofanti-inflammatorycytokines
[99]
Redprop
olisDalbergia
ecastaphyllum
PEE
MaleW
istar
rats
Decreaseinrenalm
acroph
ageinfi
ltrationin
ratswith
chronic
kidn
eydisease
[100]
Nepal
Nepalesep
ropo
lisprobablyShorea
robu
staD
albergiasissooAc
acia
catechuandBo
mbaxcie
ba
PEE
3101584041015840-dihydroxy-4-
metho
xydalbergion
e4-etho
xydalbergion
cearoin
andchrysin
Bone
marrow-derived
mast
cells
(BMMC)
from
C57B
L6
mice
Inhibitin
gIL-6T
NF-120572and
IL-13gene
expressio
nin
BMMC
andalso
inhibitin
gthea
ctivationof
IKKleadingto
NF-120581B
inactiv
ation
[96]
8 Evidence-Based Complementary and Alternative Medicine
mechanisms investigated with propolis and its chemicalconstituents Recently the role of the flavonoids quercetinflavonols and flavones in modulating inflammatory cellfunction was studied [92] Funakoshi-Tago et al [96] inves-tigated the anti-inflammatory effects of flavonoids isolatedfrom Nepalese PEE on the IL-33 signaling pathway Theisolated flavonoids 3101584041015840-dihydroxy-4-methoxydalbergione4-methoxydalbergion cearoin and chrysin inhibited theexpression of inflammatory genes including IL-6 TNF-120572and IL-13 in bone marrow-derived mast cells (BMMC) andalso inhibited the activation of IKK which leads to thedegradation of I120581B120572 and inhibits the activation of nuclearfactor 120581B (NF-120581B)
The release and oxygenation of arachidonic acid are acritical event in inflammation Mirzoeva and Calder [90]demonstrated that propolis components such as CAPE caf-feic acid quercetin andnaringenin among others inhibit theproduction of eicosanoids In fact these components signif-icantly suppressed the lipoxygenase pathway of arachidonicacid metabolism CAPE being the most potent modulatorAnother study indicated that CAPE treatment improveshepatic steatosis induced by high-fat diet in a mouse modelThis effect was attributed to the reduction of c-Jun-N-terminal kinase (JNK12) andNF-120581B activationwith decreasein COX-2 expression [97] Recently it was reported thatCAPE exhibits inhibitory effects on the production of proin-flammatory cytokines (interleukin-1120573 (IL-1120573)) tumor necro-sis factor-120572 (TNF-120572) and monocyte chemoattractant pro-tein 1 (MCP-1) from lipopolysaccharide- (LPS-) stimulatedRAW2647 macrophages [98] Machado et al [99] showedthat Brazilian green propolis water extracts (PWE) modulatean anti-inflammatory cellular response in the model of LPS-induced pulmonary inflammation by decreasing the numberof macrophages and neutrophils Additionally it induced areduction in the secretion of IL-6 and TNF-120572 and an increasein TGF-120573 and IL-10 Another study showed that Brazilianred PEE promotes a significant decrease in renal macrophageinfiltration in rats with chronic kidney disease [100] Bufaloet al [101] demonstrated that Brazilian PEE and caffeicacid inhibited LPS-induced NO production by RAW2647macrophages acting at the transcriptional level and sug-gesting that their anti-inflammatory effects were mediatedby downregulating NF-120581B p38 MAP kinase and JNK12According to Naito et al [95] topical application of BrazilianPEE is effective in inhibiting carrageenan-induced rat hindpaw edemaThis sample appears to inhibit the chemotaxis ofhuman polymorphonuclear leukocytes (PMNs) which alsocontributes to its anti-inflammatory effects Another studyshowed the topical anti-inflammatory activity of propolisfrom Chile in mice ear with induced-edema In fact PEEfrom Buin Chile was the most active against the inflamma-tion induced by 12-O-tetradeca-noylphorbol-13-acetate andarachidonic acid and also inhibits significantly NO releaseby the macrophages [102] More recently Boudreau et al[103] indicated that CAPE is a potent leukotriene biosynthesisinhibitor in PMNs that blocks 5-lipoxygenase (5-LO) activityand arachidonic acid release A Croatian PEE may improvepsoriatic-like skin lesions whichwere induced in the study byirritant agents like n-hexyl salicylate or di-n-propyl disulfide
by reducing the lipid peroxidation in the skin and totalnumber of inflammatory cells in the skin and peritonealcavity more specially by suppressing functional activity ofmacrophages [104]
43 Immunomodulatory Activity Natural substances areconsidered alternative adjuvant therapies in the treatment ofdifferent diseases due to their immunomodulatory effectsInformation about this type of activity was scarce for propolisuntil the 1990s but published work in the last years has pro-vided information about the influence of different propolissamples on the immune system [65 105ndash112] (Table 4)
In a study using Brazilian green propolis it was seenthat the administration for 3 days of a PEE to male BALBcmice modulated the activation of the initial steps of theimmune response by upregulating toll-like receptor- (TLR-)2 and toll-like receptor-4 expression and proinflammatorycytokines (IL-1 and IL-6) production by macrophages andspleen cells [105] Another study demonstrated that BraziliangreenPEEupregulates TLR-4 andCD80 expression in humanmonocytes as well as TNF-120572 and IL-10 production [113] Itwas also shown that caffeic acid stimulates the activity ofmonocytes againstC albicans but it inhibits TLR-2 andHLA-DR expression as well as TNF-120572 and IL-10 production [114]
Additionally Missima et al [115] showed that Braziliangreen PEE administered to stressed mice reduces the proin-flammatory cytokines IL-1120573 and IL-6 When administered tomelanoma-bearing mice submitted or not to chronic stressit induces high levels of IL-1120573 and IL-6 and also stimu-lates Th1 cytokines production indicating the activation ofantitumour cell-mediated immunity Bachiega et al [116]investigated the immunomodulatory effect of propolis andcinnamic and coumaric acids on cytokines IL-1120573 IL-6 andIL-10 production Peritonealmacrophages fromBALBcmicewere incubated with different concentrations of propolis(5 50 and 100mgwell) and coumaric and cinnamic acid(50 and 100mgwell) Propolis and the acids stimulated IL-1120573 production and significantly inhibited IL-6 productionThen after LPS incubation the inhibitory concentrations ofcinnamic and coumaric acids prevented efficiently its effectson IL-6 production whereas propolis inhibited LPS effectsboth before and after its addition Additionally propolis andcoumaric and cinnamic acids inhibited IL-10 production Astudy which evaluated the effect of Brazilian green propolison macrophage activation by H
2O2and NO metabolite
determination [107] showed that propolis increased H2O2
generation and decreased NO generation which favoursthe microbicidal activity Recently the immunomodulatoryeffect of propolis collected in Brazil was evaluated in Leish-mania (Viannia) braziliensis experimental infection Datashows that macrophages incubated with propolis showed asignificant increase in interiorization and further killing ofparasites Also an increased TNF-120572 production was seen inpropolis-pretreated mice whereas IL-12 was downregulatedduring the infection [117]
The immunomodulatory action of propolis does notoccur only at the macrophage level In fact some studiesshow that this action has also an effect on lymphocyte pro-liferation [106 108] Sa-Nunes et al [108] showed inhibitory
Evidence-Based Complementary and Alternative Medicine 9
Table4Im
mun
omod
ulatoryactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
MaleB
ALB
cmice
Upregulationof
toll-lik
ereceptor-2andreceptor-4
expressio
nand
increasesininterle
ukin-1andinterle
ukin-6
prod
uctio
n[105]
Upregulationof
toll-lik
ereceptor-2andreceptor-4
mRN
Aexpressio
n[111]
MaleC
57BL
6miceB16F
10cell
line
Stim
ulationof
thee
xpressionandprod
uctio
nof
interle
ukin-2
and
interle
ukin-10andTh
1cytokine(interle
ukin-2
andIFN-120574)p
rodu
ction
[192]
MaleB
ALB
cmice
Inhibitio
nof
Th1cellsgeneratio
nredu
ctionof
thefrequ
ency
ofIFN-120574-produ
cing
CD4+
Tcells
underTh
1-polarizingcond
ition
s[118]
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecreasesintheN
Ogeneratio
nin
periton
ealm
acroph
ages
[109]
MaleB
ALB
cmice
Increase
intheinterioriz
ationandkilling
ofthep
arasitesL
eishm
ania
(Viann
ia)b
raziliensisby
macroph
agesincreaseinTN
F-120572prod
uctio
nanddecrease
ininterle
ukin-12prod
uctio
n[117]
Mon
ocytes
from
human
bloo
dTL
R-4andCD
80expressio
nin
human
mon
ocytes
aswellasT
NF-120572
andIL-10prod
uctio
n[113]
Mela
nomac
ells(B16F10)m
ale
C57B
L6mice
Redu
ctionof
IL-1120573andIL-6
inLP
S-str
essedmiceindu
ctionof
IL-1120573
andIL-6
andTh
1cytok
ines
inmela
noma-bearingmices
ubmitted
orno
ttochronics
tress
[115]
Brazil
PurchasedAc
rosO
rganics
Green
prop
olisB
dracun
culifolia
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
PEE
cinn
amicandcoum
aricacids
MaleB
ALB
cmice
Stim
ulationof
interle
ukin-1120573prod
uctio
nandinhibitio
nof
interle
ukin-6
andinterle
ukin-10prod
uctio
ns[116]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
and
Mediterraneanprop
olis
Caffeicacid
Mon
ocytes
from
human
bloo
dStim
ulationof
mon
ocytes
activ
ityagainstC
albica
nsdow
nregulation
ofTL
R-2andHLA
-DRexpressio
nandinhibitio
nof
cytokine
prod
uctio
n[114]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
Cinn
amicacid
Mon
ocytes
from
human
bloo
dDow
nregulationof
toll-lik
ereceptor-2HLA
-DRmolecules
from
human
antig
en-presentingcellsand
CD80upregulationof
toll-lik
ereceptor-4inh
ibition
ofTN
F-120572andinterle
ukin-10prod
uctio
n[19
3]
PurchasedSigm
aAldric
hCo
Cinn
amicacid
FemaleIRC
mice
Increase
oflymph
ocytep
roliferationandreleaseo
fcytok
ines
interle
ukin-1andinterle
ukin-2
[106]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Hydroalcoho
lic(H
PE)solution
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecrease
ofNOgeneratio
n[107]
MaleB
ALB
cmice
Decreaseo
fsplenocytep
roliferationandincrease
ofIFN-120574
prod
uctio
nby
spleen
cells
[108]
Indo
nesia
TheP
acificr
egionprop
olisMacaranga
tanariu
sand
Mind
icaHPE
MaleB
ALB
cmice
Increase
ofIgGgeneratio
nandmacroph
agep
hagocytosis
activ
ityand
capacity
[110]
Turkey
Mediterraneanprop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
neasativa
PEE
Perip
heralblood
mon
onuclear
cells
from
healthyhu
mans
Supp
ressionof
neop
terin
releasea
ndtryptoph
andegradation
downregulationof
thee
nzym
eind
oleamine2
3-dioxygenase
(IDO)and
decrease
ofIFN-120574
andTN
F-120572levels
[194]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
CAPE
Hum
anmon
ocyte-deriv
eddend
riticcells
(MoD
Cs)g
enerated
from
perip
heralm
onocytes
Inhibitio
nof
IL-12p4
0IL-12p70IL-10IFN-120574-in
duciblep
rotein-(IP-)
10levels
inhibitio
nof
I120581B120572
phosph
orylationandNF-120581Bactiv
ation
[112]
FemaleB
ALB
cmice
Increase
ofIgM
antib
odyprod
uctio
nTlymph
ocytep
roliferation
interle
ukin-4
andinterle
ukin-2
prod
uctio
nby
spleno
cytesandIFN-120574
prod
uctio
n[195]
Hum
anperip
heralblood
mon
onuclear
cellsjurkatcells
Inhibitio
nof
transcrip
tionfactorsN
F-120581BandNFA
Tinhibitio
nof
interle
ukin-2
gene
transcrip
tion
interle
ukin-2
receptor
expressio
nand
proliferatio
nof
human
Tcells
[94]
10 Evidence-Based Complementary and Alternative Medicine
effects of Brazilian green propolis on splenocyte proliferationeffect that was attributed to flavonoids and enhancementeffects on interferon- (IFN-) 120574 production by spleen cellsCAPE displays inhibitory effects on transcription factors NF-120581B and NFAT and as a consequence inhibits IL-2 genetranscription IL-2 receptor expression and proliferation ofhuman T cells [94] This provides new information into themolecular mechanisms involved in the anti-inflammatoryand immunomodulatory activities of propolis CAPE hasvarious biological activities but its effect on the immunomod-ulatory activity remains little studied According to Wanget al [112] CAPE can be useful in the treatment of asthmaand other allergic diseases because it can inhibit cytokinesand chemokines production by human monocyte-deriveddendritic cells (MoDCs) which might be related to theNF-120581B signalling pathway Another study demonstrated forthe first time that Brazilian propolis significantly inhibitedthe generation of Th1 cells Furthermore the effects ofpropolis were investigated on 246-trinitrobenzene sulfonicacid- (TNBS-) induced colitis in a mouse model Propolisreduced the frequency of IFN-120574-producing CD4 T cellsin a dose-dependent way under Th1-polarizing conditionsThe inhibitory effect of propolis on Th1 differentiation wasdemonstrated in vivo too and the severity of colitis inpropolis-fed mice was significantly lower than that of micefed with the control diet [118]
44 Antiviral Activity Propolis comprises a complexity ofcompounds which play a role in antiviral protection Despitethe few data available regarding this activity it was shown thatpropolis from different geographic regions has considerableantiviral activity by acting at different levels and interferingwith the replication of some viruses [12] like herpes simplextypes 1 and 2 adenovirus type 2 influenza virus or humanimmunodeficiency virus (HIV) among others [7 60 119ndash124] Table 5 summarizes the antiviral activity of propolis andits chemical constituents
Schnitzler et al [123] analysed the antiviral effect ofPWE and PEE from Czech Republic as well as that ofthe constituents caffeic acid p-coumaric acid benzoic acidgalangin pinocembrin and chrysin against herpes simplexvirus type 1 (HSV-1) in cell culture Both extracts exhibitedhigh anti-HSV-1 activity when cells were treated prior toviral infection galangin and chrysin being the main bioac-tive compounds Amoros et al [60] showed the antiviralactivity of the major flavonoids of propolis more specificallyflavonols and flavones the first being more active againstHSV-1 Additionally they analysed the effect of propolis onseveral DNA and RNA viruses (HSV-1 HSV-2 adenovirustype 2 vesicular stomatitis virus (VSV) and poliovirus type2) Propolis at a concentration of 30120583gmL reduced thetiter of herpes virus however vesicular stomatitis virusand adenovirus were less susceptible In addition propo-lis appears to exert a virucidal action on the envelopedviruses HSV and VSV [120] Recently it was shown thathydromethanolic extract of geopropolis from the stinglessbee Scaptotrigona postica (Brazil) inhibits theHSV replicationand also the entry of the virus into cells effect that wasattributed to the C-glycosyl flavones catechin-3-O-gallate
and 34-dicaffeoylquinic acid [125] According to Tait etal [126] natural and synthetic flavonoids might interferewith picornavirus replication preventing the decapsidationof viral particles and RNA release within cells or blockingviral RNA synthesis These authors also showed that differ-ent homoisoflavonoids have good antiviral activity againstthe coxsackie viruses B3 B4 and A9 and echovirus 30Shvarzbeyn and Huleihel [127] tried to determine whichstep of Tax oncoprotein-induced NF-120581B activation is blockedby propolis and CAPE and showed that both substantiallyinhibited the activation of NF-120581B-dependent promoter byTax Also they strongly prevented both Tax binding to I120581B120572and its induced degradation by Tax Ma et al [128] showedthat nanometer propolis flavones could significantly inhibitin vitro porcine parvovirus (PPV) infecting PK-15 cells andin vivo they restrain the PPV copy in lung gonad and blooddecrease the impact of PPV on weight of guinea pigs andincrease hemagglutination inhibition of PPV in serum as wellas improving the contents of IL-2 IL-6 and 120574-IFN
Over recent years therapeutic benefits of propolis andorits isolated compounds have been described in HIV treat-ment Ito et al [129] tested the anti-HIV activity in H9lymphocytes of triterpenoids melliferone moronic acidanwuweizonic acid and betulonic acid and four knownaromatic compounds isolated from Brazilian propolis andshowed that moronic acid had significant anti-HIV activityGekker et al [119] assessed the anti-HIV-1 activity of propolisin CD4+ lymphocytes and microglial cell cultures observ-ing the inhibition of viral expression in a concentration-dependent wayThe possible mechanism of propolis antiviralproperty was suggested to involve inhibition of viral entry
45 Antimicrobial Activity Antimicrobial activity one ofthe most studied propolis biological properties is very welldocumented This bioactivity has been largely investigatedin the last years due to the need of new treatments againstinfectious diseases especially with the increase of resistantpathogens to current antibiotics Tables 6 and 7 summarisethe antibacterial and antifungal activities found in propolisfrom different geographic origin andor its chemical con-stituents
451 Antibacterial Activity Propolis effect against severalbacterial strains has evaluated [7 56ndash59 130] and supportedthe fact that propolis is more active against Gram-positivebacteria than Gram-negative bacteria [12 59] Briefly datafrom different studies showed that propolis inhibits bac-terial motility and enzyme activity exhibits bacteriostaticactivity against different bacterial genera can be bactericidalin high concentrations and affects cytoplasmic membrane[130]
Mirzoeva et al [130] investigated the effect of PEEon the physiology of Bacillus subtilis Escherichia coli andRhodobacter sphaeroides proposing that propolis and someof its components like cinnamic acid and flavonoids affectthe ion permeability of the inner bacterial membrane causingthe dissipation of the membrane potential and inhibitingbacterial motility A recent study [131] provided valuableinformation for understanding the potential anti-H pylori
Evidence-Based Complementary and Alternative Medicine 11
Table5Antivira
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescellsviru
ses
Effect
References
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
Caffeicacidp-cou
maricacid
benzoica
cidgalang
in
pino
cembrinand
chrysin
RC-37cellsherpessim
plex
virustype1
(HSV
-1)
strainKO
SHighanti-HSV
-1activ
ityforb
othextractswhencells
weretreated
prior
toviralinfectio
n[123]
CzechRe
public
European
prop
olisPopu
lusn
igra
PEEandPW
ERC
-37cellsherpessim
plex
virustype2
(HSV
-2)
Highantih
erpetic
activ
ityforb
othextractswhenvirusesw
ere
pretreated
priortoinfection
[196]
Brazil
Brow
nprop
olisB
dracun
culifolia
HPE
HSV
-2str
ainprop
agated
inVe
rocellsfem
aleB
ALB
cmice
Effectiv
eagainstHSV
-2infectionandin
redu
cing
extravaginallesio
nsby
actin
gon
inflammatoryandoxidativep
rocessesreducingreactiv
especiestyrosin
enitration
ascorbicacid
levels
andmyeloperoxidase
activ
ityandprotectin
gagainstinh
ibition
ofcatalase
activ
ity
[124]
Characteris
ticof
Brazilian
prop
olis
Isop
entylferulate(
isolatedfro
man
PEE)
Influ
enza
virusesA
PR834
(H1N
1)
AKrasnod
ar10
159(H
2N2)and
AH
ongKo
ng168
(H3N
2)Supp
ressionof
influ
enza
virusA
Hon
gKo
ngreprod
uctio
nin
vitro
[121]
Green
prop
olisB
dracun
culifolia
Beriocla
daM
yrceugeniaeuosma
PEE
Influ
enza
APR834
(H1N
1)virusp
ropagated
Madin-D
arby
canine
kidn
ey(M
DCK
)cells
female
DBA
2Cr
mice
Redu
ctionof
body
weightlosso
finfectedmicea
ndvirusy
ieldsinthe
bron
choalveolarlavagefl
uids
oflung
s[122]
France
European
prop
olisPopu
lusn
igra
PEE
RC-37cellsH
SV-1str
ainH29Sacyclovirresistant
mutantH
SV1-R
strainH29R
HSV
-2adeno
virustype
2po
liovirustype2
and
vesic
ular
stomatitisv
irus
(VSV
)
Redu
ctionof
titre
ofherpes
virusbeingvesic
ular
stomatitisv
irusa
ndadenoviru
slesssusceptibleviru
cidalactionon
thee
nvelo
pedviruses
HSV
andVS
V[120]
Brazil
Geoprop
olisfro
mthes
tinglessb
eeScaptotrigona
postica
Hydromethano
licextract
African
greenmon
keykidn
eycells
(ATC
CCC
L-81)
herpes
simplex
virusstrain(M
cIntyre)
Inhibitio
nof
HSV
replicationandentryinto
cells
[125]
Synthesiz
edCh
aracteris
ticof
Brazilian
redand
greenprop
olis
Hom
oisoflavono
idsspecially
3-benzyl-4-chrom
ones
BGM
(Buff
aloGreen
Mon
key)
cellscoxsackieviruses
B3B
4andA9andecho
virus3
0Goo
dantiv
iralactivity
againstthe
coxsackiev
irusesB
3B4
and
A9and
echo
virus3
0[126]
Canada
European
prop
olisPtrichocarpa
andPtre
muloides
PEE
HSV
-1andHSV
-2virusreplicated
inMDBK
(mon
olayer
cultu
reso
fMadin-D
arby
bovine
kidn
ey)
cells
Impairing
thea
bilityof
thev
irustoadsorb
orto
penetratethe
hostcells
[197]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Water
extracts
FemaleB
ALB
cmiceInflu
enza
Avirusstrain
AW
SN33(H
1N1)
Extensionof
thelifetim
eofm
ice34-dicaffeoylquinica
cidwhich
increasesm
RNAlevelsof
tumor
necrosisfactor-related
apop
tosis
-indu
cing
anddecreasesH
1N1h
emagglutinin
mRN
A[19
8]Ch
aracteris
ticof
Brazilian
green
prop
olis
34-dicaffeoylquinica
cid
(Isolated
from
Brazilian
prop
olis)
Brazil
Characteris
ticof
Brazilian
green
prop
olis
Melliferon
emoron
icacid
anwuw
eizonica
cidand
betulonica
cid(isolated
from
Brazilian
prop
olis)
H9lymph
ocytesH
IV-1
Moron
icacid
inhibitin
ganti-HIV
replication
[129]
Israel
Mediterraneanprop
olisPopu
lus
sppE
ucalyptusspp
andCa
stanea
sativa
PWE
Jurkatuninfectedhu
man
T-celllin
esand
MT2
(HTL
V-1infectedhu
man
Tcells)cells
Inhibitio
nof
thea
ctivationof
NF-120581B-depend
entp
romoter
byTaxand
preventio
nof
Taxbind
ingto
I120581B120572
andits
degradation
[127]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Provided
byBinzho
uAnimal
Sciencea
ndVe
terin
ary
MedicineA
cademyof
Shando
ngProvince
Nanom
eter
prop
olisFlavon
eKidn
eycells
(PK-
15)
Porcinep
arvovirus(PP
V)
Britain
Whiteguinea
pigs
Inhibitio
nof
PPVinfectingpo
rcinek
idney-
(PK-
)15cells
Restr
aining
ofPP
Vcopy
inlung
gon
adand
bloo
ddecrease
ofthe
impactof
PPVon
weighto
fguineap
igsandincrease
ofhemagglutinationinhibitio
nof
PPVin
serum
aswellasimprovingthe
contentsof
IL-2IL-6and120574-IFN
[128]
USA
andCh
ina
European
prop
olisPopu
lusn
igra
PEE
Perip
heralblood
mon
onuclear
cells
obtained
from
bloo
dof
healthyd
onorsmicroglialcellsiso
latedfro
mhu
man
fetalbrain
tissueHIV-1ATH
IV-1SF162
Inhibitio
nof
HIV-1varia
ntse
xpression
[119]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
12 Evidence-Based Complementary and Alternative Medicine
Table6Antibacteria
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
PurchasedBe
eHealth
Ltd
(Scarborou
ghYorkshire
UK)
Eu
ropean
prop
olisPopu
lusn
igra
PEE
BsubtilisS
G38E
coliandR
sphaeroides
Influ
encing
theion
perm
eabilityof
theinn
erbacterial
mem
brane
Inhibitio
nof
bacterialm
otility
[130]
PurchasedSigm
aCh
emicalCo(Poo
leDorsetUK)
Characteris
ticof
EuropeanB
razilian
andMediterraneanprop
olis
CaffeicacidC
APE
qu
ercetin
and
narin
genin
Greece
Mediterraneanprop
olisprob
ablyCo
nifer
spp
Terpenes
(isolated
from
Cretan
prop
olis)
Saureus
(ATC
C25923)Sepiderm
idis(ATC
C12228)E
coli
(ATC
C25922)E
cloacae
(ATC
C13047)K
pneumoniae
(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Influ
encing
theG
ram-positive
andGram-negativeb
acteria
viability
[199]
France
European
prop
olisPopu
lusn
igra
Dichlorom
ethane
extract
Gram-negative7Ac
inetobacterb
aumannii(RC
HSAN00812
AYE
CIP7
034107292and
5377)2Escherich
iacoli(ATC
C25922andac
linicaliso
late)3
Pseudomonas
aeruginosa
(ATC
C27853andtwoclinicalisolates)and4clinicalisolates
ofEn
terobacterclo
acaeE
aerogenesK
lebsiella
oxytocaand
Salm
onellaenteritidis(phage
type
4)Gram-negative13
Staphylococcus
aureus
(ATC
C25923six
methicillin-susceptib
leclinicalisolatesandsix
methicillin-resistant
clinicalisolates)2
clinicalisolates
ofS
epidermidis(m
ethiSandmethiR)3
clinicalisolates
ofEn
terococcus
faecalisand1E
faeciu
mand
1clin
icaliso
lateof
Corynebacterium
striatum
Influ
encing
theG
ram-positive
bacteriaviabilityspecially
Saureus
andseveralofitsmethicillin-resistant
and
methicillin-susceptib
le[133]
Bulgaria
Mediterraneanprop
olis
PEE
Saureus
209E
coliWF+
Decreaseo
fSaureusg
rowth
andweakor
lack
ofactiv
ityagainstE
coli
[28]
Greece
Popu
lusspp
Tu
rkey
Conifer
spp
Algeria
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativaPopu
lusspp
Cistu
sspp
Austr
alia
Austr
alianprop
olisfro
msting
lessbee
Tetra
gonu
lacarbonariaCtorelliana
trees
(fruitresins)
PEE
Saureus
(ATC
C25923)
Paeruginosa
(ATC
C27853)
Inhibitio
nof
Saureus
grow
th[42]
Cameroo
nandCon
goAfrican
prop
olisprob
ablyM
schw
einfurthii
PEE
Saureus
(ATC
C25923)Sepiderm
is(ATC
C13047)E
coli
(ATC
C25922)K
lebsiella
pneumonia(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Inhibitio
nof
Saureus
grow
th[53]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Saureus
2979
andSaureus
4118
isolated
from
mastiticcows
Saureus
(ATC
C29213)
Decreaseo
fSaureusg
rowth
incomplex
mediaandkilling
ofSaureus
cells
resuspendedin
milk
promotionof
changesin
morph
olog
yandcellsiz
e[200]
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsu
lfoxide
extract
Saureus
(CAPM
5970)E
faecalis(C
APM
5613
(EBF
3039))
Ecoli(C
AMP3101
T(U
541))and
Lmonocytogenes(C
CM5580)
Differentcon
centratio
nsaffectthe
grow
thofthetestedbacteria
[201]
Italy
Mediterraneanprop
olisCrup
essusspp
PE
E
Staphylococcus
sppstr
ains
(35Saureus63Sepidermidis
7S
hominis
18Shaem
olyticu
s10
Swa
rneri4Scapitisand
3S
auric
ularis)
andStreptococcusspp
strains
(59Sfaecalis
30S
virid
ans15
S120573-haemolyticu
sand19
Spn
eumoniae)
Com
pletes
uppressio
nof
thefactorc
oagu
lasereductio
nof
lipasea
ndpreventio
nof
biofi
lmform
ationof
Staphylococcus
increase
ofthee
ffectof
ampicillingentam
ycinand
streptomycin
andmod
eratingthea
ctionof
chloramph
enicol
ceftriaxoneand
vancom
ycin
[56]
Brazil
Redprop
olisDecasto
phyllum
Green
prop
olisB
dracun
culifolia
PEE
Saureus
(ATC
C25923)
NanoH
Amatrix
with
redandgreenprop
oliswhich
redu
ces
bacterialgrowth
andbiofi
lmform
ation
then
anoH
Awith
red
prop
olisbeingthem
ostefficient
[136]
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
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[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
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[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
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24 Evidence-Based Complementary and Alternative Medicine
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[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
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[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
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Evidence-Based Complementary and Alternative Medicine 25
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[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
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[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 7
Table3Anti-infl
ammatorymechanism
sinvestig
ated
with
prop
olis
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
PurchasedSigm
aAldric
hCo
Synthesiz
ed
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacidquercetin
narin
genin
CAPE
Periton
ealm
acroph
ages
Supp
ressionof
lipoxygenasep
athw
ayof
arachido
nica
cid
metabolism
CAPE
beingthem
ostp
otentm
odulator
ofthea
rachidon
icacid
cascade
[90]
Croatia
European
prop
olisPopu
lusn
igra
Water-solub
lederiv
atives
Swiss
albino
mice
Redu
ctionof
DNAdamageinperip
herallym
phocytes
[188]
PEE
MaleS
wiss
albino
mice
Supp
ressionof
functio
nalactivity
ofmacroph
ages
[104]
PurchasedSigm
aAldric
hCo
J774
macroph
agesM
ale
Wistar
rats
Invitro
andin
vivo
inhibitio
nof
cyclo
oxygenase1
and
cyclo
oxygenase2
activ
ity[91189]
MaleW
istar
albino
rats
Decreaseo
fpolym
orph
onuclear
neutroph
ilicleuko
cyte
infiltra
tionin
thelun
gstissues
[190]
Characteristic
ofEu
ropean
type
prop
olis
CAPE
Gastricepith
elialcelllin
e(A
GS)H
pylori(str
ainNCT
C116
38)
Inhibitio
nof
Hpylori-ind
uced
NF-kB
andactiv
ator
protein
1-DNA-
bind
ingactiv
itypreventionof
IkB120572
degradationin
AGSandsupp
ressionof
TNF-120572andinterle
ukin
8prod
uctio
n[191]
PurchasedWakoPu
reCh
emicalIndu
stries
Ltd
RAW2647macroph
ages
Decreaseo
fthe
prod
uctio
nof
interle
ukin-1120573m
onocyte
chem
oattractant
protein1andthep
rodu
ctionandexpressio
nof
tumor
necrosisfactor120572(TNF-120572)
[98]
MaleS
wiss
inbred
strainmice
Decreaseo
fcyclooxygenase2
expressio
nNF-120581Bactiv
ity
c-Jun-N-te
rminalkinaseinh
ibito
rofN
F-120581Bkinase
(IKK
)andinhibitoro
fNF-120581B(IkB
)pho
spho
rylatio
n[97]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
RAW2647macroph
ages
Dow
nregulationof
NF-120581B
p38mito
gen-activ
ated
protein
kinaseand
c-Jun-N-te
rminalkinase
[101]
PurchasedAc
ros
Organics
Characteristic
ofEu
ropeanB
razilian
andMediterraneanprop
olis
Caffeicacid
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Sprague-Daw
leyrats
Inhibitio
nof
carrageenan-indu
cedrath
indpawse
demaa
ndthec
hemotaxisof
human
polymorph
onuclear
leuk
ocytes
(PMNs)
[95]
Synthesiz
edCh
aracteristic
ofEu
ropean
type
prop
olis
CAPE
Polymorph
onuclear
leuk
ocytes
obtained
from
Hum
anbloo
dInhibitio
nof
5-lip
oxygenasea
ctivity
andarachido
nica
cid
release
[103]
Chile
European
prop
olispo
plar
trees
PEE
MaleC
F-1m
ice
Inhibitio
nof
NOreleaseb
ythem
acroph
ages
[102]
China
European
prop
olisPopu
lusn
igra
PEEandPW
EMaleICR
micea
ndmale
Wistar
rats
Inhibitio
nof
thea
ctivationanddifferentiatio
nof
mon
onuclear
macroph
agesdecreasep
rosta
glandin-E2
(PGE2)
andnitric
oxide(NO)levels
[61]
Brazil
Green
prop
olisB
dracun
culifolia
PWE
Swiss
andBA
LBcmice
Decreaseinthen
umbero
fmacroph
ages
andneutroph
ils
inhibitio
nof
proinfl
ammatorycytokinesa
ndincrease
ofanti-inflammatorycytokines
[99]
Redprop
olisDalbergia
ecastaphyllum
PEE
MaleW
istar
rats
Decreaseinrenalm
acroph
ageinfi
ltrationin
ratswith
chronic
kidn
eydisease
[100]
Nepal
Nepalesep
ropo
lisprobablyShorea
robu
staD
albergiasissooAc
acia
catechuandBo
mbaxcie
ba
PEE
3101584041015840-dihydroxy-4-
metho
xydalbergion
e4-etho
xydalbergion
cearoin
andchrysin
Bone
marrow-derived
mast
cells
(BMMC)
from
C57B
L6
mice
Inhibitin
gIL-6T
NF-120572and
IL-13gene
expressio
nin
BMMC
andalso
inhibitin
gthea
ctivationof
IKKleadingto
NF-120581B
inactiv
ation
[96]
8 Evidence-Based Complementary and Alternative Medicine
mechanisms investigated with propolis and its chemicalconstituents Recently the role of the flavonoids quercetinflavonols and flavones in modulating inflammatory cellfunction was studied [92] Funakoshi-Tago et al [96] inves-tigated the anti-inflammatory effects of flavonoids isolatedfrom Nepalese PEE on the IL-33 signaling pathway Theisolated flavonoids 3101584041015840-dihydroxy-4-methoxydalbergione4-methoxydalbergion cearoin and chrysin inhibited theexpression of inflammatory genes including IL-6 TNF-120572and IL-13 in bone marrow-derived mast cells (BMMC) andalso inhibited the activation of IKK which leads to thedegradation of I120581B120572 and inhibits the activation of nuclearfactor 120581B (NF-120581B)
The release and oxygenation of arachidonic acid are acritical event in inflammation Mirzoeva and Calder [90]demonstrated that propolis components such as CAPE caf-feic acid quercetin andnaringenin among others inhibit theproduction of eicosanoids In fact these components signif-icantly suppressed the lipoxygenase pathway of arachidonicacid metabolism CAPE being the most potent modulatorAnother study indicated that CAPE treatment improveshepatic steatosis induced by high-fat diet in a mouse modelThis effect was attributed to the reduction of c-Jun-N-terminal kinase (JNK12) andNF-120581B activationwith decreasein COX-2 expression [97] Recently it was reported thatCAPE exhibits inhibitory effects on the production of proin-flammatory cytokines (interleukin-1120573 (IL-1120573)) tumor necro-sis factor-120572 (TNF-120572) and monocyte chemoattractant pro-tein 1 (MCP-1) from lipopolysaccharide- (LPS-) stimulatedRAW2647 macrophages [98] Machado et al [99] showedthat Brazilian green propolis water extracts (PWE) modulatean anti-inflammatory cellular response in the model of LPS-induced pulmonary inflammation by decreasing the numberof macrophages and neutrophils Additionally it induced areduction in the secretion of IL-6 and TNF-120572 and an increasein TGF-120573 and IL-10 Another study showed that Brazilianred PEE promotes a significant decrease in renal macrophageinfiltration in rats with chronic kidney disease [100] Bufaloet al [101] demonstrated that Brazilian PEE and caffeicacid inhibited LPS-induced NO production by RAW2647macrophages acting at the transcriptional level and sug-gesting that their anti-inflammatory effects were mediatedby downregulating NF-120581B p38 MAP kinase and JNK12According to Naito et al [95] topical application of BrazilianPEE is effective in inhibiting carrageenan-induced rat hindpaw edemaThis sample appears to inhibit the chemotaxis ofhuman polymorphonuclear leukocytes (PMNs) which alsocontributes to its anti-inflammatory effects Another studyshowed the topical anti-inflammatory activity of propolisfrom Chile in mice ear with induced-edema In fact PEEfrom Buin Chile was the most active against the inflamma-tion induced by 12-O-tetradeca-noylphorbol-13-acetate andarachidonic acid and also inhibits significantly NO releaseby the macrophages [102] More recently Boudreau et al[103] indicated that CAPE is a potent leukotriene biosynthesisinhibitor in PMNs that blocks 5-lipoxygenase (5-LO) activityand arachidonic acid release A Croatian PEE may improvepsoriatic-like skin lesions whichwere induced in the study byirritant agents like n-hexyl salicylate or di-n-propyl disulfide
by reducing the lipid peroxidation in the skin and totalnumber of inflammatory cells in the skin and peritonealcavity more specially by suppressing functional activity ofmacrophages [104]
43 Immunomodulatory Activity Natural substances areconsidered alternative adjuvant therapies in the treatment ofdifferent diseases due to their immunomodulatory effectsInformation about this type of activity was scarce for propolisuntil the 1990s but published work in the last years has pro-vided information about the influence of different propolissamples on the immune system [65 105ndash112] (Table 4)
In a study using Brazilian green propolis it was seenthat the administration for 3 days of a PEE to male BALBcmice modulated the activation of the initial steps of theimmune response by upregulating toll-like receptor- (TLR-)2 and toll-like receptor-4 expression and proinflammatorycytokines (IL-1 and IL-6) production by macrophages andspleen cells [105] Another study demonstrated that BraziliangreenPEEupregulates TLR-4 andCD80 expression in humanmonocytes as well as TNF-120572 and IL-10 production [113] Itwas also shown that caffeic acid stimulates the activity ofmonocytes againstC albicans but it inhibits TLR-2 andHLA-DR expression as well as TNF-120572 and IL-10 production [114]
Additionally Missima et al [115] showed that Braziliangreen PEE administered to stressed mice reduces the proin-flammatory cytokines IL-1120573 and IL-6 When administered tomelanoma-bearing mice submitted or not to chronic stressit induces high levels of IL-1120573 and IL-6 and also stimu-lates Th1 cytokines production indicating the activation ofantitumour cell-mediated immunity Bachiega et al [116]investigated the immunomodulatory effect of propolis andcinnamic and coumaric acids on cytokines IL-1120573 IL-6 andIL-10 production Peritonealmacrophages fromBALBcmicewere incubated with different concentrations of propolis(5 50 and 100mgwell) and coumaric and cinnamic acid(50 and 100mgwell) Propolis and the acids stimulated IL-1120573 production and significantly inhibited IL-6 productionThen after LPS incubation the inhibitory concentrations ofcinnamic and coumaric acids prevented efficiently its effectson IL-6 production whereas propolis inhibited LPS effectsboth before and after its addition Additionally propolis andcoumaric and cinnamic acids inhibited IL-10 production Astudy which evaluated the effect of Brazilian green propolison macrophage activation by H
2O2and NO metabolite
determination [107] showed that propolis increased H2O2
generation and decreased NO generation which favoursthe microbicidal activity Recently the immunomodulatoryeffect of propolis collected in Brazil was evaluated in Leish-mania (Viannia) braziliensis experimental infection Datashows that macrophages incubated with propolis showed asignificant increase in interiorization and further killing ofparasites Also an increased TNF-120572 production was seen inpropolis-pretreated mice whereas IL-12 was downregulatedduring the infection [117]
The immunomodulatory action of propolis does notoccur only at the macrophage level In fact some studiesshow that this action has also an effect on lymphocyte pro-liferation [106 108] Sa-Nunes et al [108] showed inhibitory
Evidence-Based Complementary and Alternative Medicine 9
Table4Im
mun
omod
ulatoryactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
MaleB
ALB
cmice
Upregulationof
toll-lik
ereceptor-2andreceptor-4
expressio
nand
increasesininterle
ukin-1andinterle
ukin-6
prod
uctio
n[105]
Upregulationof
toll-lik
ereceptor-2andreceptor-4
mRN
Aexpressio
n[111]
MaleC
57BL
6miceB16F
10cell
line
Stim
ulationof
thee
xpressionandprod
uctio
nof
interle
ukin-2
and
interle
ukin-10andTh
1cytokine(interle
ukin-2
andIFN-120574)p
rodu
ction
[192]
MaleB
ALB
cmice
Inhibitio
nof
Th1cellsgeneratio
nredu
ctionof
thefrequ
ency
ofIFN-120574-produ
cing
CD4+
Tcells
underTh
1-polarizingcond
ition
s[118]
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecreasesintheN
Ogeneratio
nin
periton
ealm
acroph
ages
[109]
MaleB
ALB
cmice
Increase
intheinterioriz
ationandkilling
ofthep
arasitesL
eishm
ania
(Viann
ia)b
raziliensisby
macroph
agesincreaseinTN
F-120572prod
uctio
nanddecrease
ininterle
ukin-12prod
uctio
n[117]
Mon
ocytes
from
human
bloo
dTL
R-4andCD
80expressio
nin
human
mon
ocytes
aswellasT
NF-120572
andIL-10prod
uctio
n[113]
Mela
nomac
ells(B16F10)m
ale
C57B
L6mice
Redu
ctionof
IL-1120573andIL-6
inLP
S-str
essedmiceindu
ctionof
IL-1120573
andIL-6
andTh
1cytok
ines
inmela
noma-bearingmices
ubmitted
orno
ttochronics
tress
[115]
Brazil
PurchasedAc
rosO
rganics
Green
prop
olisB
dracun
culifolia
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
PEE
cinn
amicandcoum
aricacids
MaleB
ALB
cmice
Stim
ulationof
interle
ukin-1120573prod
uctio
nandinhibitio
nof
interle
ukin-6
andinterle
ukin-10prod
uctio
ns[116]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
and
Mediterraneanprop
olis
Caffeicacid
Mon
ocytes
from
human
bloo
dStim
ulationof
mon
ocytes
activ
ityagainstC
albica
nsdow
nregulation
ofTL
R-2andHLA
-DRexpressio
nandinhibitio
nof
cytokine
prod
uctio
n[114]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
Cinn
amicacid
Mon
ocytes
from
human
bloo
dDow
nregulationof
toll-lik
ereceptor-2HLA
-DRmolecules
from
human
antig
en-presentingcellsand
CD80upregulationof
toll-lik
ereceptor-4inh
ibition
ofTN
F-120572andinterle
ukin-10prod
uctio
n[19
3]
PurchasedSigm
aAldric
hCo
Cinn
amicacid
FemaleIRC
mice
Increase
oflymph
ocytep
roliferationandreleaseo
fcytok
ines
interle
ukin-1andinterle
ukin-2
[106]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Hydroalcoho
lic(H
PE)solution
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecrease
ofNOgeneratio
n[107]
MaleB
ALB
cmice
Decreaseo
fsplenocytep
roliferationandincrease
ofIFN-120574
prod
uctio
nby
spleen
cells
[108]
Indo
nesia
TheP
acificr
egionprop
olisMacaranga
tanariu
sand
Mind
icaHPE
MaleB
ALB
cmice
Increase
ofIgGgeneratio
nandmacroph
agep
hagocytosis
activ
ityand
capacity
[110]
Turkey
Mediterraneanprop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
neasativa
PEE
Perip
heralblood
mon
onuclear
cells
from
healthyhu
mans
Supp
ressionof
neop
terin
releasea
ndtryptoph
andegradation
downregulationof
thee
nzym
eind
oleamine2
3-dioxygenase
(IDO)and
decrease
ofIFN-120574
andTN
F-120572levels
[194]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
CAPE
Hum
anmon
ocyte-deriv
eddend
riticcells
(MoD
Cs)g
enerated
from
perip
heralm
onocytes
Inhibitio
nof
IL-12p4
0IL-12p70IL-10IFN-120574-in
duciblep
rotein-(IP-)
10levels
inhibitio
nof
I120581B120572
phosph
orylationandNF-120581Bactiv
ation
[112]
FemaleB
ALB
cmice
Increase
ofIgM
antib
odyprod
uctio
nTlymph
ocytep
roliferation
interle
ukin-4
andinterle
ukin-2
prod
uctio
nby
spleno
cytesandIFN-120574
prod
uctio
n[195]
Hum
anperip
heralblood
mon
onuclear
cellsjurkatcells
Inhibitio
nof
transcrip
tionfactorsN
F-120581BandNFA
Tinhibitio
nof
interle
ukin-2
gene
transcrip
tion
interle
ukin-2
receptor
expressio
nand
proliferatio
nof
human
Tcells
[94]
10 Evidence-Based Complementary and Alternative Medicine
effects of Brazilian green propolis on splenocyte proliferationeffect that was attributed to flavonoids and enhancementeffects on interferon- (IFN-) 120574 production by spleen cellsCAPE displays inhibitory effects on transcription factors NF-120581B and NFAT and as a consequence inhibits IL-2 genetranscription IL-2 receptor expression and proliferation ofhuman T cells [94] This provides new information into themolecular mechanisms involved in the anti-inflammatoryand immunomodulatory activities of propolis CAPE hasvarious biological activities but its effect on the immunomod-ulatory activity remains little studied According to Wanget al [112] CAPE can be useful in the treatment of asthmaand other allergic diseases because it can inhibit cytokinesand chemokines production by human monocyte-deriveddendritic cells (MoDCs) which might be related to theNF-120581B signalling pathway Another study demonstrated forthe first time that Brazilian propolis significantly inhibitedthe generation of Th1 cells Furthermore the effects ofpropolis were investigated on 246-trinitrobenzene sulfonicacid- (TNBS-) induced colitis in a mouse model Propolisreduced the frequency of IFN-120574-producing CD4 T cellsin a dose-dependent way under Th1-polarizing conditionsThe inhibitory effect of propolis on Th1 differentiation wasdemonstrated in vivo too and the severity of colitis inpropolis-fed mice was significantly lower than that of micefed with the control diet [118]
44 Antiviral Activity Propolis comprises a complexity ofcompounds which play a role in antiviral protection Despitethe few data available regarding this activity it was shown thatpropolis from different geographic regions has considerableantiviral activity by acting at different levels and interferingwith the replication of some viruses [12] like herpes simplextypes 1 and 2 adenovirus type 2 influenza virus or humanimmunodeficiency virus (HIV) among others [7 60 119ndash124] Table 5 summarizes the antiviral activity of propolis andits chemical constituents
Schnitzler et al [123] analysed the antiviral effect ofPWE and PEE from Czech Republic as well as that ofthe constituents caffeic acid p-coumaric acid benzoic acidgalangin pinocembrin and chrysin against herpes simplexvirus type 1 (HSV-1) in cell culture Both extracts exhibitedhigh anti-HSV-1 activity when cells were treated prior toviral infection galangin and chrysin being the main bioac-tive compounds Amoros et al [60] showed the antiviralactivity of the major flavonoids of propolis more specificallyflavonols and flavones the first being more active againstHSV-1 Additionally they analysed the effect of propolis onseveral DNA and RNA viruses (HSV-1 HSV-2 adenovirustype 2 vesicular stomatitis virus (VSV) and poliovirus type2) Propolis at a concentration of 30120583gmL reduced thetiter of herpes virus however vesicular stomatitis virusand adenovirus were less susceptible In addition propo-lis appears to exert a virucidal action on the envelopedviruses HSV and VSV [120] Recently it was shown thathydromethanolic extract of geopropolis from the stinglessbee Scaptotrigona postica (Brazil) inhibits theHSV replicationand also the entry of the virus into cells effect that wasattributed to the C-glycosyl flavones catechin-3-O-gallate
and 34-dicaffeoylquinic acid [125] According to Tait etal [126] natural and synthetic flavonoids might interferewith picornavirus replication preventing the decapsidationof viral particles and RNA release within cells or blockingviral RNA synthesis These authors also showed that differ-ent homoisoflavonoids have good antiviral activity againstthe coxsackie viruses B3 B4 and A9 and echovirus 30Shvarzbeyn and Huleihel [127] tried to determine whichstep of Tax oncoprotein-induced NF-120581B activation is blockedby propolis and CAPE and showed that both substantiallyinhibited the activation of NF-120581B-dependent promoter byTax Also they strongly prevented both Tax binding to I120581B120572and its induced degradation by Tax Ma et al [128] showedthat nanometer propolis flavones could significantly inhibitin vitro porcine parvovirus (PPV) infecting PK-15 cells andin vivo they restrain the PPV copy in lung gonad and blooddecrease the impact of PPV on weight of guinea pigs andincrease hemagglutination inhibition of PPV in serum as wellas improving the contents of IL-2 IL-6 and 120574-IFN
Over recent years therapeutic benefits of propolis andorits isolated compounds have been described in HIV treat-ment Ito et al [129] tested the anti-HIV activity in H9lymphocytes of triterpenoids melliferone moronic acidanwuweizonic acid and betulonic acid and four knownaromatic compounds isolated from Brazilian propolis andshowed that moronic acid had significant anti-HIV activityGekker et al [119] assessed the anti-HIV-1 activity of propolisin CD4+ lymphocytes and microglial cell cultures observ-ing the inhibition of viral expression in a concentration-dependent wayThe possible mechanism of propolis antiviralproperty was suggested to involve inhibition of viral entry
45 Antimicrobial Activity Antimicrobial activity one ofthe most studied propolis biological properties is very welldocumented This bioactivity has been largely investigatedin the last years due to the need of new treatments againstinfectious diseases especially with the increase of resistantpathogens to current antibiotics Tables 6 and 7 summarisethe antibacterial and antifungal activities found in propolisfrom different geographic origin andor its chemical con-stituents
451 Antibacterial Activity Propolis effect against severalbacterial strains has evaluated [7 56ndash59 130] and supportedthe fact that propolis is more active against Gram-positivebacteria than Gram-negative bacteria [12 59] Briefly datafrom different studies showed that propolis inhibits bac-terial motility and enzyme activity exhibits bacteriostaticactivity against different bacterial genera can be bactericidalin high concentrations and affects cytoplasmic membrane[130]
Mirzoeva et al [130] investigated the effect of PEEon the physiology of Bacillus subtilis Escherichia coli andRhodobacter sphaeroides proposing that propolis and someof its components like cinnamic acid and flavonoids affectthe ion permeability of the inner bacterial membrane causingthe dissipation of the membrane potential and inhibitingbacterial motility A recent study [131] provided valuableinformation for understanding the potential anti-H pylori
Evidence-Based Complementary and Alternative Medicine 11
Table5Antivira
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescellsviru
ses
Effect
References
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
Caffeicacidp-cou
maricacid
benzoica
cidgalang
in
pino
cembrinand
chrysin
RC-37cellsherpessim
plex
virustype1
(HSV
-1)
strainKO
SHighanti-HSV
-1activ
ityforb
othextractswhencells
weretreated
prior
toviralinfectio
n[123]
CzechRe
public
European
prop
olisPopu
lusn
igra
PEEandPW
ERC
-37cellsherpessim
plex
virustype2
(HSV
-2)
Highantih
erpetic
activ
ityforb
othextractswhenvirusesw
ere
pretreated
priortoinfection
[196]
Brazil
Brow
nprop
olisB
dracun
culifolia
HPE
HSV
-2str
ainprop
agated
inVe
rocellsfem
aleB
ALB
cmice
Effectiv
eagainstHSV
-2infectionandin
redu
cing
extravaginallesio
nsby
actin
gon
inflammatoryandoxidativep
rocessesreducingreactiv
especiestyrosin
enitration
ascorbicacid
levels
andmyeloperoxidase
activ
ityandprotectin
gagainstinh
ibition
ofcatalase
activ
ity
[124]
Characteris
ticof
Brazilian
prop
olis
Isop
entylferulate(
isolatedfro
man
PEE)
Influ
enza
virusesA
PR834
(H1N
1)
AKrasnod
ar10
159(H
2N2)and
AH
ongKo
ng168
(H3N
2)Supp
ressionof
influ
enza
virusA
Hon
gKo
ngreprod
uctio
nin
vitro
[121]
Green
prop
olisB
dracun
culifolia
Beriocla
daM
yrceugeniaeuosma
PEE
Influ
enza
APR834
(H1N
1)virusp
ropagated
Madin-D
arby
canine
kidn
ey(M
DCK
)cells
female
DBA
2Cr
mice
Redu
ctionof
body
weightlosso
finfectedmicea
ndvirusy
ieldsinthe
bron
choalveolarlavagefl
uids
oflung
s[122]
France
European
prop
olisPopu
lusn
igra
PEE
RC-37cellsH
SV-1str
ainH29Sacyclovirresistant
mutantH
SV1-R
strainH29R
HSV
-2adeno
virustype
2po
liovirustype2
and
vesic
ular
stomatitisv
irus
(VSV
)
Redu
ctionof
titre
ofherpes
virusbeingvesic
ular
stomatitisv
irusa
ndadenoviru
slesssusceptibleviru
cidalactionon
thee
nvelo
pedviruses
HSV
andVS
V[120]
Brazil
Geoprop
olisfro
mthes
tinglessb
eeScaptotrigona
postica
Hydromethano
licextract
African
greenmon
keykidn
eycells
(ATC
CCC
L-81)
herpes
simplex
virusstrain(M
cIntyre)
Inhibitio
nof
HSV
replicationandentryinto
cells
[125]
Synthesiz
edCh
aracteris
ticof
Brazilian
redand
greenprop
olis
Hom
oisoflavono
idsspecially
3-benzyl-4-chrom
ones
BGM
(Buff
aloGreen
Mon
key)
cellscoxsackieviruses
B3B
4andA9andecho
virus3
0Goo
dantiv
iralactivity
againstthe
coxsackiev
irusesB
3B4
and
A9and
echo
virus3
0[126]
Canada
European
prop
olisPtrichocarpa
andPtre
muloides
PEE
HSV
-1andHSV
-2virusreplicated
inMDBK
(mon
olayer
cultu
reso
fMadin-D
arby
bovine
kidn
ey)
cells
Impairing
thea
bilityof
thev
irustoadsorb
orto
penetratethe
hostcells
[197]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Water
extracts
FemaleB
ALB
cmiceInflu
enza
Avirusstrain
AW
SN33(H
1N1)
Extensionof
thelifetim
eofm
ice34-dicaffeoylquinica
cidwhich
increasesm
RNAlevelsof
tumor
necrosisfactor-related
apop
tosis
-indu
cing
anddecreasesH
1N1h
emagglutinin
mRN
A[19
8]Ch
aracteris
ticof
Brazilian
green
prop
olis
34-dicaffeoylquinica
cid
(Isolated
from
Brazilian
prop
olis)
Brazil
Characteris
ticof
Brazilian
green
prop
olis
Melliferon
emoron
icacid
anwuw
eizonica
cidand
betulonica
cid(isolated
from
Brazilian
prop
olis)
H9lymph
ocytesH
IV-1
Moron
icacid
inhibitin
ganti-HIV
replication
[129]
Israel
Mediterraneanprop
olisPopu
lus
sppE
ucalyptusspp
andCa
stanea
sativa
PWE
Jurkatuninfectedhu
man
T-celllin
esand
MT2
(HTL
V-1infectedhu
man
Tcells)cells
Inhibitio
nof
thea
ctivationof
NF-120581B-depend
entp
romoter
byTaxand
preventio
nof
Taxbind
ingto
I120581B120572
andits
degradation
[127]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Provided
byBinzho
uAnimal
Sciencea
ndVe
terin
ary
MedicineA
cademyof
Shando
ngProvince
Nanom
eter
prop
olisFlavon
eKidn
eycells
(PK-
15)
Porcinep
arvovirus(PP
V)
Britain
Whiteguinea
pigs
Inhibitio
nof
PPVinfectingpo
rcinek
idney-
(PK-
)15cells
Restr
aining
ofPP
Vcopy
inlung
gon
adand
bloo
ddecrease
ofthe
impactof
PPVon
weighto
fguineap
igsandincrease
ofhemagglutinationinhibitio
nof
PPVin
serum
aswellasimprovingthe
contentsof
IL-2IL-6and120574-IFN
[128]
USA
andCh
ina
European
prop
olisPopu
lusn
igra
PEE
Perip
heralblood
mon
onuclear
cells
obtained
from
bloo
dof
healthyd
onorsmicroglialcellsiso
latedfro
mhu
man
fetalbrain
tissueHIV-1ATH
IV-1SF162
Inhibitio
nof
HIV-1varia
ntse
xpression
[119]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
12 Evidence-Based Complementary and Alternative Medicine
Table6Antibacteria
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
PurchasedBe
eHealth
Ltd
(Scarborou
ghYorkshire
UK)
Eu
ropean
prop
olisPopu
lusn
igra
PEE
BsubtilisS
G38E
coliandR
sphaeroides
Influ
encing
theion
perm
eabilityof
theinn
erbacterial
mem
brane
Inhibitio
nof
bacterialm
otility
[130]
PurchasedSigm
aCh
emicalCo(Poo
leDorsetUK)
Characteris
ticof
EuropeanB
razilian
andMediterraneanprop
olis
CaffeicacidC
APE
qu
ercetin
and
narin
genin
Greece
Mediterraneanprop
olisprob
ablyCo
nifer
spp
Terpenes
(isolated
from
Cretan
prop
olis)
Saureus
(ATC
C25923)Sepiderm
idis(ATC
C12228)E
coli
(ATC
C25922)E
cloacae
(ATC
C13047)K
pneumoniae
(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Influ
encing
theG
ram-positive
andGram-negativeb
acteria
viability
[199]
France
European
prop
olisPopu
lusn
igra
Dichlorom
ethane
extract
Gram-negative7Ac
inetobacterb
aumannii(RC
HSAN00812
AYE
CIP7
034107292and
5377)2Escherich
iacoli(ATC
C25922andac
linicaliso
late)3
Pseudomonas
aeruginosa
(ATC
C27853andtwoclinicalisolates)and4clinicalisolates
ofEn
terobacterclo
acaeE
aerogenesK
lebsiella
oxytocaand
Salm
onellaenteritidis(phage
type
4)Gram-negative13
Staphylococcus
aureus
(ATC
C25923six
methicillin-susceptib
leclinicalisolatesandsix
methicillin-resistant
clinicalisolates)2
clinicalisolates
ofS
epidermidis(m
ethiSandmethiR)3
clinicalisolates
ofEn
terococcus
faecalisand1E
faeciu
mand
1clin
icaliso
lateof
Corynebacterium
striatum
Influ
encing
theG
ram-positive
bacteriaviabilityspecially
Saureus
andseveralofitsmethicillin-resistant
and
methicillin-susceptib
le[133]
Bulgaria
Mediterraneanprop
olis
PEE
Saureus
209E
coliWF+
Decreaseo
fSaureusg
rowth
andweakor
lack
ofactiv
ityagainstE
coli
[28]
Greece
Popu
lusspp
Tu
rkey
Conifer
spp
Algeria
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativaPopu
lusspp
Cistu
sspp
Austr
alia
Austr
alianprop
olisfro
msting
lessbee
Tetra
gonu
lacarbonariaCtorelliana
trees
(fruitresins)
PEE
Saureus
(ATC
C25923)
Paeruginosa
(ATC
C27853)
Inhibitio
nof
Saureus
grow
th[42]
Cameroo
nandCon
goAfrican
prop
olisprob
ablyM
schw
einfurthii
PEE
Saureus
(ATC
C25923)Sepiderm
is(ATC
C13047)E
coli
(ATC
C25922)K
lebsiella
pneumonia(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Inhibitio
nof
Saureus
grow
th[53]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Saureus
2979
andSaureus
4118
isolated
from
mastiticcows
Saureus
(ATC
C29213)
Decreaseo
fSaureusg
rowth
incomplex
mediaandkilling
ofSaureus
cells
resuspendedin
milk
promotionof
changesin
morph
olog
yandcellsiz
e[200]
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsu
lfoxide
extract
Saureus
(CAPM
5970)E
faecalis(C
APM
5613
(EBF
3039))
Ecoli(C
AMP3101
T(U
541))and
Lmonocytogenes(C
CM5580)
Differentcon
centratio
nsaffectthe
grow
thofthetestedbacteria
[201]
Italy
Mediterraneanprop
olisCrup
essusspp
PE
E
Staphylococcus
sppstr
ains
(35Saureus63Sepidermidis
7S
hominis
18Shaem
olyticu
s10
Swa
rneri4Scapitisand
3S
auric
ularis)
andStreptococcusspp
strains
(59Sfaecalis
30S
virid
ans15
S120573-haemolyticu
sand19
Spn
eumoniae)
Com
pletes
uppressio
nof
thefactorc
oagu
lasereductio
nof
lipasea
ndpreventio
nof
biofi
lmform
ationof
Staphylococcus
increase
ofthee
ffectof
ampicillingentam
ycinand
streptomycin
andmod
eratingthea
ctionof
chloramph
enicol
ceftriaxoneand
vancom
ycin
[56]
Brazil
Redprop
olisDecasto
phyllum
Green
prop
olisB
dracun
culifolia
PEE
Saureus
(ATC
C25923)
NanoH
Amatrix
with
redandgreenprop
oliswhich
redu
ces
bacterialgrowth
andbiofi
lmform
ation
then
anoH
Awith
red
prop
olisbeingthem
ostefficient
[136]
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
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[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
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[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
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24 Evidence-Based Complementary and Alternative Medicine
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[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
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[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
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Evidence-Based Complementary and Alternative Medicine 25
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[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
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[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
8 Evidence-Based Complementary and Alternative Medicine
mechanisms investigated with propolis and its chemicalconstituents Recently the role of the flavonoids quercetinflavonols and flavones in modulating inflammatory cellfunction was studied [92] Funakoshi-Tago et al [96] inves-tigated the anti-inflammatory effects of flavonoids isolatedfrom Nepalese PEE on the IL-33 signaling pathway Theisolated flavonoids 3101584041015840-dihydroxy-4-methoxydalbergione4-methoxydalbergion cearoin and chrysin inhibited theexpression of inflammatory genes including IL-6 TNF-120572and IL-13 in bone marrow-derived mast cells (BMMC) andalso inhibited the activation of IKK which leads to thedegradation of I120581B120572 and inhibits the activation of nuclearfactor 120581B (NF-120581B)
The release and oxygenation of arachidonic acid are acritical event in inflammation Mirzoeva and Calder [90]demonstrated that propolis components such as CAPE caf-feic acid quercetin andnaringenin among others inhibit theproduction of eicosanoids In fact these components signif-icantly suppressed the lipoxygenase pathway of arachidonicacid metabolism CAPE being the most potent modulatorAnother study indicated that CAPE treatment improveshepatic steatosis induced by high-fat diet in a mouse modelThis effect was attributed to the reduction of c-Jun-N-terminal kinase (JNK12) andNF-120581B activationwith decreasein COX-2 expression [97] Recently it was reported thatCAPE exhibits inhibitory effects on the production of proin-flammatory cytokines (interleukin-1120573 (IL-1120573)) tumor necro-sis factor-120572 (TNF-120572) and monocyte chemoattractant pro-tein 1 (MCP-1) from lipopolysaccharide- (LPS-) stimulatedRAW2647 macrophages [98] Machado et al [99] showedthat Brazilian green propolis water extracts (PWE) modulatean anti-inflammatory cellular response in the model of LPS-induced pulmonary inflammation by decreasing the numberof macrophages and neutrophils Additionally it induced areduction in the secretion of IL-6 and TNF-120572 and an increasein TGF-120573 and IL-10 Another study showed that Brazilianred PEE promotes a significant decrease in renal macrophageinfiltration in rats with chronic kidney disease [100] Bufaloet al [101] demonstrated that Brazilian PEE and caffeicacid inhibited LPS-induced NO production by RAW2647macrophages acting at the transcriptional level and sug-gesting that their anti-inflammatory effects were mediatedby downregulating NF-120581B p38 MAP kinase and JNK12According to Naito et al [95] topical application of BrazilianPEE is effective in inhibiting carrageenan-induced rat hindpaw edemaThis sample appears to inhibit the chemotaxis ofhuman polymorphonuclear leukocytes (PMNs) which alsocontributes to its anti-inflammatory effects Another studyshowed the topical anti-inflammatory activity of propolisfrom Chile in mice ear with induced-edema In fact PEEfrom Buin Chile was the most active against the inflamma-tion induced by 12-O-tetradeca-noylphorbol-13-acetate andarachidonic acid and also inhibits significantly NO releaseby the macrophages [102] More recently Boudreau et al[103] indicated that CAPE is a potent leukotriene biosynthesisinhibitor in PMNs that blocks 5-lipoxygenase (5-LO) activityand arachidonic acid release A Croatian PEE may improvepsoriatic-like skin lesions whichwere induced in the study byirritant agents like n-hexyl salicylate or di-n-propyl disulfide
by reducing the lipid peroxidation in the skin and totalnumber of inflammatory cells in the skin and peritonealcavity more specially by suppressing functional activity ofmacrophages [104]
43 Immunomodulatory Activity Natural substances areconsidered alternative adjuvant therapies in the treatment ofdifferent diseases due to their immunomodulatory effectsInformation about this type of activity was scarce for propolisuntil the 1990s but published work in the last years has pro-vided information about the influence of different propolissamples on the immune system [65 105ndash112] (Table 4)
In a study using Brazilian green propolis it was seenthat the administration for 3 days of a PEE to male BALBcmice modulated the activation of the initial steps of theimmune response by upregulating toll-like receptor- (TLR-)2 and toll-like receptor-4 expression and proinflammatorycytokines (IL-1 and IL-6) production by macrophages andspleen cells [105] Another study demonstrated that BraziliangreenPEEupregulates TLR-4 andCD80 expression in humanmonocytes as well as TNF-120572 and IL-10 production [113] Itwas also shown that caffeic acid stimulates the activity ofmonocytes againstC albicans but it inhibits TLR-2 andHLA-DR expression as well as TNF-120572 and IL-10 production [114]
Additionally Missima et al [115] showed that Braziliangreen PEE administered to stressed mice reduces the proin-flammatory cytokines IL-1120573 and IL-6 When administered tomelanoma-bearing mice submitted or not to chronic stressit induces high levels of IL-1120573 and IL-6 and also stimu-lates Th1 cytokines production indicating the activation ofantitumour cell-mediated immunity Bachiega et al [116]investigated the immunomodulatory effect of propolis andcinnamic and coumaric acids on cytokines IL-1120573 IL-6 andIL-10 production Peritonealmacrophages fromBALBcmicewere incubated with different concentrations of propolis(5 50 and 100mgwell) and coumaric and cinnamic acid(50 and 100mgwell) Propolis and the acids stimulated IL-1120573 production and significantly inhibited IL-6 productionThen after LPS incubation the inhibitory concentrations ofcinnamic and coumaric acids prevented efficiently its effectson IL-6 production whereas propolis inhibited LPS effectsboth before and after its addition Additionally propolis andcoumaric and cinnamic acids inhibited IL-10 production Astudy which evaluated the effect of Brazilian green propolison macrophage activation by H
2O2and NO metabolite
determination [107] showed that propolis increased H2O2
generation and decreased NO generation which favoursthe microbicidal activity Recently the immunomodulatoryeffect of propolis collected in Brazil was evaluated in Leish-mania (Viannia) braziliensis experimental infection Datashows that macrophages incubated with propolis showed asignificant increase in interiorization and further killing ofparasites Also an increased TNF-120572 production was seen inpropolis-pretreated mice whereas IL-12 was downregulatedduring the infection [117]
The immunomodulatory action of propolis does notoccur only at the macrophage level In fact some studiesshow that this action has also an effect on lymphocyte pro-liferation [106 108] Sa-Nunes et al [108] showed inhibitory
Evidence-Based Complementary and Alternative Medicine 9
Table4Im
mun
omod
ulatoryactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
MaleB
ALB
cmice
Upregulationof
toll-lik
ereceptor-2andreceptor-4
expressio
nand
increasesininterle
ukin-1andinterle
ukin-6
prod
uctio
n[105]
Upregulationof
toll-lik
ereceptor-2andreceptor-4
mRN
Aexpressio
n[111]
MaleC
57BL
6miceB16F
10cell
line
Stim
ulationof
thee
xpressionandprod
uctio
nof
interle
ukin-2
and
interle
ukin-10andTh
1cytokine(interle
ukin-2
andIFN-120574)p
rodu
ction
[192]
MaleB
ALB
cmice
Inhibitio
nof
Th1cellsgeneratio
nredu
ctionof
thefrequ
ency
ofIFN-120574-produ
cing
CD4+
Tcells
underTh
1-polarizingcond
ition
s[118]
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecreasesintheN
Ogeneratio
nin
periton
ealm
acroph
ages
[109]
MaleB
ALB
cmice
Increase
intheinterioriz
ationandkilling
ofthep
arasitesL
eishm
ania
(Viann
ia)b
raziliensisby
macroph
agesincreaseinTN
F-120572prod
uctio
nanddecrease
ininterle
ukin-12prod
uctio
n[117]
Mon
ocytes
from
human
bloo
dTL
R-4andCD
80expressio
nin
human
mon
ocytes
aswellasT
NF-120572
andIL-10prod
uctio
n[113]
Mela
nomac
ells(B16F10)m
ale
C57B
L6mice
Redu
ctionof
IL-1120573andIL-6
inLP
S-str
essedmiceindu
ctionof
IL-1120573
andIL-6
andTh
1cytok
ines
inmela
noma-bearingmices
ubmitted
orno
ttochronics
tress
[115]
Brazil
PurchasedAc
rosO
rganics
Green
prop
olisB
dracun
culifolia
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
PEE
cinn
amicandcoum
aricacids
MaleB
ALB
cmice
Stim
ulationof
interle
ukin-1120573prod
uctio
nandinhibitio
nof
interle
ukin-6
andinterle
ukin-10prod
uctio
ns[116]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
and
Mediterraneanprop
olis
Caffeicacid
Mon
ocytes
from
human
bloo
dStim
ulationof
mon
ocytes
activ
ityagainstC
albica
nsdow
nregulation
ofTL
R-2andHLA
-DRexpressio
nandinhibitio
nof
cytokine
prod
uctio
n[114]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
Cinn
amicacid
Mon
ocytes
from
human
bloo
dDow
nregulationof
toll-lik
ereceptor-2HLA
-DRmolecules
from
human
antig
en-presentingcellsand
CD80upregulationof
toll-lik
ereceptor-4inh
ibition
ofTN
F-120572andinterle
ukin-10prod
uctio
n[19
3]
PurchasedSigm
aAldric
hCo
Cinn
amicacid
FemaleIRC
mice
Increase
oflymph
ocytep
roliferationandreleaseo
fcytok
ines
interle
ukin-1andinterle
ukin-2
[106]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Hydroalcoho
lic(H
PE)solution
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecrease
ofNOgeneratio
n[107]
MaleB
ALB
cmice
Decreaseo
fsplenocytep
roliferationandincrease
ofIFN-120574
prod
uctio
nby
spleen
cells
[108]
Indo
nesia
TheP
acificr
egionprop
olisMacaranga
tanariu
sand
Mind
icaHPE
MaleB
ALB
cmice
Increase
ofIgGgeneratio
nandmacroph
agep
hagocytosis
activ
ityand
capacity
[110]
Turkey
Mediterraneanprop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
neasativa
PEE
Perip
heralblood
mon
onuclear
cells
from
healthyhu
mans
Supp
ressionof
neop
terin
releasea
ndtryptoph
andegradation
downregulationof
thee
nzym
eind
oleamine2
3-dioxygenase
(IDO)and
decrease
ofIFN-120574
andTN
F-120572levels
[194]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
CAPE
Hum
anmon
ocyte-deriv
eddend
riticcells
(MoD
Cs)g
enerated
from
perip
heralm
onocytes
Inhibitio
nof
IL-12p4
0IL-12p70IL-10IFN-120574-in
duciblep
rotein-(IP-)
10levels
inhibitio
nof
I120581B120572
phosph
orylationandNF-120581Bactiv
ation
[112]
FemaleB
ALB
cmice
Increase
ofIgM
antib
odyprod
uctio
nTlymph
ocytep
roliferation
interle
ukin-4
andinterle
ukin-2
prod
uctio
nby
spleno
cytesandIFN-120574
prod
uctio
n[195]
Hum
anperip
heralblood
mon
onuclear
cellsjurkatcells
Inhibitio
nof
transcrip
tionfactorsN
F-120581BandNFA
Tinhibitio
nof
interle
ukin-2
gene
transcrip
tion
interle
ukin-2
receptor
expressio
nand
proliferatio
nof
human
Tcells
[94]
10 Evidence-Based Complementary and Alternative Medicine
effects of Brazilian green propolis on splenocyte proliferationeffect that was attributed to flavonoids and enhancementeffects on interferon- (IFN-) 120574 production by spleen cellsCAPE displays inhibitory effects on transcription factors NF-120581B and NFAT and as a consequence inhibits IL-2 genetranscription IL-2 receptor expression and proliferation ofhuman T cells [94] This provides new information into themolecular mechanisms involved in the anti-inflammatoryand immunomodulatory activities of propolis CAPE hasvarious biological activities but its effect on the immunomod-ulatory activity remains little studied According to Wanget al [112] CAPE can be useful in the treatment of asthmaand other allergic diseases because it can inhibit cytokinesand chemokines production by human monocyte-deriveddendritic cells (MoDCs) which might be related to theNF-120581B signalling pathway Another study demonstrated forthe first time that Brazilian propolis significantly inhibitedthe generation of Th1 cells Furthermore the effects ofpropolis were investigated on 246-trinitrobenzene sulfonicacid- (TNBS-) induced colitis in a mouse model Propolisreduced the frequency of IFN-120574-producing CD4 T cellsin a dose-dependent way under Th1-polarizing conditionsThe inhibitory effect of propolis on Th1 differentiation wasdemonstrated in vivo too and the severity of colitis inpropolis-fed mice was significantly lower than that of micefed with the control diet [118]
44 Antiviral Activity Propolis comprises a complexity ofcompounds which play a role in antiviral protection Despitethe few data available regarding this activity it was shown thatpropolis from different geographic regions has considerableantiviral activity by acting at different levels and interferingwith the replication of some viruses [12] like herpes simplextypes 1 and 2 adenovirus type 2 influenza virus or humanimmunodeficiency virus (HIV) among others [7 60 119ndash124] Table 5 summarizes the antiviral activity of propolis andits chemical constituents
Schnitzler et al [123] analysed the antiviral effect ofPWE and PEE from Czech Republic as well as that ofthe constituents caffeic acid p-coumaric acid benzoic acidgalangin pinocembrin and chrysin against herpes simplexvirus type 1 (HSV-1) in cell culture Both extracts exhibitedhigh anti-HSV-1 activity when cells were treated prior toviral infection galangin and chrysin being the main bioac-tive compounds Amoros et al [60] showed the antiviralactivity of the major flavonoids of propolis more specificallyflavonols and flavones the first being more active againstHSV-1 Additionally they analysed the effect of propolis onseveral DNA and RNA viruses (HSV-1 HSV-2 adenovirustype 2 vesicular stomatitis virus (VSV) and poliovirus type2) Propolis at a concentration of 30120583gmL reduced thetiter of herpes virus however vesicular stomatitis virusand adenovirus were less susceptible In addition propo-lis appears to exert a virucidal action on the envelopedviruses HSV and VSV [120] Recently it was shown thathydromethanolic extract of geopropolis from the stinglessbee Scaptotrigona postica (Brazil) inhibits theHSV replicationand also the entry of the virus into cells effect that wasattributed to the C-glycosyl flavones catechin-3-O-gallate
and 34-dicaffeoylquinic acid [125] According to Tait etal [126] natural and synthetic flavonoids might interferewith picornavirus replication preventing the decapsidationof viral particles and RNA release within cells or blockingviral RNA synthesis These authors also showed that differ-ent homoisoflavonoids have good antiviral activity againstthe coxsackie viruses B3 B4 and A9 and echovirus 30Shvarzbeyn and Huleihel [127] tried to determine whichstep of Tax oncoprotein-induced NF-120581B activation is blockedby propolis and CAPE and showed that both substantiallyinhibited the activation of NF-120581B-dependent promoter byTax Also they strongly prevented both Tax binding to I120581B120572and its induced degradation by Tax Ma et al [128] showedthat nanometer propolis flavones could significantly inhibitin vitro porcine parvovirus (PPV) infecting PK-15 cells andin vivo they restrain the PPV copy in lung gonad and blooddecrease the impact of PPV on weight of guinea pigs andincrease hemagglutination inhibition of PPV in serum as wellas improving the contents of IL-2 IL-6 and 120574-IFN
Over recent years therapeutic benefits of propolis andorits isolated compounds have been described in HIV treat-ment Ito et al [129] tested the anti-HIV activity in H9lymphocytes of triterpenoids melliferone moronic acidanwuweizonic acid and betulonic acid and four knownaromatic compounds isolated from Brazilian propolis andshowed that moronic acid had significant anti-HIV activityGekker et al [119] assessed the anti-HIV-1 activity of propolisin CD4+ lymphocytes and microglial cell cultures observ-ing the inhibition of viral expression in a concentration-dependent wayThe possible mechanism of propolis antiviralproperty was suggested to involve inhibition of viral entry
45 Antimicrobial Activity Antimicrobial activity one ofthe most studied propolis biological properties is very welldocumented This bioactivity has been largely investigatedin the last years due to the need of new treatments againstinfectious diseases especially with the increase of resistantpathogens to current antibiotics Tables 6 and 7 summarisethe antibacterial and antifungal activities found in propolisfrom different geographic origin andor its chemical con-stituents
451 Antibacterial Activity Propolis effect against severalbacterial strains has evaluated [7 56ndash59 130] and supportedthe fact that propolis is more active against Gram-positivebacteria than Gram-negative bacteria [12 59] Briefly datafrom different studies showed that propolis inhibits bac-terial motility and enzyme activity exhibits bacteriostaticactivity against different bacterial genera can be bactericidalin high concentrations and affects cytoplasmic membrane[130]
Mirzoeva et al [130] investigated the effect of PEEon the physiology of Bacillus subtilis Escherichia coli andRhodobacter sphaeroides proposing that propolis and someof its components like cinnamic acid and flavonoids affectthe ion permeability of the inner bacterial membrane causingthe dissipation of the membrane potential and inhibitingbacterial motility A recent study [131] provided valuableinformation for understanding the potential anti-H pylori
Evidence-Based Complementary and Alternative Medicine 11
Table5Antivira
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescellsviru
ses
Effect
References
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
Caffeicacidp-cou
maricacid
benzoica
cidgalang
in
pino
cembrinand
chrysin
RC-37cellsherpessim
plex
virustype1
(HSV
-1)
strainKO
SHighanti-HSV
-1activ
ityforb
othextractswhencells
weretreated
prior
toviralinfectio
n[123]
CzechRe
public
European
prop
olisPopu
lusn
igra
PEEandPW
ERC
-37cellsherpessim
plex
virustype2
(HSV
-2)
Highantih
erpetic
activ
ityforb
othextractswhenvirusesw
ere
pretreated
priortoinfection
[196]
Brazil
Brow
nprop
olisB
dracun
culifolia
HPE
HSV
-2str
ainprop
agated
inVe
rocellsfem
aleB
ALB
cmice
Effectiv
eagainstHSV
-2infectionandin
redu
cing
extravaginallesio
nsby
actin
gon
inflammatoryandoxidativep
rocessesreducingreactiv
especiestyrosin
enitration
ascorbicacid
levels
andmyeloperoxidase
activ
ityandprotectin
gagainstinh
ibition
ofcatalase
activ
ity
[124]
Characteris
ticof
Brazilian
prop
olis
Isop
entylferulate(
isolatedfro
man
PEE)
Influ
enza
virusesA
PR834
(H1N
1)
AKrasnod
ar10
159(H
2N2)and
AH
ongKo
ng168
(H3N
2)Supp
ressionof
influ
enza
virusA
Hon
gKo
ngreprod
uctio
nin
vitro
[121]
Green
prop
olisB
dracun
culifolia
Beriocla
daM
yrceugeniaeuosma
PEE
Influ
enza
APR834
(H1N
1)virusp
ropagated
Madin-D
arby
canine
kidn
ey(M
DCK
)cells
female
DBA
2Cr
mice
Redu
ctionof
body
weightlosso
finfectedmicea
ndvirusy
ieldsinthe
bron
choalveolarlavagefl
uids
oflung
s[122]
France
European
prop
olisPopu
lusn
igra
PEE
RC-37cellsH
SV-1str
ainH29Sacyclovirresistant
mutantH
SV1-R
strainH29R
HSV
-2adeno
virustype
2po
liovirustype2
and
vesic
ular
stomatitisv
irus
(VSV
)
Redu
ctionof
titre
ofherpes
virusbeingvesic
ular
stomatitisv
irusa
ndadenoviru
slesssusceptibleviru
cidalactionon
thee
nvelo
pedviruses
HSV
andVS
V[120]
Brazil
Geoprop
olisfro
mthes
tinglessb
eeScaptotrigona
postica
Hydromethano
licextract
African
greenmon
keykidn
eycells
(ATC
CCC
L-81)
herpes
simplex
virusstrain(M
cIntyre)
Inhibitio
nof
HSV
replicationandentryinto
cells
[125]
Synthesiz
edCh
aracteris
ticof
Brazilian
redand
greenprop
olis
Hom
oisoflavono
idsspecially
3-benzyl-4-chrom
ones
BGM
(Buff
aloGreen
Mon
key)
cellscoxsackieviruses
B3B
4andA9andecho
virus3
0Goo
dantiv
iralactivity
againstthe
coxsackiev
irusesB
3B4
and
A9and
echo
virus3
0[126]
Canada
European
prop
olisPtrichocarpa
andPtre
muloides
PEE
HSV
-1andHSV
-2virusreplicated
inMDBK
(mon
olayer
cultu
reso
fMadin-D
arby
bovine
kidn
ey)
cells
Impairing
thea
bilityof
thev
irustoadsorb
orto
penetratethe
hostcells
[197]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Water
extracts
FemaleB
ALB
cmiceInflu
enza
Avirusstrain
AW
SN33(H
1N1)
Extensionof
thelifetim
eofm
ice34-dicaffeoylquinica
cidwhich
increasesm
RNAlevelsof
tumor
necrosisfactor-related
apop
tosis
-indu
cing
anddecreasesH
1N1h
emagglutinin
mRN
A[19
8]Ch
aracteris
ticof
Brazilian
green
prop
olis
34-dicaffeoylquinica
cid
(Isolated
from
Brazilian
prop
olis)
Brazil
Characteris
ticof
Brazilian
green
prop
olis
Melliferon
emoron
icacid
anwuw
eizonica
cidand
betulonica
cid(isolated
from
Brazilian
prop
olis)
H9lymph
ocytesH
IV-1
Moron
icacid
inhibitin
ganti-HIV
replication
[129]
Israel
Mediterraneanprop
olisPopu
lus
sppE
ucalyptusspp
andCa
stanea
sativa
PWE
Jurkatuninfectedhu
man
T-celllin
esand
MT2
(HTL
V-1infectedhu
man
Tcells)cells
Inhibitio
nof
thea
ctivationof
NF-120581B-depend
entp
romoter
byTaxand
preventio
nof
Taxbind
ingto
I120581B120572
andits
degradation
[127]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Provided
byBinzho
uAnimal
Sciencea
ndVe
terin
ary
MedicineA
cademyof
Shando
ngProvince
Nanom
eter
prop
olisFlavon
eKidn
eycells
(PK-
15)
Porcinep
arvovirus(PP
V)
Britain
Whiteguinea
pigs
Inhibitio
nof
PPVinfectingpo
rcinek
idney-
(PK-
)15cells
Restr
aining
ofPP
Vcopy
inlung
gon
adand
bloo
ddecrease
ofthe
impactof
PPVon
weighto
fguineap
igsandincrease
ofhemagglutinationinhibitio
nof
PPVin
serum
aswellasimprovingthe
contentsof
IL-2IL-6and120574-IFN
[128]
USA
andCh
ina
European
prop
olisPopu
lusn
igra
PEE
Perip
heralblood
mon
onuclear
cells
obtained
from
bloo
dof
healthyd
onorsmicroglialcellsiso
latedfro
mhu
man
fetalbrain
tissueHIV-1ATH
IV-1SF162
Inhibitio
nof
HIV-1varia
ntse
xpression
[119]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
12 Evidence-Based Complementary and Alternative Medicine
Table6Antibacteria
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
PurchasedBe
eHealth
Ltd
(Scarborou
ghYorkshire
UK)
Eu
ropean
prop
olisPopu
lusn
igra
PEE
BsubtilisS
G38E
coliandR
sphaeroides
Influ
encing
theion
perm
eabilityof
theinn
erbacterial
mem
brane
Inhibitio
nof
bacterialm
otility
[130]
PurchasedSigm
aCh
emicalCo(Poo
leDorsetUK)
Characteris
ticof
EuropeanB
razilian
andMediterraneanprop
olis
CaffeicacidC
APE
qu
ercetin
and
narin
genin
Greece
Mediterraneanprop
olisprob
ablyCo
nifer
spp
Terpenes
(isolated
from
Cretan
prop
olis)
Saureus
(ATC
C25923)Sepiderm
idis(ATC
C12228)E
coli
(ATC
C25922)E
cloacae
(ATC
C13047)K
pneumoniae
(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Influ
encing
theG
ram-positive
andGram-negativeb
acteria
viability
[199]
France
European
prop
olisPopu
lusn
igra
Dichlorom
ethane
extract
Gram-negative7Ac
inetobacterb
aumannii(RC
HSAN00812
AYE
CIP7
034107292and
5377)2Escherich
iacoli(ATC
C25922andac
linicaliso
late)3
Pseudomonas
aeruginosa
(ATC
C27853andtwoclinicalisolates)and4clinicalisolates
ofEn
terobacterclo
acaeE
aerogenesK
lebsiella
oxytocaand
Salm
onellaenteritidis(phage
type
4)Gram-negative13
Staphylococcus
aureus
(ATC
C25923six
methicillin-susceptib
leclinicalisolatesandsix
methicillin-resistant
clinicalisolates)2
clinicalisolates
ofS
epidermidis(m
ethiSandmethiR)3
clinicalisolates
ofEn
terococcus
faecalisand1E
faeciu
mand
1clin
icaliso
lateof
Corynebacterium
striatum
Influ
encing
theG
ram-positive
bacteriaviabilityspecially
Saureus
andseveralofitsmethicillin-resistant
and
methicillin-susceptib
le[133]
Bulgaria
Mediterraneanprop
olis
PEE
Saureus
209E
coliWF+
Decreaseo
fSaureusg
rowth
andweakor
lack
ofactiv
ityagainstE
coli
[28]
Greece
Popu
lusspp
Tu
rkey
Conifer
spp
Algeria
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativaPopu
lusspp
Cistu
sspp
Austr
alia
Austr
alianprop
olisfro
msting
lessbee
Tetra
gonu
lacarbonariaCtorelliana
trees
(fruitresins)
PEE
Saureus
(ATC
C25923)
Paeruginosa
(ATC
C27853)
Inhibitio
nof
Saureus
grow
th[42]
Cameroo
nandCon
goAfrican
prop
olisprob
ablyM
schw
einfurthii
PEE
Saureus
(ATC
C25923)Sepiderm
is(ATC
C13047)E
coli
(ATC
C25922)K
lebsiella
pneumonia(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Inhibitio
nof
Saureus
grow
th[53]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Saureus
2979
andSaureus
4118
isolated
from
mastiticcows
Saureus
(ATC
C29213)
Decreaseo
fSaureusg
rowth
incomplex
mediaandkilling
ofSaureus
cells
resuspendedin
milk
promotionof
changesin
morph
olog
yandcellsiz
e[200]
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsu
lfoxide
extract
Saureus
(CAPM
5970)E
faecalis(C
APM
5613
(EBF
3039))
Ecoli(C
AMP3101
T(U
541))and
Lmonocytogenes(C
CM5580)
Differentcon
centratio
nsaffectthe
grow
thofthetestedbacteria
[201]
Italy
Mediterraneanprop
olisCrup
essusspp
PE
E
Staphylococcus
sppstr
ains
(35Saureus63Sepidermidis
7S
hominis
18Shaem
olyticu
s10
Swa
rneri4Scapitisand
3S
auric
ularis)
andStreptococcusspp
strains
(59Sfaecalis
30S
virid
ans15
S120573-haemolyticu
sand19
Spn
eumoniae)
Com
pletes
uppressio
nof
thefactorc
oagu
lasereductio
nof
lipasea
ndpreventio
nof
biofi
lmform
ationof
Staphylococcus
increase
ofthee
ffectof
ampicillingentam
ycinand
streptomycin
andmod
eratingthea
ctionof
chloramph
enicol
ceftriaxoneand
vancom
ycin
[56]
Brazil
Redprop
olisDecasto
phyllum
Green
prop
olisB
dracun
culifolia
PEE
Saureus
(ATC
C25923)
NanoH
Amatrix
with
redandgreenprop
oliswhich
redu
ces
bacterialgrowth
andbiofi
lmform
ation
then
anoH
Awith
red
prop
olisbeingthem
ostefficient
[136]
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 9
Table4Im
mun
omod
ulatoryactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
MaleB
ALB
cmice
Upregulationof
toll-lik
ereceptor-2andreceptor-4
expressio
nand
increasesininterle
ukin-1andinterle
ukin-6
prod
uctio
n[105]
Upregulationof
toll-lik
ereceptor-2andreceptor-4
mRN
Aexpressio
n[111]
MaleC
57BL
6miceB16F
10cell
line
Stim
ulationof
thee
xpressionandprod
uctio
nof
interle
ukin-2
and
interle
ukin-10andTh
1cytokine(interle
ukin-2
andIFN-120574)p
rodu
ction
[192]
MaleB
ALB
cmice
Inhibitio
nof
Th1cellsgeneratio
nredu
ctionof
thefrequ
ency
ofIFN-120574-produ
cing
CD4+
Tcells
underTh
1-polarizingcond
ition
s[118]
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecreasesintheN
Ogeneratio
nin
periton
ealm
acroph
ages
[109]
MaleB
ALB
cmice
Increase
intheinterioriz
ationandkilling
ofthep
arasitesL
eishm
ania
(Viann
ia)b
raziliensisby
macroph
agesincreaseinTN
F-120572prod
uctio
nanddecrease
ininterle
ukin-12prod
uctio
n[117]
Mon
ocytes
from
human
bloo
dTL
R-4andCD
80expressio
nin
human
mon
ocytes
aswellasT
NF-120572
andIL-10prod
uctio
n[113]
Mela
nomac
ells(B16F10)m
ale
C57B
L6mice
Redu
ctionof
IL-1120573andIL-6
inLP
S-str
essedmiceindu
ctionof
IL-1120573
andIL-6
andTh
1cytok
ines
inmela
noma-bearingmices
ubmitted
orno
ttochronics
tress
[115]
Brazil
PurchasedAc
rosO
rganics
Green
prop
olisB
dracun
culifolia
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
PEE
cinn
amicandcoum
aricacids
MaleB
ALB
cmice
Stim
ulationof
interle
ukin-1120573prod
uctio
nandinhibitio
nof
interle
ukin-6
andinterle
ukin-10prod
uctio
ns[116]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
and
Mediterraneanprop
olis
Caffeicacid
Mon
ocytes
from
human
bloo
dStim
ulationof
mon
ocytes
activ
ityagainstC
albica
nsdow
nregulation
ofTL
R-2andHLA
-DRexpressio
nandinhibitio
nof
cytokine
prod
uctio
n[114]
PurchasedAc
rosO
rganics
Characteris
ticof
EuropeanB
razilian
Russian
Mediterranean
andAu
stralian
type
prop
olis
Cinn
amicacid
Mon
ocytes
from
human
bloo
dDow
nregulationof
toll-lik
ereceptor-2HLA
-DRmolecules
from
human
antig
en-presentingcellsand
CD80upregulationof
toll-lik
ereceptor-4inh
ibition
ofTN
F-120572andinterle
ukin-10prod
uctio
n[19
3]
PurchasedSigm
aAldric
hCo
Cinn
amicacid
FemaleIRC
mice
Increase
oflymph
ocytep
roliferationandreleaseo
fcytok
ines
interle
ukin-1andinterle
ukin-2
[106]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Hydroalcoho
lic(H
PE)solution
MaleB
ALB
cmice
Increase
ofH
2O2generatio
nanddecrease
ofNOgeneratio
n[107]
MaleB
ALB
cmice
Decreaseo
fsplenocytep
roliferationandincrease
ofIFN-120574
prod
uctio
nby
spleen
cells
[108]
Indo
nesia
TheP
acificr
egionprop
olisMacaranga
tanariu
sand
Mind
icaHPE
MaleB
ALB
cmice
Increase
ofIgGgeneratio
nandmacroph
agep
hagocytosis
activ
ityand
capacity
[110]
Turkey
Mediterraneanprop
olisPopu
lusspp
Eu
calyptus
sppand
Casta
neasativa
PEE
Perip
heralblood
mon
onuclear
cells
from
healthyhu
mans
Supp
ressionof
neop
terin
releasea
ndtryptoph
andegradation
downregulationof
thee
nzym
eind
oleamine2
3-dioxygenase
(IDO)and
decrease
ofIFN-120574
andTN
F-120572levels
[194]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
CAPE
Hum
anmon
ocyte-deriv
eddend
riticcells
(MoD
Cs)g
enerated
from
perip
heralm
onocytes
Inhibitio
nof
IL-12p4
0IL-12p70IL-10IFN-120574-in
duciblep
rotein-(IP-)
10levels
inhibitio
nof
I120581B120572
phosph
orylationandNF-120581Bactiv
ation
[112]
FemaleB
ALB
cmice
Increase
ofIgM
antib
odyprod
uctio
nTlymph
ocytep
roliferation
interle
ukin-4
andinterle
ukin-2
prod
uctio
nby
spleno
cytesandIFN-120574
prod
uctio
n[195]
Hum
anperip
heralblood
mon
onuclear
cellsjurkatcells
Inhibitio
nof
transcrip
tionfactorsN
F-120581BandNFA
Tinhibitio
nof
interle
ukin-2
gene
transcrip
tion
interle
ukin-2
receptor
expressio
nand
proliferatio
nof
human
Tcells
[94]
10 Evidence-Based Complementary and Alternative Medicine
effects of Brazilian green propolis on splenocyte proliferationeffect that was attributed to flavonoids and enhancementeffects on interferon- (IFN-) 120574 production by spleen cellsCAPE displays inhibitory effects on transcription factors NF-120581B and NFAT and as a consequence inhibits IL-2 genetranscription IL-2 receptor expression and proliferation ofhuman T cells [94] This provides new information into themolecular mechanisms involved in the anti-inflammatoryand immunomodulatory activities of propolis CAPE hasvarious biological activities but its effect on the immunomod-ulatory activity remains little studied According to Wanget al [112] CAPE can be useful in the treatment of asthmaand other allergic diseases because it can inhibit cytokinesand chemokines production by human monocyte-deriveddendritic cells (MoDCs) which might be related to theNF-120581B signalling pathway Another study demonstrated forthe first time that Brazilian propolis significantly inhibitedthe generation of Th1 cells Furthermore the effects ofpropolis were investigated on 246-trinitrobenzene sulfonicacid- (TNBS-) induced colitis in a mouse model Propolisreduced the frequency of IFN-120574-producing CD4 T cellsin a dose-dependent way under Th1-polarizing conditionsThe inhibitory effect of propolis on Th1 differentiation wasdemonstrated in vivo too and the severity of colitis inpropolis-fed mice was significantly lower than that of micefed with the control diet [118]
44 Antiviral Activity Propolis comprises a complexity ofcompounds which play a role in antiviral protection Despitethe few data available regarding this activity it was shown thatpropolis from different geographic regions has considerableantiviral activity by acting at different levels and interferingwith the replication of some viruses [12] like herpes simplextypes 1 and 2 adenovirus type 2 influenza virus or humanimmunodeficiency virus (HIV) among others [7 60 119ndash124] Table 5 summarizes the antiviral activity of propolis andits chemical constituents
Schnitzler et al [123] analysed the antiviral effect ofPWE and PEE from Czech Republic as well as that ofthe constituents caffeic acid p-coumaric acid benzoic acidgalangin pinocembrin and chrysin against herpes simplexvirus type 1 (HSV-1) in cell culture Both extracts exhibitedhigh anti-HSV-1 activity when cells were treated prior toviral infection galangin and chrysin being the main bioac-tive compounds Amoros et al [60] showed the antiviralactivity of the major flavonoids of propolis more specificallyflavonols and flavones the first being more active againstHSV-1 Additionally they analysed the effect of propolis onseveral DNA and RNA viruses (HSV-1 HSV-2 adenovirustype 2 vesicular stomatitis virus (VSV) and poliovirus type2) Propolis at a concentration of 30120583gmL reduced thetiter of herpes virus however vesicular stomatitis virusand adenovirus were less susceptible In addition propo-lis appears to exert a virucidal action on the envelopedviruses HSV and VSV [120] Recently it was shown thathydromethanolic extract of geopropolis from the stinglessbee Scaptotrigona postica (Brazil) inhibits theHSV replicationand also the entry of the virus into cells effect that wasattributed to the C-glycosyl flavones catechin-3-O-gallate
and 34-dicaffeoylquinic acid [125] According to Tait etal [126] natural and synthetic flavonoids might interferewith picornavirus replication preventing the decapsidationof viral particles and RNA release within cells or blockingviral RNA synthesis These authors also showed that differ-ent homoisoflavonoids have good antiviral activity againstthe coxsackie viruses B3 B4 and A9 and echovirus 30Shvarzbeyn and Huleihel [127] tried to determine whichstep of Tax oncoprotein-induced NF-120581B activation is blockedby propolis and CAPE and showed that both substantiallyinhibited the activation of NF-120581B-dependent promoter byTax Also they strongly prevented both Tax binding to I120581B120572and its induced degradation by Tax Ma et al [128] showedthat nanometer propolis flavones could significantly inhibitin vitro porcine parvovirus (PPV) infecting PK-15 cells andin vivo they restrain the PPV copy in lung gonad and blooddecrease the impact of PPV on weight of guinea pigs andincrease hemagglutination inhibition of PPV in serum as wellas improving the contents of IL-2 IL-6 and 120574-IFN
Over recent years therapeutic benefits of propolis andorits isolated compounds have been described in HIV treat-ment Ito et al [129] tested the anti-HIV activity in H9lymphocytes of triterpenoids melliferone moronic acidanwuweizonic acid and betulonic acid and four knownaromatic compounds isolated from Brazilian propolis andshowed that moronic acid had significant anti-HIV activityGekker et al [119] assessed the anti-HIV-1 activity of propolisin CD4+ lymphocytes and microglial cell cultures observ-ing the inhibition of viral expression in a concentration-dependent wayThe possible mechanism of propolis antiviralproperty was suggested to involve inhibition of viral entry
45 Antimicrobial Activity Antimicrobial activity one ofthe most studied propolis biological properties is very welldocumented This bioactivity has been largely investigatedin the last years due to the need of new treatments againstinfectious diseases especially with the increase of resistantpathogens to current antibiotics Tables 6 and 7 summarisethe antibacterial and antifungal activities found in propolisfrom different geographic origin andor its chemical con-stituents
451 Antibacterial Activity Propolis effect against severalbacterial strains has evaluated [7 56ndash59 130] and supportedthe fact that propolis is more active against Gram-positivebacteria than Gram-negative bacteria [12 59] Briefly datafrom different studies showed that propolis inhibits bac-terial motility and enzyme activity exhibits bacteriostaticactivity against different bacterial genera can be bactericidalin high concentrations and affects cytoplasmic membrane[130]
Mirzoeva et al [130] investigated the effect of PEEon the physiology of Bacillus subtilis Escherichia coli andRhodobacter sphaeroides proposing that propolis and someof its components like cinnamic acid and flavonoids affectthe ion permeability of the inner bacterial membrane causingthe dissipation of the membrane potential and inhibitingbacterial motility A recent study [131] provided valuableinformation for understanding the potential anti-H pylori
Evidence-Based Complementary and Alternative Medicine 11
Table5Antivira
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescellsviru
ses
Effect
References
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
Caffeicacidp-cou
maricacid
benzoica
cidgalang
in
pino
cembrinand
chrysin
RC-37cellsherpessim
plex
virustype1
(HSV
-1)
strainKO
SHighanti-HSV
-1activ
ityforb
othextractswhencells
weretreated
prior
toviralinfectio
n[123]
CzechRe
public
European
prop
olisPopu
lusn
igra
PEEandPW
ERC
-37cellsherpessim
plex
virustype2
(HSV
-2)
Highantih
erpetic
activ
ityforb
othextractswhenvirusesw
ere
pretreated
priortoinfection
[196]
Brazil
Brow
nprop
olisB
dracun
culifolia
HPE
HSV
-2str
ainprop
agated
inVe
rocellsfem
aleB
ALB
cmice
Effectiv
eagainstHSV
-2infectionandin
redu
cing
extravaginallesio
nsby
actin
gon
inflammatoryandoxidativep
rocessesreducingreactiv
especiestyrosin
enitration
ascorbicacid
levels
andmyeloperoxidase
activ
ityandprotectin
gagainstinh
ibition
ofcatalase
activ
ity
[124]
Characteris
ticof
Brazilian
prop
olis
Isop
entylferulate(
isolatedfro
man
PEE)
Influ
enza
virusesA
PR834
(H1N
1)
AKrasnod
ar10
159(H
2N2)and
AH
ongKo
ng168
(H3N
2)Supp
ressionof
influ
enza
virusA
Hon
gKo
ngreprod
uctio
nin
vitro
[121]
Green
prop
olisB
dracun
culifolia
Beriocla
daM
yrceugeniaeuosma
PEE
Influ
enza
APR834
(H1N
1)virusp
ropagated
Madin-D
arby
canine
kidn
ey(M
DCK
)cells
female
DBA
2Cr
mice
Redu
ctionof
body
weightlosso
finfectedmicea
ndvirusy
ieldsinthe
bron
choalveolarlavagefl
uids
oflung
s[122]
France
European
prop
olisPopu
lusn
igra
PEE
RC-37cellsH
SV-1str
ainH29Sacyclovirresistant
mutantH
SV1-R
strainH29R
HSV
-2adeno
virustype
2po
liovirustype2
and
vesic
ular
stomatitisv
irus
(VSV
)
Redu
ctionof
titre
ofherpes
virusbeingvesic
ular
stomatitisv
irusa
ndadenoviru
slesssusceptibleviru
cidalactionon
thee
nvelo
pedviruses
HSV
andVS
V[120]
Brazil
Geoprop
olisfro
mthes
tinglessb
eeScaptotrigona
postica
Hydromethano
licextract
African
greenmon
keykidn
eycells
(ATC
CCC
L-81)
herpes
simplex
virusstrain(M
cIntyre)
Inhibitio
nof
HSV
replicationandentryinto
cells
[125]
Synthesiz
edCh
aracteris
ticof
Brazilian
redand
greenprop
olis
Hom
oisoflavono
idsspecially
3-benzyl-4-chrom
ones
BGM
(Buff
aloGreen
Mon
key)
cellscoxsackieviruses
B3B
4andA9andecho
virus3
0Goo
dantiv
iralactivity
againstthe
coxsackiev
irusesB
3B4
and
A9and
echo
virus3
0[126]
Canada
European
prop
olisPtrichocarpa
andPtre
muloides
PEE
HSV
-1andHSV
-2virusreplicated
inMDBK
(mon
olayer
cultu
reso
fMadin-D
arby
bovine
kidn
ey)
cells
Impairing
thea
bilityof
thev
irustoadsorb
orto
penetratethe
hostcells
[197]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Water
extracts
FemaleB
ALB
cmiceInflu
enza
Avirusstrain
AW
SN33(H
1N1)
Extensionof
thelifetim
eofm
ice34-dicaffeoylquinica
cidwhich
increasesm
RNAlevelsof
tumor
necrosisfactor-related
apop
tosis
-indu
cing
anddecreasesH
1N1h
emagglutinin
mRN
A[19
8]Ch
aracteris
ticof
Brazilian
green
prop
olis
34-dicaffeoylquinica
cid
(Isolated
from
Brazilian
prop
olis)
Brazil
Characteris
ticof
Brazilian
green
prop
olis
Melliferon
emoron
icacid
anwuw
eizonica
cidand
betulonica
cid(isolated
from
Brazilian
prop
olis)
H9lymph
ocytesH
IV-1
Moron
icacid
inhibitin
ganti-HIV
replication
[129]
Israel
Mediterraneanprop
olisPopu
lus
sppE
ucalyptusspp
andCa
stanea
sativa
PWE
Jurkatuninfectedhu
man
T-celllin
esand
MT2
(HTL
V-1infectedhu
man
Tcells)cells
Inhibitio
nof
thea
ctivationof
NF-120581B-depend
entp
romoter
byTaxand
preventio
nof
Taxbind
ingto
I120581B120572
andits
degradation
[127]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Provided
byBinzho
uAnimal
Sciencea
ndVe
terin
ary
MedicineA
cademyof
Shando
ngProvince
Nanom
eter
prop
olisFlavon
eKidn
eycells
(PK-
15)
Porcinep
arvovirus(PP
V)
Britain
Whiteguinea
pigs
Inhibitio
nof
PPVinfectingpo
rcinek
idney-
(PK-
)15cells
Restr
aining
ofPP
Vcopy
inlung
gon
adand
bloo
ddecrease
ofthe
impactof
PPVon
weighto
fguineap
igsandincrease
ofhemagglutinationinhibitio
nof
PPVin
serum
aswellasimprovingthe
contentsof
IL-2IL-6and120574-IFN
[128]
USA
andCh
ina
European
prop
olisPopu
lusn
igra
PEE
Perip
heralblood
mon
onuclear
cells
obtained
from
bloo
dof
healthyd
onorsmicroglialcellsiso
latedfro
mhu
man
fetalbrain
tissueHIV-1ATH
IV-1SF162
Inhibitio
nof
HIV-1varia
ntse
xpression
[119]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
12 Evidence-Based Complementary and Alternative Medicine
Table6Antibacteria
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
PurchasedBe
eHealth
Ltd
(Scarborou
ghYorkshire
UK)
Eu
ropean
prop
olisPopu
lusn
igra
PEE
BsubtilisS
G38E
coliandR
sphaeroides
Influ
encing
theion
perm
eabilityof
theinn
erbacterial
mem
brane
Inhibitio
nof
bacterialm
otility
[130]
PurchasedSigm
aCh
emicalCo(Poo
leDorsetUK)
Characteris
ticof
EuropeanB
razilian
andMediterraneanprop
olis
CaffeicacidC
APE
qu
ercetin
and
narin
genin
Greece
Mediterraneanprop
olisprob
ablyCo
nifer
spp
Terpenes
(isolated
from
Cretan
prop
olis)
Saureus
(ATC
C25923)Sepiderm
idis(ATC
C12228)E
coli
(ATC
C25922)E
cloacae
(ATC
C13047)K
pneumoniae
(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Influ
encing
theG
ram-positive
andGram-negativeb
acteria
viability
[199]
France
European
prop
olisPopu
lusn
igra
Dichlorom
ethane
extract
Gram-negative7Ac
inetobacterb
aumannii(RC
HSAN00812
AYE
CIP7
034107292and
5377)2Escherich
iacoli(ATC
C25922andac
linicaliso
late)3
Pseudomonas
aeruginosa
(ATC
C27853andtwoclinicalisolates)and4clinicalisolates
ofEn
terobacterclo
acaeE
aerogenesK
lebsiella
oxytocaand
Salm
onellaenteritidis(phage
type
4)Gram-negative13
Staphylococcus
aureus
(ATC
C25923six
methicillin-susceptib
leclinicalisolatesandsix
methicillin-resistant
clinicalisolates)2
clinicalisolates
ofS
epidermidis(m
ethiSandmethiR)3
clinicalisolates
ofEn
terococcus
faecalisand1E
faeciu
mand
1clin
icaliso
lateof
Corynebacterium
striatum
Influ
encing
theG
ram-positive
bacteriaviabilityspecially
Saureus
andseveralofitsmethicillin-resistant
and
methicillin-susceptib
le[133]
Bulgaria
Mediterraneanprop
olis
PEE
Saureus
209E
coliWF+
Decreaseo
fSaureusg
rowth
andweakor
lack
ofactiv
ityagainstE
coli
[28]
Greece
Popu
lusspp
Tu
rkey
Conifer
spp
Algeria
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativaPopu
lusspp
Cistu
sspp
Austr
alia
Austr
alianprop
olisfro
msting
lessbee
Tetra
gonu
lacarbonariaCtorelliana
trees
(fruitresins)
PEE
Saureus
(ATC
C25923)
Paeruginosa
(ATC
C27853)
Inhibitio
nof
Saureus
grow
th[42]
Cameroo
nandCon
goAfrican
prop
olisprob
ablyM
schw
einfurthii
PEE
Saureus
(ATC
C25923)Sepiderm
is(ATC
C13047)E
coli
(ATC
C25922)K
lebsiella
pneumonia(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Inhibitio
nof
Saureus
grow
th[53]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Saureus
2979
andSaureus
4118
isolated
from
mastiticcows
Saureus
(ATC
C29213)
Decreaseo
fSaureusg
rowth
incomplex
mediaandkilling
ofSaureus
cells
resuspendedin
milk
promotionof
changesin
morph
olog
yandcellsiz
e[200]
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsu
lfoxide
extract
Saureus
(CAPM
5970)E
faecalis(C
APM
5613
(EBF
3039))
Ecoli(C
AMP3101
T(U
541))and
Lmonocytogenes(C
CM5580)
Differentcon
centratio
nsaffectthe
grow
thofthetestedbacteria
[201]
Italy
Mediterraneanprop
olisCrup
essusspp
PE
E
Staphylococcus
sppstr
ains
(35Saureus63Sepidermidis
7S
hominis
18Shaem
olyticu
s10
Swa
rneri4Scapitisand
3S
auric
ularis)
andStreptococcusspp
strains
(59Sfaecalis
30S
virid
ans15
S120573-haemolyticu
sand19
Spn
eumoniae)
Com
pletes
uppressio
nof
thefactorc
oagu
lasereductio
nof
lipasea
ndpreventio
nof
biofi
lmform
ationof
Staphylococcus
increase
ofthee
ffectof
ampicillingentam
ycinand
streptomycin
andmod
eratingthea
ctionof
chloramph
enicol
ceftriaxoneand
vancom
ycin
[56]
Brazil
Redprop
olisDecasto
phyllum
Green
prop
olisB
dracun
culifolia
PEE
Saureus
(ATC
C25923)
NanoH
Amatrix
with
redandgreenprop
oliswhich
redu
ces
bacterialgrowth
andbiofi
lmform
ation
then
anoH
Awith
red
prop
olisbeingthem
ostefficient
[136]
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
10 Evidence-Based Complementary and Alternative Medicine
effects of Brazilian green propolis on splenocyte proliferationeffect that was attributed to flavonoids and enhancementeffects on interferon- (IFN-) 120574 production by spleen cellsCAPE displays inhibitory effects on transcription factors NF-120581B and NFAT and as a consequence inhibits IL-2 genetranscription IL-2 receptor expression and proliferation ofhuman T cells [94] This provides new information into themolecular mechanisms involved in the anti-inflammatoryand immunomodulatory activities of propolis CAPE hasvarious biological activities but its effect on the immunomod-ulatory activity remains little studied According to Wanget al [112] CAPE can be useful in the treatment of asthmaand other allergic diseases because it can inhibit cytokinesand chemokines production by human monocyte-deriveddendritic cells (MoDCs) which might be related to theNF-120581B signalling pathway Another study demonstrated forthe first time that Brazilian propolis significantly inhibitedthe generation of Th1 cells Furthermore the effects ofpropolis were investigated on 246-trinitrobenzene sulfonicacid- (TNBS-) induced colitis in a mouse model Propolisreduced the frequency of IFN-120574-producing CD4 T cellsin a dose-dependent way under Th1-polarizing conditionsThe inhibitory effect of propolis on Th1 differentiation wasdemonstrated in vivo too and the severity of colitis inpropolis-fed mice was significantly lower than that of micefed with the control diet [118]
44 Antiviral Activity Propolis comprises a complexity ofcompounds which play a role in antiviral protection Despitethe few data available regarding this activity it was shown thatpropolis from different geographic regions has considerableantiviral activity by acting at different levels and interferingwith the replication of some viruses [12] like herpes simplextypes 1 and 2 adenovirus type 2 influenza virus or humanimmunodeficiency virus (HIV) among others [7 60 119ndash124] Table 5 summarizes the antiviral activity of propolis andits chemical constituents
Schnitzler et al [123] analysed the antiviral effect ofPWE and PEE from Czech Republic as well as that ofthe constituents caffeic acid p-coumaric acid benzoic acidgalangin pinocembrin and chrysin against herpes simplexvirus type 1 (HSV-1) in cell culture Both extracts exhibitedhigh anti-HSV-1 activity when cells were treated prior toviral infection galangin and chrysin being the main bioac-tive compounds Amoros et al [60] showed the antiviralactivity of the major flavonoids of propolis more specificallyflavonols and flavones the first being more active againstHSV-1 Additionally they analysed the effect of propolis onseveral DNA and RNA viruses (HSV-1 HSV-2 adenovirustype 2 vesicular stomatitis virus (VSV) and poliovirus type2) Propolis at a concentration of 30120583gmL reduced thetiter of herpes virus however vesicular stomatitis virusand adenovirus were less susceptible In addition propo-lis appears to exert a virucidal action on the envelopedviruses HSV and VSV [120] Recently it was shown thathydromethanolic extract of geopropolis from the stinglessbee Scaptotrigona postica (Brazil) inhibits theHSV replicationand also the entry of the virus into cells effect that wasattributed to the C-glycosyl flavones catechin-3-O-gallate
and 34-dicaffeoylquinic acid [125] According to Tait etal [126] natural and synthetic flavonoids might interferewith picornavirus replication preventing the decapsidationof viral particles and RNA release within cells or blockingviral RNA synthesis These authors also showed that differ-ent homoisoflavonoids have good antiviral activity againstthe coxsackie viruses B3 B4 and A9 and echovirus 30Shvarzbeyn and Huleihel [127] tried to determine whichstep of Tax oncoprotein-induced NF-120581B activation is blockedby propolis and CAPE and showed that both substantiallyinhibited the activation of NF-120581B-dependent promoter byTax Also they strongly prevented both Tax binding to I120581B120572and its induced degradation by Tax Ma et al [128] showedthat nanometer propolis flavones could significantly inhibitin vitro porcine parvovirus (PPV) infecting PK-15 cells andin vivo they restrain the PPV copy in lung gonad and blooddecrease the impact of PPV on weight of guinea pigs andincrease hemagglutination inhibition of PPV in serum as wellas improving the contents of IL-2 IL-6 and 120574-IFN
Over recent years therapeutic benefits of propolis andorits isolated compounds have been described in HIV treat-ment Ito et al [129] tested the anti-HIV activity in H9lymphocytes of triterpenoids melliferone moronic acidanwuweizonic acid and betulonic acid and four knownaromatic compounds isolated from Brazilian propolis andshowed that moronic acid had significant anti-HIV activityGekker et al [119] assessed the anti-HIV-1 activity of propolisin CD4+ lymphocytes and microglial cell cultures observ-ing the inhibition of viral expression in a concentration-dependent wayThe possible mechanism of propolis antiviralproperty was suggested to involve inhibition of viral entry
45 Antimicrobial Activity Antimicrobial activity one ofthe most studied propolis biological properties is very welldocumented This bioactivity has been largely investigatedin the last years due to the need of new treatments againstinfectious diseases especially with the increase of resistantpathogens to current antibiotics Tables 6 and 7 summarisethe antibacterial and antifungal activities found in propolisfrom different geographic origin andor its chemical con-stituents
451 Antibacterial Activity Propolis effect against severalbacterial strains has evaluated [7 56ndash59 130] and supportedthe fact that propolis is more active against Gram-positivebacteria than Gram-negative bacteria [12 59] Briefly datafrom different studies showed that propolis inhibits bac-terial motility and enzyme activity exhibits bacteriostaticactivity against different bacterial genera can be bactericidalin high concentrations and affects cytoplasmic membrane[130]
Mirzoeva et al [130] investigated the effect of PEEon the physiology of Bacillus subtilis Escherichia coli andRhodobacter sphaeroides proposing that propolis and someof its components like cinnamic acid and flavonoids affectthe ion permeability of the inner bacterial membrane causingthe dissipation of the membrane potential and inhibitingbacterial motility A recent study [131] provided valuableinformation for understanding the potential anti-H pylori
Evidence-Based Complementary and Alternative Medicine 11
Table5Antivira
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescellsviru
ses
Effect
References
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
Caffeicacidp-cou
maricacid
benzoica
cidgalang
in
pino
cembrinand
chrysin
RC-37cellsherpessim
plex
virustype1
(HSV
-1)
strainKO
SHighanti-HSV
-1activ
ityforb
othextractswhencells
weretreated
prior
toviralinfectio
n[123]
CzechRe
public
European
prop
olisPopu
lusn
igra
PEEandPW
ERC
-37cellsherpessim
plex
virustype2
(HSV
-2)
Highantih
erpetic
activ
ityforb
othextractswhenvirusesw
ere
pretreated
priortoinfection
[196]
Brazil
Brow
nprop
olisB
dracun
culifolia
HPE
HSV
-2str
ainprop
agated
inVe
rocellsfem
aleB
ALB
cmice
Effectiv
eagainstHSV
-2infectionandin
redu
cing
extravaginallesio
nsby
actin
gon
inflammatoryandoxidativep
rocessesreducingreactiv
especiestyrosin
enitration
ascorbicacid
levels
andmyeloperoxidase
activ
ityandprotectin
gagainstinh
ibition
ofcatalase
activ
ity
[124]
Characteris
ticof
Brazilian
prop
olis
Isop
entylferulate(
isolatedfro
man
PEE)
Influ
enza
virusesA
PR834
(H1N
1)
AKrasnod
ar10
159(H
2N2)and
AH
ongKo
ng168
(H3N
2)Supp
ressionof
influ
enza
virusA
Hon
gKo
ngreprod
uctio
nin
vitro
[121]
Green
prop
olisB
dracun
culifolia
Beriocla
daM
yrceugeniaeuosma
PEE
Influ
enza
APR834
(H1N
1)virusp
ropagated
Madin-D
arby
canine
kidn
ey(M
DCK
)cells
female
DBA
2Cr
mice
Redu
ctionof
body
weightlosso
finfectedmicea
ndvirusy
ieldsinthe
bron
choalveolarlavagefl
uids
oflung
s[122]
France
European
prop
olisPopu
lusn
igra
PEE
RC-37cellsH
SV-1str
ainH29Sacyclovirresistant
mutantH
SV1-R
strainH29R
HSV
-2adeno
virustype
2po
liovirustype2
and
vesic
ular
stomatitisv
irus
(VSV
)
Redu
ctionof
titre
ofherpes
virusbeingvesic
ular
stomatitisv
irusa
ndadenoviru
slesssusceptibleviru
cidalactionon
thee
nvelo
pedviruses
HSV
andVS
V[120]
Brazil
Geoprop
olisfro
mthes
tinglessb
eeScaptotrigona
postica
Hydromethano
licextract
African
greenmon
keykidn
eycells
(ATC
CCC
L-81)
herpes
simplex
virusstrain(M
cIntyre)
Inhibitio
nof
HSV
replicationandentryinto
cells
[125]
Synthesiz
edCh
aracteris
ticof
Brazilian
redand
greenprop
olis
Hom
oisoflavono
idsspecially
3-benzyl-4-chrom
ones
BGM
(Buff
aloGreen
Mon
key)
cellscoxsackieviruses
B3B
4andA9andecho
virus3
0Goo
dantiv
iralactivity
againstthe
coxsackiev
irusesB
3B4
and
A9and
echo
virus3
0[126]
Canada
European
prop
olisPtrichocarpa
andPtre
muloides
PEE
HSV
-1andHSV
-2virusreplicated
inMDBK
(mon
olayer
cultu
reso
fMadin-D
arby
bovine
kidn
ey)
cells
Impairing
thea
bilityof
thev
irustoadsorb
orto
penetratethe
hostcells
[197]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Water
extracts
FemaleB
ALB
cmiceInflu
enza
Avirusstrain
AW
SN33(H
1N1)
Extensionof
thelifetim
eofm
ice34-dicaffeoylquinica
cidwhich
increasesm
RNAlevelsof
tumor
necrosisfactor-related
apop
tosis
-indu
cing
anddecreasesH
1N1h
emagglutinin
mRN
A[19
8]Ch
aracteris
ticof
Brazilian
green
prop
olis
34-dicaffeoylquinica
cid
(Isolated
from
Brazilian
prop
olis)
Brazil
Characteris
ticof
Brazilian
green
prop
olis
Melliferon
emoron
icacid
anwuw
eizonica
cidand
betulonica
cid(isolated
from
Brazilian
prop
olis)
H9lymph
ocytesH
IV-1
Moron
icacid
inhibitin
ganti-HIV
replication
[129]
Israel
Mediterraneanprop
olisPopu
lus
sppE
ucalyptusspp
andCa
stanea
sativa
PWE
Jurkatuninfectedhu
man
T-celllin
esand
MT2
(HTL
V-1infectedhu
man
Tcells)cells
Inhibitio
nof
thea
ctivationof
NF-120581B-depend
entp
romoter
byTaxand
preventio
nof
Taxbind
ingto
I120581B120572
andits
degradation
[127]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Provided
byBinzho
uAnimal
Sciencea
ndVe
terin
ary
MedicineA
cademyof
Shando
ngProvince
Nanom
eter
prop
olisFlavon
eKidn
eycells
(PK-
15)
Porcinep
arvovirus(PP
V)
Britain
Whiteguinea
pigs
Inhibitio
nof
PPVinfectingpo
rcinek
idney-
(PK-
)15cells
Restr
aining
ofPP
Vcopy
inlung
gon
adand
bloo
ddecrease
ofthe
impactof
PPVon
weighto
fguineap
igsandincrease
ofhemagglutinationinhibitio
nof
PPVin
serum
aswellasimprovingthe
contentsof
IL-2IL-6and120574-IFN
[128]
USA
andCh
ina
European
prop
olisPopu
lusn
igra
PEE
Perip
heralblood
mon
onuclear
cells
obtained
from
bloo
dof
healthyd
onorsmicroglialcellsiso
latedfro
mhu
man
fetalbrain
tissueHIV-1ATH
IV-1SF162
Inhibitio
nof
HIV-1varia
ntse
xpression
[119]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
12 Evidence-Based Complementary and Alternative Medicine
Table6Antibacteria
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
PurchasedBe
eHealth
Ltd
(Scarborou
ghYorkshire
UK)
Eu
ropean
prop
olisPopu
lusn
igra
PEE
BsubtilisS
G38E
coliandR
sphaeroides
Influ
encing
theion
perm
eabilityof
theinn
erbacterial
mem
brane
Inhibitio
nof
bacterialm
otility
[130]
PurchasedSigm
aCh
emicalCo(Poo
leDorsetUK)
Characteris
ticof
EuropeanB
razilian
andMediterraneanprop
olis
CaffeicacidC
APE
qu
ercetin
and
narin
genin
Greece
Mediterraneanprop
olisprob
ablyCo
nifer
spp
Terpenes
(isolated
from
Cretan
prop
olis)
Saureus
(ATC
C25923)Sepiderm
idis(ATC
C12228)E
coli
(ATC
C25922)E
cloacae
(ATC
C13047)K
pneumoniae
(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Influ
encing
theG
ram-positive
andGram-negativeb
acteria
viability
[199]
France
European
prop
olisPopu
lusn
igra
Dichlorom
ethane
extract
Gram-negative7Ac
inetobacterb
aumannii(RC
HSAN00812
AYE
CIP7
034107292and
5377)2Escherich
iacoli(ATC
C25922andac
linicaliso
late)3
Pseudomonas
aeruginosa
(ATC
C27853andtwoclinicalisolates)and4clinicalisolates
ofEn
terobacterclo
acaeE
aerogenesK
lebsiella
oxytocaand
Salm
onellaenteritidis(phage
type
4)Gram-negative13
Staphylococcus
aureus
(ATC
C25923six
methicillin-susceptib
leclinicalisolatesandsix
methicillin-resistant
clinicalisolates)2
clinicalisolates
ofS
epidermidis(m
ethiSandmethiR)3
clinicalisolates
ofEn
terococcus
faecalisand1E
faeciu
mand
1clin
icaliso
lateof
Corynebacterium
striatum
Influ
encing
theG
ram-positive
bacteriaviabilityspecially
Saureus
andseveralofitsmethicillin-resistant
and
methicillin-susceptib
le[133]
Bulgaria
Mediterraneanprop
olis
PEE
Saureus
209E
coliWF+
Decreaseo
fSaureusg
rowth
andweakor
lack
ofactiv
ityagainstE
coli
[28]
Greece
Popu
lusspp
Tu
rkey
Conifer
spp
Algeria
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativaPopu
lusspp
Cistu
sspp
Austr
alia
Austr
alianprop
olisfro
msting
lessbee
Tetra
gonu
lacarbonariaCtorelliana
trees
(fruitresins)
PEE
Saureus
(ATC
C25923)
Paeruginosa
(ATC
C27853)
Inhibitio
nof
Saureus
grow
th[42]
Cameroo
nandCon
goAfrican
prop
olisprob
ablyM
schw
einfurthii
PEE
Saureus
(ATC
C25923)Sepiderm
is(ATC
C13047)E
coli
(ATC
C25922)K
lebsiella
pneumonia(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Inhibitio
nof
Saureus
grow
th[53]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Saureus
2979
andSaureus
4118
isolated
from
mastiticcows
Saureus
(ATC
C29213)
Decreaseo
fSaureusg
rowth
incomplex
mediaandkilling
ofSaureus
cells
resuspendedin
milk
promotionof
changesin
morph
olog
yandcellsiz
e[200]
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsu
lfoxide
extract
Saureus
(CAPM
5970)E
faecalis(C
APM
5613
(EBF
3039))
Ecoli(C
AMP3101
T(U
541))and
Lmonocytogenes(C
CM5580)
Differentcon
centratio
nsaffectthe
grow
thofthetestedbacteria
[201]
Italy
Mediterraneanprop
olisCrup
essusspp
PE
E
Staphylococcus
sppstr
ains
(35Saureus63Sepidermidis
7S
hominis
18Shaem
olyticu
s10
Swa
rneri4Scapitisand
3S
auric
ularis)
andStreptococcusspp
strains
(59Sfaecalis
30S
virid
ans15
S120573-haemolyticu
sand19
Spn
eumoniae)
Com
pletes
uppressio
nof
thefactorc
oagu
lasereductio
nof
lipasea
ndpreventio
nof
biofi
lmform
ationof
Staphylococcus
increase
ofthee
ffectof
ampicillingentam
ycinand
streptomycin
andmod
eratingthea
ctionof
chloramph
enicol
ceftriaxoneand
vancom
ycin
[56]
Brazil
Redprop
olisDecasto
phyllum
Green
prop
olisB
dracun
culifolia
PEE
Saureus
(ATC
C25923)
NanoH
Amatrix
with
redandgreenprop
oliswhich
redu
ces
bacterialgrowth
andbiofi
lmform
ation
then
anoH
Awith
red
prop
olisbeingthem
ostefficient
[136]
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 11
Table5Antivira
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescellsviru
ses
Effect
References
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
type
prop
olis
Caffeicacidp-cou
maricacid
benzoica
cidgalang
in
pino
cembrinand
chrysin
RC-37cellsherpessim
plex
virustype1
(HSV
-1)
strainKO
SHighanti-HSV
-1activ
ityforb
othextractswhencells
weretreated
prior
toviralinfectio
n[123]
CzechRe
public
European
prop
olisPopu
lusn
igra
PEEandPW
ERC
-37cellsherpessim
plex
virustype2
(HSV
-2)
Highantih
erpetic
activ
ityforb
othextractswhenvirusesw
ere
pretreated
priortoinfection
[196]
Brazil
Brow
nprop
olisB
dracun
culifolia
HPE
HSV
-2str
ainprop
agated
inVe
rocellsfem
aleB
ALB
cmice
Effectiv
eagainstHSV
-2infectionandin
redu
cing
extravaginallesio
nsby
actin
gon
inflammatoryandoxidativep
rocessesreducingreactiv
especiestyrosin
enitration
ascorbicacid
levels
andmyeloperoxidase
activ
ityandprotectin
gagainstinh
ibition
ofcatalase
activ
ity
[124]
Characteris
ticof
Brazilian
prop
olis
Isop
entylferulate(
isolatedfro
man
PEE)
Influ
enza
virusesA
PR834
(H1N
1)
AKrasnod
ar10
159(H
2N2)and
AH
ongKo
ng168
(H3N
2)Supp
ressionof
influ
enza
virusA
Hon
gKo
ngreprod
uctio
nin
vitro
[121]
Green
prop
olisB
dracun
culifolia
Beriocla
daM
yrceugeniaeuosma
PEE
Influ
enza
APR834
(H1N
1)virusp
ropagated
Madin-D
arby
canine
kidn
ey(M
DCK
)cells
female
DBA
2Cr
mice
Redu
ctionof
body
weightlosso
finfectedmicea
ndvirusy
ieldsinthe
bron
choalveolarlavagefl
uids
oflung
s[122]
France
European
prop
olisPopu
lusn
igra
PEE
RC-37cellsH
SV-1str
ainH29Sacyclovirresistant
mutantH
SV1-R
strainH29R
HSV
-2adeno
virustype
2po
liovirustype2
and
vesic
ular
stomatitisv
irus
(VSV
)
Redu
ctionof
titre
ofherpes
virusbeingvesic
ular
stomatitisv
irusa
ndadenoviru
slesssusceptibleviru
cidalactionon
thee
nvelo
pedviruses
HSV
andVS
V[120]
Brazil
Geoprop
olisfro
mthes
tinglessb
eeScaptotrigona
postica
Hydromethano
licextract
African
greenmon
keykidn
eycells
(ATC
CCC
L-81)
herpes
simplex
virusstrain(M
cIntyre)
Inhibitio
nof
HSV
replicationandentryinto
cells
[125]
Synthesiz
edCh
aracteris
ticof
Brazilian
redand
greenprop
olis
Hom
oisoflavono
idsspecially
3-benzyl-4-chrom
ones
BGM
(Buff
aloGreen
Mon
key)
cellscoxsackieviruses
B3B
4andA9andecho
virus3
0Goo
dantiv
iralactivity
againstthe
coxsackiev
irusesB
3B4
and
A9and
echo
virus3
0[126]
Canada
European
prop
olisPtrichocarpa
andPtre
muloides
PEE
HSV
-1andHSV
-2virusreplicated
inMDBK
(mon
olayer
cultu
reso
fMadin-D
arby
bovine
kidn
ey)
cells
Impairing
thea
bilityof
thev
irustoadsorb
orto
penetratethe
hostcells
[197]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
Water
extracts
FemaleB
ALB
cmiceInflu
enza
Avirusstrain
AW
SN33(H
1N1)
Extensionof
thelifetim
eofm
ice34-dicaffeoylquinica
cidwhich
increasesm
RNAlevelsof
tumor
necrosisfactor-related
apop
tosis
-indu
cing
anddecreasesH
1N1h
emagglutinin
mRN
A[19
8]Ch
aracteris
ticof
Brazilian
green
prop
olis
34-dicaffeoylquinica
cid
(Isolated
from
Brazilian
prop
olis)
Brazil
Characteris
ticof
Brazilian
green
prop
olis
Melliferon
emoron
icacid
anwuw
eizonica
cidand
betulonica
cid(isolated
from
Brazilian
prop
olis)
H9lymph
ocytesH
IV-1
Moron
icacid
inhibitin
ganti-HIV
replication
[129]
Israel
Mediterraneanprop
olisPopu
lus
sppE
ucalyptusspp
andCa
stanea
sativa
PWE
Jurkatuninfectedhu
man
T-celllin
esand
MT2
(HTL
V-1infectedhu
man
Tcells)cells
Inhibitio
nof
thea
ctivationof
NF-120581B-depend
entp
romoter
byTaxand
preventio
nof
Taxbind
ingto
I120581B120572
andits
degradation
[127]
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Provided
byBinzho
uAnimal
Sciencea
ndVe
terin
ary
MedicineA
cademyof
Shando
ngProvince
Nanom
eter
prop
olisFlavon
eKidn
eycells
(PK-
15)
Porcinep
arvovirus(PP
V)
Britain
Whiteguinea
pigs
Inhibitio
nof
PPVinfectingpo
rcinek
idney-
(PK-
)15cells
Restr
aining
ofPP
Vcopy
inlung
gon
adand
bloo
ddecrease
ofthe
impactof
PPVon
weighto
fguineap
igsandincrease
ofhemagglutinationinhibitio
nof
PPVin
serum
aswellasimprovingthe
contentsof
IL-2IL-6and120574-IFN
[128]
USA
andCh
ina
European
prop
olisPopu
lusn
igra
PEE
Perip
heralblood
mon
onuclear
cells
obtained
from
bloo
dof
healthyd
onorsmicroglialcellsiso
latedfro
mhu
man
fetalbrain
tissueHIV-1ATH
IV-1SF162
Inhibitio
nof
HIV-1varia
ntse
xpression
[119]
Brazil
Green
prop
olisBa
ccharis
dracun
culifolia
12 Evidence-Based Complementary and Alternative Medicine
Table6Antibacteria
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
PurchasedBe
eHealth
Ltd
(Scarborou
ghYorkshire
UK)
Eu
ropean
prop
olisPopu
lusn
igra
PEE
BsubtilisS
G38E
coliandR
sphaeroides
Influ
encing
theion
perm
eabilityof
theinn
erbacterial
mem
brane
Inhibitio
nof
bacterialm
otility
[130]
PurchasedSigm
aCh
emicalCo(Poo
leDorsetUK)
Characteris
ticof
EuropeanB
razilian
andMediterraneanprop
olis
CaffeicacidC
APE
qu
ercetin
and
narin
genin
Greece
Mediterraneanprop
olisprob
ablyCo
nifer
spp
Terpenes
(isolated
from
Cretan
prop
olis)
Saureus
(ATC
C25923)Sepiderm
idis(ATC
C12228)E
coli
(ATC
C25922)E
cloacae
(ATC
C13047)K
pneumoniae
(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Influ
encing
theG
ram-positive
andGram-negativeb
acteria
viability
[199]
France
European
prop
olisPopu
lusn
igra
Dichlorom
ethane
extract
Gram-negative7Ac
inetobacterb
aumannii(RC
HSAN00812
AYE
CIP7
034107292and
5377)2Escherich
iacoli(ATC
C25922andac
linicaliso
late)3
Pseudomonas
aeruginosa
(ATC
C27853andtwoclinicalisolates)and4clinicalisolates
ofEn
terobacterclo
acaeE
aerogenesK
lebsiella
oxytocaand
Salm
onellaenteritidis(phage
type
4)Gram-negative13
Staphylococcus
aureus
(ATC
C25923six
methicillin-susceptib
leclinicalisolatesandsix
methicillin-resistant
clinicalisolates)2
clinicalisolates
ofS
epidermidis(m
ethiSandmethiR)3
clinicalisolates
ofEn
terococcus
faecalisand1E
faeciu
mand
1clin
icaliso
lateof
Corynebacterium
striatum
Influ
encing
theG
ram-positive
bacteriaviabilityspecially
Saureus
andseveralofitsmethicillin-resistant
and
methicillin-susceptib
le[133]
Bulgaria
Mediterraneanprop
olis
PEE
Saureus
209E
coliWF+
Decreaseo
fSaureusg
rowth
andweakor
lack
ofactiv
ityagainstE
coli
[28]
Greece
Popu
lusspp
Tu
rkey
Conifer
spp
Algeria
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativaPopu
lusspp
Cistu
sspp
Austr
alia
Austr
alianprop
olisfro
msting
lessbee
Tetra
gonu
lacarbonariaCtorelliana
trees
(fruitresins)
PEE
Saureus
(ATC
C25923)
Paeruginosa
(ATC
C27853)
Inhibitio
nof
Saureus
grow
th[42]
Cameroo
nandCon
goAfrican
prop
olisprob
ablyM
schw
einfurthii
PEE
Saureus
(ATC
C25923)Sepiderm
is(ATC
C13047)E
coli
(ATC
C25922)K
lebsiella
pneumonia(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Inhibitio
nof
Saureus
grow
th[53]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Saureus
2979
andSaureus
4118
isolated
from
mastiticcows
Saureus
(ATC
C29213)
Decreaseo
fSaureusg
rowth
incomplex
mediaandkilling
ofSaureus
cells
resuspendedin
milk
promotionof
changesin
morph
olog
yandcellsiz
e[200]
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsu
lfoxide
extract
Saureus
(CAPM
5970)E
faecalis(C
APM
5613
(EBF
3039))
Ecoli(C
AMP3101
T(U
541))and
Lmonocytogenes(C
CM5580)
Differentcon
centratio
nsaffectthe
grow
thofthetestedbacteria
[201]
Italy
Mediterraneanprop
olisCrup
essusspp
PE
E
Staphylococcus
sppstr
ains
(35Saureus63Sepidermidis
7S
hominis
18Shaem
olyticu
s10
Swa
rneri4Scapitisand
3S
auric
ularis)
andStreptococcusspp
strains
(59Sfaecalis
30S
virid
ans15
S120573-haemolyticu
sand19
Spn
eumoniae)
Com
pletes
uppressio
nof
thefactorc
oagu
lasereductio
nof
lipasea
ndpreventio
nof
biofi
lmform
ationof
Staphylococcus
increase
ofthee
ffectof
ampicillingentam
ycinand
streptomycin
andmod
eratingthea
ctionof
chloramph
enicol
ceftriaxoneand
vancom
ycin
[56]
Brazil
Redprop
olisDecasto
phyllum
Green
prop
olisB
dracun
culifolia
PEE
Saureus
(ATC
C25923)
NanoH
Amatrix
with
redandgreenprop
oliswhich
redu
ces
bacterialgrowth
andbiofi
lmform
ation
then
anoH
Awith
red
prop
olisbeingthem
ostefficient
[136]
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
12 Evidence-Based Complementary and Alternative Medicine
Table6Antibacteria
lactivity
ofprop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
PurchasedBe
eHealth
Ltd
(Scarborou
ghYorkshire
UK)
Eu
ropean
prop
olisPopu
lusn
igra
PEE
BsubtilisS
G38E
coliandR
sphaeroides
Influ
encing
theion
perm
eabilityof
theinn
erbacterial
mem
brane
Inhibitio
nof
bacterialm
otility
[130]
PurchasedSigm
aCh
emicalCo(Poo
leDorsetUK)
Characteris
ticof
EuropeanB
razilian
andMediterraneanprop
olis
CaffeicacidC
APE
qu
ercetin
and
narin
genin
Greece
Mediterraneanprop
olisprob
ablyCo
nifer
spp
Terpenes
(isolated
from
Cretan
prop
olis)
Saureus
(ATC
C25923)Sepiderm
idis(ATC
C12228)E
coli
(ATC
C25922)E
cloacae
(ATC
C13047)K
pneumoniae
(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Influ
encing
theG
ram-positive
andGram-negativeb
acteria
viability
[199]
France
European
prop
olisPopu
lusn
igra
Dichlorom
ethane
extract
Gram-negative7Ac
inetobacterb
aumannii(RC
HSAN00812
AYE
CIP7
034107292and
5377)2Escherich
iacoli(ATC
C25922andac
linicaliso
late)3
Pseudomonas
aeruginosa
(ATC
C27853andtwoclinicalisolates)and4clinicalisolates
ofEn
terobacterclo
acaeE
aerogenesK
lebsiella
oxytocaand
Salm
onellaenteritidis(phage
type
4)Gram-negative13
Staphylococcus
aureus
(ATC
C25923six
methicillin-susceptib
leclinicalisolatesandsix
methicillin-resistant
clinicalisolates)2
clinicalisolates
ofS
epidermidis(m
ethiSandmethiR)3
clinicalisolates
ofEn
terococcus
faecalisand1E
faeciu
mand
1clin
icaliso
lateof
Corynebacterium
striatum
Influ
encing
theG
ram-positive
bacteriaviabilityspecially
Saureus
andseveralofitsmethicillin-resistant
and
methicillin-susceptib
le[133]
Bulgaria
Mediterraneanprop
olis
PEE
Saureus
209E
coliWF+
Decreaseo
fSaureusg
rowth
andweakor
lack
ofactiv
ityagainstE
coli
[28]
Greece
Popu
lusspp
Tu
rkey
Conifer
spp
Algeria
Popu
lusspp
Eu
calyptus
sppand
Casta
neasativaPopu
lusspp
Cistu
sspp
Austr
alia
Austr
alianprop
olisfro
msting
lessbee
Tetra
gonu
lacarbonariaCtorelliana
trees
(fruitresins)
PEE
Saureus
(ATC
C25923)
Paeruginosa
(ATC
C27853)
Inhibitio
nof
Saureus
grow
th[42]
Cameroo
nandCon
goAfrican
prop
olisprob
ablyM
schw
einfurthii
PEE
Saureus
(ATC
C25923)Sepiderm
is(ATC
C13047)E
coli
(ATC
C25922)K
lebsiella
pneumonia(ATC
C13883)and
Paeruginosa
(ATC
C227853)
Inhibitio
nof
Saureus
grow
th[53]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Saureus
2979
andSaureus
4118
isolated
from
mastiticcows
Saureus
(ATC
C29213)
Decreaseo
fSaureusg
rowth
incomplex
mediaandkilling
ofSaureus
cells
resuspendedin
milk
promotionof
changesin
morph
olog
yandcellsiz
e[200]
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsu
lfoxide
extract
Saureus
(CAPM
5970)E
faecalis(C
APM
5613
(EBF
3039))
Ecoli(C
AMP3101
T(U
541))and
Lmonocytogenes(C
CM5580)
Differentcon
centratio
nsaffectthe
grow
thofthetestedbacteria
[201]
Italy
Mediterraneanprop
olisCrup
essusspp
PE
E
Staphylococcus
sppstr
ains
(35Saureus63Sepidermidis
7S
hominis
18Shaem
olyticu
s10
Swa
rneri4Scapitisand
3S
auric
ularis)
andStreptococcusspp
strains
(59Sfaecalis
30S
virid
ans15
S120573-haemolyticu
sand19
Spn
eumoniae)
Com
pletes
uppressio
nof
thefactorc
oagu
lasereductio
nof
lipasea
ndpreventio
nof
biofi
lmform
ationof
Staphylococcus
increase
ofthee
ffectof
ampicillingentam
ycinand
streptomycin
andmod
eratingthea
ctionof
chloramph
enicol
ceftriaxoneand
vancom
ycin
[56]
Brazil
Redprop
olisDecasto
phyllum
Green
prop
olisB
dracun
culifolia
PEE
Saureus
(ATC
C25923)
NanoH
Amatrix
with
redandgreenprop
oliswhich
redu
ces
bacterialgrowth
andbiofi
lmform
ation
then
anoH
Awith
red
prop
olisbeingthem
ostefficient
[136]
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 13
Table6Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Species
Effect
References
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lus
glutin
osaAe
sculus
hippocastanu
mFagus
sylva
tica
Coagu
lase-positive
Saureus
strains
isolatedfro
mbloo
dclinicalsam
plesSaureus(AT
CC25923)Saureus(AT
CC43300)m
ethicillin-sensitive
andresistant
Saureus
Inhibitio
nof
Saureus
grow
thandbactericidalactiv
ity
potentiatio
nof
antistaph
ylococcald
rugs
actio
neffectiv
eagainsttwelv
eSaureusstrainsw
ithMIC
values
with
in039
to078
mgmLandMBC
with
in078
to313mgmL
[132]
Brazil
Bulgaria
Green
prop
olisB
dracun
culifolia
Mediterraneanprop
olisPopu
lusspp
PEE
Styphi(00238)
Brazilian
prop
olishaving
bacteriosta
ticactiv
ityB
ulgaria
nprop
olishaving
bactericidalactiv
itybothhaving
similar
synergeticeffectw
henin
combinatio
nwith
amoxicillin
ampicillinandceph
alexin
[202]
Styphim
urium
MaleB
ALB
cmice
Increase
ofbactericidalactiv
ityof
macroph
ages
[203]
Styphim
urium
Both
samples
having
antib
acteria
lactivity
butn
osynergistic
effectswith
ciprofl
oxacinnorflo
xacin
andcotrim
oxazole
[135]
Turkey
Mediterran
eanpropolisPopu
lusspp
Eu
calyptus
sppan
dCa
staneasativa
PWE
Mtub
erculosis
(H37R v
)maleg
uinea-pig
Inhibitio
nof
tuberculosisinfectionin
guinea-pigssince
itprom
otes
adecreaseinnecrosisform
ationandincrease
ingranulom
aformation
[204
]
PEE
Ecoli(ATC
C35218)K
pneum
oniae(AT
CC27736)P
aeruginosa
(ATC
C27853)M
organella
morganii(clinical
isolate)Saureus
(ATC
C25923)B
subtilis(ATC
C6633)and
Proteusv
ulgaris
Inhibitio
nof
Gram-negativeb
acteria
grow
th[134]
Purchasedfro
mSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
Hpylori
Com
petitiveinh
ibito
ragainstHpylorip
eptid
edeformylase
blocking
substratee
ntrance
[131]
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
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[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
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[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
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[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
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[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
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[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
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[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
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[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
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Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
14 Evidence-Based Complementary and Alternative Medicine
Table7Antifu
ngalactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
CalbicansC
tropicalisC
kruseiandC
guillier
mondiiadultvolun
teer
patie
ntssho
wing
symptom
sofstomatitis
Inhibitio
nof
cellgrow
thC
albica
nsbeingthem
ostsensitivea
ndC
guillier
mondiithe
mostresistantredu
ctionof
then
umbero
fCan
dida
yeastsin
thes
aliva
[141]
Green
prop
olisB
dracun
culifoliared
prop
olisDecasta
phyllum
PEE
Trubrum
TtonsuransTm
entagrophytesandT
mentagrophytes(AT
CC9533)(control)
Both
samples
which
decrease
cellgrow
thred
PEEbeingmoree
fficient
than
theg
reen
one
[143]
Green
prop
olisB
dracun
culifolia
PEE
PWE
matric
ial
microparticlesandsolubled
ryextract
Calbicans
strains
SC5314
(wild
type)CA
I4and
3153A(w
ildtype)femaleB
ALB
cmice
PEEbeingthem
ostp
otentininhibitin
gcellgrow
thfollo
wed
byprop
olissolubled
ryextractprop
olismatric
ialm
icroparticlesandPW
EDifferentgelform
ulations
ofprop
olis
prop
olisbasedCa
rbop
ol940gel
(CP1)prop
olisbasedpo
loxamer
407gelw
ithCa
rbop
ol940(PP1)
prop
olisalginatewith
pectin
(AlP1
)andprop
olisbasedchito
sangel
with
Natrosol(Ch
P1)CP
1andchito
sangelsbeingthem
ost
pseudo
plastic
onespropo
lisbasedgelspresentin
gantifun
galaction
similartoclo
trim
azolec
ream
[150]
Green
prop
olisB
dracun
culifolia
PEE
gels
andcream
obtained
from
thee
xtract
Calbicans
strains
used
wereS
C5314CA
I4
BWP17DAY
2863153Aand
529L
(wild
type)
femaleB
ALB
cmice(murinem
odelof
vulvovaginalcand
idiasis
)
Indu
ctionof
celldeathin
Calbicans
mediatedviam
etacaspase
and
RASpathway
Inhibitio
nof
allthree
Calbicans
morph
ogenetictypesseveralm
utants
ingenesinvolvedeither
inthem
orph
ologicaltransitions
orin
the
maintenance
ofas
pecific
morph
otypew
hich
arem
ores
ensitiveto
prop
olis
Prop
olisbasedgelsandcream
which
werep
artia
llyableto
control
vulvovaginalcand
idiasis
[151]
Green
prop
olisB
dracun
culifolia
PEE
Calbicans
(ATC
C90028)29C
albicans
isolates
from
patie
ntsw
ithvulvovaginalcand
idiasis
Inhibitin
gbiofi
lmform
ationby
Calbicans
from
vulvovaginal
cand
idiasis
[149]
Redprop
olisDecasta
phyllum
n-Hexanee
xtract
5C
parapsilosis
(RL0
1RL
07R
L11RL
13and
RL27)5C
glabrata(RL0
3RL
09R
L12RL
34and
RL37)C
tropicalis
72Aand
Ckrusei(ATC
C6258)
Activ
eagainstflu
conazoleresistant
Cand
idaspp
[148]
France
European
prop
olisPopu
lusn
igra
PEE
PWE
methano
licextract
anddichloromethane
extract
Calbicans
(ATC
C66396)C
glabrata(LMA
90ndash1085)and
Afumigates(C
BS11326)
Antifu
ngalactiv
ityagainstC
albica
nsandC
glabratabu
tonlyhaving
aweakactiv
itytowards
Afumigates
[133]
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Pbrasiliensisperito
nealmacroph
ages
obtained
from
maleB
ALB
cmice
Increase
offung
icidalactiv
ityof
macroph
ages
againstPbrasilien
sis[14
2]Bu
lgaria
Mediterraneanprop
olisPopu
lusspp
CzechRe
public
European
prop
olisPopu
lusn
igra
Dim
ethylsulfoxide
extract
CalbicansA
fumigatusM
gypseum
and
M
canis
Affectingtheg
rowth
ofthetestedbacteriain
different
waysb
ydifferent
concentrations
[201]
Portugal(Bragancaa
ndLeiria)
European
prop
olisPopu
lusn
igra
PEE
CalbicansTrubrumand
Afumigatus
Plantextractsn
otexhibitin
grelevant
antifun
galactivitybut
ingeneral
both
prop
olissamples
affectin
gthefun
galgrowth
[140]
Poland
European
prop
olisPopu
lusn
igra
and
somes
pecies
ofBetulaalbaA
lnus
glutin
osaAe
sculus
hippocastanu
m
andFagussylv
atica
PEE
20iso
latedC
albicans14iso
latedC
glabrataand
10C
krusei
Inhibitio
nof
fung
algrow
th[14
7]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
CalbicansC
tropicalisC
kefyrC
kruseiM
globosaM
slooffi
aeand
Mpachyderm
atis
all
obtained
from
patie
ntsw
ithclinicalfeatureso
fon
ycho
mycosis
Decreaseo
fCan
dida
andMalasseziastr
ains
grow
thisolatedfro
mon
ycho
mycosis
even
inthefl
ucon
azole-resistant
strains
[205]
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
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[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
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[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
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[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
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[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
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[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
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Disease Markers
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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ObesityJournal of
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Research and TreatmentAIDS
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 15
Table7Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effectstim
ulus
References
Brazil
Green
prop
olisB
dracun
culifolia
PEEandprop
olismicroparticles
89yeaststrains
from
vaginalexu
dateso
fthe
vulvovaginalcand
idiasis
patie
nts58
Calbicans
and17
Cgla
brata1C
tropicalis8
Cguillier
mondiiand5C
parapsilosis
Inhibitio
nof
allyeasts
grow
thby
ethano
lextractandprop
olis
microparticleswith
smallvariatio
nindepend
ento
fthe
specieso
fyeast
[144]
Argentin
aTrop
icalregion
prop
olisSalix
humboldtia
naP
inus
sppE
ucalyptus
sppand
Popu
lusspp
PE
E
Xyloph
agou
s(G
applan
atum
Leleg
ansP
sanguineusand
Scommun
e)and
phytop
atho
genic(A
nigerFu
sariu
msp
Macrophom
inaspPnotatumand
Rhodotorula
spp)
Inhibitio
nof
fung
algrow
th[14
6]
Spain(Basqu
eCou
ntry)
European
prop
olisPopu
lusn
igra
PEEandprop
yleneg
lycol
extracts
Calbicans
(CEC
T1394)Scerevisia
e(CE
CT1383)
Inhibitio
nof
fung
algrow
th[14
5]
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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EndocrinologyInternational Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
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Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
16 Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE H pylori a major factor for gas-trointestinal illnesses contains the enzyme H pylori peptidedeformylase that catalyses the removal of formyl group fromthe N-terminus of nascent polypeptide chains Since theaction of this enzyme is essential for H pylori survival it isconsidered a promising therapeutic drug target Results fromabsorption spectra and crystal structural characterizationshowed that CAPE is a competitive inhibitor of peptidedeformylase blocking the substrate entrance and preventingsubstrate from approaching the active site [131]
It has been suggested that the combination of propoliswith other antibiotics would allow dose reduction of selectedantibiotics thus potentiating their effect The antibacterialactivity of Italian PEE in some clinically isolated Gram-positive strains as well as the synergetic effect with someantibiotics was assessed by Scazzocchio et al [56] Ital-ian PEE drastically increased the effect of ampicillin gen-tamycin and streptomycin and moderated the action ofchloramphenicol ceftriaxone and vancomycin No effectwas observed when used simultaneously with erythromycinWojtyczka et al [132] evaluated the in vitro antimicrobialactivity of a Polish PEE against methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA) clinicalisolates and also the combined effect of propolis with tenselected antistaphylococcal drugs PEE displayed varyingeffectiveness against twelve S aureus strains and potentiatedthe antimicrobial effect of eight antistaphylococcal againstall tested strains No synergism was observed in the caseof ciprofloxacin and chloramphenicol In another study theeffect of dichloromethane extract of French propolis againstdifferent human pathogenic bacterial strains was also testedAlthough Gram-negative bacteria were not susceptible tothe extract a significant antibacterial activity against bothmethicillin-resistant and methicillin-susceptible S aureusstrains was observed [133] The same was confirmed byVelikova et al [28] using different PEE from BulgariaGreece Turkey and Algeria All the samples showed agood antibacterial activity against S aureus but a week orlacking effect against E coli Australian PEE from stinglessbee Tetragonula carbonaria also inhibited the growth of Saureus Nevertheless it was less active against P aeruginosa[42] The same was observed by Papachroni et al [53]using PEE from Cameroon and CongoContrary to thesestudies Katircioglu and Mercan [134] showed that TurkishPEE was effective against Gram-negative bacteria like E coliOrsi et al [135] investigated the possible synergism betweenBrazilian and Bulgarian propolis and antibiotics acting onDNA (ciprofloxacin and norfloxacin) and on metabolism(cotrimoxazole) in Salmonella typhi Both samples hadantibacterial activity but no synergistic effect was detected
Recently the suitability of nanohydroxyapatite- (nano-HA-) based surfaces containing two Brazilian PEE (greenand red ones) to prevent S aureus bacterial growth andbiofilm was studied The nanoHA impregnated with thetwo highest concentrations (12 and 25120583gmL) of red PEEshowed a remarkable reduction of 99 in the number ofviable bacteria while nanoHA with green PEE at sameconcentrations showed a reduction of 45 and 61 Moreoverthe nanoHA impregnated with the highest concentration of
red PEE was able to inhibit 80 of the staphylococcal biofilmformation [136]
Diverse studies show that as the composition of propolisvaries from region to region the antibacterial activity alsodisplays some variations [59] Susceptibility of differentGram-positive bacteria to PEE varies with the place ofpropolis collection [137] The antibacterial effect was shownto be higher for samples from a wet-tropical rain forest-type climate Other studies revealed the influence of propolisgeographical origin on its antibacterial properties [57 58 138139] Propolis from the north and centre of Portugal has agreat activity against S aureus [58 140]
452 Antifungal Activity Antifungal activity is also influ-enced by the chemical variation of propolis [59] Severalstudies have shown the effect of propolis from differentgeographic origin against different fungi particularly ofclinical interest [141ndash145] Quiroga et al [146] demonstratedthe antifungal activity of propolis from the northwest ofArgentina focusing their study on the environment andthe development of agrochemicals with reduced economiccosts possibly containing propolis extracts and its isolatedcompounds such as pinocembrin and galangin as activeprinciples
Recently Falcao et al [140] screened the antifungalactivity of Portuguese propolis and its potential floral sourcesPopulus x Canadensis and Cistus ladanifer against Candidaalbicans Trichophyton rubrum and Aspergillus fumigatusPlant extracts did not exhibit relevant antifungal activity withexception of T rubrum but both propolis samples revealedsimilar antifungal activity the highest being obtained againstT rubrum and the lowest against A fumigatus A sample ofPEE from Poland showed a high fungicidal activity againstC albicans C glabrata and C krusei [147] Recently it wasshown that different organic extracts of French propolis (PEEPWEmethanolic extract and dichloromethane extract) wereeffective against C albicans and C glabrata but only have aweak activity towards A fumigates [133]
Brazilian PEE was proved to be active against severalCandida strains (C albicans C tropicalis C krusei andC guilliermondii) C albicans being the most sensitive andC guilliermondii the most resistant [141] Brazilian greenand red propolis display activity against different fungalspecies of Trichophyton which cause dermatophytosis redPEE being more efficient than the green one [143] Also itwas shown that n-hexane extract of Brazilian red propolisdid not induce resistance in Candida spp In fact it wasactive against Candida spp resistant to antifungal agentslike fluconazole [148] Dota et al [144] evaluated the in vitroantifungal activity of PEE and propolis microparticles (PMs)obtained from a sample from Argentina against clinical yeastisolates of importance in the vulvovaginal candidiasis Calbicans and non-C albicanswere inhibited by PEE and PMswith small variation Additionally it was shown that Braziliangreen PEE has the ability to inhibit growth and biofilmformation by C albicans from vulvovaginal candidiasis [149]Another study showed fungicide action of propolis (PEEPWE propolis matricial microparticles (PMM) and propolissoluble dry extract after 6ndash8-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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EndocrinologyInternational Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
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Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 17
C albicansmorphotypes (yeast pseudohyphae and hyphae)PEE being the most potent followed by PSDE PM andPWE [150] Brazilian propolis induces C albicans cell deathmediated via metacaspase since the metacaspase mutant inC albicans showed reduced sensitivity to propolis and bythe Ras pathway Using C albicans deletion libraries it waspossible to screen several mutants in genes involved eitherin the morphological transitions or in the maintenance of aspecific morphotype that are more sensitive to propolis Toconclude the study the authors also showed that propolisbased gels and cream were partially able to control vulvo-vaginal candidiasis in a mouse model [151] These studies[144] strongly indicate that propolis has a great potential tocontrol vulvovaginal candidiasis representing a promisingalternative therapeutic strategy
46 Antitumour Activity Recognition of the hallmarks ofcancer affects the search and development of new meth-ods and therapeutic agents with a sufficiently large thera-peutic window to kill tumour cells while sparing normalcells In the last years the natural product propolis hasattracted a growing interest by a large number of researcherssince it contains a variety of phytochemical compoundsthat may act through multiple pathways to reduce thedevelopment and other malignant characteristics of cancercells
Recently several in vitro studies have demonstrated acytotoxic action of propolis from different geographic originand of some of its isolated compounds on various tumourcells In vivo studies also show a potential in the developmentof new antitumor agents since propolis administration tomammals (eg rats) does not lead to detectable side effects[3] Briefly this natural product can block specific oncogenesignalling pathways which in turn lead to a decrease in cellproliferation and growth and can also act by decreasing thecancer stem cell population increasing apoptosis exertingantiangiogenic effects and modulating the tumour microen-vironment [66 152 153] Table 8 summarizes the antitumouractivity of propolis from different geographic origin and itschemical constituents
Some researchers showed the effect of different types ofpropolis and its constituents on cancer cell growth prolifera-tion and apoptosisThe hexane extract of propolis fromThai-land collected by the stingless bee Trigona laeviceps whichhas a different behavior in propolis collection compared tothe honey bees exerts antiproliferative activity against fivetested cancer cell lines (Chago KATO-III SW620 BT474and Hep-G2) but not against the normal cell lines tested(HS27 fibroblast and CH-liver) [5] A sample of PEE fromPoland inhibited human malignant melanoma (Me45) andcolorectal cancer (HCT 116) cells growth as well as reducedcell size [154]Other studies reported the antitumor activity ofBrazilianPEE [155ndash158]which regulate the protein expressionof cyclin D1 B1 and cyclin dependent kinase (CDK) as wellas p21 in human prostate cancer cells significantly affectingproliferation [158]
Although propolis containing CAPE is different fromthose with artepillin C it is possible to obtain a similarinhibitory effect from both types The effect of CAPE on
different cancer cell lines was analysed and many of itseffects have been shown to be mediated through inhibitionof NF-120581B [66 159] CAPE can inhibit the proliferation of thecolorectal cell line SW480 by decreasing the 120573-catenin c-myc and cyclin D1 protein expression [160] Chuu et al [161]observed that CAPE suppressed the proliferation of LNCaPDU-145 and PC-3 human prostate cancer cells in a dose-dependent manner and also inhibited the tumour growthof LNCaP xenografts in nude mice It was suggested that itacted through inhibition of p70S6K (an intermediary of thePI3KAKTpathway responsible for the protein synthesis) andsome Akt signalling networks Wu et al [162] demonstratedthat CAPE inhibits in vitro and in vivoMCF-7 andMDA-MB-231 tumour growthwithoutmuch effect on normalmammarycells by reducing the expression of growth and transcriptionfactors including NF-120581B Recently it was demonstrated thatCAPE effect on genes that are associated with tumour cellgrowth and survival is related in part to its role as a histonedeacetylase inhibitor [163]
As previously said propolis can also act by decreasingthe cancer stem cell population Using the putative CD44(+)CD24 (minuslow) breast cancer stem cells able to generatemammospheres from single cells Omene et al [164] showedthat CAPE caused a dose-dependent inhibition of cancerstem cells self-renewal progenitor formation and clonalgrowth
Concerning cell death some in vitro studies showeddifferent sensitivities of tumour cells to propolis extractsPWE from Iraq inhibits the proliferation of HL-60 cellsand leads to downregulation of Bcl-2 and activation of Bax[13] Alizadeh et al [165] investigated the protective effectsof Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-(MNNG-) initiated gastric cancer in rats Results showedthat tumour incidence the number of lesions structuralabnormalities and beta-catenin of the animals group treatedwith PEE significantly declined compared with the controlPEE also induced the expression of proapoptotic Bax andreduced antiapoptotic Bcl-2 expression Propolis inhibitscolony formation potential and promotes necrotic changes inHCT-116 cells and decreases mitotic cells and increases p53and Ki-67 expression in HCT-116 tumor-bearing mice [13]Szliszkarsquos group have performed many studies to analyze theantitumour effect of different propolis and its constituentson prostate cancer cells (LNCaP and DU145) [166ndash168]Brazilian green PEE sensitized these cells to TRAIL-induceddeath enhanced the expression of TRAIL-R2 and decreasedthe activity of NF-120581B in LNCaP cells [167] Cotreatment ofTRAIL with artepillin C induced the significant activation ofcaspase-8 and caspase-3 as well as a significant disruption ofthe mitochondrial membrane potential [169] Many studieshave been conducted to understand the pathways involvedin the apoptotic effect of CAPE CAPE induces cell cyclearrest and apoptosis and reduces expression of NF-120581B inMDA-MB-231 and MCF-7 human breast cancer cells [162]In PC3 prostate cancer cells CAPE induced apoptosis in adose-dependent manner that was associated with the loss ofexpression of the inhibitors of apoptosis cIAP-1 cIAP-2 andXIAP [170] Cavaliere et al [171] showed that CAPE treatment
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
18 Evidence-Based Complementary and Alternative Medicine
Table8Antitu
moralactiv
ityof
prop
olisandits
chem
icalconstituents
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Thailand
Prop
olisfro
msting
lessbeeT
rigona
laevice
psHexanee
xtract
Colon
(SW620)breast(BT
474)hepatic
(Hep-G
2)lun
g(C
hago)andsto
mach(K
ato-III)
cells
Normalcelllin
esliver
(CH-liver)andfib
roblast
(HS-27)
Highantip
roliferativea
ctivity
againstthe
fivec
ancerc
elllines
andlow
cytotoxica
ctivity
onthen
ormalcelllin
es[5]
Poland
European
prop
olisPopu
lus
nigraandsome
specieso
fBetula
albaA
lnus
glutin
osaAe
sculus
hippocastanu
mand
Fagussylv
atica
PEE
Hum
anmalignant
melanom
acelllineM
e45
colorectalcancer
celllin
eHCT
116Inhibitio
nof
cellgrow
thandredu
ctionof
cellsiz
eofthe
teste
dcancer
cells
[154]
Synthesiz
ed
Characteris
ticof
prop
olisfro
mthe
Pacific
region
Th
ailand
Africa
Australiaand
Brazil
Prenylated
flavano
nes
Prostatecancer
celllin
esPC
-3andDU-145
Hum
anhepatomac
elllineH
ep-3B
Indu
ctionof
amorep
otentcytotoxicity
againstthe
PC-3
celllin
ethan
5-flu
rouracilindu
ctionof
apop
tosis
[45]
Characteris
ticof
European
prop
olis
CAPE
C6celllin
eesta
blish
edfro
mag
liomag
enerated
byintravenou
sexp
osureo
fmaleW
istar
ratsto
N-nitrosom
ethylureaB
ALB
c-numice
Inhibitio
nof
C6gliomac
ellsgrow
thincreaseinthep
ercentageo
fcellsin
the
G0G1p
haseand
decrease
inthep
rotein
levelofh
yperph
osph
orylated
pRb
increase
incyclindepend
entk
inaseinh
ibito
rsp21p27andp16decrease
intumor
grow
thin
xeno
graft
sredu
ctionof
then
umbero
fmito
ticcells
and
proliferatin
gcellnu
clear
antig
en-(PC
NA-
)positive
cells
inC6
glioma
[206]
HL-60
celllin
eIndu
ctionof
apop
tosis
byactiv
ationof
caspase-3do
wnregulationof
Bcl-2
and
upregu
latio
nof
Bax
[207]
Brazil
Characteris
ticof
Brazilian
prop
olis
Drupanin
baccharin
((E)-3-prenyl-4
-(23-
dihydrocinnamoyloxy)
cinn
amicacid)a
ndartepillinC(isolated
from
PEEs
ofprop
olis)
Hum
anleuk
emiacelllin
eHL-60colon
cancer
celllin
eSW480
Inhibitio
nof
cells
grow
thpromotionof
morph
ologicalchangesa
ndnu
cleosom
alDNAfragmentatio
n(artepillin
Cgtbaccharingtdrup
anin)
[208]
Redprop
olisD
ecastaphyllum
Methano
licextract
Hum
anpancreaticcancer
cells
(PANC-
1)Killing
100
ofPA
NC-
1cellsin
then
utrie
nt-depriv
edcond
ition
[157]
Green
prop
olisB
dracun
culifolia
PEE
DU145andPC
-3celllin
es
telomerase-im
mortalized
prim
aryhu
man
prostatecancer-derived
cell(RC-
58ThSA
4)
andprim
aryhu
man
prostateepith
elialcells
(PrEC)
Inhibitio
nof
human
prostatecancer
cells
proliferatio
nby
regu
latin
gthe
proteinexpressio
nof
cyclinD1B1
andcyclindepend
entk
inase(CD
K)p21
[158]
Green
prop
olisB
dracun
culifolia
Baccharin
beturetol
kaem
pferide
isosaku
ranetin
and
drup
anin
(isolated
from
PEE)
Hum
anem
bryonick
idney293(H
EK293)
cell
HCT
116celllin
e
Inhibitio
nof
HIF-1120572glucose
transporter1hexok
inase2
and
vascular
endo
thelialgrowth
factor
A(V
EGF-A)expression
exhibitin
ganti-angiogenic
effectsin
thec
hick
chorioallantoicm
embrane
[209]
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
scells
Indu
ctionof
apop
tosis
intube-fo
rmingendo
thelialcellsthroug
hthe
inactiv
ationof
thes
urvivalsignalE
RK12
andby
thea
ctivationof
caspase-3
[175]
Green
prop
olisB
dracun
culifolia
PWE
FemaleW
istar
rats
Inhibitio
nof
angiogenesisin
N-butyl-(-4-hydroxybu
tyl)nitro
samine-
(BBN
-)indu
cedratb
ladd
ercancer
[210]
Redprop
olisD
ecastaphyllum
PEE
Hum
anim
mortalized
endo
thelial-likec
ellline
EAhy926renalcellcarcinom
acelllineR
CC4
andmou
seem
bryonics
tem
celllin
eCGR
Redu
ctionof
migratio
nandsproutingof
endo
thelialcells
andattenu
ationof
newbloo
dvessels
form
ation
decrease
inthed
ifferentiatio
nof
embryonics
tem
cells
into
CD31
positivec
ells
decrease
inHIF1-120572
proteinaccumulationwhich
attenu
ates
VEG
Fgene
expressio
nincreasesthe
vonHippel-L
indau-
(pVHL-)
depend
entp
roteasom
aldegradationof
HIF1-120572
and
downregulates
Cdc42
proteinexpressio
n
[211]
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
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[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
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[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
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24 Evidence-Based Complementary and Alternative Medicine
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[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
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[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
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Evidence-Based Complementary and Alternative Medicine 25
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[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
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[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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ObesityJournal of
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Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 19
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Brazil
Green
prop
olisB
dracun
culifolia
PEE
Hum
anum
bilicalvein
endo
thelialcells
(HUVEC
s)N
F1-deficientM
PNST
(S-462)and
NF2-deficientschwanno
ma(
HEI-193)celllines
Femalen
unu
mice
Blocking
PAK1
signalin
gselectively
with
outaffectingAKT
sup
pressin
galmost
completely
theg
rowth
ofhu
man
neurofi
brom
atosistumor
xeno
graft
sinmice
[156]
Synthesiz
edCh
aracteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
HUVEC
sFemaleICR
mice
Redu
ctionof
then
umbero
fnew
lyform
edvessels
invivo
Supp
ressionof
HUVEC
sproliferationandinhibitio
nof
tube
form
ation
[174]
PurchasedWakoPu
reCh
emicalsInd
ustries
(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
C
Brazil
Green
prop
olisB
dracun
culifolia
PEE
LNCa
Pcelllin
e
Sensitizing
TRAIL-resistantL
NCa
Pcells
toTR
AIL-in
ducedapop
tosis
Indu
ctionof
asignificantd
isrup
tionof
ΔΨm
Enhancingthee
xpressionof
TRAIL-R2anddecreasin
gthea
ctivity
ofNF-120581B
Artepillin
Cqu
ercetin
kaempferoland
p-coum
aricacid
stron
glycoop
erating
with
TRAIL
toindu
ceapop
tosis
[167]
PurchasedAlexis
Biochemicals(SanDiego
CAU
SA)
Characteris
ticof
Brazilian
prop
olis
Quercetinkaempferoland
p-coum
aricacid
PurchasedWakoPu
reCh
emicals(OsakaJapan)
Artepillin
C
Brazil
Redprop
olisD
ecastaphyllum
PEE
MCF
-7celllin
eRe
ducing
cellviabilitythroug
hindu
ctionof
mito
chon
driald
ysfunctio
ncaspase-3activ
ityand
DNAfragmentatio
nandincrease
inexpressio
nof
CCAAT
enh
ancer-bind
ingproteinho
mologou
sprotein
(CHOP)
[212]
PurchasedAp
iCoLtd
Gifu
Japan
Characteris
ticof
European
prop
olis
CAPE
PurchasedSigm
aAldric
hCo
Characteris
ticof
European
prop
olis
CAPE
LNCa
P104-SDU-145and
PC-3
celllin
esMaleB
ALB
cmice
Supp
ressingtheg
rowth
ofLN
CaPDU-145and
PC-3
andinhibitin
gthetum
orgrow
thof
LNCa
Pxeno
graft
spo
ssibleinhibitio
nof
p70S6K
andsomeA
ktsig
nalin
gnetworks
[161]
PC-3
celllin
e
Supp
ressingproliferatio
ncolony
form
ation
andcellcycle
progression
decrease
inproteinexpressio
nof
cyclinD1cyclinE
SKP2
c-M
ycA
kt1Akt2
Akt3totalA
ktm
TOR
andBc
l-2R
bas
wellasp
hospho
rylationof
Rb
ERK1
2A
ktm
TOR
GSK
3aG
SK3band
PDK1
and
increase
inKL
F6and
p21C
ip1proteinexpressio
n
[213]
Breastcelllin
esMDA-
MB-231MCF
-7M
CF-10A
andMCF
-12A
Bovine
capillary
endo
thelial(BC
E)cells
Female(Ncr-nu-nu
)mice
Inhibitio
nof
invitro
andin
vivo
MCF
-7andMDA-
MB-231tum
orgrow
thwith
outm
ucheffecto
nno
rmalmam
marycellsind
uctio
nof
cellcycle
arrest
andapop
tosis
bydo
wnregulationof
Bcl-2
proteinsreductio
nof
NF-120581Band
mdr-1gene
expressio
nandsupp
ressionof
VEG
Fprod
uctio
nby
MDA-
231cells
andform
ationof
capillary-like
tubesb
yendo
thelialcells
[162]
Breastcancer
celllin
esMDA-
MB-231MCF
-7and
SKBR
3
Prom
otionof
anaccumulationof
acetylated
histo
neproteins
inMCF
-7(ER+
)andMDA-
MB-231(ERminusPRminus
Her2minus
)decrease
ofER
andPR
inMCF
-7cells
andup
regu
latio
nof
ERanddecrease
ofEG
FRin
MDA-
MB-231cells
redu
ction
ofHer2proteinin
SKBR
3(H
er2+
)cells
[163]
Hum
anoralsquamou
scellcarcino
maT
W26
Supp
ressionof
cellproliferatio
nandcolony
form
ation
decrease
ofG1p
hase
cellpo
pulatio
nincrease
ofG2M
phasec
ellp
opulation
indu
ctionof
apop
tosis
decreaseo
fAktA
kt1Akt2Akt3ph
osph
o-Akt
Ser473
phosph
o-Akt
Thr3
08G
SK3120573
FOXO
1FO
XO3apho
spho
-FOXO
1Thr24
phosph
o-Fo
xO3a
Thr32NF-120581B
phosph
o-NF-120581BSer536R
bph
osph
o-Rb
Ser807811
Skp2and
cyclinD1andincrease
ofcellcycle
inhibitorp
27Kip
[214]
MDA-
MB-231cellline
Inhibitio
nof
cancer
stem
cells
self-renewalprogenitorformation
andclo
nal
grow
thanddecrease
ofCD
44levels
[164
]
Hum
anhepatocellu
larc
arcino
mac
ellline
SK-H
ep1
Supp
ressionof
thea
dhesionandinvasio
npo
tentialofthe
cells
byinhibitin
gcompletely
thee
xpressionof
MMP-2andmetalloproteinase-9
(MMP-9)
and
theN
F-120581B
[172]
Hum
anfib
rosarcom
acelllineH
T1080
Decreaseo
fMMPandtissueinh
ibito
rmetalloproteinase-2
(TIM
P-2)
mRN
Alevels
downregulationof
MMP-2andMMP-9expressio
ninhibitio
nof
MMP-2activ
itydecreaseo
finvasion
motilitycellm
igratio
nandcolony
form
ation
[215]
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Research and TreatmentAIDS
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
20 Evidence-Based Complementary and Alternative Medicine
Table8Con
tinued
Orig
inProp
olistypeplant
source
Type
ofextractisolated
compo
und(s)
Speciescells
Effect
References
Turkey
Mediterranean
prop
olisPopu
lus
sppE
ucalyptusspp
andCa
staneasativa
PEE
MCF
-7celllin
eIncrease
ofapop
tosis
throug
hthec
aspase
pathway
[216]
Iraq
European
prop
olisPopu
lus
nigra
PWE
HL-60
celllin
ecoloncancer
cellHCT
-116
Femalea
thym
icFo
xN1-n
unu
mice
Inhibitio
nof
HL-60
cells
proliferatio
nandindu
ctionof
apop
tosis
bydo
wnregulatingBc
l-2proteinandup
regu
latingBa
xinhibitio
nof
HCT
-116
cells
colony
form
ationpo
tentialand
prom
otionof
necroticchangesdecrease
ofmito
ticcells
andincrease
ofp53andKi-67expressio
nin
HCT
-116
tumor-bearin
gmice
[13]
Iran
European
prop
olisPoplar
spp
Ferulaovina
PEE
MaleW
istar
rats
Decreaseo
ftum
ourincidencenum
bero
flesionsstructuralabn
ormalities
andbeta-catenin
andindu
ctionof
proapo
ptoticBa
xexpressio
nandredu
ction
ofantia
poptoticBc
l-2expressio
n[165]
Provided
byWakoPu
reCh
emicals(OsakaJapan)
Characteris
ticof
Brazilian
prop
olis
Artepillin
CLN
CaPcelllin
eIndu
ctionof
caspase-8andcaspase-3activ
ationanddisrup
tionof
mito
chon
drialm
embranep
otentia
lbyac
otreatmentw
ithTR
AIL
and
artepillinC
[169]
Purchased
Characteris
ticof
European
prop
olis
CAPE
MCF
-7celllin
eIndu
ctionof
apop
tosis
viaF
assig
nalindu
ctionof
Baxproteinandactiv
ation
ofcaspases
andMAPK
family
proteins
p38andJN
K[217]
PurchasedCa
lbiochem
(San
DiegoC
AU
SA)
Characteris
ticof
European
prop
olis
CAPE
Lymph
oblasto
idcelllin
ePL104
Indu
ctionof
apop
tosis
throug
hph
osph
atidylserin
e(PS
)exp
osurea
ndnu
clear
fragmentatio
nIncrease
ofsub-G1D
NAcontentdo
wnregulationof
survivingandBc
l-2expressio
nandincrease
ofBA
Xproteins
levels
indu
ctionof
mito
chon
drial
mem
branep
otentia
l(Δ120595m)collapseindu
ctionof
cytochromec
releasefrom
mito
chon
driaandindu
ctionof
caspases
37and9activ
ation
[171]
China
European
prop
olisPopu
lus
nigra
PEE
HUVEC
sInhibitio
nof
VEG
Fexpressio
n[179]
PurchasedAp
iCoLtd
(Gifu
Japan)
Characteris
ticof
European
prop
olis
CAPE
Korea
European
prop
olisPopu
lus
nigra
PEE
Fertilizedchickeneggs
Calfpu
lmon
aryarteria
lend
othelial(CP
AE)
cells
Inhibitio
nof
angiogenesisin
chickem
bryo
chorioallantoicm
embranea
ndinhibitio
nof
CPAEcells
proliferatio
n[176]
Synthesiz
edCh
aracteris
ticof
European
prop
olis
CAPE
Portugal(Serrad
eBornes
andFu
ndao)
European
prop
olisPopu
lus
nigra
Methano
licextract
Normalandcancerou
srenalcells
deriv
edfro
mhu
man
renalcellcarcino
map
atientshu
man
renal
carcinom
acelllineA
-498
Inhibitio
ntumor
cells
grow
thexhibitin
gselectivetoxicity
againstm
alignant
cells
comparedto
norm
alcells
[64]
(Ang
adoHeroısm
oAzores)
PEEandhexane
chloroform
and
resid
ual
ethano
lextractfractio
nsob
tained
from
theP
EE
Hum
ancolorectaladenocarcino
mac
ellline
HCT
-15
Allthes
amples
exhibitin
gcytotoxice
ffectagainsttum
orcellschloroform
fractio
ndecreasin
gcellviabilitypromotingcelldeathanddistu
rbingtumor
cellglycolyticmetabolism
[218]
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] M Gordaliza ldquoNatural products as leads to anticancer drugsrdquoClinical and Translational Oncology vol 9 no 12 pp 767ndash7762007
[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Disease Markers
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OncologyJournal of
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Research and TreatmentAIDS
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Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 21
of lymphoblastoid cell line PL104 induced apoptosis throughthe mitochondrial intrinsic pathway
It has been known that cancer microenvironment isvery important for carcinogenesis and it consists of stromalendothelial immune and cancer cells Natural productslike propolis and their constituents have been shown tointerfere with this symbiosis It was demonstrated by Lee et al[172] that CAPE could effectively suppress the adhesion andinvasion potential of human hepatocellular carcinoma cells(SK-Hep1) by inhibiting the expression ofMMP-2 andMMP-9 and NF-120581B
Angiogenesis has a crucial role in tumour growth dueto the requirement of oxygen and nutrients to sustain rapiduncontrolled proliferation and metastization Both tumourand stromal cells can secrete proangiogenic factors thatstimulate the formation andmaintenance of new vessels suchas vascular endothelial growth factor (VEGF) [173] BrazilianPEE could significantly reduce the number of newly formedvessels and suppress the proliferation of human umbilicalvein endothelial cells (HUVECs) [174] this antiangiogeniceffect being mainly mediated via inducing apoptosis in tube-forming endothelial cells through the inactivation of the sur-vival signal ERK12 [175] Yun et al [176] observed that CAPEinhibited angiogenesis using the in vivo assay chick embryochorioallantoic membrane (CAM) CAPE also suppressesVEGF formation by MDA-MB-231 cells and formation ofcapillary-like tubes by endothelial cells [162 177] Extractsof propolis containing artepillin C and CAPE significantlyreduced the newly formed vessels and expression of MMPsand VEGF production from various cells [178] and inaccordance with this study Izuta et al [179] described thatCAPE promotes inhibition of VEGF expression in HUVECcells
The first study on the antitumor activity of Portuguesepropolis was only performed in 2010 Using normal andcancerous renal cells derived from human renal cell carci-noma (RCC) patients in addition to A-498 cell line Valenteet al [64] showed that methanolic extract of Portuguesepropolis exhibited selective toxicity against malignant cellscompared to normal cells and in vitro RCC growth wasstrongly inhibited Recently our group demonstrated theantitumour and antiangiogenic activity of the ethanol extractof Pereiro propolis (P10EE) collected in the district ofGuarda Portugal P10EE affects cell viability of differenttumour cells MDA-MB-231 (breast) and DU145 (prostate)being two of the most sensitive ones but was less cytotoxicagainst nontumour cells and fibroblasts Also it signifi-cantly decreased MDA-MB-231 and DU145 cell prolifera-tion and migration along time with cell cycle changesand increased cell death The significant increase observedin glucose consumption and lactate production could beexplained in MDA-MB-231 by an increased expression ofhypoxia inducible factor-1120572 pyruvate dehydrogenase kinaseglucose transporter 1 lactate dehydrogenase and carbonicanhydrase Furthermore P10EE induced a decrease inHBMECs total biomass and proliferation and decreasedvessel sprouting in the chicken chorioallantoic membrane[23]
5 Conclusions
From ancient to modern times herbs and other plant prod-ucts have been widely used as medicinal agents first in folkmedicine and other activities in many parts of the world andlater developed and improved on a scientific basis into drugsthat are used in the health system Propolis is one of thefew natural products that has maintained its popularity overa long period of time As reviewed here propolis containsa broad spectrum of compounds that may be useful in thetreatment of different pathological conditions In fact there ismuch literature that deals with the in vitro and in vivo biologi-cal properties of propolisThis wide range of bioactivities thecontinuous discovery of new compounds the long history ofpropolis use and its safety profile make propolis a potentialcandidate for drug discovery that may be useful in severalclinical scenarios Nevertheless it is necessary to make aneffort to standardize propolis composition since it seems thatpropolis biological properties and chemical composition notonly are variable but also are strictly linked In our opinionpropolis extracts may be important economically and wouldallow a relatively inexpensive treatment in different diseaseshowever to promote its use in modern medicine it will benecessary to identify and isolate the bioactive compoundsto be tested separately or in combination with other drugsalready available
Drug discovery does not consist only of the isolationof bioactive lead compounds from the natural sources Infact this process continues outside the academic laboratoriesthrough preclinical studies followed by clinical trials Thusdespite the in vitro and in vivo assays which provide newvaluable information on propolis biological properties andmechanisms of action it will be necessary to analyse theeffectiveness of propolis clinically to complement the basicresearch available and to evaluate the potential of propolis inhuman health promotion
Abbreviations
CAPE Caffeic acid phenethyl esterPEE Propolis ethanol extractPWE Propolis water extractRNS Reactive nitrogen speciesROS Reactive oxygen speciesVEGF Vascular endothelial growth factor
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
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[2] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
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[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
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[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
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[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
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[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
22 Evidence-Based Complementary and Alternative Medicine
[3] M A E Watanabe M K Amarante B J Conti and J MSforcin ldquoCytotoxic constituents of propolis inducing anticancereffects a reviewrdquo Journal of Pharmacy and Pharmacology vol63 no 11 pp 1378ndash1386 2011
[4] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[5] S Umthong P Phuwapraisirisan S Puthong andC ChanchaoldquoIn vitro antiproliferative activity of partially purified Trigonalaeviceps propolis from Thailand on human cancer cell linesrdquoBMC Complementary and Alternative Medicine vol 11 article37 2011
[6] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011
[7] MMarcucci ldquoPropolis chemical composition biological prop-erties and therapeutic activityrdquoApidologie vol 26 no 2 pp 83ndash99 1995
[8] Y Barlak O Deger M Colak S C Karatayli A M Bozdayiand F Yucesan ldquoEffect of Turkish propolis extracts on proteomeof prostate cancer cell linerdquo Proteome Science vol 9 article 742011
[9] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005
[10] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000
[11] S M Cardoso M Ribeiro I L Ferreira and A Cristina RegoldquoNortheast Portuguese propolis protects against staurosporineand hydrogen peroxide-induced neurotoxicity in primary cor-tical neuronsrdquo Food and Chemical Toxicology vol 49 no 11 pp2862ndash2868 2011
[12] H Fokt A Pereira A M Ferreira A Cunha and C AguiarldquoHow do bees prevent hive infections The antimicrobial prop-erties of propolisrdquo in Current Research Technology and Educa-tion Topics in AppliedMicrobiology andMicrobial BiotechnologyA Mendez-Vilas Ed vol 1 of Microbiology Book SeriesmdashNumber 2 pp 481ndash493 2010
[13] G M Sulaiman A H Adrsquohiah K W Al-Sammarrae et alldquoAssessing the anti-tumour properties of Iraqi propolis in vitroand in vivordquo Food and Chemical Toxicology vol 50 no 5 pp1632ndash1641 2012
[14] N Orsolic S Terzic Z Mihaljevic L Sver and I BasicldquoEffects of local administration of propolis and its polyphenoliccompounds on tumor formation and growthrdquo Biological andPharmaceutical Bulletin vol 28 no 10 pp 1928ndash1933 2005
[15] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002
[16] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998
[17] M L Khalil ldquoBiological activity of bee propolis in health anddiseaserdquo Asian Pacific Journal of Cancer Prevention vol 7 no 1pp 22ndash31 2006
[18] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012
[19] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001
[20] S I Falcao M Vilas-Boas L M Estevinho C Barros M R MDomingues and S M Cardoso ldquoPhenolic characterization ofNortheast Portuguese propolis usual and unusual compoundsrdquoAnalytical and Bioanalytical Chemistry vol 396 no 2 pp 887ndash897 2010
[21] S I Falcao N Vale P Gomes et al ldquoPhenolic profilingof Portuguese propolis by LC-MS spectrometry uncommonpropolis rich in flavonoid glycosidesrdquo Phytochemical Analysisvol 24 no 4 pp 309ndash318 2013
[22] L-P Sun A-L Chen H-C Hung et al ldquoChrysin a histonedeacetylase 8 inhibitor with anticancer activity and a suitablecandidate for the standardization of Chinese propolisrdquo Journalof Agricultural and Food Chemistry vol 60 no 47 pp 11748ndash11758 2012
[23] R Silva-Carvalho V Miranda-Goncalves A M Ferreira etal ldquoAntitumoural and antiangiogenic activity of Portuguesepropolis in in vitro and in vivo modelsrdquo Journal of FunctionalFoods vol 11 pp 160ndash171 2014
[24] M P Popova K Graikou I Chinou and V S Bankova ldquoGC-MS profiling of diterpene compounds in mediterranean propo-lis fromGreecerdquo Journal of Agricultural andFoodChemistry vol58 no 5 pp 3167ndash3176 2010
[25] O G Celemli F Hatjina L Charistos A Schiesser and AOzkirim ldquoMore insight into the chemical composition of Greekpropolis differences and similarities with Turkish propolisrdquoZeitschrift fur Naturforschung C vol 68 no 11-12 pp 429ndash4382013
[26] V Bankova M Popova S Bogdanov and A-G SabatinildquoChemical composition of European propolis expected andunexpected resultsrdquo Zeitschrift fur Naturforschung Section Cvol 57 no 5-6 pp 530ndash533 2002
[27] M Popova B Trusheva D Antonova et al ldquoThe specificchemical profile of Mediterranean propolis from Maltardquo FoodChemistry vol 126 no 3 pp 1431ndash1435 2011
[28] M Velikova V Bankova K Sorkun S Houcine I Tsvetkovaand A Kujumgiev ldquoPropolis from the Mediterranean regionchemical composition and antimicrobial activityrdquoZeitschrift furNaturforschung C vol 55 no 9-10 pp 790ndash793 2000
[29] S Silici M Unlu and G Vardar-Unlu ldquoAntibacterial activityand phytochemical evidence for the plant origin of Turkishpropolis from different regionsrdquoWorld Journal of Microbiologyand Biotechnology vol 23 no 12 pp 1797ndash1803 2007
[30] N Duran M Muz G Culha G Duran and B Ozer ldquoGC-MSanalysis and antileishmanial activities of two Turkish propolistypesrdquo Parasitology Research vol 108 no 1 pp 95ndash105 2011
[31] A L Piccinelli T Mencherini R Celano et al ldquoChemicalcomposition and antioxidant activity of Algerian propolisrdquoJournal of Agricultural and Food Chemistry vol 61 no 21 pp5080ndash5088 2013
[32] Y K Park S M Alencar and C L Aguiar ldquoBotanical originand chemical composition of Brazilian propolisrdquo Journal ofAgricultural and Food Chemistry vol 50 no 9 pp 2502ndash25062002
[33] C O da Silva Frozza C S C Garcia G Gambato et alldquoChemical characterization antioxidant and cytotoxic activitiesof Brazilian red propolisrdquo Food andChemical Toxicology vol 52pp 137ndash142 2013
[34] A Daugsch C S Moraes P Fort and Y K Park ldquoBrazilianred propolismdashchemical composition and botanical originrdquo
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 23
Evidence-Based Complementary and Alternative Medicine vol5 no 4 pp 435ndash441 2008
[35] B B Silva P L Rosalen J A Cury et al ldquoChemical compositionand botanical origin of red propolis a new type of Brazil-ian propolisrdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 3 pp 313ndash316 2008
[36] O Cuesta-Rubio B A Frontana-Uribe T Ramırez-Apanand J Cardenas ldquoPolyisoprenylated benzophenones in Cubanpropolis biological activity of nemorosonerdquo Zeitschrift furNaturforschung C vol 57 no 3-4 pp 372ndash378 2002
[37] B Trusheva M Popova H Naydenski I Tsvetkova J GRodriguez andV Bankova ldquoNew polyisoprenylated benzophe-nones from Venezuelan propolisrdquo Fitoterapia vol 75 no 7-8pp 683ndash689 2004
[38] F A Tomas-Barberan C Garcıa-Viguera P Vit-Olivier FFerreres and F Tomas-Lorente ldquoPhytochemical evidence forthe botanical origin of tropical propolis from VenezuelardquoPhytochemistry vol 34 no 1 pp 191ndash196 1993
[39] A Abu-Mellal N Koolaji R K Duke V H Tran and CC Duke ldquoPrenylated cinnamate and stilbenes from KangarooIsland propolis and their antioxidant activityrdquo Phytochemistryvol 77 pp 251ndash259 2012
[40] VH Tran RKDukeAAbu-Mellal andCCDuke ldquoPropoliswith high flavonoid content collected by honey bees fromAcacia paradoxardquo Phytochemistry vol 81 pp 126ndash132 2012
[41] E L Ghisalberti P R Jefferies R Lanteri and J MatisonsldquoConstituents of propolisrdquo Experientia vol 34 no 2 pp 157ndash158 1978
[42] C FMassaroM Katouli T Grkovic et al ldquoAnti-staphylococcalactivity of C-methyl flavanones from propolis of Australianstingless bees (Tetragonula carbonaria) and fruit resins ofCorymbia torelliana (Myrtaceae)rdquo Fitoterapia vol 95 pp 247ndash257 2014
[43] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004
[44] S Inui T Hosoya and S Kumazawa ldquoHawaiian propoliscomparative analysis and botanical originrdquo Natural ProductCommunications vol 9 no 2 pp 165ndash166 2014
[45] C-N Chen C-J Hsiao S-S Lee et al ldquoChemical modificationand anticancer effect of prenylated flavanones from Taiwanesepropolisrdquo Natural Product Research vol 26 no 2 pp 116ndash1242012
[46] B Trusheva M Popova E B Koendhori I Tsvetkova CNaydenski and V Bankova ldquoIndonesian propolis chemicalcomposition biological activity and botanical originrdquo NaturalProduct Research vol 25 no 6 pp 606ndash613 2011
[47] F Li S Awale H Zhang Y Tezuka H Esumi and S KadotaldquoChemical constituents of propolis from Myanmar and theirpreferential cytotoxicity against a human pancreatic cancer celllinerdquo Journal of Natural Products vol 72 no 7 pp 1283ndash12872009
[48] S Athikomkulchai S Awale N Ruangrungsi S Ruchirawatand S Kadota ldquoChemical constituents ofThai propolisrdquo Fitoter-apia vol 88 pp 96ndash100 2013
[49] V S Bankova R S Christov and A D Tejera ldquoLignansand other constituents of propolis from the canary islandsrdquoPhytochemistry vol 49 no 5 pp 1411ndash1415 1998
[50] A Petrova M Popova C Kuzmanova et al ldquoNew biologicallyactive compounds from Kenyan propolisrdquo Fitoterapia vol 81no 6 pp 509ndash514 2010
[51] M Popova R Dimitrova H T Al-Lawati I Tsvetkova H Naj-denski and V Bankova ldquoOmani propolis chemical profilingantibacterial activity andnewpropolis plant sourcesrdquoChemistryCentral Journal vol 7 no 1 article 158 2013
[52] A I Rushdi N Adgaba N I Bayaqoob et al ldquoCharacter-istics and chemical compositions of propolis from EthiopiardquoSpringerPlus vol 3 no 1 p 253 2014
[53] D Papachroni K Graikou I Kosalec H Damianakos VIngram and I Chinou ldquoPhytochemical analysis and biologicalevaluation of selectedAfrican propolis samples fromCameroonand CongordquoNatural Product Communications vol 10 no 1 pp67ndash70 2015
[54] T Zhang R Omar W Siheri et al ldquoChromatographic analysiswith different detectors in the chemical characterisation anddereplication of African propolisrdquo Talanta vol 120 pp 181ndash1902014
[55] A Kurek-Gorecka A Rzepecka-Stojko M Gorecki J StojkoM Sosada and G Swierczek-Zieba ldquoStructure and antioxidantactivity of polyphenols derived from propolisrdquo Molecules vol19 no 1 pp 78ndash101 2014
[56] F Scazzocchio F D DrsquoAuria D Alessandrini and F PantanellaldquoMultifactorial aspects of antimicrobial activity of propolisrdquoMicrobiological Research vol 161 no 4 pp 327ndash333 2006
[57] R M Ordonez I C Zampini M I N Moreno and MI Isla ldquoPotential application of Northern Argentine propolisto control some phytopathogenic bacteriardquo MicrobiologicalResearch vol 166 no 7 pp 578ndash584 2011
[58] J C Silva S Rodrigues X Feas and L M Estevinho ldquoAntimi-crobial activity phenolic profile and role in the inflammationof propolisrdquo Food and Chemical Toxicology vol 50 no 5 pp1790ndash1795 2012
[59] A Kujumgiev I Tsvetkova Y Serkedjieva V Bankova RChristov and S Popov ldquoAntibacterial antifungal and antiviralactivity of propolis of different geographic originrdquo Journal ofEthnopharmacology vol 64 no 3 pp 235ndash240 1999
[60] M Amoros C M O Simoes L Girre F Sauvager and MCormier ldquoSynergistic effect of flavones and flavonols againstherpes simplex virus type 1 in cell culture Comparison with theantiviral activity of propolisrdquo Journal of Natural Products vol55 no 12 pp 1732ndash1740 1992
[61] F Hu H R Hepburn Y Li M Chen S E Radloff andS Daya ldquoEffects of ethanol and water extracts of propolis(bee glue) on acute inflammatory animal modelsrdquo Journal ofEthnopharmacology vol 100 no 3 pp 276ndash283 2005
[62] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008
[63] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholicextracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010
[64] M J Valente A F Baltazar R Henrique L Estevinho andM Carvalho ldquoBiological activities of Portuguese propolisprotection against free radical-induced erythrocyte damage andinhibition of human renal cancer cell growth in vitrordquo Food andChemical Toxicology vol 49 no 1 pp 86ndash92 2011
[65] N Orsolic and I Basic ldquoImmunomodulation by water-solublederivative of propolis a factor of antitumor reactivityrdquo Journalof Ethnopharmacology vol 84 no 2-3 pp 265ndash273 2003
[66] G C-F Chan K-W Cheung and D M-Y Sze ldquoTheimmunomodulatory and anticancer properties of propolisrdquo
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
24 Evidence-Based Complementary and Alternative Medicine
Clinical Reviews in Allergy and Immunology vol 44 no 3 pp262ndash273 2013
[67] R C Calhelha S Falcao M J Queiroz M Vilas-Boas and IC Ferreira ldquoCytotoxicity of portuguese propolis the proximityof the in vitro doses for tumor and normal cell linesrdquo BioMedResearch International vol 2014 7 pages 2014
[68] V Sosa T Moline R Somoza R Paciucci H Kondoh and ME LLeonart ldquoOxidative stress and cancer an overviewrdquo AgeingResearch Reviews vol 12 no 1 pp 376ndash390 2013
[69] T B Salmon B A Evert B Song and PWDoetsch ldquoBiologicalconsequences of oxidative stress-induced DNA damage inSaccharomyces cerevisiaerdquoNucleic Acids Research vol 32 no 12pp 3712ndash3723 2004
[70] M Viuda-Martos Y Ruiz-Navajas J Fernandez-Lopez andJ A Perez-Alvarez ldquoFunctional properties of honey propolisand royal jellyrdquo Journal of Food Science vol 73 no 9 pp R117ndashR124 2008
[71] Z Wu Y Zhao and B Zhao ldquoSuperoxide anion uncouplingproteins and Alzheimerrsquos diseaserdquo Journal of Clinical Biochem-istry and Nutrition vol 46 no 3 pp 187ndash194 2010
[72] F J Pashkow ldquoOxidative stress and inflammation in heartdisease do antioxidants have a role in treatment andor preven-tionrdquo International Journal of Inflammation vol 2011 ArticleID 514623 9 pages 2011
[73] R Schnabel and S Blankenberg ldquoOxidative stress in cardiovas-cular disease successful translation from bench to bedsiderdquoCirculation vol 116 no 12 pp 1338ndash1340 2007
[74] W Ladiges J Wanagat B Preston L Loeb and P RabinovitchldquoA Mitochondrial view of aging reactive oxygen species andmetastatic cancerrdquo Aging Cell vol 9 no 4 pp 462ndash465 2010
[75] M A Nader D S El-Agamy and G M Suddek ldquoProtectiveeffects of propolis and thymoquinone on development ofatherosclerosis in cholesterol-fed rabbitsrdquo Archives of Pharma-cal Research vol 33 no 4 pp 637ndash643 2010
[76] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 supplement pp 215Sndash217S 2005
[77] N Almaraz-Abarca M da Graca Campos J A Avila-Reyes NNaranjo-Jimenez J Herrera Corral and L S Gonzalez-ValdezldquoAntioxidant activity of polyphenolic extract of monofloralhoneybee-collected pollen from mesquite (Prosopis julifloraLeguminosae)rdquo Journal of Food Composition and Analysis vol20 no 2 pp 119ndash124 2007
[78] S Fabris M Bertelle O Astafyeva et al ldquoAntioxidant proper-ties and chemical composition relationship of europeans andBrazilians propolisrdquo Pharmacology amp Pharmacy vol 4 no 1pp 46ndash51 2013
[79] C M Mihai L A Marghitas D S Daniel S Dezmireanand L Barnutiu ldquoCorrelation between polyphenolic profileand antioxidant activity of propolis from Transylvaniardquo AnimalScience and Biotechnologies vol 44 no 2 pp 100ndash103 2011
[80] G G Duthie P T Gardner and J A M Kyle ldquoPlant polyphe-nols are they the newmagic bulletrdquoProceedings of theNutritionSociety vol 62 no 3 pp 599ndash603 2003
[81] H Yang Y Dong H Du H Shi Y Peng and X Li ldquoAntiox-idant compounds from propolis collected in Anhui ChinardquoMolecules vol 16 no 4 pp 3444ndash3455 2011
[82] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011
[83] P Bolfa R Vidrighinescu A Petruta et al ldquoPhotoprotectiveeffects of Romanian propolis on skin of mice exposed to UVBirradiationrdquo Food andChemical Toxicology vol 62 pp 329ndash3422013
[84] Z Talas I Ozdemir O Ciftci M Gulhan and A SavcildquoAntioxidant effect of ethanolic extract of propolis in liver ofL-name treated ratsrdquo Advances in Clinical and ExperimentalMedicine vol 24 no 2 pp 227ndash232 2015
[85] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002
[86] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004
[87] Y-J Chen A-C Huang H-H Chang et al ldquoCaffeic acidphenethyl ester an antioxidant from propolis protects periph-eral blood mononuclear cells of competitive cyclists againsthyperthermal stressrdquo Journal of Food Science vol 74 no 6 ppH162ndashH167 2009
[88] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010
[89] G Costa V Francisco M C Lopes M T Cruz and MT Batista ldquoIntracellular signaling pathways modulated byphenolic compounds application for new anti-inflammatorydrugs discoveryrdquo Current Medicinal Chemistry vol 19 no 18pp 2876ndash2900 2012
[90] O K Mirzoeva and P C Calder ldquoThe effect of propolis and itscomponents on eicosanoid production during the inflamma-tory responserdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 55 no 6 pp 441ndash449 1996
[91] A Rossi A Ligresti R Longo A Russo F Borrelli andL Sautebin ldquoThe inhibitory effect of propolis and caf-feic acid phenethyl ester on cyclooxygenase activity in J774macrophagesrdquo Phytomedicine vol 9 no 6 pp 530ndash535 2002
[92] S Chirumbolo ldquoThe role of quercetin flavonols and flavonesin modulating inflammatory cell functionrdquo Inflammation andAllergymdashDrug Targets vol 9 no 4 pp 263ndash285 2010
[93] E-H Park and J-H Kahng ldquoSuppressive effects of propolis inrat adjuvant arthritisrdquo Archives of Pharmacal Research vol 22no 6 pp 554ndash558 1999
[94] N Marquez R Sancho A Macho M A Calzado B L Fiebichand E Munoz ldquoCaffeic acid phenethyl ester inhibits T-cellactivation by targeting both nuclear factor of activated T-cellsand NF-120581B transcription factorsrdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 3 pp 993ndash1001 2004
[95] Y Naito M Yasumuro K Kondou and N Ohara ldquoAnti-inflammatory effect of topically applied propolis extractin carrageenan-induced rat hind paw edemardquo PhytotherapyResearch vol 21 no 5 pp 452ndash456 2007
[96] M Funakoshi-Tago K Okamoto R Izumi et al ldquoAnti-inflammatory activity of flavonoids in Nepalese propolis isattributed to inhibition of the IL-33 signaling pathwayrdquo Inter-national Immunopharmacology vol 25 no 1 pp 189ndash198 2015
[97] R M N Bezerra L F Veiga A C Caetano et al ldquoCaffeicacid phenethyl ester reduces the activation of the nuclear factorkappab pathway by high-fat diet-induced obesity in micerdquoMetabolism Clinical and Experimental vol 61 no 11 pp 1606ndash1614 2012
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 25
[98] S Juman N Yasui K Ikeda et al ldquoCaffeic acid phenethylester suppresses the production of pro-inflammatory cytokinesin hypertrophic adipocytes through lipopolysaccharide-stimulated macrophagesrdquo Biological and PharmaceuticalBulletin vol 35 no 11 pp 1941ndash1946 2012
[99] J L Machado A K Assuncao M C da Silva et alldquoBrazilian green propolis anti-inflammatory property by animmunomodulatory activityrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 157652 10 pages2012
[100] F Teles T M da Silva F P da Cruz Junior et al ldquoBrazilian redpropolis attenuates hypertension and renal damage in 56 renalablation modelrdquo PLoS ONE vol 10 no 1 Article ID e01165352015
[101] M C Bufalo I Ferreira G Costa et al ldquoPropolis andits constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-120581B and MAPK activa-tion in macrophagesrdquo Journal of Ethnopharmacology vol 149no 1 pp 84ndash92 2013
[102] G Valenzuela-Barra C Castro C Figueroa et al ldquoAnti-inflammatory activity and phenolic profile of propolis from twolocations in Region Metropolitana de Santiago Chilerdquo Journalof Ethnopharmacology vol 168 pp 37ndash44 2015
[103] L H Boudreau J Maillet L M LeBlanc et al ldquoCaffeic acidphenethyl ester and its amide analogue are potent inhibitors ofleukotriene biosynthesis in human polymorphonuclear leuko-cytesrdquo PLoS ONE vol 7 no 2 Article ID e31833 2012
[104] N Orsolic J Skuric D Crossed D Signikic and G StanicldquoInhibitory effect of a propolis on Di-n-Propyl Disulfide orn-Hexyl salycilate-induced skin irritation oxidative stress andinflammatory responses in micerdquo Fitoterapia vol 93 pp 18ndash302014
[105] C L Orsatti F Missima A C Pagliarone et al ldquoPropolisimmunomodulatory action in vivo on toll-like receptors 2 and4 expression and on pro-inflammatory cytokines production inmicerdquo Phytotherapy Research vol 24 no 8 pp 1141ndash1146 2010
[106] N Ivanovska H Neychev Z Stefanova V Bankova andS Popov ldquoInfluence of cinnamic acid on lymphocyte pro-liferation cytokine release and Klebsiella infection in micerdquoApidologie vol 26 no 2 pp 73ndash81 1995
[107] R O Orsi S R Funari A M V C Soares and et alldquoImmunomodulatory action of propolis onmacrophage activa-tionrdquo Journal of Venomous Animals and Toxins vol 6 no 2 pp205ndash219 2000
[108] A Sa-Nunes L H Faccioli and J M Sforcin ldquoPropolisLymphocyte proliferation and IFN-120574 productionrdquo Journal ofEthnopharmacology vol 87 no 1 pp 93ndash97 2003
[109] F Missima and J M Sforcin ldquoGreen Brazilian propolisaction on macrophages and lymphoid organs of chronicallystressed micerdquo Evidence-Based Complementary and AlternativeMedicine vol 5 no 1 pp 71ndash75 2008
[110] Syamsudin R M Dewi and Kusmardi ldquoImmunomodulatoryand in vivo antiplasmodial activities of propolis extractsrdquoAmerican Journal of Pharmacology and Toxicology vol 4 no3 pp 75ndash79 2009
[111] C L Orsatti and J M Sforcin ldquoPropolis immunomodulatoryactivity on TLR-2 and TLR-4 expression by chronically stressedmicerdquo Natural Product Research vol 26 no 5 pp 446ndash4532012
[112] L-C Wang Y-L Lin Y-C Liang et al ldquoThe effect of caffeicacid phenethyl ester on the functions of human monocyte-derived dendritic cellsrdquo BMC Immunology vol 10 article 392009
[113] M C Bufalo A P Bordon-Graciani B J Conti M de AssisGolim and J M Sforcin ldquoThe immunomodulatory effect ofpropolis on receptors expression cytokine production andfungicidal activity of human monocytesrdquo Journal of Pharmacyand Pharmacology vol 66 no 10 pp 1497ndash1504 2014
[114] MC Bufalo and JM Sforcin ldquoThemodulatory effects of caffeicacid on human monocytes and its involvement in propolisactionrdquo Journal of Pharmacy and Pharmacology vol 67 no 5pp 740ndash745 2015
[115] F Missima A C Pagliarone C L Orsatti and J M SforcinldquoThe effect of propolis on pro-inflammatory cytokines pro-duced by melanoma-bearing mice submitted to chronic stressrdquoJournal of ApiProduct amp ApiMedical Science vol 1 no 1 pp 11ndash15 2009
[116] T F Bachiega C L Orsatti A C Pagliarone and J M SforcinldquoThe effects of propolis and its isolated compounds on cytokineproduction by murine macrophagesrdquo Phytotherapy Researchvol 26 no 9 pp 1308ndash1313 2012
[117] S S da Silva S Thome Gda A H Cataneo et al ldquoBrazil-ian propolis antileishmanial and immunomodulatory effectsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 673058 7 pages 2013
[118] Y Okamoto T Hara T Ebato T Fukui and T MasuzawaldquoBrazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiationrdquo Inter-national Immunopharmacology vol 16 no 2 pp 178ndash183 2013
[119] G Gekker S Hu M Spivak J R Lokensgard and P KPeterson ldquoAnti-HIV-1 activity of propolis in CD4+ lymphocyteandmicroglial cell culturesrdquo Journal of Ethnopharmacology vol102 no 2 pp 158ndash163 2005
[120] M Amoros F Sauvager L Girre and M Cormier ldquoIn vitroantiviral activity of propolisrdquo Apidologie vol 23 no 3 pp 231ndash240 1992
[121] J Serkedjieva N Manolova and V Bankova ldquoAnti-influenzavirus effect of some propolis constituents and their analogues(esters of substituted cinnamic acids)rdquo Journal of NaturalProducts vol 55 no 3 pp 294ndash297 1992
[122] T Shimizu A Hino A Tsutsumi Y K Park WWatanabe andM Kurokawa ldquoAnti-influenza virus activity of propolis in vitroand its efficacy against influenza infection in micerdquo AntiviralChemistry and Chemotherapy vol 19 no 1 pp 7ndash13 2008
[123] P Schnitzler A Neuner S Nolkemper et al ldquoAntiviral activityand mode of action of propolis extracts and selected com-poundsrdquo Phytotherapy Research vol 24 supplement 1 pp S20ndashS28 2010
[124] G Sartori A P Pesarico S Pinton et al ldquoProtective effect ofbrown Brazilian propolis against acute vaginal lesions caused byherpes simplex virus type 2 in mice involvement of antioxidantand anti-inflammatory mechanismsrdquo Cell Biochemistry andFunction vol 30 no 1 pp 1ndash10 2012
[125] G R Coelho R ZMendonca KDVilar et al ldquoAntiviral actionof hydromethanolic extract of geopropolis from Scaptotrigonapostica against antiherpes simplex virus (HSV-1)rdquo Evidence-Based Complementary and Alternative Medicine vol 2015Article ID 296086 10 pages 2015
[126] S Tait A L Salvati N Desideri and L Fiore ldquoAntiviral activityof substituted homoisoflavonoids on enterovirusesrdquo AntiviralResearch vol 72 no 3 pp 252ndash255 2006
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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EndocrinologyInternational Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
26 Evidence-Based Complementary and Alternative Medicine
[127] J Shvarzbeyn and M Huleihel ldquoEffect of propolis and caffeicacid phenethyl ester (CAPE) on NF120581B activation by HTLV-1Taxrdquo Antiviral Research vol 90 no 3 pp 108ndash115 2011
[128] X Ma Z Guo Z Shen Y Liu J Wang and Y Fan ldquoTheanti-porcine parvovirus activity of nanometer propolis flavoneand propolis flavone in vitro and in vivordquo Evidence-BasedComplementary and Alternative Medicine vol 2015 Article ID472876 10 pages 2015
[129] J Ito F-R Chang H-K Wang et al ldquoAnti-AIDS agents48 Anti-HIV activity of moronic acid derivatives and thenew melliferone-related triterpenoid isolated from Brazilianpropolisrdquo Journal of Natural Products vol 64 no 10 pp 1278ndash1281 2001
[130] O K Mirzoeva R N Grishanin and P C Calder ldquoAntimi-crobial action of propolis and some of its components theeffects on growthmembrane potential andmotility of bacteriardquoMicrobiological Research vol 152 no 3 pp 239ndash246 1997
[131] K Cui W Lu L Zhu X Shen and J Huang ldquoCaffeic acidphenethyl ester (CAPE) an active component of propolisinhibits Helicobacter pylori peptide deformylase activityrdquo Bio-chemical and Biophysical Research Communications vol 435no 2 pp 289ndash294 2013
[132] R D Wojtyczka A Dziedzic D Idzik et al ldquoSusceptibility ofStaphylococcus aureus clinical isolates to propolis extract aloneor in combination with antimicrobial drugsrdquoMolecules vol 18no 8 pp 9623ndash9640 2013
[133] S Boisard A Le Ray A Landreau et al ldquoAntifungal andantibacterial metabolites from a French poplar type propolisrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 319240 10 pages 2015
[134] H Katircioglu and N Mercan ldquoAntimicrobial activity andchemical compositions of Turkish propolis from differentregionsrdquoAfrican Journal of Biotechnology vol 5 no 11 pp 1151ndash1153 2006
[135] R O Orsi A Fernandes Jr V Bankova and J M SforcinldquoAntibacterial effects of Brazilian and Bulgarian propolis andsynergistic effects with antibiotics acting on the bacterial DNAand folic acidrdquoNatural Product Research vol 26 no 4 pp 344ndash349 2012
[136] L Grenho J Barros C Ferreira et al ldquoIn vitro antimicrobialactivity and biocompatibility of propolis containing nanohy-droxyapatiterdquo Biomedical Materials vol 10 no 2 Article ID025004 2015
[137] V Seidel E Peyfoon D G Watson and J Fearnley ldquoCompara-tive study of the antibacterial activity of propolis from differentgeographical and climatic zonesrdquo Phytotherapy Research vol22 no 9 pp 1256ndash1263 2008
[138] L Monzote O Cuesta-Rubio M C Fernandez et al ldquoIn vitroantimicrobial assessment ofCubanpropolis extractsrdquoMemoriasdo Instituto Oswaldo Cruz vol 107 no 8 pp 978ndash984 2012
[139] L G Dias A P Pereira and L M Estevinho ldquoComparativestudy of different Portuguese samples of propolis pollinicsensorial physicochemical microbiological characterizationand antibacterial activityrdquo Food and Chemical Toxicology vol50 no 12 pp 4246ndash4253 2012
[140] S I Falcao N Vale P Cos et al ldquoIn vitro evaluationof portuguese propolis and floral sources for antiprotozoalantibacterial and antifungal activityrdquo Phytotherapy Researchvol 28 no 3 pp 437ndash443 2014
[141] C Ota C Unterkircher V Fantinato and M T ShimizuldquoAntifungal activity of propolis on different species of CandidardquoMycoses vol 44 no 9-10 pp 375ndash378 2001
[142] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002
[143] A B S Siqueira B S Gomes I Cambuim et al ldquoTrichophytonspecies susceptibility to green and red propolis from BrazilrdquoLetters in Applied Microbiology vol 48 no 1 pp 90ndash96 2009
[144] K F D Dota M E L Consolaro T I E Svidzinski and ML Bruschi ldquoAntifungal activity of brazilian propolis micropar-ticles against yeasts isolated from vulvovaginal candidiasisrdquoEvidence-Based Complementary and Alternative Medicine vol2011 Article ID 201953 8 pages 2011
[145] J S Bonvehı and A L Gutierrez ldquoThe antimicrobial effects ofpropolis collected in different regions in the Basque Country(Northern Spain)rdquo World Journal of Microbiology and Biotech-nology vol 28 no 4 pp 1351ndash1358 2012
[146] E N Quiroga D A Sampietro J R Soberon M A SgarigliaandM A Vattuone ldquoPropolis from the northwest of Argentinaas a source of antifungal principlesrdquo Journal of Applied Microbi-ology vol 101 no 1 pp 103ndash110 2006
[147] P Szweda K Gucwa E Kurzyk et al ldquoEssential oils silvernanoparticles and propolis as alternative agents against flucona-zole resistant Candida albicans Candida glabrata and Candidakrusei clinical isolatesrdquo Indian Journal of Microbiology vol 55no 2 pp 175ndash183 2015
[148] B Pippi A Lana R Moraes et al ldquoIn vitro evaluation of theacquisition of resistance antifungal activity and synergism ofBrazilian red propolis with antifungal drugs on Candida spprdquoJournal of Applied Microbiology vol 118 no 4 pp 839ndash8502015
[149] I R G Capoci P de Souza Bonfim-Mendonca G S Arita etal ldquoPropolis is an efficient fungicide and inhibitor of biofilmproduction by vaginal Candida albicansrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2015 Article ID287693 9 pages 2015
[150] A A Berretta P A de Castro A H Cavalheiro et alldquoEvaluation of mucoadhesive gels with propolis (EPP-AF) inpreclinical treatment of candidiasis vulvovaginal infectionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 641480 18 pages 2013
[151] P A De Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013
[152] D Sawicka H Car M H Borawska and J Niklinski ldquoThe anti-cancer activity of propolisrdquo Folia Histochemica et Cytobiologicavol 50 no 1 pp 25ndash37 2012
[153] J R Araujo P Goncalves and F Martel ldquoChemopreventiveeffect of dietary polyphenols in colorectal cancer cell linesrdquoNutrition Research vol 31 no 2 pp 77ndash87 2011
[154] R Kubina A Kabała-Dzik A Dziedzic et al ldquoThe ethanolextract of polish propolis exhibits anti-proliferative andor pro-apoptotic effect on HCT 116 colon cancer and me45 malignantmelanoma cells in vitro conditionsrdquo Advances in Clinical andExperimental Medicine vol 24 no 2 pp 203ndash212 2015
[155] M Ishihara KNaoiMHashita Y Itoh andM Suzui ldquoGrowthinhibitory activity of ethanol extracts of Chinese and Brazilianpropolis in four human colon carcinoma cell linesrdquo OncologyReports vol 22 no 2 pp 349ndash354 2009
[156] S M Messerli M-R Ahn K Kunimasa et al ldquoArtepillin C(ARC) in Brazilian green propolis selectively blocks oncogenic
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 27
PAK1 signaling and suppresses the growth of NF tumors inmicerdquo Phytotherapy Research vol 23 no 3 pp 423ndash427 2009
[157] S Awale F Li H Onozuka H Esumi Y Tezuka and S KadotaldquoConstituents of Brazilian red propolis and their preferentialcytotoxic activity against human pancreatic PANC-1 cancer cellline in nutrient-deprived conditionrdquo Bioorganic amp MedicinalChemistry vol 16 no 1 pp 181ndash189 2008
[158] H Li A Kapur J X Yang et al ldquoAntiproliferation of humanprostate cancer cells by ethanolic extracts of Brazilian propolisand its botanical originrdquo International Journal of Oncology vol31 no 3 pp 601ndash606 2007
[159] G Ozturk Z Ginis S Akyol G Erden A Gurel and OAkyol ldquoThe anticancer mechanism of caffeic acid phenethylester (CAPE) review of melanomas lung and prostate cancersrdquoEuropean Review for Medical and Pharmacological Sciences vol16 no 15 pp 2064ndash2068 2012
[160] Y-J He B-H Liu D-B Xiang Z-Y Qiao T Fu and Y-HHe ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of SW480 colorectal tumor cells involves 120573-cateninassociated signaling pathway down-regulationrdquo World Journalof Gastroenterology vol 12 no 31 pp 4981ndash4985 2006
[161] C-P Chuu H-P Lin M F Ciaccio et al ldquoCaffeic acidphenethyl ester suppresses the proliferation of human prostatecancer cells through inhibition of p70S6K and Akt signalingnetworksrdquo Cancer Prevention Research vol 5 no 5 pp 788ndash797 2012
[162] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011
[163] C Omene M Kalac J Wu E Marchi K Frenkel and OA OrsquoConnor ldquoPropolis and its active component caffeic acidphenethyl ester (CAPE) modulate breast cancer therapeutictargets via an epigenetically mediated mechanism of actionrdquoJournal of Cancer Science and Therapy vol 5 no 10 pp 334ndash342 2013
[164] C O Omene J Wu and K Frenkel ldquoCaffeic Acid PhenethylEster (CAPE) derived from propolis a honeybee productinhibits growth of breast cancer stem cellsrdquo Investigational NewDrugs vol 30 no 4 pp 1279ndash1288 2012
[165] A M Alizadeh H Afrouzan N Dinparast-Djadid et alldquoChemoprotection of MNNG-initiated gastric cancer in ratsusing Iranian propolisrdquoArchives of IranianMedicine vol 18 no1 pp 18ndash23 2015
[166] E Szliszka Z P Czuba J Bronikowska A Mertas A Paradyszand W Krol ldquoEthanolic extract of propolis augments TRAIL-induced apoptotic death in prostate cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2011Article ID 535172 11 pages 2011
[167] E Szliszka G Zydowicz B Janoszka C Dobosz G Kowalczyk-Ziomek and W Krol ldquoEthanolic extract of Brazilian greenpropolis sensitizes prostate cancer cells to TRAIL-inducedapoptosisrdquo International Journal of Oncology vol 38 no 4 pp941ndash953 2011
[168] E Szliszka and W Krol ldquoPolyphenols isolated from propolisaugment TRAIL-induced apoptosis in cancer cellsrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 731940 10 pages 2013
[169] E Szliszka G Zydowicz E Mizgala and W Krol ldquoArtepillinC (35-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP
prostate cancer cells to TRAIL-induced apoptosisrdquo Interna-tional Journal of Oncology vol 41 no 3 pp 818ndash828 2012
[170] K McEleny R Coffey C Morrissey J M Fitzpatrick and RW G Watson ldquoCaffeic acid phenethyl ester-induced PC-3 cellapoptosis is caspase-dependent and mediated through the lossof inhibitors of apoptosis proteinsrdquo BJU International vol 94no 3 pp 402ndash406 2004
[171] V Cavaliere D L Papademetrio T Lombardo S NCostantino G A Blanco and E M C Alvarez ldquoCaffeicacid phenylethyl ester and MG132 two novel nonconventionalchemotherapeutic agents induce apoptosis of human leukemiccells by disrupting mitochondrial functionrdquo Targeted Oncologyvol 9 no 1 pp 25ndash42 2014
[172] K W Lee N J Kang J H Kim et al ldquoCaffeic acid phenethylester inhibits invasion and expression of matrix metallopro-teinase in SK-Hep1 human hepatocellular carcinoma cells bytargeting nuclear factor kappa Brdquo Genes and Nutrition vol 2no 4 pp 319ndash322 2008
[173] P Saharinen L Eklund K Pulkki P Bono and K AlitaloldquoVEGF and angiopoietin signaling in tumor angiogenesis andmetastasisrdquo Trends in Molecular Medicine vol 17 no 7 pp 347ndash362 2011
[174] M-R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007
[175] T Ohta K Kunimasa M-R Ahn et al ldquoBrazilian propo-lis suppresses angiogenesis by inducing apoptosis in tube-forming endothelial cells through inactivation of survival sig-nal ERK12rdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 870753 8 pages 2011
[176] S S Yun E H Park J J Kyung and C Jin ldquoInhibition ofangiogenesis by propolisrdquo Archives of Pharmacal Research vol25 no 4 pp 500ndash504 2002
[177] T Ohta K Kunimasa T Kobayashi M Sakamoto and K KajildquoPropolis suppresses tumor angiogenesis by inducing apoptosisin tube-forming endothelial cellsrdquoBioscience Biotechnology andBiochemistry vol 72 no 9 pp 2436ndash2440 2008
[178] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquoArchives of Medical Research vol 40 no 1 pp59ndash61 2009
[179] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009
[180] V A Isidorov L Szczepaniak and S Bakier ldquoRapid GCMSdetermination of botanical precursors of eurasian propolisrdquoFood Chemistry vol 142 pp 101ndash106 2014
[181] S D Leonhardt H M Wallace and T Schmitt ldquoThe cuticularprofiles of Australian stingless bees are shaped by resin of theeucalypt tree Corymbia torellianardquo Austral Ecology vol 36 no5 pp 537ndash543 2011
[182] R Christov V Bankova I Tsvetkova A Kujumgiev and ADelgado Tejera ldquoAntibacterial furofuran lignans from CanaryIslands propolisrdquo Fitoterapia vol 70 no 1 pp 89ndash92 1999
[183] J F Campos U P dos Santos L F B Macorini et alldquoAntimicrobial antioxidant and cytotoxic activities of propolisfrom Melipona orbignyi (Hymenoptera Apidae)rdquo Food andChemical Toxicology vol 65 pp 374ndash380 2014
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
28 Evidence-Based Complementary and Alternative Medicine
[184] A Mavri H Abramovic T Polak et al ldquoChemical propertiesand antioxidant and antimicrobial activities of Slovenian propo-lisrdquoChemistry and Biodiversity vol 9 no 8 pp 1545ndash1558 2012
[185] A A Lopes T S Ferreira R T Nesi et al ldquoAntioxidant actionof propolis on mouse lungs exposed to short-term cigarettesmokerdquo Bioorganic and Medicinal Chemistry vol 21 no 24 pp7570ndash7577 2013
[186] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of turkish propolis on H
2O2-induced DNA
damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011
[187] M E Yonar S M Yonar M S Ural S Silici andM DusukcanldquoProtective role of propolis in chlorpyrifos-induced changes inthe haematological parameters and the oxidativeantioxidativestatus ofCyprinus carpio carpiordquo Food and Chemical Toxicologyvol 50 no 8 pp 2703ndash2708 2012
[188] N Orsolic D Sirovina G Gajski V Garaj-Vrhovac MJazvinscak Jembrek and I Kosalec ldquoAssessment of DNA dam-age and lipid peroxidation in diabetic mice effects of propolisand epigallocatechin gallate (EGCG)rdquo Mutation Research vol757 no 1 pp 36ndash44 2013
[189] A Rossi R Longo A Russo F Borrelli and L SautebinldquoThe role of the phenethyl ester of caffeic acid (CAPE) inthe inhibition of rat lung cyclooxygenase activity by propolisrdquoFitoterapia vol 73 supplement 1 pp S30ndashS37 2002
[190] O Koksel A Ozdulger L Tamer et al ldquoEffects of caffeic acidphenethyl ester on lipopolysaccharide-induced lung injury inratsrdquo Pulmonary Pharmacology and Therapeutics vol 19 no 2pp 90ndash95 2006
[191] MMM Abdel-Latif H JWindle B S El Homasany K Sabraand D Kelleher ldquoCaffeic acid phenethyl ester modulates Heli-cobacter pylori-induced nuclear factor-kappa B and activatorprotein-1 expression in gastric epithelial cellsrdquo British Journalof Pharmacology vol 146 no 8 pp 1139ndash1147 2005
[192] F Missima A C Pagliarone C L Orsatti J P Araujo Jr and JM Sforcin ldquoThe Effect of propolis onTh1Th2 cytokine expres-sion and production by melanoma-bearing mice submitted tostressrdquo Phytotherapy Research vol 24 no 10 pp 1501ndash15072010
[193] B J Conti M C Bufalo M D A Golim V Bankova andJ M Sforcin ldquoCinnamic acid is partially involved in propolisimmunomodulatory action on human monocytesrdquo Evidence-based Complementary and Alternative Medicine vol 2013Article ID 109864 7 pages 2013
[194] G Girgin T Baydar M Ledochowski et al ldquoImmunomodu-latory effects of Turkish propolis changes in neopterin releaseand tryptophan degradationrdquo Immunobiology vol 214 no 2pp 129ndash134 2009
[195] J H Park J K Lee H S Kim et al ldquoImmunomodulatory effectof caffeic acid phenethyl ester in Balbc micerdquo InternationalImmunopharmacology vol 4 no 3 pp 429ndash436 2004
[196] S Nolkemper J Reichling K H Sensch and P SchnitzlerldquoMechanism of herpes simplex virus type 2 suppression bypropolis extractsrdquo Phytomedicine vol 17 no 2 pp 132ndash1382010
[197] V Bankova A Galabov D Antonova N Vilhelmova and BDi Perri ldquoChemical composition of Propolis Extract ACF andactivity against herpes simplex virusrdquoPhytomedicine vol 21 no11 pp 1432ndash1438 2014
[198] K Kuwata T Takemura T Urushisaki et al ldquo34-dicaffeoylquinic acid a major constituent of Brazilian propolis
increases TRAIL expression and extends the lifetimes ofmice infected with the influenza a virusrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID946867 7 pages 2012
[199] M P Popova I B Chinou I N Marekov and V S BankovaldquoTerpenes with antimicrobial activity from Cretan propolisrdquoPhytochemistry vol 70 no 10 pp 1262ndash1271 2009
[200] H F Santana A A T Barbosa S O Ferreira and H CMantovani ldquoBactericidal activity of ethanolic extracts of propo-lis against Staphylococcus aureus isolated from mastitic cowsrdquoWorld Journal of Microbiology and Biotechnology vol 28 no 2pp 485ndash491 2012
[201] L Netıkova P Bogusch and P Heneberg ldquoCzech ethanol-free propolis extract displays inhibitory activity against a broadspectrum of bacterial and fungal pathogensrdquo Journal of FoodScience vol 78 no 9 pp M1421ndashM1429 2013
[202] R D O Orsi J M Sforcin S R Cunha Funari A Fernandes Jrand V Bankova ldquoSynergistic effect of propolis and antibioticson the Salmonella typhirdquo Brazilian Journal of Microbiology vol37 no 2 pp 108ndash112 2006
[203] ROOrsi JM Sforcin S R C Funari andV Bankova ldquoEffectsof Brazilian and Bulgarian propolis on bactericidal activity ofmacrophages against Salmonella Typhimuriumrdquo InternationalImmunopharmacology vol 5 no 2 pp 359ndash368 2005
[204] Z Yildirim S Hacievliyagil N O Kutlu et al ldquoEffect of waterextract of Turkish propolis on tuberculosis infection in guinea-pigsrdquo Pharmacological Research vol 49 no 3 pp 287ndash2922004
[205] A R Khosravi H Shokri D Nikaein et al ldquoYeasts as importantagents of onychomycosis in vitro activity of propolis againstyeasts isolated from patients with nail infectionrdquo Journal ofAlternative and Complementary Medicine vol 19 no 1 pp 57ndash62 2013
[206] H C Kuo W H Kuo Y J Lee W L Lin F P Chou and T HTseng ldquoInhibitory effect of caffeic acid phenethyl ester on thegrowth of C6 glioma cells in vitro and in vivordquo Cancer Lettersvol 234 no 2 pp 199ndash208 2006
[207] Y-J Chen M-S Shiao M-L Hsu T-H Tsai and S-Y WangldquoEffect of caffeic acid phenethyl ester an antioxidant frompropolis on inducing apoptosis in human leukemic HL-60cellsrdquo Journal of Agricultural and Food Chemistry vol 49 no11 pp 5615ndash5619 2001
[208] Y Akao H Maruyama K Matsumoto et al ldquoCell growthinhibitory effect of cinnamic acid derivatives from propolis onhuman tumor cell linesrdquoBiological and Pharmaceutical Bulletinvol 26 no 7 pp 1057ndash1059 2003
[209] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011
[210] C A Dornelas F V Fechine-Jamacaru I L Albuquerque et alldquoAngiogenesis inhibition by green propolis and the angiogeniceffect of L-lysine on bladder cancer in ratsrdquo Acta CirurgicaBrasileira vol 27 no 8 pp 529ndash536 2012
[211] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012
[212] T Kamiya H Nishihara H Hara and T Adachi ldquoEthanolextract of Brazilian red propolis induces apoptosis in humanbreast cancer MCF-7 cells through endoplasmic reticulum
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 29
stressrdquo Journal of Agricultural and Food Chemistry vol 60 no44 pp 11065ndash11070 2012
[213] H-P Lin S S Jiang and C-P Chuu ldquoCaffeic acid phenethylester causes p21CIP1 induction Akt signaling reduction andgrowth inhibition in PC-3 human prostate cancer cellsrdquo PLoSONE vol 7 no 2 Article ID e31286 2012
[214] Y-Y Kuo H-P Lin C Huo et al ldquoCaffeic acid phenethyl estersuppresses proliferation and survival of TW26 human oralcancer cells via inhibition of akt signalingrdquo International Journalof Molecular Sciences vol 14 no 5 pp 8801ndash8817 2013
[215] H J Hwang H J Park H-J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006
[216] H Seda Vatansever K Sorkun S Ismet Deliloglu Gurhan etal ldquoPropolis from Turkey induces apoptosis through activatingcaspases in human breast carcinoma cell linesrdquoActaHistochem-ica vol 112 no 6 pp 546ndash556 2010
[217] M Watabe K Hishikawa A Takayanagi N Shimizu andT Nakaki ldquoCaffeic acid phenethyl ester induces apoptosis byinhibition of NFkappaB and activation of Fas in human breastcancer MCF-7 cellsrdquo The Journal of Biological Chemistry vol279 no 7 pp 6017ndash6026 2004
[218] I Valenca F Morais-Santos V Miranda-Goncalves A M Fer-reira C Almeida-Aguiar and F Baltazar ldquoPortuguese propolisdisturbs glycolytic metabolism of human colorectal cancer invitrordquo BMC Complementary and Alternative Medicine vol 13article 184 2013
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Top Related