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Critical Reviews in Food Science and Nutrition

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Anti-inflammatory effects of phytochemicals fromfruits, vegetables, and food legumes: A review

Fengmei Zhu, Bin Du & Baojun Xu

To cite this article: Fengmei Zhu, Bin Du & Baojun Xu (2018) Anti-inflammatory effects ofphytochemicals from fruits, vegetables, and food legumes: A review, Critical Reviews in FoodScience and Nutrition, 58:8, 1260-1270, DOI: 10.1080/10408398.2016.1251390

To link to this article: https://doi.org/10.1080/10408398.2016.1251390

Published online: 12 Jun 2017.

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Anti-inflammatory effects of phytochemicals from fruits, vegetables, and foodlegumes: A review

Fengmei Zhua, Bin Dua,b, and Baojun Xub

aHebei Normal University of Science and Technology, Qinhuangdao, Hebei, China; bFood Science and Technology Program, Beijing NormalUniversity—Hong Kong Baptist University United International College, Zhuhai, Guangdong, China

ABSTRACTInflammation is the first biological response of the immune system to infection, injury or irritation.Evidence suggests that the anti-inflammatory effect is mediated through the regulation of variousinflammatory cytokines, such as nitric oxide, interleukins, tumor necrosis factor alpha-a, interferongamma-g as well as noncytokine mediator, prostaglandin E2. Fruits, vegetables, and food legumes containhigh levels of phytochemicals that show anti-inflammatory effect, but their mechanisms of actions havenot been completely identified. The aim of this paper was to summarize the recent investigations andfindings regarding in vitro and animal model studies on the anti-inflammatory effects of fruits, vegetables,and food legumes. Specific cytokines released for specific type of physiological event might shed somelight on the specific use of each source of phytochemicals that can benefit to counter the inflammatoryresponse. As natural modulators of proinflammatory gene expressions, phytochemical from fruits,vegetables, and food legumes could be incorporated into novel bioactive anti-inflammatory formulationsof various nutraceuticals and pharmaceuticals. Finally, these phytochemicals are discussed as the naturalpromotion strategy for the improvement of human health status. The phenolics and triterpenoids in fruitsand vegetables showed higher anti-inflammatory activity than other compounds. In food legumes, lectinsand peptides had anti-inflammatory activity in most cases. However, there are lack of human study dataon the anti-inflammatory activity of phytochemicals from fruits, vegetables, and food legumes.

KEYWORDSFruits and vegetables; foodlegumes; anti-inflammatoryproperty; phytochemicals;animal model

Introduction

Inflammation is a biological process in response to infec-tion, injury or irritation (Wang et al., 2013). Chronicinflammation seems to be associated with different types ofdiseases, such as arthritis, allergy, atherosclerosis, and evencancer (Devi et al., 2015). The process of inflammation is acomplicated immune response that can be defined as thesequential release of pro-inflammatory cytokines (Lin andTang, 2008). Therefore, inhibition of the overproduction ofinflammatory mediators, especially pro-inflammatory cyto-kines, such as interleukin (IL)-1b, IL-6, and tumor necrosisfactor alpha (TNF-a), may prevent or suppress a variety ofinflammatory diseases (Kim et al., 2003). Since ancienttimes, inflammatory conditions and their related disordershave been treated with plants or plant-derived formulations.Furthermore, numerous natural products rich in antioxi-dants display protective effects against inflammation. Theanti-inflammatory activities of several plant extracts andisolated compounds have already been scientifically demon-strated (Mueller et al., 2010). The anti-inflammatory prop-erties of naturally occurring phytochemicals are attributedto the decrease in certain cancers in both in vitro and invivo studies (Kang et al., 2005).

Nitric oxide (NO) is one of the major inflammatory media-tors. The phytochemicals that reduce NO production by induc-ible NOS (iNOS) without affecting endothelial NOS orneuronal NOS may be beneficial for the development of anti-inflammatory agents (Kim et al., 2004). Therefore, inhibition ofiNOS activity or down-regulation of iNOS expression is desir-able to reduce the extent of inflammatory response. In additionto iNOS, cyclooxygenase-2 (COX-2) is involved with variousinflammatory processes and is highly expressed in cell typesrelated to inflammatory processes including macrophages andmast cells, when stimulated with pro-inflammatory cytokinesand bacterial lipopolysaccharide (LPS) (Needleman andIsakson, 1997). However, TNF-a and IL-1b are also prominentcontributors to chronic inflammatory diseases (Mcinnes andGeorg, 2011). Phytochemicals mediate inflammation via kin-ases such as protein kinase C and mitogen-activated proteinkinase. Phytochemicals inhibit these aforementioned enzymesby altering the DNA-binding capacities of transcription factorssuch as nuclear factor kappa-B (NF-kB). Consequently, theexpression rate of the target gene is controlled. NF-kB is amajor effector pathway involved in inflammation (Garc�ıa-Lafuente et al., 2009). Another anti-inflammatory effect of

CONTACT Baojun Xu baojunxu@uic.edu.hk Food Science and Technology Program, Beijing Normal University—Hong Kong Baptist University UnitedInternational College, Zhuhai, Guangdong 519085, China.

Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/bfsn.Authors Fengmei Zhu and Bin Du contributed equally to this work.© 2018 Taylor & Francis Group, LLC

CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION2018, VOL. 58, NO. 8, 1260–1270https://doi.org/10.1080/10408398.2016.1251390

phytochemicals during the allergic reaction is inhibition of therelease of histamine (Rathee et al., 2009).

We recently reviewed the anti-inflammatory effects of fungalbeta-glucans (Du et al., 2015). A wide array of phytochemicals,particularly those present in edible and medicinal plants, havebeen reported to possess substantial anti-inflammatory activi-ties. However, the exact mechanisms of action of phytochemi-cals need to be ascertained for majority of the fruits, vegetables,and food legumes. Herein, this review commences with therecent insights gained on the in vitro and in vivo studies onanti-inflammatory activities of phytochemicals from fruits, veg-etables, and food legumes (Table 1 and Figure 1). The generalanti-inflammation response pathways of phytochemicals arelisted in Figure 2. However, the phytochemicals from differentfruits, vegetables, and food legumes may dramatically differbased upon their species, investigation methods, and the mediaof extraction, the anti-inflammation response pathways of dif-ferent food may differ in certain circumstances. The detailedmechanisms in terms of anti-inflammatory effects of individualcompound or food were presented in the following text.Figure 3 presented the typical chemical structures of commoncompounds from fruits, vegetable, and food legumes thatexhibited anti-inflammation effects.

Anti-inflamatory properties of fruits and vegetables

Crude extracts

Cytokine secretion regulatory activities using ethanolic extractsof strawberry and mulberry fruit juice were assessed in murineprimary splenocytes and peritoneal macrophages (Liu and Lin,2013). Strawberry and mulberry extracts with pine bark extract(0.5 g L¡1) significantly decreased (IFN-g C IL-2 C IL-12)/IL-10 (Th1/Th2) cytokine secretion ratios of splenocytes in theabsence or presence of LPS and TNF-a/IL-10 (pro-/anti-inflammatory) cytokine secretion ratios in the presence of LPSin dose-dependent manners. Frontela-Saseta et al. (2013) intheir experiment with co-culture system showed cell barrierdysfunction and over-production of IL-8, NO and reactive oxy-gen species (ROS). In the inflamed cells, incubation with nondi-gested samples reduced (p < 0.05) the production of IL-8 andNO compared with the digested samples. ROS productionincreased in the inflamed cells exposed to the digested commer-cial red fruit juice (86.8 § 1.3%) compared with fresh juice(77.4 § 0.8%).

According to Etoh et al. (2013), citrus peel extract decreasedthe release of TNF-a and NO from RAW264.7 cells stimulatedby LPS in a dose-dependent manner. In addition, citrus peelextract suppressed the expression of iNOS and nuclear translo-cation of NF-kB in RAW 264.7 cells. Fazio et al. (2013) evalu-ated Sambucus and Rubus spp. seeds extracts for theirinhibitory effects on the production of LPS-induced inflamma-tory mediators (NO, CCL-20) in RAW 264.7 cells. Blackberryextract decreased NO release in a concentration-dependentway with almost 60% inhibition at the highest dose (50 mg/mL). The results showed that the methanolic extracts fromRubus seeds have strong anti-inflammatory properties.

Li et al. (2012) investigated the anti-inflammatory effects ofthe fractions of Chinese pear fractionated with petroleum ether,

ethyl acetate, and n-butanol, respectively. In the carrageenan-induced rat paw edema test, the ethyl acetate fraction showedthe strongest inhibition of edema formation 0.5–5 h afterinduction of edema, followed by n-butanol fraction. Ethyl ace-tate fraction also displayed potent anti-inflammatory activityagainst xylene-induced ear edema (22.0% and 43.7%, respec-tively) and acetic acid-induced extravasation of Evan’s blue dye(39.58% and 49.92%, respectively) at a dose of 200 and 400 mg/kg, respectively. In another study, Hsu et al. (2012) evaluatedthe inhibitory effect of wild bitter melons on Propionibacteriumacnes-induced inflammation. The results showed that ethyl ace-tate extract of wild bitter melons in vitro potently suppressedpro-inflammatory cytokine and matrix metalloproteinase-9 lev-els in P. acnes-stimulated THP-1 human monocytic cells.

Phenolics

Epidemiological evidence shows that supplementations withfruits and vegetables rich in polyphenols are beneficial in bothforestalling and reversing the deleterious effects of aging onneuronal communication and behavior. For example, phyto-chemicals, especially phenolics in fruits and vegetables, are themajor bioactive components known to show various healthbenefits (Pereira and Maraschin, 2015; Chen et al., 2016; Xiao,2016; Xiao et al., 2016). The observed health benefits are due tothe antioxidant and anti-inflammatory properties of the poly-phenolic compounds found in these fruits and vegetables(Rice-Evans and Miller, 1996). Lau et al. (2007) found the pre-ventive effect of blueberry polyphenols against inflammation-induced activation of microglia. Their results indicate thattreatments with phenolic extract of blueberry inhibited the pro-duction of NO as well as IL-1b and TNF-a in cell-conditionedmedia from LPS-activated BV2 microglia. Furthermore, mRNAand protein levels of iNOS and COX-2 in LPS-activated BV2cells were significantly reduced by treatments with blueberryphenolic extract. In another study, the inhibitory effects of phe-nolic compounds in ginger on NO and prostaglandin E2(PGE2) production in LPS-induced RAW 264.7 macrophageswere measured (Chien et al., 2008). Zerumbone and 3-O-methyl kaempferol demonstrated potent inhibition on nitricoxide (NO) production, and also significantly suppressed iNOSexpression in a dose-dependent manner. However, zerumbonehad greater anti-inflammatory effects than 3-O-methyl kaemp-ferol. Comalada et al. (2006) elucidated that quercetin andluteolin inhibited the production of TNF-a and NO, and sup-pressed iNOS expression in LPS-activated macrophages, aneffect that has been associated with the inhibition of the NF-kBpathway. Furthermore, Garc�ıa-Mediavilla et al. (2007) sug-gested that kaempferol significantly decreased iNOS, COX-2,and reactive C-protein (CRP) in a concentration-dependentmanner at all concentration levels. The study suggests that themodulation of iNOS, COX-2, and CRP by kaempferol maycontribute to the anti-inflammatory effects of these two struc-turally similar flavonoids in Chang Liver cells, via mechanismslikely to involve blockade of NF-kB activation and the resultantup-regulation of the pro-inflammatory genes. In another study,the effect of naringenin was characterized using LPS-stimulatedmacrophages (Bodet et al., 2008). The results indicate that nar-ingenin is a potent inhibitor of the pro-inflammatory cytokine

CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1261

Table1.

Summaryoftheanti-inflam

matoryeffectsofph

ytochemicalsfrom

fruits,vegetables,andfood

legu

mes.

Classesof

Phytochemicals

Components

DietarySources

Mechanism

ofActio

nsExperim

entalM

odel

References

Crud

eextracts

Procyanind

inextract

Grape

seeds

Inhibitthe

overproductio

nofNOandPG

E 2RA

W264.7macroph

ages

model

(Terraet

al.,2007)

Fruitjuice

ethanolextracts

Strawberryandmulberry

Decreasesplenocytes’(IFN-g

CIL-2C

IL-12)/IL-10(Th1/Th2)cytokine

secretionratio

sMurineprimarysplenocytesand

peritonealm

acroph

ages

model

(LiuandLin,2013)

Fruitjuice

with

pine

barkextract

Pine

bark

Redu

ce(p

<0.05)the

productio

nofIL-8andNO

Caco-2cells

andRA

W264.7

macroph

ages

asmodel

(Frontela-Sasetaetal.,

2013)

Citrus

peelextract

Citrus

Decreasethereleaseof

TNF-aandNO

RAW264.7cells

model

(Etohetal.,2013)

SambucusandRubusspeciesseedsextracts

SambucusandRubus

species

Inhibitoryeffectson

theproductio

nof

NOandCC

L-20

RAW

264.7cells

model

(Garc� ıa-Lafuenteet

al.,

2009)

Ethylacetateextract

Chinesepear

Inhibitio

nofedem

aform

ation0.5–5hafteredemaindu

ction

Carrageenan-indu

cedratp

awedem

amodel

(Lietal.,2012)

Ethylacetateextract

Wild

bittermelons

Supp

resspro-inflam

matorycytokine

andmatrix

metalloproteinase-9

levels

THP-1cells

model

(Hsu

etal.,2012)

Aqueousextract

Mun

gbean

Potent

inflam

matorymediator(NO)inhibito

rs;reduceearedemain

mice

Invitroandinvivo

modelS

(Aliet

al.,2014)

Acetone-waterextracts

Mun

gbean

Sign

ificant

anti-inflam

matoryeffects

RAW

264.7macroph

ages

model

(Zhang

etal.,2013)

Extracts

Mun

gbean

AttenuateLPS-indu

cedreleaseof

severalchemokines

RAW

264.7macroph

ages

model

(Zhu

etal.,2012b)

Acetoneextract

Blackbean

Strong

COX-1andCO

X-2inhibitoryeffects

Invitromodel

(Oom

ahet

al.,2010)

Ethanolextract

Adzukibean

Supp

ressthereleaseof

PGE 2

andNO;dow

n-regu

latedLPS-indu

ced

mRN

Aexpression

ofiNOSandCO

X-2.

RAW

264.7macroph

ages

model

(Yuet

al.,2011)

Crud

emethanolic

extracts

Legu

mes

InhibitP

GE 2

Invitromodel

(Zia-Ul-H

aqetal.,

2013)

Phenolicrichextracts

Whitekidn

eybeansand

roun

dpu

rplebeans

Redu

ctionofNOproductio

nandcytokine

mRN

Aexpression

RAW

264.7macroph

ages

model

(Garc� ıa-Lafuenteet

al.,

2014)

Ethanolextract

Redbean

InhibitN

Oproductio

nInvitroandinvivo

models

(Parketal.,2011)

Phenolics

Polyph

enols

Blueberry

Inhibitthe

productio

nof

NO,IL-1b

andTN

F-a

LPS-activated

BV2microgliamodel

(Lau

etal.,2007)

Zerumbone

and3-O-m

ethylkaempferol

Ginger

InhibitN

OandPG

E 2productio

n,iNOSexpression

RAW

264.7macroph

ages

model

(Chien

etal.,2008)

Quercetinandluteolin

—InhibitTNF-aproductio

nas

wellasiNOSexpression

andNOproductio

nRA

W264.7macroph

ages

model

(Com

aladaet

al.,2006)

Kaem

pferol

—Decreaseof

iNOS,CO

X-2andreactiveCR

Plevel

Livercellsmodel

(Garc� ıa-Mediavilla

etal.,2007)

Naringenin

—Apotent

inhibitoro

fthe

pro-inflam

matorycytokine

RAW

264.7macroph

ages

model

(Bodetet

al.,2008)

Punicalagin,pu

nicalin,strictin

inAand

granatinB

Pomegranate

redu

ceproductio

nofNOandPG

E 2RA

W264.7macroph

ages

model

(Lee

etal.,2008;

Romieretal.,2008)

Granatin

BPomegranate

Astrong

inhibitoryeffectagainstinflam

mationstimulators

Carrageenan-indu

cedpawedem

amodel

(Lee

etal.,2010)

Nariru

tinCitrus

Inhibitthe

releaseofNO,PGE 2,IL-1b

andTN

F-a

RAW

264.7macroph

ages

model

(Haet

al.,2012)

Flavonevelutin

Acaifruit

Show

excellent

anti-inflam

matorycapacity

RAW

264.7macroph

ages

model

(Kanget

al.,2011)

Anthocyanin

Blacksoybean

Haveanti-inflam

matoryactivity

forp

enile

plaque

form

ation

RatP

eyroniediseasemodels

(Sohnetal.,2014)

Phenoliccompounds

Navyandblackbean

Redu

cemRN

Aexpression

ofcolonicinflam

matorycytokines(IL-6,IL-9,

IFN-g

andIL-17A

)and

increase

anti-inflam

matoryIL-10

Amouse

modelof

acutecolitis

(Zhang

etal.,2014)

Triterpenoids

monom

ericcompounds

Pear

Indicatestrong

eranti-inflam

matoryactivities

RAW

264.7macroph

ages

model

(Lietal.,2014)

Pentacyclic

triterpenoids

Apple

Implicateintheanti-inflam

matoryproperties

T84coloncarcinom

acells

model

(Muelleretal.,2013)

Saponins

Soybeansaponins

Soybean

Inhibitthe

releaseofPG

E 2,N

O,TNF-aandMCP-1

RAW

264.7macroph

ages

model

(Kanget

al.,2005)

Soyasaponins

Soybean

Supp

resstheiNOSenzymeactivity

anddown-regu

latedtheiNOSmRN

Aexpression

RAW

264.7macroph

ages

model

(Zha

etal.,2011)

Soyasaponins

Soybean

Redu

ceinflam

matorymarkers,colon

leng

th,m

yeloperoxidase,lipid

peroxide,proinflam

matorycytokinesandNF-kBactivationinthe

colon

TNBS-indu

cedcoliticmicemodel

(Lee

etal.,2010)

Angu

larin

A,angu

lasaponins

A-C,and

azukisaponinsIIIandVI

Adzukibean

InhibitN

Oproductio

nRA

W264.7macroph

ages

model

(Jiang

etal.,2014)

Lectins

Lectins

Butterflypea

Anti-inflam

matoryactivity

Thepawedem

aindu

cedby

carrageenanmodel

(Leite

etal.,2012)

1262 F. ZHU ET AL.

Monocot

lectin

Cannalim

bata

seeds

Redu

ctionofinflam

mation

Form

alinmodel

(Ara� ujoetal.,2013)

Lectin

Canavalia

boliviana

Inhibitthe

pawoedemaindu

cedby

carrageenan

Invivo

model

(Bezerraet

al.,2014)

Soybeanagglutinin

Soybean

Inhibitoryeffecton

neutroph

ilmigratio

nInvitromodel

(Benjaminetal.,1997)

Polysaccharid

esPolysaccharid

eWelsh

onion

reactivenitrogen

speciesredu

ction;theincrease

intheactivities

ofantio

xidant

enzyme

Micemodel

(Wangetal.,2013)

Water-solub

lepolysaccharid

eChaenomeles

speciosa

fruit

Redu

cedthegene

indu

ctionofTN

F-a,IFN

-gandgranulocytecolony-

stimulatingfactor

RAW

264.7macroph

ages

model

(Zhu

etal.,2012a)

Peptides

Bioactivepeptides

Soybean

Inhibitio

non

inflam

matorymarkerssuch

asNO,iNOS,PG

E 2,COX-2and

TNF-a

RAW

264.7macroph

ages

model

(Vernaza

etal.,2012)

Lunasin

Soybean

Redu

cetheproductio

nofRO

S;inhibitthe

releaseof

pro-inflam

matory

cytokines(TNF-a)and

IL-6

RAW

264.7macroph

ages

model

(Hern� and

ez-Ledesma

etal.,2009)

Other

compounds

Monogalactosyldiacylglycerol

Citrus

hystrix

Exhibith

igheranti-inflam

matoryactivity

TPA-indu

cededem

aearsmice

model

(Murakam

ietal.,1995)

Monogalactosyldiacylglycerol

Vegetables

Dow

nstreaminflam

matorymediators,COX-2,iNOS,NOandPG

E 2RA

W264.7macroph

ages

model

(Hou

etal.,2007)

Phenethylisothiocyanate

Cruciferous

vegetables

Sppression

ofTRIF-dependent

pathwaysof

TLR3

andTLR4

RAW

264.7macroph

ages

model

(Parketal.,2013)

Indole-3-carbinol

Broccoli,cabb

age,

cauliflow

er,brussels

sprouts.

Attenuatetheproductio

nofpro-inflam

matorymediatorssuch

asNO,IL-

6,andIL-1b

RAW264.7cells

andTH

P-1cells

models

(Jiang

etal.,2013)

CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1263

response induced by LPS in both macrophages and in wholeblood.

Pomegranate peels are characterized with substantialamounts of phenolic compounds, including flavonoids (antho-cyanins, catechins, and other complex flavonoids) and hydro-lyzable tannins (punicalin, pedunculagin, punicalagin, gallicacid, and ellagic acid) (Ismail et al., 2012). The anti-inflamma-tory components of pomegranate peel, that is, punicalagin,

punicalin, strictinin A, and granatin B significantly reduced theproduction of NO and PGE2 by inhibiting the expression ofpro-inflammatory cytokines (Lee et al., 2008; Romier et al.,2008). In case of animal models, Ouachrif et al. (2012) investi-gated anti-inflammatory properties of the pomegranate peelfollowing intraperitoneal (25, 50, and 100 mg/kg) and intra-cerebroventricular (10, 25, and 50 mg/3 mL/rat) administrationin rats. The results indicated pain index reduction of 52–82%

Figure 1. Causal relationship of inflammation and anti-inflammation.

Figure 2. The pathway of anti-inflammatory effect of phytochemicals.

1264 F. ZHU ET AL.

and a significant reduction in egg albumin-induced hind pawinflammation at the same levels of dosage as intra-peritonealtest. Moreover, Lee et al. (2010) evaluated a strong inhibitoryeffect against inflammatory stimulators during carrageenan-

induced paw edema in mice following oral administration ofgranatin B (2.5 and 10 mg/kg). Significant inhibitory effectswere observed after 6 h of pomegranate peel active componentadministration when compared to indomethacin. As a result ofthese properties, pomegranate peel extract and hydrolyzabletannins, in the form of standardized active components, are avery effective treatment strategy against inflammatory disor-ders. In one study, narirutin fraction from citrus peels inhibitedthe release of NO and PGE2 through suppressing the expres-sion of iNOS and COX-2, respectively in LPS-stimulated mac-rophages. The release of IL-1b and TNF-a was also reduced bynarirutin fraction in a dose-dependent manner (Ha et al.,2012). Thus, narirutin fraction has the potential to be used as afunctional dietary supplement and as an effective anti-inflam-matory agent. The presence of polyphenolic components inacai (one of the Amazon’s most popular fruits) is linked mainlyto the antioxidant, anti-inflammatory, anti-proliferative, andcardioprotective activities (Yamaguchi et al., 2015). Kang et al.(2011) isolated five compounds from acai pulps. The flavones,velutin, from acai pulps showed excellent anti-inflammatorycapacity in mouse macrophages, indicating a potential athero-protective effect. Moreover, Terra et al. (2007) evaluated theanti-inflammatory effect of procyanindin extract from grapeseeds in RAW 264.7 macrophages stimulated with LPS plusIFN-g. The results showed that procyanindin extract fromgrape seeds caused a rapid enhanced production of PGE2 andNO. The results demonstrated that procyanindin extract signif-icantly inhibited the over production of NO in both dose andtime dependent manners. Procyanindin extract caused amarked inhibition of PGE2 synthesis when administered duringactivation.

Polysaccharides

Wang et al. (2013) investigated the anti-inflammatory effects ofan aqueous extract (mainly polysaccharide) of Welsh oniongreen leaves with mice model. According to them, the anti-inflammatory and analgesic effects of Welsh onion green leavesmay be related to the decrease in reactive nitrogen species andassociated with the increase in antioxidant enzymes (catalase,superoxide dismutase (SOD), and glutathione peroxidase).Another study reported that water-soluble polysaccharide fromfruits of Chaenomeles speciosa suppressed the gene induction ofTNF-a, IFN-g, and granulocyte colony-stimulating factor inLPS-induced RAW 264.7 cells (Zhu et al., 2012a).

Triterpenoids

Li et al. (2014) compared the contents of total triterpenesbetween peel and flesh of 10 different pear cultivars. The anti-inflammatory activities of monomeric compounds were alsomeasured. All the chemical components found in the pear peelwere approximately 6–20 times higher than those in the fleshof pear. Peel and flesh from Yaguang, Hongpi, Qingpi, and Gui-fei varieties contained relatively more total triterpenes and indi-cated stronger anti-inflammatory activities. In another study,Mueller et al. (2013) studied pentacyclic triterpenoids in applepeel for detecting in vitro anti-inflammatory effects using T84colon carcinoma cells. Their results showed that triterpenoids

Figure 3. The typical chemical structures of anti-inflammatory phytochemicals infruits, vegetables, and food legumes.

CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1265

present in apple peel could be implicated in the anti-inflamma-tory properties of apple constituents, suggesting that these sub-stances might be helpful in the treatment of inflammatorybowel disease (IBD) when given as nutrient supplements.

Other compounds

Galactolipids are a class of compounds widely found in theplant kingdom, including edible plants, and are importantcomponents of their cell membranes. Several galactolipids havebeen shown to possess in vitro and/or in vivo anti-inflamma-tory activity (Christensen, 2009). In one study, monogalactosyl-diacylglycerol, which is a predominant membrane lipid in seedplants and the most abundant polar lipid, exhibited potentanti-inflammatory activity in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced edema formation on mouse ears(Murakami et al., 1995). Hou et al. (2007) found that monoga-lactosyldiacylglycerol had chemopreventive effects by suppress-ing cytoplasmic NF-kB and downstream inflammatorymediators, COX-2, iNOS, NO, and PGE2. Moreover, phenethylisothiocyanate (PEITC) found in cruciferous vegetables showeda positive effect on chronic inflammatory diseases, which aremediated through modulation of Toll/IL-1 receptor domain-containing adapter-inducing interferon-b (TRIF)-dependentsignaling pathway of Toll-like receptors (TLR) (Park et al.,2013). The suppression of TRIF-dependent pathways of TLR3and TLR4 by PEITC is accompanied by the down-regulation ofthe NF-kB activation and interferon regulatory factor 3, andthe expression of their target genes, including IFN-b and IFNinducible protein-10. Similarly, Jiang et al. (2013) assessed invitro and in vivo anti-inflammatory effects of indole-3-carbinoland its molecular mechanisms. Indole-3-carbinol attenuatedthe production of pro-inflammatory mediators such as NO, IL-6, and IL-1b in LPS-induced RAW 264.7 cells and THP-1 cellsthrough the attenuation of TRIF-dependent signaling pathway.

Anti-inflammatory properties of food legumes

A large range of species of food legumes are cultivated and con-sumed throughout the world (Patto et al., 2014). In recentyears, colored common beans, including pinto beans and blackbeans, have attracted a great deal of attention because of theirfunctional pigments and health-promoting effects in relation toprevention of chronic diseases, including cancers, cardiovascu-lar diseases, obesity, and diabetes (Xu and Chang, 2009). Phe-nolic compounds, such as phenolic acids, flavonols, flavones,isoflavones, anthocyanins, and condensed tannins, have beenidentified and characterized in food legumes (Xu and Chang,2011; Djordjevic, 2011; Sreerama et al., 2012; Das and Parida,2014).

Crude extracts

Ali et al. (2014) evaluated the anti-inflammatory and antinoci-ceptive activities of untreated mung bean, germinated mungbean, and fermented mung bean on both in vitro and in vivostudies. The results indicated that both germinated andfermented mung bean aqueous extract exhibited potent anti-inflammatory and anti-nociceptive activities in a dose-

dependent manner. In vitro results showed that both germi-nated and fermented mung bean were potent inhibitors ofinflammatory mediator (NO) at both 2.5 and 5 mg/mL. Furtherin vivo studies showed that both germinated and fermentedmung bean aqueous extract at 1000 mg/kg can significantlyreduce ear edema in mice caused by arachidonic acid. More-over, Oomah et al. (2010) reported that acetone extract of blackbean hull exhibited strong COX-1 (IC50 D 1.2 mg/mL) andCOX-2 (IC50 D 38 mg/mL) inhibitory effects, even outperform-ing than aspirin. Bean hull water extracts were stronger inhibi-tors of 15-lipoxygenase (15-LOX), than corresponding acetoneextracts. In another study, Yu et al. (2011) suggested thatadzuki bean (Phaseolus angularis) ethanol extract dose-depen-dently suppressed the release of PGE2 and NO in macrophagesand strongly down-regulated LPS-induced mRNA expressionof iNOS and COX-2. The results showed that adzuki bean etha-nol extract can be further developed as a promising anti-inflammatory remedy because it targets multiple inflammatoryenzymes and transcription factors. Zhang et al. (2013) foundthat mung bean acetone-water extracts possessed significantanti-inflammatory effects in LPS-stimulated RAW264.7 mousemacrophage cells at 100 mg/mL concentration.

Furthermore, Zia-Ul-Haq et al. (2013) investigated crudemethanolic extracts of black gram, green gram, soybean, andlentil for anti-inflammatory activity by COX-2 producing PGE2inhibitory assay. They observed 73.9%, 79.8%, 92.2%, and74.5% inhibition for black gram, green gram, soybean, and len-til, respectively, at 20 mg/mL extract concentration.Garc�ıa-Lafuente et al. (2014) determined the anti-inflammatoryactivities of phenol rich extracts obtained from white kidneybeans and round purple beans. Round purple bean extractsindicated a higher anti-inflammatory activity by decreasing theproduction of NO and expression of cytokine mRNA of LPS-stimulated macrophages. In another study, mung bean extractsdose-dependently attenuated LPS-induced release of severalchemokines in macrophage cultures. Oral administration ofmung bean extracts significantly increased animal survival ratesfrom 29.4% to 70% (Zhu et al., 2012b).

Park et al. (2011) used in vitro and in vivo experimentalmodels to investigate the anti-inflammatory potential of thebutanol fraction of red bean ethanol extract. Treatment withbutanol fraction of red bean ethanol extract inhibited NO pro-duction in LPS-stimulated macrophages through suppressionof extracellular signal regulated kinase and inhibitory kappa Balpha (IkBa) activation. The result suggested the possible use-fulness of red beans in the treatment of inflammatory diseases.

Saponins

Soyasaponins are found in soybeans and other legumes (Guanget al., 2014). Saponins have received much attention in relationto the health effects of food legumes. Kang et al. (2005)investigated the effects of soybean saponins on the productionof pro-inflammatory mediators in LPS-stimulated peritonealmacrophages. Soybean saponins significantly inhibited therelease of PGE2, NO, TNF-a, and monocyte chemotactic pro-tein-1 (MCP-1) in a dose-dependent manner. Soybean sapo-nins also down-regulated the expression of COX-2 and iNOSat mRNA/protein levels. Moreover, soybean saponins

1266 F. ZHU ET AL.

suppressed NF-kB activation by blocking IkBa degradation.Successful in vitro assays indicated that soybean saponinsexhibit anti-inflammatory properties by suppressing the tran-scription of inflammatory cytokine genes through the NF-kBsignaling pathway. In addition, Zha et al. (2011) investigatedthe inhibitory effects of soyasaponins (25–200 mg/mL) on theinduction of NO and iNOS in murine RAW 264.7 cells acti-vated with LPS. The soyasaponins suppressed both the iNOSenzyme activity and down-regulated the iNOS mRNA expres-sion in a dose-dependent manner. The findings showed thatsoyasaponin exhibited anti-inflammatory properties by sup-pressing NO production in LPS-stimulated RAW264.7 cellsthrough attenuation of NF-kB-mediated iNOS expression. In astudy based on animal model, Lee et al. (2010) investigated theinhibitory effects on inflammatory markers in 3,4,5-trinitro-benzenosulfonic acid (TNBS)-induced colitic mice. Oraladministration of soyasaponin (10 and 20 mg/kg) to TNBS-treated colitic mice significantly reduced inflammatorymarkers, colon length, myeloperoxidase, lipid peroxide, proin-flammatory cytokines, and NF-kB activation in the colon, aswell as increased glutathione content, SOD, and catalase activ-ity. Moreover, Jiang et al. (2014) reported that angularin A,angulasaponins A-C, and adzukisaponins III and VI fromadzuki bean (Vigna angularis) presented inhibitory effects onNO production in LPS-activated RAW264.7 macrophages,with IC50 values ranging from 13 to 24 mM.

Peptides

Legumes are an important source of proteins from food. Bio-logical activities of proteins and peptides from legume seedshave been observed (Duranti, 2006). Vernaza et al. (2006)investigated that soybean flours with bioactive peptides showeda significant (p < 0.05) inhibition on inflammatory markerssuch as NO (20.5–69.3%), iNOS (22.8–93.6%), PGE2 (64.0–88.3%), COX-2 (36.2–76.7%), and TNF-a (93.9–99.5%) inLPS-induced RAW 264.7 macrophages. Moreover, Hern�andez-Ledesma et al. (2009) found peptide lunasin reduced the pro-duction of ROS in LPS-induced RAW 264.7 macrophages in asignificant dose-dependent manner. Lunasin also inhibited therelease of pro-inflammatory cytokines (TNF-a) and IL-6.

Phenolics

Dry beans are typically processed and the seed coats may beremoved and discarded prior to consumption. Therefore, a bet-ter understanding of the anti-inflammatory activity of coloreddry bean seed coats would be beneficial in determining theirpotential use as an ingredient in the functional food and nutra-ceutical industry (Pitura, 2011). Legume seed hulls are richsources of polyphenolics and natural antioxidants (Moise et al.,2005; Luo, Cai, Wu, Xu, 2016). Boudjou et al. (2013) found thataqueous ethanolic (80%) extract of lentil hulls had high anti-inflammatory activities preferentially inhibiting 15-LOX (IC50

D 55 mg/mL), with moderate COX-1 (IC50 D 66 mg/mL) andCOX-2 (IC50 D 119 mg/mL) inhibitory effects on the COXpathway. In addition, Pitura (2011) measured the cellular anti-inflammatory activity of seed coat crude extracts of coloredcommon beans (P. vulgaris L.) in LPS-induced murine

macrophage RAW 264.7 cells, the results showed anti-inflam-matory activity of colored bean seed coat. For example, extractsof pinto bean (P. vulgaris cv. Windbreaker) and black bean (P.vulgaris cv. Eclipse) decreased TNF-a levels suggesting anti-inflammatory properties. In another study, Sohn et al. (2014)suggested that anthocyanins extracted from black soybean mayhave anti-inflammatory activity for penile plaque formation inrat Peyronie disease models. Zhang et al. (2014) assessed the invivo effect of 20% navy and black bean (P. vulgaris L.) flours,with different phenolic compound levels and profiles, in amouse model of acute colitis. The results showed that beandiets reduced mRNA expression of colonic inflammatory cyto-kines (IL-6, IL-9, IFN-g, and IL-17A) and increased anti-inflammatory IL-10 (p < 0.05), while simultaneously reducingcirculating cytokines (IL-1b, TNF-a, IFN-g, and IL-17A, p <

0.05) and dextran sulfate sodium (DSS)-induced oxidativestress.

Lectins

Lectins are proteins that have the ability to bind specifically andreversibly to carbohydrates and glycoconjugates without alter-ing the structure of the glycosyl ligand (Leite et al., 2012). Inlegumes, lectins make up about 10% of the total nitrogen of theseeds (Oliveira et al., 2008). Plant lectins can display either pro-or anti-inflammatory actions depending on the administrationroute used via lectin domain interaction (Assreuy et al., 1997;Assreuy et al., 1999; Alencar et al., 1999; Alencar et al., 2004).Leite et al. (2012) purified and characterized lectins in the seedsof butterfly pea (Clitoria fairchildiana) and verified their anti-inflammatory activity. It was observed that lectin had anti-inflammatory activity in the carrageenan induced paw edemainflammation model, in which a 64% diminution in edema wasobserved. Moreover, Ara�ujo et al. (2013) evaluated anti-inflam-matory activity of monocot lectin from the Canna limbataseeds. The lectin showed anti-inflammatory effect with thereduction of inflammation in the formalin test and neutrophilmigration into the peritoneal cavity. Bezerra et al. (2014) char-acterized the anti-inflammatory properties of lectin from Cana-valia boliviana using in vivo model. The paw edema induced bycarrageenan was also inhibited in presence of lectin at 1 mg/kgconcentration. In another study, when soybean agglutinin ispresent in the blood circulation, an inhibitory effect on neutro-phil migration was observed suggesting an anti-inflammatoryeffect (Benjamin et al., 1997). The results showed that soybeanagglutinin (5–200 mg/cavity) injected into rats with differentcavities induced a typical inflammatory response characterizedby dose-dependent exudation and neutrophil migration 4 hafter injection.

Future perspective

The pharmacological relevance of active constituents is fullyjustified by the most recent findings indicating that fruits, vege-tables, and food legumes are the medicinal and nutritionalagents useful for treating a wide range of human disorders. Fur-ther investigations are needed to fully understand the modes ofactions of phytochemicals and to fully exploit their preventiveand therapeutic potential. Phytochemicals definitely deserve

CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1267

further studies with regard to biological activity, including stud-ies into mechanism of action and structure-activity relation-ships. Other fruits, vegetables, and food legumes should beinvestigated in terms of a potential source of new chemicalstructures and biological activities. Future research works couldfocus on combining in vitro model, animal model, and humantrials to thoroughly identify the anti-inflammatory propertiesof phytochemicals. In addition, it is difficult to make a judg-ment to say which food is the best for anti-inflammatory dietary therapy based on the literature data pre-sented in this review work, because the investigations weredone by different research groups with different experimentalmodels and methodologies. Therefore, a future in-depth studyis suggested to incorporate these commonly consumed fruits,vegetables and food legumes into one study, and compare theiranti-inflammatory potential based on the same conditions, sothat we can recommend the most potent food to consumers forgaining anti-inflammatory benefits. Processing methods forfruits, vegetables, and food legumes, such as boiling, pressurecooking, roasting, sprouting, and so on, should also be opti-mized to minimize the loss of therapeutic effects. The advancesin biotechnological tools and the research community’s capac-ity to develop imaginative strategies will help in framing afruits, vegetables, and food legumes’ development program forensuring the nutritional security of the world. Moreover, foodlegumes differ in their composition regarding the content andtype of bioactive compounds. Further studies should be aimedat random clinical trials to compare diverse types of foodlegumes to determine the most beneficial for a particular dis-ease prevention and treatment. Although fruits, vegetables, andfood legumes are natural foods and nontoxic substances, thepurified compounds from fruits, vegetables and food legumesmay still have certain potential side-effects, the over-dose usagemay also cause side- effects. Therefore, the further study shouldalso look on this point so that food scientist can give a rationalsuggestion to consumers in either choosing the original fruits,vegetables, and food legumes or choosing the purified com-pounds or processed nutraceuticals from these foods. In addi-tion, there are lack of study on structure-activity relationship ofisolated compounds from fruits, vegetable, and food legumes,this could be one of the future research areas.

Acknowledgments

This project is jointly supported by one grant (project code: UIC201624)from Beijing Normal University-Hong Kong Baptist University UnitedInternational College and one grant (R1005) from Zhuhai Key Laboratoryof Agricultural Product Quality and Food Safety.

Conflict of interest

The authors have declared that there is no conflict of interest.

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