AReviewofMalaysianMedicinalPlantswithPotential...
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Review ArticleA Review of Malaysian Medicinal Plants with PotentialAnti-Inflammatory Activity
Fazleen Izzany Abu Bakar ,1,2 Mohd Fadzelly Abu Bakar ,1,2 Norazlin Abdullah ,1,2
Susi Endrini,3 and Asmah Rahmat1
1Faculty of Applied Sciences and Technology, Universiti Tun Hussein Onn Malaysia (UTHM), Hab Pendidikan Tinggi Pagoh,KM 1, Jalan Panchor, 84600 Muar, Johor, Malaysia2Centre of Research for Sustainable Uses of Natural Resources (CoR-SUNR), Universiti Tun Hussein Onn Malaysia (UTHM),Parit Raja, 86400 Batu Pahat, Johor, Malaysia3Faculty of Medicine, YARSI University, 10510 Jakarta, Indonesia
Correspondence should be addressed to Mohd Fadzelly Abu Bakar; [email protected]
Received 30 January 2018; Revised 25 April 2018; Accepted 20 May 2018; Published 9 July 2018
Academic Editor: Mohammad A. Rashid
Copyright © 2018 Fazleen Izzany Abu Bakar et al. +is is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work isproperly cited.
+is article aims to provide detailed information on Malaysian plants used for treating inflammation. An extensive search onelectronic databases including PubMed, Google Scholar, Scopus, and ScienceDirect and conference papers was done to findrelevant articles on anti-inflammatory activity of Malaysian medicinal plants. +e keyword search terms used were “in-flammation,” “Malaysia,” “medicinal plants,” “mechanisms,” “in vitro,” and “in vivo.” As a result, 96 articles on anti-inflammatoryactivity of Malaysianmedicinal plants were found and further reviewed. Forty-six (46) plants (in vitro) and 30 plants (in vivo) havebeen identified to possess anti-inflammatory activity where two plants, Melicope ptelefolia (Tenggek burung) and Portulacaoleracea (Gelang pasir), were reported to have the strongest anti-inflammatory activity of more than 90% at a concentration of250 µg/ml. It was showed that the activity was mainly due to the occurrence of diverse naturally occurring phytochemicals fromdiverse groups such as flavonoids, coumarins, alkaloids, steroids, benzophenone, triterpenoids, curcuminoids, and cinnamic acid.Hence, this current review is a detailed discussion on the potential of Malaysian medicinal plants as an anti-inflammatory agentfrom the previous studies. However, further investigation on the possible underlying mechanisms and isolation of activecompounds still remains to be investigated.
1. Introduction
A primary physiologic defence mechanism known as in-flammation helps to protect the body from noxious stimuli,resulting in the swelling or edema of tissues, pain, or even celldamage.+emain purpose of this mechanism is to repair andreturn the damaged tissue to the healthy state [1].+e increasein size of the vessels only occurs around the inflammatory loci(i.e., neutrophils, macrophages, and lymphocytes) during theearly stages of inflammation, but after 24 hours, many kindsof cells reach neutrophils, followed by macrophages within 48hours and lymphocytes after several days [1]. It is well knownthat the disruption of cells occurs during inflammationprocesses, leading to the release of arachidonic acid, andfurther undergoes two metabolic pathways known as the
cyclooxygenase (COX) and lipoxygenase (LOX) pathways.COX pathways consist of cyclooxygenase-1 (COX-1) andcyclooxygenase-2 (COX-2), while 5-lipoxygenase (5-LOX),12-lipoxygenase (12-LOX), and 15-lipoxygenase (15-LOX) arethe examples of the LOX pathway. +e products of the COXpathway are prostaglandins (mediators of acute inflamma-tion) and thromboxanes, while those of the LOX pathway areleukotrienes and hydroperoxy fatty acids [2, 3].
Clinically, the common signs of inflammation include pain,heat, redness, loss of function, and swelling on the affectedtissue [4]. Other signs include fever, leukocytosis, and sepsis.+ere are many causes of inflammation such as pathogens(e.g., bacteria, viruses, and fungi), external injuries, and effectsof chemicals or radiation. Inflammation can be classified intotwo categories: acute and chronic inflammation. Acute
HindawiAdvances in Pharmacological SciencesVolume 2018, Article ID 8603602, 13 pageshttps://doi.org/10.1155/2018/8603602
inflammation is considered as the first line of defence againstinjury. It occurs in a short period of time and is manifested bythe excretion of fluid and plasma proteins along with theemigration of leukocytes such as neutrophils. Meanwhile,chronic inflammation takes prolonged duration and is man-ifested by the action of lymphocytes andmacrophages, resultingin fibrosis and tissue necrosis. Inflammation is considered asone of the most common concern of diseases, ranging from theminor to a serious condition like cancer. Based on the recentadvancement in imaging technologies, the chronic vascularinflammation is not involved in atherosclerosis but also inarterial hypertension and metabolic syndrome [5].
Currently, nonsteroidal anti-inflammatory drugs (NSAIDs)such as ibuprofen, aspirin, diclofenac, and celecoxib are ex-tensively used for the treatment of inflammation.+ese drugsexhibit their anti-inflammatory properties by inhibiting theCOX-1 activity and thus preventing the synthesis of pros-taglandins [4]. However, the major concern is that NSAIDsmay cause various side effects such as gastrointestinal com-plications [6]. Considering this, the quests for the new drugwith anti-inflammatory properties from the medicinal plantswith free of or fewer side effects are greatly needed for thepharmaceutical industry [7, 8].
Plant-based or herbal medicine has been used traditionallyto treat pain, inflammation, and inflammatory-mediated pain[9]. Malaysia is among the world’s 12 megadiverse countrieswhere endemism is highest. At least a quarter of our tree flora isnot found elsewhere in the world, and many of our herbaceousflora and other groups of species are unique [10]. In Malaysia,about 2000 medicinal plant species are reported to possesshealth benefit properties [11]. Based on nutritional studies,these medicinal plants contain diverse nutritive values andpossess potential bioactive compounds with the activity relatedto the various inflammation disorders including gout [12] orage-related diseases [13]. Hence, this current review aims todisseminate detailed information on the anti-inflammatorypotential of Malaysian medicinal plants, focusing on the bio-active phytochemicals, and mechanisms of action against in-flammation in both in vitro and in vivo studies.
2. Methods
+e bibliographic research was performed in the followingdatabases: PubMed, Google Scholar, Scopus, and Science-Direct, where these databases were searched for relevantstudies which included at least one keyword from each of thefollowing: (i) inflammation, (ii) Malaysia, (iii) medicinalplants, (iv) mechanisms, (v) in vitro, and (vi) in vivo. Nolimit was placed on the search time frame in order to retrieveall relevant papers, and the last search was performed onApril 20, 2018. About 96 papers have been reviewed in-cluding journal articles and proceedings as well as the ref-erence lists of articles for additional relevant studies.
3. Discussion
+e World Health Organization (WHO) defines medicinalplants as plants which possess compounds that can be used forthe therapeutic purposes as well as producing useful drugs
from the metabolites. According to the WHO, medicinalplants are still being used by the people in developingcountries to treat various diseases, and these products’ marketcontinue to grow [14] which gives a good sign of economicimportance of medicinal plants. Based on the previous report,15% out of 300,000 plant species in the world have beenstudied for the pharmacological activity. Interestingly, about25% of modern medicines have been developed from thenatural resources such as medicinal plants [15]. Recently, theresearch on the medicinal plants for the health benefit pur-poses has increased worldwide and gained attention from allresearchers all over the world including Malaysia. Malaysia isknown as a country that is rich in the medicinal plant species.For instance, 1300 medicinal plant species and 7411 plantspecies have been recorded in Peninsular Malaysia and Sabah,respectively [16, 17].
Inflammation is a response of tissue to cell injury due topathogens, damaged tissues, or irritants which initiates thechemical signals to heal the afflicted tissue [18]. +e leu-kocytes such as neutrophils, monocytes, and eosinophils areactivated and migrated to the sites of damage. During theinflammatory processes, the excessive nitric oxide (NO) andprostaglandin E2 (PGE2) as well as proinflammatory cyto-kines (i.e., tumour necrosis factor-alpha (TNF-α) and in-terleukins) are secreted by the activated macrophages. +enitric oxide and prostaglandin productions from the in-ducible nitric oxide synthase (iNOS) and COX-2, re-spectively, are the proinflammatory mediators responsiblefor many inflammatory diseases [19, 20]. Inflammation canbe classified into two types known as acute and chronicinflammation. +e vascular response to inflammation in theearly stage (acute inflammation) can be clearly seen at theaffected tissue as it becomes reddened due to the increase ofblood flow and swollen due to edema fluid. +ree mainprocesses that involve during the vascular response to acuteinflammation are (1) changes in vessel caliber and bloodflow, (2) the increase in vascular permeability, and (3) fluidexudate formation. It is important to understand that anuncontrolled inflammation may contribute to many chronicillnesses [21]. For instance, chronic inflammation may leadto infectious diseases and cancer [22], while the prolongedinflammation may cause abnormal gene expression, geno-mic instability, and neoplasia [23, 24]. Currently, NSAIDsexhibit great effects in inhibiting the activity of COX-1 andCOX-2, but COX-1 inhibitors are reported to exert sideeffects such as gastrointestinal erosions and renal and he-patic insufficiency [25]. COX-2 (Vioxx) also has been re-ported to cause serious cardiovascular events [2]. Toovercome this, many studies on anti-inflammatory drugsfrom natural resources have been conducted. Enzyme in-hibitory assays (i.e., COX and LOX) have been extensivelyused to study the effectiveness of medicinal plants in treatingthe inflammation due to the presence of many phyto-chemicals, and they are being consumed as a food or foodsupplement for many years. +e Malaysian medicinal plantsthat possess an anti-inflammatory activity are shown inTables 1 and 2 for in vitro and in vivo studies, respectively.
Based on the results obtained, many studies used the NOinhibition assay as a method to show the anti-inflammatory
2 Advances in Pharmacological Sciences
Tabl
e1:
+emedicinal
plants
which
areconsidered
topo
ssessanti-inflammatoryactiv
itybasedon
invitrostud
ies.
Scientific
name
Family
Localn
ame
Part/solvent
used
Typesof
assays
Anti-
inflammatory
activ
ity(%
)IC
50Activecompo
unds
References
Agelaea
borneensis
Con
naraceae
Akarrusa-rusa
Bark/m
ethano
lLO
Xinhibitio
n71%–1
00%
at100μg/m
lNA
NA
[26]
Ana
cardium
occidentale
Anacardiaceae
Poko
kgajus
Leaves/m
ethano
lNO
inhibitio
n16.10%
at250μg/m
lNA
NA
[13]
Averrhoa
bilim
biOxalid
aceae
Belim
bing
buluh
Fruits/w
ater
NO
inhibitio
n22.30%
at250μg/m
lNA
NA
[13]
Barrington
iaracemosa
Lecythidaceae
Putatk
ampu
ng
Leaves/chloroform
Griessassay(N
Oinhibitio
n)
57.7%
at100μg/m
l
NA
NA
[27]
Leaves/ethanol
29.80%
at100μg/m
l
Leaves/hexane
42.39%
at100μg/m
lBo
esenbergia
rotund
aZing
iberaceae
Temuku
nci
Rhizom
es/hexane
Griessassay(nitrite
determ
ination)
NA
36.68μM
Boesenbergin
A[28]
Bosw
ellia
serrata
Burseraceae
Salaig
uggula
ndkemenyan
Leaves/m
ethano
lHum
anredbloo
dcell
metho
d80.00%
at2000
μg/m
lNA
NA
[29]
Buchan
ania
insig
nis
Anacardiaceae
Tais/manggahu
tan
Bark/m
ethano
lLO
Xinhibitio
n41%–7
0%at
100μg/m
lNA
NA
[26]
Cana
rium
patentinervium
Burseraceae
Kedon
dong
and
kaju
kedapak
Leaves
andbarks/hexane,
chloroform
,and
ethano
l5-LO
Xinhibitio
nNA
1.76
μMScop
oletin
[30]
Caric
apapaya
Caricaceae
Betik
Leaves/m
ethano
lGriessassay(N
Oinhibitio
n)72.63%
at100μg/m
l60.18μg/m
lNA
[31]
Chiso
cheton
polyan
drus
Meliaceae
Lisi-lisi
Bark/m
ethano
lLO
Xinhibitio
n71%–1
00%
at100μg/m
lNA
NA
[26]
Leaves/hexane,
dichloromethane,and
methano
l
SoybeanLO
Xinhibitio
nassay
NA
0.69
μMand
1.11
μM
Dam
mara-20,24-dien-3-
oneand24-
hydroxydam
mara-20,25-
dien-3-one
[32]
Citrullus
lana
tus
Cucurbitaceae
Tembikai
Fruitp
ulp/petroleum
ether,chloroform
,and
90%
ethano
l
COX-2
inhibitory
activ
ity60–7
0%at
100μM
69μM
CucurbitacinE
[33]
Griessassay(N
Oinhibitio
n)17.6μM
Cosm
oscaud
atus
Asteraceae
Ulam
raja
Leaves/m
ethano
lNO
inhibitio
n15.40%
at250μg/m
lNA
NA
[13]
Crinum
asiaticum
Amaryllid
aceae
Poko
kbaku
ngLeaves/ethanol
NO
inhibitio
nNA
58.5μg/m
lNA
[34]
Curcum
alonga
Zing
iberaceae
Kun
yit
Rhizom
es/hexane-ethyl
acetateandmethano
lCOX-2
inhibitory
activ
ity82.50%
and
58.90%
at125μg/m
lNA
Mon
odem
etho
xycurcum
inand
bisdem
etho
xycurcum
in[35]
Curcum
aman
gga
Zing
iberaceae
Temumangga
Rhizom
es/m
ethano
lNO
inhibitio
n19.20%
at250μg/m
lNA
NA
[13]
Advances in Pharmacological Sciences 3
Tabl
e1:
Con
tinued.
Scientific
name
Family
Localn
ame
Part/solvent
used
Typesof
assays
Anti-
inflammatory
activ
ity(%
)IC
50Activecompo
unds
References
Cythostema
excelsia
Ann
onaceae
Lianas
Leaves
and
stem
s/methano
lLO
Xinhibitio
n41%–7
0%at
100μg/m
lNA
NA
[26]
Desmos
chinensis
Ann
onaceae
Kenanga
hutan
Bark/m
ethano
lLO
Xinhibitio
n41%–7
0%at
100μg/m
lNA
NA
[26]
Eurycoma
longifo
liaSimarou
baceae
Tong
kata
liRo
ot/hydroalcoho
lics
Hum
anredbloo
dcell
mem
branestabilizatio
nmetho
d
70.97%
at1000
μg/m
lNA
NA
[36]
Ficusdelto
idea
Moraceae
Mas
cotek
Leaves/m
ethano
lLO
Xinhibitio
n10.35%
at100μg/m
lNA
NA
[37]
Garcinia
cuspidata
Clusia
ceae
Asam
kand
isBa
rk/m
ethano
lLO
Xinhibitio
n71%–1
00%
at100μg/m
l28.3μg/m
lNA
[26]
Garcinia
subelliptica
Guttiferae
Poko
kpenanti
Seeds/chloroform
Chemical
mediator
released
from
mastc
ell
andneutroph
ilinhibitio
nNA
15.6μM
,18.2μM
,and
20.0μM
GarsubellinA
and
garcinielliptin
oxide
[38]
Gynura
pseudochina
Asteraceae
Poko
kdaun
dewa
Leaves/ethyl
acetate
IL-6/lu
ciferase
assay
NA
11.63μg/m
lNA
[39]
Jatropha
curcas
Euph
orbiaceae
Jarakpagar
Latexandleaves/aqu
eous
methano
lNO
inhibitio
nNA
29.7
and
93.5μg/m
lNA
[40]
Kaempferia
galanga
Zing
iberaceae
Cekur
Rhizom
es/petroleum
ether,chloroform
,methano
l,andwater
COX-2
inhibitory
screeningassay
57.82%
at200μg/m
l0.83
μMEthyl-p
-metho
xycinn
amate
[41]
Labisia
pumila
var.alata
Myrsin
aceae
Kacip
fatim
ahRo
ots/methano
lColorim
etricnitric
oxide
assay(m
acroph
agecell
line)
75.68%
at100μg/m
lNA
NA
[42]
Leucas
linifo
liaLamiaceae
Ketum
bak
Who
leplant/m
ethano
lLO
Xinhibitio
n34%
at100μg/m
lNA
NA
[43]
Litsea
garciae
Lauraceae
Engkala/peng
alaban
Fruits/m
ethano
lLO
Xassay
9.42%
at2mg/ml
NA
NA
[44]
Hyaluronidase
assay
27.70%
at5mg/ml
Melicope
ptelefolia
Rutaceae
Teng
gekbu
rung
Leaves/m
ethano
lNO
inhibitio
n95%
at250μg/m
lNA
p-O-geranylcoum
aric
acid,
koku
saginine,and
scop
aron
e[13,
45]
Soybean15-LOX
inhibitio
nassay
72.3%
Moringa
oleifera
Moringaceae
Kelur
Fruits/ethyl
acetate
NO
inhibitio
nNA
0.136μg/m
l1.67
μM
(1)4-[(20-O
-Acetyl-α
-Lrham
nosyloxy)benzyl]
isothiocyanate
[46]
2.66
μM(2)4-[(30-O
-Acetyl-α
-L-
rham
nosyloxy)benzyl]
isothiocyanate
2.71
μM(3)4-[(40-O
-Acetyl-α
-L-
rham
nosyloxy)benzyl]
isothiocyanate
4 Advances in Pharmacological Sciences
Tabl
e1:
Con
tinued.
Scientific
name
Family
Localn
ame
Part/solvent
used
Typesof
assays
Anti-
inflammatory
activ
ity(%
)IC
50Activecompo
unds
References
Musa
acum
inata
Musaceae
Pisang
abunipah
Flow
ering
stalk/methano
lGriessassay(N
Oinhibitio
n)71.06%
at100μg/m
l42.24μg/m
lNA
[31]
Ocimum
basilicum
Lamiaceae
Daunselasih
Leaves/m
ethano
lNO
inhibitio
n30.00%
at250μg/m
lNA
NA
[13]
Ocimum
canu
mLamiaceae
Kem
angi
putih
Who
leplant/m
ethano
lLO
Xinhibitio
n32%
at100μg/m
lNA
NA
[43]
Oenan
the
javanica
Apiaceae
Selom
Who
leplant/m
ethano
lGriessassay(N
Oinhibitio
n)75.64%
at100μg/m
l54.12μg/m
lNA
[31]
Orthosip
hon
stam
ineus
Lamiaceae
Misa
ikucing
Leaves/petroleum
ether,
chloroform
,and
methano
lNO
inhibitio
nNA
5.2μM
(eup
atorin)
9.2μM
(sinensetin
)
Eupatorinandsin
ensetin
[47]
Pand
anus
amaryllifolius
Pand
anaceae
Pand
anLeaves/m
ethano
lNO
inhibitio
n34.10%
at250μg/m
lNA
NA
[13]
Persicaria
tenella
Polygonaceae
Daunkesum
Leaves/m
ethano
lNO
inhibitio
n87.80%
at250μg/m
l8μg/m
lNA
[13]
Phaleria
macrocarpa
+ym
elaeaceae
Mahko
tadewa
Mesocarp/methano
l
NO
inhibitio
n
69.50%
at200μg/m
l
NA
NA
[48]
Pericarp/m
ethano
l63.40%
at200μg/m
l
Seeds/methano
l38.10%
at200μg/m
lPiper
sarm
entosum
Piperaceae
Kaduk
Leaves/m
ethano
lGriessassay(N
Oinhibitio
n)62.82%
at100μg/m
l60.24μg/m
lNA
[31]
Pithecellobium
confertum
Fabaceae
Medang
Seeds/methano
lNO
inhibitio
n23.50%
at250μg/m
lNA
NA
[13]
Portulaca
oleracea
Portulacaceae
Gelangpasir
Leaves/m
ethano
lNO
inhibitio
n94.80%
at250μg/m
l44
μg/m
lNA
[13]
Psophocarpus
tetragon
olobus
Fabaceae
Kacangbo
tol
Pod/methano
lGriessassay(N
Oinhibitio
n)39.28%
at100μg/m
l>1
00μg/m
lNA
[31]
Sauropus
androgynus
Phyllanthaceae
Cekur
manis
Leaves/m
ethano
lGriessassay(N
Oinhibitio
n)68.28%
at100μg/m
l58.34μg/m
lNA
[31]
Solanu
mnigrum
Solanaceae
Terung
meranti
Leaves/m
ethano
lNO
inhibitio
n27.60%
at250μg/m
lNA
NA
[13]
Solanu
mtorvum
Solanaceae
Terung
beland
aLeaves
and
fruits/m
ethano
lNO
inhibitio
n25.20%
at250μg/m
lNA
NA
[13]
=ym
usvulgaris
Lamiaceae
Taim
Who
leplant/m
ethano
lLO
Xinhibitio
n62%
at100μg/m
lNA
NA
[43]
Timon
ius
flavescens
Rubiaceae
Batut
Leaves/m
ethano
lLO
Xinhibitio
n71%–1
00%
at100μg/m
l8.9μg/m
lNA
[26]
Advances in Pharmacological Sciences 5
Tabl
e2:
+emedicinal
plants
which
areconsidered
topo
ssessanti-inflammatoryactiv
itybasedon
invivo
stud
ies.
Scientificname
Family
Localn
ame
Part/solvent
used
Doseof
theextract
Experimentala
nimals
Results
References
Achyran
thes
aspera
Amaranthaceae
Ara
song
sang
Root/ethyl
alcoho
l50,1
00,and
200mg/kg
Wistar
rats
Allthedo
sescaused
significant
redu
ctionin
paw
edem
acomparedto
control
[49]
Ann
ona
muricata
Ann
onaceae
Durian
beland
aLeaves/aqu
eous
ethano
l10–3
00mg/kg
Sprague-Daw
leyrats
Asig
nificantd
ecreaseof
the
concentrationof
the
proinfl
ammatorycytokines
TNF-αandIL-1βwas
observed
[50]
Ardisiacrisp
aMyrsin
aceae
Matapeland
okRo
ot/ethanol
3,10,3
0,100,
and
300mg/kg
ofbo
dyweigh
tSprague-Daw
leyrats
Asig
nificantinh
ibition
(93.34%)
was
observed
incarrageenan-
indu
cededem
ain
ratsat
ado
seof
300mg/kg
[51]
Atylosia
scarabaeoides
Fabaceae
Kara-
kara/kacang
kerara
Leaves/ethanol
150,
300,
and450mg/kg
Swiss
albino
mice
+eextractd
isplayedsig
nificant
inhibitio
nof
inflammation.
Highestinhibitio
nof
pawedem
a(38.38%)at
ado
seof
450mg/kg
after4hof
administratio
n
[52]
Citrullus
lana
tus
Cucurbitaceae
Tembikai
Fruitpu
lp/petroleum
ether,
chloroform
,and
90%ethano
l30
and60
mg/kg
ofbo
dyweigh
tBA
LB/c
mice
CucurbitacinEinhibits
inflammationsig
nificantly
from
thefourth
hour
andisable
torevert
paw
edem
athroughthe
COX-2
inhibitio
n
[33]
Corchorus
capsularis
Malvaceae
Kancing
baju
Leaves/chloroform
20,1
00,and
200mg/kg
BALB
/cmiceandSprague-
Daw
leyrats
+eextractc
ausedsig
nificant
redu
ctionin
thethickn
essof
edem
atou
spaw
forthefirst
6h
[53]
Crinum
asiaticum
Amaryllid
aceae
Poko
kbaku
ngLeaves/m
ethano
l50
mg/kg
oftheextract
Mice
Inhibitio
nof
pawedem
a(94.8%)
[54]
Curcum
aaerugino
saZing
iberaceae
Temuhitam
Rhizom
es/chloroform,
methano
l,andwater
100,
200,
400,
and
800mg/kg
Swiss
miceandWistar
rats
Nosig
nificants
uppressio
nwas
observed
afteroral
administratio
nof
alld
oses
oncarrageenan-indu
cedpaw
edem
a
[55]
Curcum
alonga
Zing
iberaceae
Kun
yit
Rhizom
es/w
ater
200mg/kg
ofbo
dyweigh
tWistar
albino
rats
+eprod
uctio
nof
anti-
inflammatory/proinfl
ammatory
cytokinesisdecreasin
g[56]
Cyathu
laprostrata
Amaranthaceae
Ketum
bar
Leaves/m
ethano
l50,100,and
200mg/kg
Wistar
rats
andSw
issalbino
mice
Allextracts
displayed
asig
nificantdo
se-dependent
inhibitio
nin
thecarrageenan-,
arachido
nicacid-,andxylene-
indu
cedtests
[57]
Dicrano
pteris
linearis
Gleicheniaceae
Resam
Leaves/chloroform
10,1
00,and
200mg/kg
BALB
/cmiceandSprague-
Daw
leyrats
+eextractp
rodu
cedsig
nificant
anti-inflammatoryactiv
itythat
didno
tdependon
thedo
sesof
theextract
[58]
6 Advances in Pharmacological Sciences
Tabl
e2:
Con
tinued.
Scientificname
Family
Localn
ame
Part/solvent
used
Doseof
theextract
Experimentala
nimals
Results
References
Ficusdelto
idea
Moraceae
Mas
cotek
Who
leplant/w
ater
30,1
00,and
300mg/kg
Sprague-Daw
leyrats
+erats’p
awedem
avolume
redu
cedsig
nificantly
inado
se-
depend
entmanner
[59]
Garcinia
subelliptica
Guttiferae
Poko
kpenanti
Seeds/chloroform
3,10,30,50,and
100µM
Sprague-Daw
leyrats
Apo
tent
inhibitory
effecto
nfM
LP/CB-indu
cedsuperoxide
aniongeneratio
nwas
observed
intheiso
latedcompo
und
garcinielliptin
oxide
[38]
Justicia
gend
arussa
Acanthaceae
Daunrusa
Root/m
ethano
l50
mg/kg
oftheextract
Wistar
rats
80%
and93%
edem
ainhibitio
nat
thethirdandfifth
hours
[60]
Kaempferia
galanga
Zing
iberaceae
Cekur
Rhizom
es/chloroform
2g/kg
oftheextract
MaleSprague-Daw
leyrats
Highest
edem
ainhibitio
n(42.9%
)[41]
Man
ilkara
zapota
Sapo
taceae
Ciku
Leaves/ethyl
acetate
300mg/kg
ofbo
dyweigh
tAlbinoWistar
rats
Inhibitio
nof
paw
edem
a(92.41%)
[61]
Mitragyna
speciosa
Rubiaceae
Biak-biakand
ketom
Leaves/m
ethano
l50,1
00,and
200mg/kg
Sprague-Daw
leyrats
Both
doseso
f100
and200mg/kg
show
edasig
nificantinh
ibition
ofthepaw
edem
a(63%
)[62]
Moringa
oleifera
Moringaceae
Kelur
Leaves/w
ater
10,3
0,and100mg/kg
BALB
/cmiceandSprague-
Daw
leyrats
Highest
edem
ainhibitio
n(66.7%
)at
thesecond
hour
at100mg/kg
ofdo
se[63]
Mun
tingia
calabu
raMun
tingiaceae
Keruk
upsia
mLeaves/w
ater
27mg/kg,1
35mg/kg,
and270mg/kg
Sprague-Daw
leyrats
+eextractw
asfoun
dto
exhibit
aconcentration-independ
ent
anti-inflammatoryactiv
ity[64]
Orthosip
hon
stam
ineus
Lamiaceae
Misa
ikucing
Leaves/m
ethano
l:water
125,
250,
500,
and
1000
mg/kg
Charle
sRivermiceand
Sprague-Daw
leyrats
Increase
inedem
ainhibitio
n(26.79%)
[65]
Peperomia
pellu
cida
Piperaceae
Ketum
pang
anair
Who
leplant/p
etroleum
ether
1000
mg/kg
Sprague-Daw
leyrats
+eextracts
howed
significant
inhibitio
nin
magnitude
ofsw
ellin
gafter4hof
administratio
n
[66]
Phyllanthu
sacidus
Phyllanthaceae
Cermai
Leaves/m
ethano
l,ethyl
acetate,andpetroleum
ether
250and500mg/kg
Wistar
rats
andalbino
mice
Alltheextracts
show
edredu
ctionin
carrageenan-
indu
cedpawedem
awith
high
est
inhibitio
n(90.91%)in
the
methano
lextract
[67]
Physalis
minim
aSolanaceae
Poko
kletup-
letup
Who
leplant/m
ethano
land
chloroform
fractio
n200and400mg/kg
NMRI
miceandWistar
rats
Crude
extracta
ndchloroform
fractio
nshow
edhigh
est
inhibitio
nof
pawedem
aat
66%
and68%
at400mg/kg,
respectiv
ely
[68]
Piper
sarm
entosum
Piperaceae
Kaduk
Leaves/w
ater
30–3
00mg/kg
ofthe
extract
Sprague-Daw
leyrats
and
maleBA
LB/c
mice
Alldo
sesexertedanti-
inflammatoryactiv
ityin
ado
se-
depend
entmanner
[69]
Advances in Pharmacological Sciences 7
Tabl
e2:
Con
tinued.
Scientificname
Family
Localn
ame
Part/solvent
used
Doseof
theextract
Experimentala
nimals
Results
References
Polygonu
mminus
Polygonaceae
Kesum
Aerialp
arts/w
ater
100mg/kg
and
300mg/kg
Wistar
albino
rats
+eextracts
significantly
redu
cedthepaw
edem
avolume
intherats
after4h
[70]
Sand
oricum
koetjape
Meliaceae
Sentul
Stem
s/methano
l5mg/ear
BALB
/cmice
Asig
nificantinh
ibition
(94%
)in
TPA-in
ducededem
awas
observed
intheiso
lated
compo
und3-oxo-12-oleanen-
29-oic
acid
[71]
Solanu
mnigrum
Solanaceae
Terung
meranti
Leaves/w
ater
10,5
0,and100%
ofconcentration
BALB
/cmiceandSprague-
Daw
leyrats
Extracts
prod
uceapparently
two-ph
aseanti-inflammatory
activ
ity:the
firstph
aseb
etween1
and2handthesecond
phase
between5and7hafter
carrageenanadministratio
n
[72]
Stachytarpheta
jamaicensis
Verbenaceae
Selasih
dand
iLeaves/ethanol
50,1
00,and
150mg/kg
BALB
/calbino
strain
mice
andSprague-Daw
leyrats
Asig
nificantdo
se-dependent
anti-inflammatoryactiv
itywas
observed
30min
afterthe
administratio
nof
theextracta
talld
oses
[73]
Vitexnegund
oLamiaceae
Legund
iLeaves/ethanol
2mg/ear
Mice
+ee
xtractshow
edan
inhibitory
activ
ityof
54.1%
[74]
Zingiber
zerumbet
Zing
iberaceae
Lempo
yang
Rhizom
es/m
ethano
l
25,5
0,and100mg/kg
BALB
/cmice
Asig
nificantantiedemaactiv
itywas
observed
atalld
oses
inado
se-dependent
manner(i.e.,
50and100mg/kg
dosesof
the
extracte
xhibitedactiv
ityat
90min
afteradministratio
n,while
25mg/kg
exhibitedat
150min)
[75]
5,10,5
0,and100mg/kg
ICRmice
+eiso
latedcompo
und
(zerum
bone)sig
nificantly
show
eddo
se-dependent
inhibitio
nof
paw
edem
aindu
cedby
carrageenanat
all
doses(5,10,50,and
100mg/kg)
inmicewith
percentage
ofinhibitio
nof
33.3,66.7,83.3,and
83.3%,respectively
[76]
8 Advances in Pharmacological Sciences
activity of the plants. Many diseases such as rheumatoidarthritis, diabetes, and hypertension have been reported tobe occurred due to the excessive production of NO [77]. NOis synthesized by inducible NO synthase which has threeisomers: (i) neuronal nitric oxide synthase (nNOS), (ii)endothelial nitric oxide synthase (eNOS), and (iii) iNOS[78]. For instance, signaling molecules such as mitogen-activated protein kinases (MAPKs), nuclear factor-kappa B(NF-κB), activator protein-1 (AP-1), and signal transducerand activator of transcription (STAT) regulate the inducibleenzyme (i.e., iNOS), which then make this enzyme to beexpressed in some tissues [79]. Apart from the nitric oxideinhibition assay, some studies used the LOX assay in order toevaluate the anti-inflammatory of the plants. In thismechanism, arachidonic acid is metabolized by 5-LOX tovarious forms of inflammatory leukotrienes such as leu-kotriene (LT) A4, LTB4, LTC4, LTD4, and LTE4 [80], whereLTB4 (one of the mediators of inflammation) is reported tobe the most crucial in the inflammatory response [81]. Tosupport this, it is reported that patients with rheumatoidarthritis and inflammatory bowel disease possess high levelsof LTB4 [82, 83]. In addition, LTs are reported to be linkedwith few diseases such as bronchial asthma and skin in-flammatory disorders [84]. In 2011, Kwon et al. [85]demonstrated that esculetin, one of the examples of cou-marins, exhibited anti-inflammatory activity in vivo againstanimal models of skin inflammation. In the LOX assay, anyLOX inhibitors will reduce Fe3+ to Fe2+, providing a rapidcolorimetric assay [26]. Another common assay in de-termining the anti-inflammatory activity is COX. Twoisoforms of COX, COX-1 (mainly involved in physiologicalfunctions and constitutively expressed) and COX-2 (in-volved in inflammation and induced in the inflamed tissue),are the enzymes responsible for the synthesis of prosta-glandins [86]. Besides, the COX-2 gene is also a gene foriNOS induced during inflammation and cell growth [87].+e Griess assay is another assay commonly used in themurine macrophage cell line (RAW 264.7) as a culturemedium in the cell-based study in order to determine theconcentration of nitrite (NO2−), the stable metabolite of NO.
Based on Table 1 (in vitro study), 46 plants have beenidentified and studied for the anti-inflammatory activityfrom the previous studies. As a result, only two plants havebeen reported to exhibit more than 90% of anti-inflammatory activity using the nitric oxide inhibition as-say, which were Melicope ptelefolia (Tenggek burung) andPortulaca oleracea (Gelang pasir) with the values of 95.00%and 94.80% at 250 µg/ml, respectively [13]. Besides that,many previous studies had reported the plants which exertedanti-inflammatory activity between 70% and 80% at100 µg/ml to 2000 µg/ml which can be considered to behigher such as Jatropha curcas (Jarak pagar), Curcumalonga (Kunyit), Boswellia serrata (Kemenyan), Labisiapumila (Kacip fatimah), Oenanthe javanica (Selom),Carica papaya (Betik), and Eurycoma longifolia (Tongkat ali)with the values of 86.00%, 82.50%, 80.00%, 75.68%, 75.64%,72.63%, and 70.97%, respectively [29, 31, 35, 36, 40, 42].+e moderate result of anti-inflammatory activity(50%–60%) also had been showed by several plants such as
Phaleria macrocarpa (69.50%), Sauropus androgynus(68.28%), Piper sarmentosum (62.82%), =ymus vulgaris(62.00%), Barringtonia racemosa (57.70%), and Kaempferiagalanga (57.82%) at 100 µg/ml to 2000 µg/ml[27, 31, 41, 43, 48]. In addition, plants from the Zingiber-aceae, Lamiaceae, Annonaceae, and Fabaceae families havebeen studied extensively for the anti-inflammatory activity.Among these families, the active compound of Curcumalonga from the Zingiberaceae family, mono-demethoxycurcumin, had the highest activity with 82.50% at125 µg/ml [35]. Of the other study, Kaempferia galanga fromthe Zingiberaceae family exhibited moderate activity with57.82% at 200 µg/ml where the isolated compound, ethyl-p-methoxycinnamate, was found to have anti-inflammatoryactivity via inhibiting the actions of COX-1 and COX-2[41]. In the Lamiaceae family, =ymus vulgaris showed thehighest percentage of anti-inflammatory activity compared toother plants with 62% at 100 µg/ml [43], with the totalphenolic content of 350 µg GAE/ml.
In this study, it was found that the results of anti-inflammatory activity of the methanolic extract of the leavesof Melicope ptelefolia (Tenggek burung) varied between twoprevious studies due to the different types of assays used byboth studies: nitric oxide inhibition and soybean 15-lip-oxygenase inhibition assays with the values of 95% and 72.3%,respectively [13, 45]. Another study also reported that the anti-inflammatory activity of the methanolic extract of Litseagarciae fruits showed 9.42% (lipoxygenase assay) and 27.70%(hyaluronidase assay) [44]. Based on these results, it can beconcluded that different assays used might produce differentresults. For the COX inhibition assay, all the curcumins isolatedfrom Curcuma longa rhizomes (i.e., curcumin I, curcumin II(monodemethoxycurcumin), and curcumin III (bisdeme-thoxycurcumin)) displayed greater inhibition of COX-2compared to COX-1 at the same test concentration [35].For the Griess assay, all the species tested such as the leaves ofCarica papaya, Sauropus androgynus, and Piper sarmentosum,the flowering stalk ofMusa acuminata, and the whole plant ofOenanthe javanica displayed significant NO inhibitory activityin a concentration-dependent manner against IFN-c/LPS-treated macrophages [31].
For the in vivo study (Table 2), 30 plants have beenidentified in this study for the anti-inflammatory activity.Many of the studies from the previous years used thecarrageenan-induced rat paw edema method (a reliableinflammation model) as this carrageenan has been found tobe more trenchant in producing the edema compared toformalin [88]. It is also one of the conventional methodsused to evaluate the anti-inflammatory effect of drugs ormedicinal plants at the acute stage [89] and involves a bi-phasic event. Normally, the release of histamine and sero-tonin happens in the early phase (1-2 h), while the secondphase (3–5 h) involves the release of prostaglandins andkinins [90, 91]. For the edema formation, the rat paw isinjected with carrageenan. +is method is also a COX-dependent reaction with the control of arachidonate COX[92]. +e ability of the plant extracts to lessen the thicknessof the rats’ paw edema indicates the ability of these plantextracts to exert the anti-inflammatory properties. Based on
Advances in Pharmacological Sciences 9
Table 2, the highest dose of the extract used was 1000mg/kgof body weight, while the lowest one was 3mg/kg of bodyweight. Most of the previous studies reported that the extractwas able to inhibit paw edema induced by carrageenan. Forinstance, a significant highest paw edema inhibition(93.34%) was observed in rats at a dose of 300mg/kg of theArdisia crispa (Mata pelandok) root extract [51]. Anotherstudy also showed that a significant highest inhibition wasobserved in two isolated compounds from Sandoricumkoetjape stems, 3-oxo-12-oleanen-29-oic acid and katonicacid with 94% and 81%, respectively, where 3-oxo-olean-12-en-29-oic acid had the percentage inhibition almost similarto the reference drug, indomethacin (97%) [71].
Based on the results obtained, few studies isolated thebioactive compounds to be further analyzed for the anti-inflammatory activity such as flavonoids (boesenbergin A,eupatorin, and sinensetin), coumarins (scopoletin andscoparone), triterpenoids (dammara-20,24-dien-3-one and24-hydroxydammara-20,25-dien-3-one), steroids (cucurbitacinE), curcuminoids (monodemethoxycurcumin and bisdeme-thoxycurcumin), benzophenones (garsubellin A and garci-nielliptin oxide), cinnamic acid (ethyl-p-methoxycinnamate),alkaloids (kokusaginine), benzene (p-O-geranylcoumaric acid),4-[(20-O-acetyl-α-L-rhamnosyloxy)benzyl]isothiocyanate,4-[(30-O-acetyl-α-L-rhamnosyloxy)benzyl]isothiocyanate,and 4-[(40-O-acetyl-α-L-rhamnosyloxy)benzyl]isothiocyanate[28, 30, 32, 33, 35, 38, 41, 45–47]. Interestingly, some ofthem exerted significant inhibition on inflammation. In 2000,Abad et al. [93] evaluated the common anti-inflammatory drugnaproxene isolated from Musa acuminate (pisang abu nipah)which exhibited good inhibition in COX-1 and COX-2 ac-tivities. Besides, in Carica papaya leaves, coumarin was isolatedand exerted anti-inflammatory activity by suppressing thecytokine TNF-α production [94, 95]. A compound known asdammara-20,24-dien-3-one was isolated from Chisochetonpolyandrus and displayed good inhibition of both human5-LOX and COX-2 [32]. Flavonoids have been confirmed by invitro studies to be able to suppress iNOS expression and toprevent nitric oxide production, depending on their structureor subclass of flavonoids for the strength level [96].
4. Conclusion
In overall, this review clearly demonstrates the potential ofMalaysianmedicinal plants as anti-inflammatory agents inwhichMelicope ptelefolia (Tenggek burung) and Portulaca oleracea(Gelang pasir) were found to exhibit potent anti-inflammatoryactivity in vitro. Pharmacological studies revealed that chemicaldiverse groups of naturally occurring substances derived from theplants show promising anti-inflammatory activity. +erefore,this review suggests further research needs to be carried out onthe bioactive compounds present in the particular plants whichhave a potential to treat an inflammation and the possible un-derlying mechanisms of inflammation.
Conflicts of Interest
+e authors do not have any conflicts of interest regardingthe content of the present work.
Acknowledgments
+is research was financially supported by Universiti TunHussein Onn Malaysia (UTHM) (Vot No. U758, U673, andU908).
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