review article role of polyphenols and other...

Review ArticleRole of Polyphenols and Other Phytochemicals onMolecular Signaling

Swapna Upadhyay and Madhulika Dixit

Laboratory of Vascular Biology Department of Biotechnology Bhupat and Jyoti Mehta School of Biosciences andBioengineering Building Indian Institute of Technology Madras Chennai Tamil Nadu 600036 India

Correspondence should be addressed to Swapna Upadhyay swapnaupadhyayiitmgmailcom

Received 20 October 2014 Revised 30 December 2014 Accepted 31 December 2014

Academic Editor Cristina Angeloni

Copyright copy 2015 S Upadhyay and M Dixit 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

Optimized nutrition through supplementation of diet with plant derived phytochemicals has attracted significant attentionto prevent the onset of many chronic diseases including cardiovascular impairments cancer and metabolic disorder Thesephytonutrients alone or in combination with others are believed to impart beneficial effects and play pivotal role in metabolicabnormalities such as dyslipidemia insulin resistance hypertension glucose intolerance systemic inflammation and oxidativestress Epidemiological and preclinical studies demonstrated that fruits vegetables and beverages rich in carotenoids isoflavonesphytoestrogens and phytosterols delay the onset of atherosclerosis or act as a chemoprotective agent by interacting with theunderlying pathomechanisms Phytochemicals exert their beneficial effects either by reducing the circulating levels of cholesterolor by inhibiting lipid oxidation while others exhibit anti-inflammatory and antiplatelet activities Additionally they reduceneointimal thickening by inhibiting proliferation of smooth muscle cells and also improve endothelium dependent vasorelaxationbymodulating bioavailability of nitric-oxide and voltage-gated ion channels However detailed and profound knowledge on specificmolecular targets of each phytochemical is very important to ensure safe use of these active compounds as a therapeutic agentThusthis paper reviews the active antioxidative antiproliferative anti-inflammatory or antiangiogenesis role of various phytochemicalsfor prevention of chronic diseases

1 Introduction

Overwhelming evidence from epidemiological in vivo invitro and clinical trial data indicates that the plant-based dietcan reduce the risk of chronic diseases (eg cardiovasculardisease hypertension diabetes and cancer) due to presenceof biologically active plant compounds or phytochemicalsSteinmetz and Potter identified more than a dozen classes ofphytochemicals fromplant based diets (fruits vegetable nutsetc) such as carotenoids phenolic compounds (flavonoidsisoflavonoids and lignin) phenolic acid phytosterols andphytostanols tocotrienols organosulfur compounds andnondigestible carbohydrates (dietary fiber Table 1) [1]According to many researchers regular consumption of dietrich in vegetables fruits whole grains herbs nuts seedswhich contain plenty of phenolic compounds terpenoidsphytosterols organosulfur exert their beneficial effect indisease prevention by regulating several cellular molecular

pathways like regulation of inflammation redox potentialsmetabolic disorder apoptosis and so forth [2] Polyphenols(flavonoids lignans stilbenes etc see Table 1) are the mostdiverse group of phytochemicals distributed in vegetablesfruits olive oil and wine and exhibit wide range of protectiveroles such as hypolipidemic antioxidative antiproliferativeand anti-inflammatory effects to reduce the onset of dis-ease progression [3ndash5] Similarly terpenoids (carotene lyco-pene etc) another important chemically active natural hydro-carbon contain oxygen rich moieties like alcohol aldehydesand ketones Epidemiological studies have shown that theoral supplementation of tomato extract (rich in caroten-oid lycopene) significantly control the risk of hyperlipidemiaCVD metabolic syndrome by regulating several physiologi-cal phenonmenon like reduction of blood pressure of lowden-sity lipoprotein oxidation hypertension [6] Organosulfurphytosterols are the other widely distributed active phyto-chemicals which have been found to reduce the generation

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2015 Article ID 504253 15 pageshttpdxdoiorg1011552015504253

2 Oxidative Medicine and Cellular Longevity

Table1Classifi

catio

nof

phytochemicals(adaptedfro

mGon

zalez-Ca

stejonandRo

driguez-Ca

sado

[3692107])

Dietary

phytochemicals

Functio

nald

erivatives

Sources

Therapeutic

seffect

Polyph

enols

Phenolicacid

Curcum

inoids

Flavon

oids

Chalcones

Stilb

enes

Lign

ans

Isofl

avon

oids

Caffeicacid

Ferulic

acid

Chlorogenica

cid

Curcum

inFlavon

olsFlavanon

esAntho

cyanins

Flavanon

oles

Phloriz

inRe

sveratol

Sesamin

Pino

resin

olGenistein

Daidzein

Coff

eebeanssoybeans

Turm

eric

Teafruits(citrusapp

legrapes)

Vegetables

Tomatoestea

Grapesredwine

Who

legrainslegum

es

Soya

Antioxidativ

eeffect

(1)C

urcuminresveratro

lteap

olypheno

landiso

thiocyanatesuarrthep

hase

IIdetoxifyingandantio

xidant

enzymes

likeH

O-1G

STby

mod

ulationtranscrip

tionfactor

Nrf2

[2024]

(2)C

urcumin

protectsagainstn

euronaldegenerationbydarrRO

SneutralizingNOindu

cedfre

eradicalsCu

rcum

inuarr

intracellularG

SHpo

olby

triggerin

gspecifictranscriptio

nfactors(eg

TP

AE

pRE)

[4445]

(3)IsoflavonestargeteNOSandredo

xsensitive

gene

expressio

nandregulatev

ascularreactivity

[3740

](4)A

gedratsfedsoyproteindietric

hin

geniste

inanddaidzeinw

hich

interactwith

estro

genreceptorsuarreN

OS

andantio

xidant

enzymes

expressio

n[39]

(5)R

esveratro

lanthocyanin

blocking

activ

ationof

NF-kB

MAPK

and

PGE2

protectneuron

aldisorder

[5152]

Anti-infl

ammatoryeffect

(1)P

rocyanidinsdarr

expressio

nof

iNOSandCO

X-2inhibitinfl

ammatoryph

enom

enon

Procyanidinsa

lsosig

nificantlydarrexpressio

nof

TNF-120572andIL-1120573by

blocking

NF-kB

activ

ityviadarr

ofMAPK

andP3

8pathways[52]

(2)T

eaandor

redwinep

olypheno

linh

ibitexpressio

nof

COX-

2LO

Xandexertanti-infl

ammatoryeffect

Similarly

kaem

pferola

flavono

idric

hin

fruits

vegetables

(broccoli)darrredu

ceinflammationby

inhibitin

gthe

generatio

nof

PGE2

[64ndash

66]

(3)O

ralsup

plem

entatio

nof

curcum

in(45m

gkg)inmalem

icedarr

stemicinflammationby

blocking

ther

eleaseo

fTN

F-120572andCR

P[68]

(4)C

innamon

bark

extract(contentT

APP

)protectsfrom

AHRor

asthmab

yredu

cing

inflammatorymediators

likeIL-4andIL-13[69]

(5)C

innamon

bark

extractp

rotectsa

gainstsyste

micinflammationin

rheumatoidarthritisby

redu

cing

CRPand

stimulatingautoim

mun

esystem

bydarrexpressio

nof

manyinflammatorymediators(prosta

glandinE2

NO)inRA

rats[69]

Metabolism

regu

lation

(1)A

ntho

cyanin

andmyrtillin

ofblueberryextractsho

whypo

glycem

iceffectinhu

mansSupp

lementatio

nof

3blueberryenric

heddietfor8

weeks

andor

05

GSE

-sup

plem

enteddietsig

nificantly

redu

cedthea

rterialblood

pressure

inSH

Rsviae

ndotheliu

mmediatedstimulationof

NOmetabolism

andactiv

ationof

COX-

indu

ced

prod

uct[7475]

(2)T

APPthe

mainactiv

ecom

ponent

ofCinn

amon

extractsig

nificantlydarrtheb

lood

HbA

1cleveland

improves

the

insulin

signalin

gin

diabeticanim

alstu

dy[73]

(3)P

heno

liccompo

undsn

amely

chlorogenicacid

andferulic

acidand

aplant

alkaloidberberin

earec

onsid

ered

aspo

tent

antid

iabetic

agentas

thesep

hytochem

icalse

nhance

theu

ptakeo

f2DGin

time-

anddo

se-dependent

mannera

ndsig

nificantly

upregulatethe

expressio

nof

GLU

T4andPP

AR-120574andPK

13Kexpressio

n[9091]

Antiproliferativee

ffect

(1)T

eapo

lyph

enolse

xertantip

roliferativee

ffectsb

yinteractingwith

MMPsyste

mTea

polyph

enoldarrSM

Cproliferatio

nby

blocking

cyclinD1and

CyclinEandby

inhibitin

gthec

ellgrowth

markersPC

NA[9495]

(2)R

esveratro

luarrapop

tosis

byup

regulationof

tumor

supp

ressor

genesp

21Cip1W

AF1p53the

proapo

ptotic

proteinBa

xexpressio

nuarrcaspasea

poptoticsig

nals

anddarrantiapo

ptoticproteins

Bcl-2

Bcl-

XLand

survivin

expressio

n[103104]

(3)P

olypheno

ls(resveratro

lgeniste

incurcuminC

-phycocyaninand

quercetin

)inh

ibitproliferatio

nandmotility

ofcells

bysupp

ressionof

celladhesio

nmoleculeC

D44

expressio

n[102]

(4)E

llagica

cidiso

vitexindarrSM

Cproliferatio

nmight

bebydarrRO

Sgeneratio

nanddarrof

ERK1

2andiN

OS

expressio

n[101]

Antiang

iogenice

ffect

(1)E

llagica

cidsig

nificantlydarrangiogenesisin

hamste

rbuccalpun

chbydarrPI3K

Akt

andMAPK

andVEG

Fsig

nalin

gpathwayssupp

ressingHDAC

6andhypo

xia-indu

cibleH

IF-1120572respon

ses[105]

(2)T

ephrociapurpurea

richin

flavono

idsw

asfoun

dto

exertw

ound

healingeffectb

ysig

nificantuarr

ofangiogenesis

orbloo

dvessels

form

ation

fibroblastcells

andgeneratio

nof

collagenfib

res[106]

(3)A

staxanthin(non

-provitamin

Acaroteno

id)p

redo

minantly

distr

ibuted

inmicroalgaefung

iplants

andsea

food

sinhibitstumor

progressionby

regulatingST

AT3JAK-

2[108]

Oxidative Medicine and Cellular Longevity 3

Table1Con

tinued

Dietary

phytochemicals

Functio

nald

erivatives

Sources

Therapeutic

seffect

Terpenoids

Caroteno

ids

Sesquiterpenes

Lycopene

Lutein

Carotene

Acyclic

compo

und(Farnesol

Nerolidol)

Cyclicc

ompo

und(A

bscisic

acid)

Tomatoesspinachcarrot

Fruits

vegetables

Antioxidativ

eeffectcon

sumptionof

lycopene

(richin

tomatospinachetc)

significantlyuarrantio

xidant

enzymes

SODG

SH-PxGR

andGSH

anddarrlevelsof

MDAin

hypertensiv

epatientsLycopenedarrMDAlevelsanduarrGSH

levelsin

postm

enop

ausalw

omen

andprotectsfro

mcardiovascular

disorder

Anti-infl

ammatoryeffectlycopenedarrther

eleaseo

fproinflammatorycytokine

TNF-120572bydarrNF-kB

activ

ationand

indu

cesa

nti-infl

ammatoryeffectMoreoversignificantinh

ibition

oflip

idperoxidatio

nby

thec

ombinatio

nof

ascorbicacid

and120572-to

coph

erolisthec

omplem

entary

tothea

nti-infl

ammatoryeffecto

flycop

ene

Organosulfur

Allicin

Allylsulfid

eGarliconion

Metabolism

regu

lation

(1)Invivo

antid

iabetic

effecto

fgarlic

iswelld

ocum

entedin

diabeticratsandmiceAllicin(m

ainactiv

ecompo

nent)ind

uces

pancreaticsecretionof

insulin

orits

releasefrom

boun

dinsulin

[8081]

(2)G

arlic

andgarlicp

rotein

dietsig

nificantlydarrserum

cholesteroltriglycerid

eandLD

Lcholesterolbyallicin

mediatedinhibitio

nof

cholesterolsynthesis[83ndash85]

(3)G

amma-glutam

ylcyste

ines

compo

nent

ofgarlicdarr

bloo

dpressure

byinhibitin

gangiotensin

-con

vertingenzyme

[148085]

Phytosterols

SterolStano

lsCa

mpesta

nols

Diosgenin

Fenu

greekwild

yam

Metabolicregulation

phytosterolinhibitin

gcholesterolabsorption[838589]


of inflammatory signaling molecules and also modulateantioxidative effect by inhibition of NF-120581B pathways [6 7]These phytochemicals (organosulfur phytosterols) also showprotective effect against atherosclerosis by regulating ofserum total and LDL-cholesterol levels Phytochemicals suchas resveratrol epigallocatechin gallate gingerol phytosteroland myricetin directly influence various molecular signaltransduction pathways like inflammation cascade cellproliferationmigration oxidative stress and metabolicdisorders which are involved in the development of severalnoncommunicable diseases Although beneficial effectsof plant based diets or phytochemicals in reducing therisk of chronic diseases have been shown through variousepidemiological and in vitroin vivo studies much moremechanistic and clinical evidence is required to define aparticular phytochemical as an inhibitor of specific cellularpathways or identify the plant derived active compoundwith specific therapeutics properties Therefore this reviewis focused on the cellular targets of naturally occurringactive compounds from various sources in order to explorethe protectivetherapeutics role as an antioxidative anti-inflammatory regulation of metabolic disorder as well asantiproliferative properties by targeting specific molecularsignal transduction which might play a crucial role in thepathogenesis of chronic disease

2 Bioavailability of Phytochemicals

Bioavailability of individual compounds of interest at thetarget site is one of the important challengesparameters todetermine the therapeutic efficiency of the target drug [8]Although accurate bioavailability of particular compoundis not possible to predict according to Lipinski et al acompound might have better bioavailability when it containsmaximum 5 hydrogen-bond donors and 10 hydrogen-bondacceptors in association with having a molecular massnot more than 500 daltons a partition coefficient log 119875value should not be more than 5 and contains less than 10rotatable bonds [9] Most of the phytochemicals includingpolyphenols such as curcumin and green tea polyphenols donot satisfy all these chemical specifications and exhibit lowbioavailability [10] Although compounds such as genisteinand biochanin A have all those good absorptive chemicalproperties high rate excretion in the gut by effluxmechanismlimits their bioavailability [10] Therefore other factors likesolubility of the compounds stability due to gastric andcolonic pH metabolism by gut microflora absorption acrossthe intestinal wall active efflux mechanism and first-passmetabolic effects may also play crucial role in limiting thebioavailability of phytochemicals [11] As an example limitedbioavailability of epigallocatechin gallate is mainly due topoor absorption and rapid first-pass metabolism Similarlylow stability increased oxidation and high hepatic uptakeare also responsible for the limited the bioavailability of somewidely distributed polyphenols such as flavonoids (flavonolsanthocyanines) resveratol 8 (grapes) [12]

Moreover it has been also reported that rapid conjugationof a phytochemicals especially by glucuronidation in theintestine and liver in associationwith reaction of cytochrome

P450 (C-P450) enzymes which are recognized as importantclearancemechanisms is primarily responsible for their poorbioavailability [12] Many researchers have shown that code-livery of lead targetmolecules (phytochemicals)with an agentthat can modulate the activity of glucuronidation or inhibitC-P450mediated clearancemechanism is possible to increasethe bioavailability of active compound of interest at the targetsite [12 13] Piperine a component of black pepper inhibitsglucuronidation and is able to enhance the bioavailability ofseveral bioactive compounds by altering the C-p450 medi-ated enzymatic biotransformation [8 14] Rapid mobilizationin the intestine is largely responsible for low bioavailabilityof curcumin at target site however consumption of cur-cumin along with piperin a known inhibitor of intestinaland hepatic 120573-glucuronidation of curcumin may inducethe bioavailability of curcumin about 20-fold [8 14] Manyphytochemicals were identified as promising therapeuticsagent in the preliminary in vitro studiesHowever when thosecompounds were tested into in vivo studies many of themfailed to translate the preclinicalclinical findings becausecompounds either were unstable in the gut or exhibitedpoor bioavailability [8 14]Therefore detailed preclinical andclinical studies on bioavailability of phytochemicalsactivecompounds are urgently needed to understand their thera-peutic limitation as well as to find out the better compounddelivery system to achieve the best efficiency level of the drugat the target organ

3 Molecular Mechanism of Photochemical inRedox Modulation

Cells use enzymes and oxygen to perform its normal physi-ological functions are continuously exposed to free radicalsFree radicals are oxygen containing highly reactivemoleculeswith one or more unpaired electrons This highly reactiveoxygen species (ROS) includes numerous partially reducedoxygen metabolites such as hydrogen peroxide (H

2O2)

hydroxyl radicals (∙OH) and superoxide anions (O∙minus2)

radicals ROS are generated intracellularly as a byproductof normal metabolism and as second messengers in varioussignal transduction pathways [15] ROS are also generatedexogenously due to direct uptake by cells from the extracel-lular sources or produced during exposure of cells to someenvironmental triggers It has been well established that ROSare heterogeneous and can exert their beneficial or detrimen-tal effect depending on the concentrations at which they arepresent in the cellular level At low levels ROS can be drivenby NADPHNADPH oxidase and is required to maintainhomeostatic signaling events as well as inducing cell prolifer-ation and survival through the posttranslationalmodificationof kinases and phosphatase [16] However overproductionof ROS or exposure of cells to ROS for extended periodmay cause irreversible damage to DNA protein and lipidsTherefore numerous innate defense systems have developedto detoxify or prevent the detrimental effect of ROS Theseinclude nonenzymatic molecules (eg glutathione vitaminsA C and E and flavonoids) as well as induction of phase IIdetoxifyingantioxidative enzymes (eg superoxide dismu-tase (SOD) catalase and glutathione peroxidase (GSH-Px)


and hemeoxygenase-1 (HO-1) which are involved to elim-inate or inactivate the ROS from cellular level) [17] Animbalance between ROS generation and defense mechanismor inadequate presence of antioxidantmolecules results in thestate known as oxidative stress Growing evidence indicatesthat chronic and acute excess generation of ROS underpathophysiologic conditions is pivotal in the development ofcardiovascular diseases (CVD) or premature atherosclerosisprogression cancer pulmonary fibrosis and neurodegenera-tive disorder [18ndash20] Oxidative modification of low densitylipoprotein (Ox-LDL) regulates many signaling pathwayswhich causes inhibition of endothelial nitric oxide synthase(eNOS) and promotes vasoconstriction expression of adhe-sionmolecules andprogression of platelet aggregationAddi-tionally proliferation of smooth muscle cell (SMC) by Ox-LDL stimulates hypertension due to reduction of blood vessellumen Similarly excessive generation of ROS particularlyH2O2 has been detected in cancer cells Though the exact

sources of H2O2generation in cancer cells are not known

the higher amount ofH2O2increases level of hydroxyl radical

(OH) which in turn mediates oxidative damage of DNA andultimately results in genomic instability Transcriptional acti-vation of some genes like cyclooxygenase-2 (COX-2) matrixmetalloproteinases (MMPs) and cyclin B1 has been reportedto be due to oxidative stress or induced generation of H

2O2

[21ndash23] Overexpression of these genes andH2O2generations

are also observed in breast cancer tissue colon cancer andcervical cancer tissue Compelling evidence from epidemio-logical clinical and experimental studies demonstrated thatphenolic and other naturally occurring compounds presentin cereals legumes nuts olive oil vegetables fruits teaand red wine exert antioxidativeanti-inflammatory effectthrough their free radical scavenging properties as well asenhancement of antioxidative enzymes [18 20]

Phytochemicals like curcumin resveratrol terpenoidsepigallocatechin-3-gallate (EGCG) and isothiocyanates sharecommon properties and play an important role to activatethe phase II detoxifying and antioxidant enzymes like HO-1 GSH-Px and glutathione-S-transferase (GST) by targetingthe common transcription factor Nrf2 [nuclear factor (ery-throid derived 2) related factor] [20 24] Epidemiologicalstudies reported regular consumption of lycopene (rich intomato spinach etc) significantly induced the antioxidantenzymes like SOD GSH-Px and glutathione reductase (GR)and reduced form of glutathione (GSH) moreover thisbioactive compound also reduced the levels of lipid per-oxide malondialdehyde (MDA) LDL oxidation and ROSmediated DNA damage Additionally lycopene was foundto induce cardioprotective effect by reducing MDA levelsand increasing GSH levels in postmenopausal women [2526] The redox-sensitive transcription factor Nrf2 plays animportant role in regulating induction of phase II detoxifyingor antioxidant enzymes (HO-1 SOD etc) which result incellular defense against oxidative stress and exert cytopro-tective mechanism [27] Many researchers have elucidatedthemolecular mechanisms responsible for activation of Nrf2A cytoskeleton binding protein called Kelch-like erythroidCNC homologue- (ECH-) associated protein 1 (Keap1) binds

to Nrf2 regulating its translocation to the nucleus or its acti-vation [28] Following nuclear translocation Nrf2 binds notonly to the specific consensus cis-element called antioxidativeresponsive element (ARE) or electrophile response element(EpRE) present in the promoter region of genes encodingmany antioxidant enzymes but also to other trans-actingfactors such as small Maf-FGK as well as the coactivatorsof ARE including cAMP response element binding protein(CREB-binding protein or CBP) p300 that can coordinatelyregulate the ARE-driven antioxidant gene transcription[28ndash30] Tea extract contain large amount of polyphenols(theaflavins catechins epicatechins epicatechins-3-gallateEGCG) which are characterized by 2 or more aromatic ringswith at least one hydroxyl group linked by a carbon bridgeHydroxyl group of tea polyphenols (TPs) are actually themain source for electron donor and efficiently scavengingsinglet oxygen (eg NO peroxynitrite) In vitro study byLeung et al found significant reduction of oxidized LDL fol-lowing application of theaflavins and catechins [31] Similarresponse was also observed by Lee et al showing decrease inoxidized LDL in plasma of individuals after 4 weeks of greentea consumption [32 33] Many researchers have reportedthat antioxidative properties of tea polyphenols (theaflavinsand catechins) might be due to inhibition of ROS-generatingenzymes (eg iNOS) which contribute for the productionof NO mediated free radicals The molecular mechanismof antioxidant enzyme induction by EGCG or other TPsand polyphones still remain unexplored in large extent [28]A widely accepted model for induction of ARE-mediatedantioxidant gene expression involves phosphorylation ofserinethreonine residues of Nrf2 by protein kinases leadingto enhanced nuclear accumulation of Nrf2 and subsequentARE binding Furthermore Wu et al observed inductionof HO-1 enzyme in endothelial cells due to activation ofAkt and Nrf2 by EGCG which impart protective measureof endothelial cell against H

2O2mediated oxidative stress

[34] Supplementation of curcumin as well as EGCGhas beenreported to enhance Nrf2 nuclear translocation and upreg-ulation of HO-1 by Akt EKR12 and p38 MAPK signalingin human breast epithelial cells as wells as B lymphoblasts[27 28 35] Other plausible mechanisms of EGCG-inducedNrf2 activation are oxidation or modification of cysteinethiols present in Keap1 by ROS andor via active formof EGCG during its redox-cycling [28] Although EGCHmediated ARE-mediated upregulation of antioxidative genemay also be plausible through activation of MAPKs whichfinally activate Nrf2 However in contrast many studieshave reported that inhibition of MAPKs by phytochemicalsfinally induced Nrf2 activity [27 28] Procyanidin B2 wasfound to increase nuclear translocation of Nrf2 via regulationof ERKs and p38 signaling [36] Similarly soy isoflavonesand polyphenols rich in red wine tea and dark chocolateregulate vascular reactivity by targeting endothelial nitricoxide synthase (eNOS) and inducing nuclear accumulationof Nrf2 Induced endothelium-dependent NO generationin response to phytochemicals (polyphenol) may furtheractivate cellular sensor(s) for oxidative stress and therebyenhance NO bioavailability [37] NO can react further withsuperoxide anions (O∙minus

2) to form peroxynitrite which fur-

ther upregulates nuclear accumulation of Nrf2 and activates


ARE dependent transcription of phase II and antioxidantdefense enzymes [37 38] Epidemiological studies have dem-onstrated that supplementation of soy isoflavones for longerperiod improves arterial compliance in men and postmen-opausal women induces plasma nitritenitrate levels anddecreases plasma endothelin-1 levels However in contrastan isoflavone deficient diet fed from conception throughoutadult life might result in decreased GSH concentrations andmRNA levels for eNOS In vivo studies on aged male ratsby Mahn et al have shown that supplementation of soyprotein diet rich in genistein and daidzein found to interactwith estrogen receptors increases mRNA levels of eNOS andantioxidant enzymes [39] Hence vascular protection andantioxidative effect of soy isoflavone dietsmostly related to anupregulation of eNOS expression and activity NO bioavail-ability in association with accumulation of Nrf2 and AREdependent activation of antioxidant defense enzymes [3740] Impaired metabolism and overproduction of ROS alsocontribute for neuronal degeneration and onset of neuronaldiseases such as Alzheimerrsquos disease (AD) and Parkinsonrsquosdisease (PD) Therefore neutralization of ROS and othertypes of free radicals by endogenous antioxidative enzymes(HO GST) or regulation of oxidative stress by inducingsupplementary intake of natural antioxidant is considered asa primary preventive therapeutic measure for the cliniciansto protect from chronic neuronal disorder Numerous piecesof evidence reported curcumin (rhizome of Curcuma longa)EGCG (tea) and resveratrol (grapes berry) as potential natu-ral occurring bioactive neuroprotective compounds becauseof their antioxidative properties [41 42] Curcumin has beenshown to exert protective effect against neuronal degenera-tion by scavenging ROS and neutralizing NO induced freeradicals In vivo study onAlzheimerrsquos disease (AD) transgenicmouse model by Lim et al demonstrated that curcuminreduces neuronal oxidative stress by inducing expressionof cytoprotective proteins or antioxidant enzymes such assuperoxide dismutase (SOD) catalase (CAT) glutathionereductase (GR) glutathione peroxidase (GPx) heme oxy-genase 1 (HO-1) and glutathione-S-transferase (GST) [43]Additionally curcumin is also able to increase the intra-cellular glutathione (GSH) pool by affecting the nuclearcontent or by triggering specific transcription factors suchas 12-tetradecanoate 13-acetate (TPA) electrophilic responseelement (EpRE) [44 45] Reversal of intracellular GSH poolin AD patient by curcumin makes it unique therapeutics forAD treatment as depletion of cellularGSH level plays a pivotalrole in AD pathogenesis However because of curcuminrsquos lowwater solubility and poor bioavailability the major challengeto use curcumin as therapeutic agent for the treatment ofAD is to cross the blood brain barrier (BBB) [42] HoweverEGCG main phenolic component of green tea has beenreported to have slow rate of BBB penetration and about5 bioavailability following oral consumption [46] Series ofrodent studies have shown the pleiotropic effect of EGCGwhich exert the neuroprotective measure by modulation ofantioxidative enzyme activity (SOD GST) in association withsuppression of ROS generation and protection of neuronalcells from glycation induced neurotoxicity

Resveratrol is one of themost widely distributed phenoliccompounds in fruits (apple berry and grapes) nuts andso forth Extensive study over resveratrol has shown itsantioxidant properties and protective role in many chronichealth issues like neural disorder (AD PD) inflammationCVD and so forth Central nervous system is one of thetarget organs for resveratrol as it is able to cross the BBBalthough bioavailability of resveratrol is very low as it ismetabolized quickly to glucuronide and sulfate conjugateSimilar to curcumin and EGCG administration of resver-atrol also mediates its neuroprotective effect via stimula-tionupregulation of various antioxidant enzymatic activitiessuch as HO GST and SOD Additionally administration ofresveratrol on transgenic mouse model of AD has shownprotective role of this particular phytochemical againstneuronal impairments mainly through inhibition of NF-120581B modulated expression of several pathways like iNOSprostaglandin E2(PGE2) [47ndash50] Recent study by Drsquoevoli etal has shown the antioxidative and cytoprotective effects ofred chicory leaf extract to improve intestinal complicationsare mainly due to its high content of both anthocyanins andphenolic compounds Molecular targets of chemopreventivedietary phytochemicals are nuclear transcription factors NF-120581B and hypoxia inducible transcription factor (HIF) [51]Thisfinding has been further supported recently by Bak et alwho demonstrated that wild grape seed procyanidins (WGP)effectively suppressed the generation of oxidative stressmedi-ators like ROS and nitric oxide (NO) mainly by preventingthe activation of NF-120581B and p38 mitogen-activated proteinkinases (MAPKs) pathway in LPS-RAW2647 cells [52] Baket al have also shown that antioxidative and chemopreventiveeffects of WGP are associated with induction of nuclear fac-tor E2-related factor 2 (Nrf2)antioxidant response element(ARE) pathway in the human hepatoma HepG2 cell line [52]

Induced oxidative stress and oxidative modification ofLDL by ROS are one of the key risk factors for atheroscleroticplaque formation which restricts blood flow and resultsin high blood pressure Numerous phenolicflavonoid com-pounds are potent inhibitors of LDL oxidation and exerttheir cardioprotective role by inducing antiplatelet and anti-inflammatory effects at localized (microvascular) andor sys-temic level Additionally polyphenols may also increase HDLlevels and improve endothelial function The mechanism ofantioxidant activity of phenolicsflavonoid compounds canbe characterized by direct scavenging or quenching of oxygenfree radicals which are mostly attributed to the o-dihydroxylgroup in the A andor B ring (catechol group) of theirdiphenylpropane structure [53] Catechol type flavonoids(eg quercetin heliosin) therefore possess powerful antioxi-dant activity

Human study by Aviram et al reported small but signifi-cant (6) decrease of lipid peroxidation in plasma following2wk consumption of pomegranate juice (PJ 50mLday) by13 healthy nonsmoking men aged 20ndash35 years comparedwith plasma obtained before study entry [54] Additionallya significant (9) increase in plasma total antioxidant statuswas also observed after 2wk of PJ consumption Supplemen-tation with 50mLPJd for additional one week resulted in afurther 21 decrease in plasma lipid peroxidation whereas


an additional increase in PJ supplementation to 80mLPJdfor another week did not inhibit plasma susceptibility to lipidperoxidation furtherThe inhibitory effect of PJ consumptionon plasma lipid peroxidation was maintained for 2wk afterPJ supplementation ended This study therefore showed thatdaily consumption of PJ may reduce the progression ofatherosclerotic lesions by reducing the plasma lipid peroxida-tion and by virtue of its ability to attenuate platelet activations[54]

4 Role of Phytochemical inInflammatory Process

Inflammation is defined as a series of immunological bio-chemical andor cellular alterations in response to exogenousor endogenous stimuli Both chronic and acute phase inflam-matory processes act locally and systematically to activatethe cells associatedwith inflammatory process (macrophagesendothelial cells and fibroblast) to induce the inflammatorymediators like ROS NO prostaglandin E2 and proinflam-matory mediators such as cytokines TNF-alpha and COX-2 Multiple studies have shown that overexpression of proin-flammatory genes including TNF-alpha and interleukin isassociated with activation of transcription factor NF-120581B [55]Activated transcription factor translocates to the nucleus andeither regulates the release of inflammatory mediators orinduces the upregulation of inflammatory gene expressionby binding with the DNA Furthermore phosphorylationof MAPK plays important role in chronic inflammation byregulating production of NO and proinflammatory genesfrom macrophages as well as in the activation of NF-120581B[52 56] Hence suppression or inhibition of those inflamma-toryproinflammatory mediators is one of the major targetsfor treatment of many chronic diseases (cancer CVD anddiabetes) using anti-inflammatory compounds

Wild grapes procyanidins (WGP) induced anti-inflam-matory effect and the molecular mechanism of procyanidinswas studied in detail by Bak et al using lipopolysaccharide(LPS) stimulated RAW 2647 [52] In this study Bak et alhave shown that incubation of RAW 2647 cells by WGPsignificantly blocked inflammatory phenomenon by reducingprotein expression of iNOS and COX-2 two importantinducible enzymes which play critical role in NO PGE2generation [52] Moreover authors have shown that WGPtreatment significantly reduced LPS stimulated expressionof proinflammatory cytokines such as tumor necrosis factor120572 (TNF-120572) and interleukin-1120573 (IL-1120573) in RAW 2647 cellsThese effects of WGP might be due to suppression of nuclearfactor-120581B (NF-120581B) activity via downregulation of MAPKand p38 pathways Hence suppression of NF-120581B by WGPwould be an important protective measure to reduce thechances of inflammation mediated chronic health issues astranscription factor NF-120581B activity plays a central role ininflammatory process [52] Similarly brassica derived phyto-chemicals like sulforaphane (SFN) phenethyl-isothiocyanate(PEITC) and indole-3-carbinol (I3C) are also found to exertanti-inflammatory effect by downregulation of LPS inducedexpression of COX-2 iNOS in mouse macrophages mainlyby inhibiting NF-120581B pathways [57ndash59] In vivo study on

C57BL6 showed that pretreatment ofmice with SFN resultedin significant reduction of dextran-sodium-sulfate inducecolitis compared to PBS treated control mice [60] Similar tobrassica phytochemicals tea polyphenols primarily EGCGepicatechin-3-gallate (ECG) and epigallocatechin (EGC)work as chemopreventive compounds by inducing anti-inflam-matory effect in cancer cells Both EGCG and theaflavinsreduced LPS-induced TNF-alpha generation and also iNOSexpression by preventing activation of NF-120581B [19 61] Invivo study by Chen et al demonstrated that tea flowerextract (TEE) rich with many polyphenols (EGCG EGCand ETC) possesses anti-inflammatory effect against chronicinflammation In this study authors have shown that oraladministration of TEE in mice is associated with significantreduction of tissue specific (liver) acute inflammation byblocking cytokines (TNF-alpha IL-1120573) expression and NOproduction [62] Recently increasing interest on beneficialeffect of extra-virgin olive oil (EVOO) is mainly focused onthe anti-inflammatory effect of phenolic compounds presentin the EVOO Glycoside oleuropein hydroxytyrosol andtyrosol are themajor phenolic component of EVOO and havebeen able to inhibit inflammation by blocking eicosanoids(prostaglandin I2 Leukotriene B

4) production enzymes

such as COX-2 lipoxygenase (LOX) and phospholipase A2(PLA2) in animal and human cells [63] Additionally hydrox-ytyrosol one of the main component of EVOV reported toimpart anti-coagulatoryanti-atherosclerotic effect in asso-ciation with their anti-inflammatory activity in individualswith type 1 diabetic by reducing the production and accu-mulation of thromboxan B2 (TXB2) and hydroxyeicosate-traenoic 27 acids (HETE) in serum which results in reducedplatelet aggregation Moreover this particular phenolic com-ponent of EVOV can also be considered as potent anti-inflammatory agent as this is able to prevent the expression ofCOX-2 and iNOS in LPS-stimulated macrophages [64 65]

Polyphenol present in red wine and black tea forinstance quercetin EGCG ECG and theflavins are ableto inhibit COX-2 and LOX in dose dependent mannerfollowing application to LPS activated murine macrophageRAW 264 cells [66] Likewise kaempferol a flavonoid widelydistributed in many natural sources including apples grapescabbage and tomato significantly reduces inflammation byinhibiting the generation of PGE2 Researchers have shownthat cocoa polyphenols (flavonols anthocyanidins catechinsetc) decrease the inflammation by numerous mechanismssuch as inhibition of mitogen induced activation of T cellsand reduced expression of IL-2 and other cytokines (IL-6 TNF-alpha) Curcumin has been identified as naturallyoccurring active component with wide range of medicinaleffects against many chronic diseases like CVD cancer andmetabolic disorder due to its strong antioxidative and anti-inflammatory response in vitro and in vivo Aggarwal andHarikumar reported oral application of 70ndash100mgkg cur-cumin reduces systemic (plasma) and tissue specific (aortictissue) inflammatory response as well as LDL oxidationand hypocholesteromic effects in rodents [67] SimilarlyNemmar et al have shown that supplementation of curcuminas oral gavage (45mgkg) in male mice significantly reducessystemic inflammation by preventing the release of TNF-120572 and C-reactive protein (CRP) [68] CRP is an acute


phase protein and has been identified to play an importantpathogenic role in the progression of many chronic degen-erative diseases like CVD arthritis Increased level of CRPhas been observed in almost every inflammation mediateddiseases onset Similar to curcumin Pauwels et al have shownantiarthriticinflammatory potentials of type-A procyanidinepolyphenol (TAPP) extracted from cinnamon bark Rheuma-toid arthritis (RA) is an acute inflammatory condition in jointwith functional impairments mainly involved with localized(skeletal join) excessive prostaglandin synthesis as well assystemic inflammation characterized by increased level ofserum CRP Oral consumption of cinnamon bark extract andits polyphenol (procyanidine) has been found to regulatesystemic inflammation by reducing CRP and was also ableto stimulate autoimmune system by blocking expression ofmany inflammatory mediators (prostaglandin E2 NO) inRA rats [69] Results showed the therapeutic value of thisparticular polyphenol and its potential to reduce or reversalof RA progression Due to its strong anti-inflammatorypotentials TAPP is found to be successfully used to regulateairway hyperresponsiveness (AHR) or asthma by reducinginflammatory mediators like IL-4 and IL-13 which playedcritical role in mucus hyper-secretion and the onset ofAHR [69] RecentlyHazewindus et al have shown synergisticeffect of bioactive compounds such as lycopene ascorbicacid and 120572-tocopherol rich in tomato In this study authorshave shown that lycopene alone significantly exerts anti-inflammatory effect by reducing the release of proinflam-matory cytokine TNF-120572 via regulation of NF-120581B activationMoreover significant inhibition of lipid peroxidation bythe combination of ascorbic acid and 120572-tocopherol is thecomplementary to the anti-inflammatory effect of lycopene

5 Role of Phytochemicals inMetabolism Regulation

Metabolism is the cascade of cellular chemical transforma-tion regulated by a pool of enzymes which break down theorganic matter harvest the energy (digestion) and allow thecells to grow reproduce and respond to molecular signal bymaintaining inter- and intracellular homeostasis Any alter-ation of this chain of chemical event may lead to metabolicdisorder or unregulated metabolism which ultimately resultsin high plasma glucose level (diabetic) obesity high bloodpressure (hypertension) CVD organ failure and so forthDiseases or cluster of physiological changes induced mostlybymetabolic disorder like diabetes CVD are themajor healthconcern for morbidity with high socioeconomic burdenworldwide Modification of dietary pattern in associationwith regulation in life style (regular exercise weight loss)plays an effective role to slow the deleterious effect metabolicsyndrome [70] Epidemiological randomized and controlleddietary studies on human or rodents provide a lot of evidenceshowing that consumption of dietary fibers improves theindices of diabetes risk by regulating glycemic and plasmaglucose level The important pathogenic factors responsiblefor the development of metabolic disorder insulin resistance120573-cells dysfunction and finally diabetes are oxidative stress

and tissue specific (localized) andor systemic inflamma-tion Phytochemicals present in the whole grains includingphytosterol flavanols anthocyanidins and cinnamic acidsmodulate the diabetic risk by exerting their antioxidativeand anti-inflammatory effect [70 71] Increasing number ofcontrolled epidemiological studies has reported significantreduction of plasma cytokines (IL-6) or CRP in healthyindividuals following regular consumption of rye bran andwhole wheat bread Furthermore short-chain fatty acidof cereal fibre prevents inflammatory response in colonicmucosa by binding to the G-protein coupled receptor andalso by blocking transcription factor NF-120581B Similarly con-sumption of brown and black rice for 4 months was foundto exert cardioprotective effect by regulating oxidative stressin individuals with preexisting complications coronary heartdisease (CHD) [72] Although the detailed molecular mech-anism is still unexplored controlled epidemiological studieshave reported the significant reduction of oxidized plasmamalondialdehyde and urine prostaglandin in subjects withCHD Similar to wholegrain fenugreek seed and cinnamonextract has been widely used for its medicinal value in thetreatment of diabetes The hypoglycemic and hypocholes-terolemic effect of fenugreek seed is mainly attributed to itshigh concentration of soluble fiber content which helps todecrease the postprandial blood glucose [70] TAPP themainactive component of cinnamon extract significantly loweredthe bloodHbA1c level and also improved the insulin signalingin murine models of diabetes [73] Hypoglycemic effect ofblueberry extract in humans is mainly due to presence ofanthocyanin and myrtillin Significant reduction of bloodpressure in salt-sensitive spontaneously hypertensive rats(SHRs) supplemented with 3 blueberry enriched diet for8 weeks might be due to vasodilator effect of blueberrypolyphenol through an endothelium mediated stimulationof NO metabolism and activation of COX-induced product[74 75] Similarly grape seed extract (GSE) which is a richsource of polyphenols (approximately 90 of which are pro-cyanidins and 7other polyphenol compounds) has becomepopular for the treatment and prevention of chronic cardiacdisease and other disorders In vivo studies on spontaneouslyhypertensive rats have shown that regular consumption of05 GSE-supplemented diet significantly reduced the arte-rial blood pressure possible due to induction of endotheliumdependent vascular dialtion [76] Aldolase reductase (AR) arate limiting enzyme in polyol pathways plays an importantrole in the progression of diabetic complications and otherchronicmetabolic disorder Detailed phytochemicals analysisby Termentzi et al has shown Sorbus domestica fruits extractcontent high concentration of flavonoids and hydroxycin-namoyl esters Further evaluation on in vitro study of Sorbusdomestica fruits extract indicates high content hydroxycin-namoyl esters possess AR blocking activityThus regular con-sumption of this particular fruit extract can be the promis-ing natural therapeutic measure for regulation of chronicor long-term diabetic complications [77 78] FurthermoreRussian tarragon (Artemisia dracunculus L) extract wasdemonstrated to attribute antidiabeticantihyperglycemiceffect in both streptozotocin induced genetically diabeticKKAy murine models In vitro study on hepatic cells showed


that bioactive components like 6-demethoxycapillarisin and2101584041015840-dihydroxy-4-methoxydihydrochalcone are involved inhepatic glucose output by inhibiting the transcription factorfor a primary enzyme phosphoenol pyruvate carboxyki-nase (PEPCK) [79] Regular consumption of fresh bittermelon juice (popular vegetables of Asian origin) or driedwhole vegetables have been found to significantly regulatethe blood glucose level and diabetes-related complicationsincluding nephropathy insulin resistance and early cataractformation The observed hypoglycemic effect of bitter melonmight be due to presence of cucurbitane-type triterpenoidssteroidal saponins called charantins insulin-like peptides andalkaloids which are associated with hypoglycemic activity[70] Similar as bitter melon antidiabetic effect of garlicwas not well documented in human studies but garlicwas found to be an effective in regulating blood glucoselevel in streptozotocin-induced as well as alloxan-induceddiabetes mellitus in rats and mice Although the exactmechanism of garlic as an antidiabetic agent is not clearlyunderstood but several in vitro studies proposed that allicin(main component of garlic) may enhance serum insulinfollowing effective combination with cystein or garlic cansimply exert its antidiabetic effect by inducing secretion ofinsulin from the pancreatic beta cells or its release frombound insulin [80 81] However cardioprotective role ofgarlic has been well documented both in vivo and controlledhuman studies mainly by regulation of metabolism anddue to its anti-atherosclerotic effect Many in vivo studiesreported supplementation of 1ndash4 garlic and garlic proteindiet in hypercholesterolemic rats significantly reduced serumcholesterol triglyceride and LDL cholesterol Similarly con-trolled human studies have shown that a dose of 4 grams ofgarlic cloves per day 6 days a week for 6months significantlyaffects the LDL-C or other plasma lipid concentrations inadults (30ndash65 years) with moderate hypercholesterolemia[82] Garlic extract contains high levels of water solublephytochemicals such as S-allyl-cystein (SAC) as well assmall amount of oil soluble compounds [14] In vitro studiesfurther demonstrated that this cholesterol-lowering effectof garlic might be because garlic triggers the formation ofallicin through action of alliinase enzymes and allicin inhibitscholesterol synthesis in vitro [83 84] Even in vitro studiesreveled that antiatherosclerotic and antiatherogenic activitiesof garlic are due to reduction of lipid content andor LDLoxidations by allicin and SAC present in the garlic extract[80] Moreover antihypertensive effect of garlic extract wasalso evaluated both in hypertensive rats and in controlledhuman (hypertensive) studies The gamma-glutamylcysteinecomponent of garlic might be responsible for lowering bloodpressure by inhibiting angiotensin-converting enzyme invitro [14 80 85] Similar to organosulfur compound in garlicphytosterols (including sitosterol campesterol and stanols)are also efficiently inducing cholesterol lowering effect bothin animal and in human studies The primary sources ofphytosterols are vegetables nuts fruits seeds and vegetableoil (olive oil canola oil) Sitosterol and campesterol are themost frequent plant sterols and constitute about 60 and35 respectively of plant sterols in food [86] Phytosterolsand cholesterol are structurally similar but are metabolized

differently Due to their structural similarity to cholesterolplant sterols are well studied for their ability to inhibit choles-terol absorption In addition to their cholesterol loweringeffect plant sterols may possess antiatherosclerosis anti-inflammation and antioxidative activities [87] Pelletier et aldemonstrated that consumption of 07 g of soy sterols fed to 12normocholesterolemic individuals reduced LDL cholesterolby 152 relative to the control [88] Many in vitro studies oncaco-2 cells have shown that the hypocholesterolemic effectof plant stanolsmight be by reduced intestinal cholesterol dueto structural similarity between plant stanols and cholesterol[89]

Phenolic compounds namely chlorogenic acid and fer-ulic acid and a plant alkaloid berberine are also consideredas potent antidiabetic agent with high therapeutic efficiencyas well as less side effect All these three phytochemicals arereported to enhance the uptake of 2 deoxyglucose (2DG) intime- and dose-dependent manner Reduced glucose trans-porter (GLUT4) translocation along with impaired glucosetransport is the major pathogenesis of diabetes progressionTreatment of L6 myoblasts with these above mentionedphytochemicals shows that chlorogenic acid and berberinesignificantly upregulate the expression of GLUT4 and per-oxisomal proliferator-activated receptors-gamma (PPAR-120574)expression whereas treatment of L6 myoblasts with fer-ulic acid results in significant induction of GLUT4 andphosphoinositide-3-kinase (PI3K) gene expression Based onthis study researchers concluded that chlorogenic acid andberberine exert their antidiabetic effect or increased glucoseuptake in PI3K independent manner however increasedglucose uptake with ferulic acid is highly dependent onPI3K pathway [90 91] Several in vivo and in vitro stud-ies have demonstrated the synergistic effect of resveratrolquercetin and genistein in preventing obesityweight gainand adipogenesis and also contribute to control multiplemetabolic disorders like dyslipidemia insulin resistance andso forth Hypolipidemic effect of resveratrol has been foundto exert significant reduction of serum total cholesteroltriglycerides and lipid content in hepatic tissue in high-fatdiet hamster [92] Lagouge et al revealed that the protectingactivity of resveratrol on regulation of metabolism is mainlyachieved due to enhancement of sirtuin 1 (Sirt1) a NAD+-dependent deacetylase activity which improving the cellularinsulin sensitivityTherefore consumption of plant based dietimparts beneficial effect by preventing the development andprogression of age chronic diseases that are highly associatedwith metabolic disorder [93]

6 Role of Phytochemicals in CellMigration and Proliferation

Abnormal proliferation and migration of vascular smoothmuscle cells (VSMC) are the primary event contributingto the pathogenesis of atherosclerosis or restenosis andis also linked with other cellular process such as local-ized inflammation arterial hypertension due to narrowingof blood vessel Similarly excessive cell proliferation andimpaired programmed cell death or apoptosis representmajor causative factors for the development and progression


of cancer [19] Therefore this particular event is consideredas a main target for the reversal of the neovascularizationmediated health effect (atherosclerosis cancer etc) Seriesof in vitro and in vivo studies has demonstrated tea ashealthy beverage as it is rich source of many polyphenols(catechins EGC and EGCG) and is capable of reducing orslowing the progression of atherosclerosis by inhibiting theSMC proliferation and arrested the cells in G1 phase [9495] EGCG is found to be effectively inducing SMC arrestby blocking cyclin D1 and cyclin E beside this EGCG isalso inhibiting the cell growth markers PCNA [94 95] Teapolyphenols exert antiproliferative effects by interacting alsowith matrix metalloproteinase (MMP) system Expression ofvarious MMPs has been found to be upregulated mostly inany type of cancer cells Many studies have already shownthat MMP transcription is induced and regulated by manyregulators like cytokines growth factor ROS and so forthSeveralMMPs have been found to be as key agonists in tumorinvasion metastasis and angiogenesis including MMPs 1 23 9 and 14 [96ndash98] Two particular subtypes of this familyMMP 2 and MMP 9 are found to be actively involved in theturnover of basement membrane collagen and alteration ofmatrix proteins during angiogenesis and also plays impor-tant role for tissue remodeling Both catechins and EGCGreduce MMP2MMP-9 secretion in VSMC by preventingNfKB and AP-1 activities [95] Khan et al have reportedadministration of green tea polyphenol (eg EGCG) in trans-genic adenocarcinoma mice results in significant inhibitionof cancer progression or metastasis of prostrate tissue byregulating MMP 2 and MMP 9 expression [99] Additionallyit has been shown that both catechins and EGCG suppressPDGF-BB induced activation of PDGF-receptor mediatedsignal transduction pathways in VSMC by blocking tyrosinephosphorylation and their downstream molecular targets[99] These findings are consistent with our recent studyon antiproliferative effect of Gentiana lutea and its mainconstituent isovitexin where Kesavan et al have reportedaqueous root extract of G lutea and isovitexin significantlyinhibit PDGF-BB induced proliferation of SMC by down-regulation of ERK12 and iNOS expression [100] Similarlyin another study we have shown significant antiproliferativeeffect of ellagic acid (EA) phenolic compound presentmainlyin barriers which might be due to prevention of PDGF-BBreceptor tyrosine phosphorylationactivation reduced ROSgeneration and downstream stimulation of ERK12 [101] Inthis study authors have also demonstrated that treatment ofstreptozotocin-induced diabetic rats with EA reduced theonset of atheroma formation by blocking SMC proliferationand downregulation of cyclin D1 expression [101] Henceall these findings suggest that regular consumption of phy-tochemicals is associated with prevention of cardiovascularcomplications Antiproliferative effect of phytochemicals arenot only inhabit the onset of CVD progressionbut also playsa significant role in cancer prevention Curcumin and itsderivatives have been found to inhibit the proliferation ofbreast cancer (BC) cell lines and by downregulation of matrixmetalloproteinase-1 (MMP-1) expression [102] Resveratrol isalso effectively preventing cell proliferation by stimulatingcell cycle arrest via regulation of cell cycle proteins such as

cyclins E and D1 Furthermore resveratrol induces apoptosisby controlling series of events including upregulation oftumor suppressor genes p21Cip1WAF1 p53 the proapoptoticprotein Bax expression activating caspase apoptotic signalsand downregulation of antiapoptotic proteins Bcl-2 Bcl-XLand survivin expression Likewise quercetin may also act asa plant derived anticancer drug by upregulating expressionof Bax which finally leads to cell apoptosis and is able toimpart antiproliferative effect by suppression of Bcl-2 proteinactivity and stimulation of DNA fragmentation procedure[103 104] Many studies reported that antimetastatic effectsof phytochemicals are mainly due to alteration of activityor expression of cell adhesion molecules (CD44) which aresignificantly upregulated during metastasis and primarilycontribute to the cancer cell growth Ouhtit et al haveshown that treatment of BC cell line with cocktail of sixphytochemicals (indole-3-carbinol resveratrol genistein andcurcumin C-phycocyanin quercetin) caused a marked inhi-bition of proliferation and motility of cells in combinationwith suppression of cell adhesionmolecule CD44 expressionwhich plays an important role as a metastasis initiating factor[102]

7 Role of Phytochemicals in Angiogenesis

Angiogenesis is a complex controlled phenomenon forgrowth and development with proangiogenic and antiangio-genenic factors Angiogenesis is well orchestrated physiolog-ical balance between the stimulatory and inhibitory signalsfor newblood vessels development or preexisting vasculatureAny alteration in normal angiogenesis results in either poorvascularisation or abnormal vasculature Chronic ischemicwound is the result of insufficient blood vessel formationor reduced angiogenesis In contrast cancer cells or tumorsinduced uncontrolled angiogenesis or abnormal blood vesselgrowth to spread metastasis by secreting proangiogenicfactors like vascular endothelial growth factors (VEGF) In avery recent work Kowshik et al have demonstrated antian-giogenic effects of ellagic acid in a hamster model of oraloncogenesis by examining the transcript and protein expres-sion of hypoxia-induced VEGF signaling cascade In thisstudy authors have found ellagic acid significantly inhibitingangiogenesis in hamster buccal punch maybe by abolishingphosphatidylinositol-45-bisphosphate 3-kinase (PI3KAkt)and MAPK and VEGF signaling pathways which involvessuppression of histone deacetylase 6 (HDAC6) and hypoxia-inducible factor 1-alpha (HIF-1120572) responses [105] Woundhealing capacity of Tephrosia purpurea was studied byLodhi et al in rats with three different types of wound suchas incision wound excision wound and dead space woundHistopathological study following treatment of wound areawith T purpurea ethanolic extract has shown significantincrease in angiogenesis or blood vessels formation fibroblastcells and collagen fibres generation due to presence oflarge amount of flavonoids in the extract [106] Severalin vivo and in vitro studies have shown combination ofEGCG and curcumin exhibited synergistic growth inhibitionof premalignant and malignant cells through the suppres-sion of angiogenesis cell proliferation and upregulation of


VEG

Fdarr

P13

Aktdarr

MAP

Kdarr

Cytokines (TNF-120572CRP darr MMP-29 darr

CD-44 darr

HbA1 darr

Plasma glucose

regulation

ROS darr

RadicalsscavengingoxLDL darrCOX iNOS 2

Anti-inflammation

Metabolic disorder

Antiangio

genesi

s

Antiproliferation

Antioxidation

HO-1 uarr

IL-1120573 IL-6) darr

AP-1 darr

NF-120581B

darr

NF-120581B

darrNF-120581B

Figure 1 The molecular mechanismsignaling targeted by phytochemicals to exert the protective effect antioxidation anti-inflammationantiproliferation metabolic disorder and antiangiogenesis

apoptosis [107] Similarly Kowshik et al have reported roleof astaxanthin as a cancer preventive agent by suppressionof angiogenesis Astaxanthin which is a non-provitamin Acarotenoid predominantly distributed in microalgae fungiplants and sea foods is found to inhibit the onset of tumorprogression by targeting signal transducer and activator oftranscription 3 (STAT3)Janus kinase 2 (JAK-2) [108]

8 Summary Future of Phytochemicals andTherapeutic Mechanism

Relationship between phytochemicals and disease preventionhas been a major focus of health research for almost halfa century Epidemiological and clinical studies indicate thatthe risk of chronic or noncommunicable diseases is reducedby a diet rich in fruits vegetables and unrefined grainsOther foods such as mono- and polyunsaturated fats bransnuts plant sterols and soy proteins have all been shown tohave a favorable effect on pathogenesis of CVD (eg lipidprofile and blood pressure lowering effect) cancer andorneurodegeneration The progression in the knowledge ofboth the disease pathomechanisms and the targeted path-ways by dietary components to exert their medicinal effect

may provide new avenues to develop dietary strategies toprevent andor to treat the numerous disorders Based onthe epidemiological andor clinical evidence it has beenfound that phytochemicals andor naturally occurring activecompounds are having broad range of physiological effectswhich include reduction of inflammatory cascades oxidativestress improved metabolic disorder vascular homeosta-sis or antiproliferation (Figure 1) However it is still notclear whether an individual component of the diet or acombination of nutrients and dietary habits is responsiblefor the observed protective effects Therefore screening oflarge scale of potential beneficial molecules present in theregular diet may provide lead molecules that may be usedin the future as inexpensive dietary supplements specific todisease prevention The products being naturally occurringin the markets would be easily available for all strata of thesociety This would also open up a huge possibility of herbalproduct based markets and scopes of employment The areaof phytochemicals and its protective effect will only growsuccessfully if preclinical andor clinical research is able tointegrate credible science with thorough consumer under-standing uncompromised taste and convenience along withawareness about the preventive role of dietary product on thedevelopment of chronic diseases


Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

Swapna Upadhyay acknowledges Council for Scientific andIndustrial Research (CSIR) Government of India [Refer-ence CSIR-SRA (13-8553A)-2012POOL] Madhulika Dixitacknowledges Department of Biotechnology Government ofIndia-sponsored Indo-EU ldquoFUNCFOODrdquo project

References

[1] K A Steinmetz and J D Potter ldquoVegetables fruit and cancerI Epidemiologyrdquo Cancer Causes and Control vol 2 no 5 pp325ndash357 1991

[2] T Maraldi D Vauzour and C Angeloni ldquoDietary polyphenolsand their effects on cell biochemistry and pathophysiology2013rdquo Oxidative Medicine and Cellular Longevity vol 2014Article ID 576363 3 pages 2014

[3] E M Alissa and G A Ferns ldquoFunctional foods and nutraceu-ticals in the primary prevention of cardiovascular diseasesrdquoJournal of Nutrition and Metabolism vol 2012 Article ID569486 16 pages 2012

[4] T W George C Niwat S Waroonphan M H Gordon andJ A Lovegrove ldquoEffects of chronic and acute consumption offruit- and vegetable-puree- based drinks on vasodilation riskfactors for CVD and the response as a result of the eNOSG298Tpolymorphismrdquo Proceedings of the Nutrition Society vol 68 no2 pp 148ndash161 2009

[5] R H Liu ldquoHealth benefits of fruit and vegetables are fromadditive and synergistic combinations of phytochemicalsrdquo TheAmerican Journal of Clinical Nutrition vol 78 no 3 supple-ment pp 517Sndash520S 2003

[6] S Hirai T Uemura N Mizoguchi et al ldquoDiosgenin attenuatesinflammatory changes in the interaction between adipocytesand macrophagesrdquoMolecular Nutrition and Food Research vol54 no 6 pp 797ndash804 2010

[7] S C Sahu ldquoDual role of organosulfur compounds in foodsa reviewrdquo Journal of Environmental Science and Health CEnvironmental Carcinogenesis amp Ecotoxicology Reviews vol 20no 1 pp 61ndash76 2002

[8] F Aqil R Munagala J Jeyabalan and M V VadhanamldquoBioavailability of phytochemicals and its enhancement by drugdelivery systemsrdquo Cancer Letters vol 334 no 1 pp 133ndash1412013

[9] C A Lipinski F Lombardo B W Dominy and P J FeeneyldquoExperimental and computational approaches to estimate sol-ubility and permeability in drug discovery and developmentsettingsrdquo Advanced Drug Delivery Reviews vol 46 no 1ndash3 pp3ndash26 2001

[10] S Gao and M Hu ldquoBioavailability challenges associated withdevelopment of anti-cancer phenolicsrdquoMini-Reviews in Medic-inal Chemistry vol 10 no 6 pp 550ndash567 2010

[11] C S Yang S Sang J D Lambert andM-J Lee ldquoBioavailabilityissues in studying the health effects of plant polyphenoliccompoundsrdquo Molecular Nutrition and Food Research vol 52supplement 1 pp S139ndashS151 2008

[12] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols Food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004

[13] B Wu K Kulkarni S Basu S Zhang and M Hu ldquoFirst-passmetabolism via UDP-glucuronosyltransferase a barrier to oralbioavailability of phenolicsrdquo Journal of Pharmaceutical Sciencesvol 100 no 9 pp 3655ndash3681 2011

[14] I Rahman S K Biswas and P A Kirkham ldquoRegulation ofinflammation and redox signaling by dietary polyphenolsrdquoBiochemical Pharmacology vol 72 no 11 pp 1439ndash1452 2006

[15] V J Thannickal and B L Fanburg ldquoReactive oxygen speciesin cell signalingrdquo American Journal of Physiology Lung CellularandMolecular Physiology vol 279 no 6 pp L1005ndashL1028 2000

[16] R A Cairns I S Harris and T W Mak ldquoRegulation of cancercell metabolismrdquo Nature Reviews Cancer vol 11 no 2 pp 85ndash95 2011

[17] J L Martindale and N J Holbrook ldquoCellular response tooxidative stress signaling for suicide and survivalrdquo Journal ofCellular Physiology vol 192 no 1 pp 1ndash15 2002

[18] G Loo ldquoRedox-sensitive mechanisms of phytochemical-mediated inhibition of cancer cell proliferationrdquoThe Journal ofNutritional Biochemistry vol 14 no 2 pp 64ndash73 2003

[19] V Stangl H Dreger K Stangl and M Lorenz ldquoMoleculartargets of tea polyphenols in the cardiovascular systemrdquo Car-diovascular Research vol 73 no 2 pp 348ndash358 2007

[20] F Tosetti D M Noonan and A Albini ldquoMetabolic regulationand redox activity as mechanisms for angioprevention bydietary phytochemicalsrdquo International Journal of Cancer vol125 no 9 pp 1997ndash2003 2009

[21] M L Parkett R EHarris F S JoarderM S Ross K P Clausenand F M Robertson ldquoCyclooxygenase-2 gene expression inhuman breast cancerrdquo International Journal of Oncology vol 10no 3 pp 503ndash507 1997

[22] H Sano Y Kawahito R L Wilder et al ldquoExpression ofcyclooxygenase-1 and -2 in human colorectal cancerrdquo CancerResearch vol 55 no 17 pp 3785ndash3789 1995

[23] J Westermarck and V-M Kahari ldquoRegulation of matrix metal-loproteinase expression in tumor invasionrdquoThe FASEB Journalvol 13 no 8 pp 781ndash792 1999

[24] K T Liby M M Yore and M B Sporn ldquoTriterpenoids andrexinoids as multifunctional agents for the prevention andtreatment of cancerrdquo Nature Reviews Cancer vol 7 no 5 pp357ndash369 2007

[25] K S C Bose andB K Agrawal ldquoEffect of lycopene from cookedtomatoes on serumantioxidant enzymes lipid peroxidation rateand lipid profile in coronary heart diseaserdquo Singapore MedicalJournal vol 48 no 5 pp 415ndash420 2007

[26] D V Ratnam D D Ankola V Bhardwaj D K Sahana andM N V R Kumar ldquoRole of antioxidants in prophylaxis andtherapy a pharmaceutical perspectiverdquo Journal of ControlledRelease vol 113 no 3 pp 189ndash207 2006

[27] J H Lee T O Khor L Shu Z-Y Su F Fuentes and A-N T Kong ldquoDietary phytochemicals and cancer preventionNrf2 signaling epigenetics and cell death mechanisms inblocking cancer initiation and progressionrdquo Pharmacology andTherapeutics vol 137 no 2 pp 153ndash171 2013

[28] H-K Na and Y-J Surh ldquoModulation of Nrf2-mediated antiox-idant and detoxifying enzyme induction by the green teapolyphenol EGCGrdquo Food and Chemical Toxicology vol 46 no4 pp 1271ndash1278 2008


[29] S Dhakshinamoorthy and A K Jaiswal ldquoSmall Maf (MafGand MafK) proteins negatively regulate antioxidant responseelement-mediated expression and antioxidant induction of theNAD(P)Hquinone oxidoreductase1 generdquo Journal of BiologicalChemistry vol 275 no 51 pp 40134ndash40141 2000

[30] G Shen V Hebbar S Nair et al ldquoRegulation of Nrf2 trans-activation domain activity the differential effects of mitogen-activated protein kinase cascades and synergistic stimulatoryeffect of Raf and CREB-binding proteinrdquo Journal of BiologicalChemistry vol 279 no 22 pp 23052ndash23060 2004

[31] L K Leung Y Su R Chen Z Zhang YHuang andZ-Y ChenldquoTheaflavins in black tea and catechins in green tea are equallyeffective antioxidantsrdquo Journal of Nutrition vol 131 no 9 pp2248ndash2251 2001

[32] P V A Babu and D Liu ldquoGreen tea catechins and cardiovascu-lar health an updaterdquo Current Medicinal Chemistry vol 15 no18 pp 1840ndash1850 2008

[33] M-J Lee Z-Y Wang H Li et al ldquoAnalysis of plasma and uri-nary tea polyphenols in human subjectsrdquo Cancer EpidemiologyBiomarkers and Prevention vol 4 no 4 pp 393ndash399 1995

[34] C C Wu M C Hsu C W Hsieh J B Lin P H Lai and B SWung ldquoUpregulation of hemeoxygenase-1 by Epigallocatechin-3-gallate via the phosphatidylinositol 3-kinaseAkt and ERKpathwaysrdquo Life Sciences vol 78 no 25 pp 2889ndash2897 2006

[35] C K Andreadi L M Howells P A Atherfold and M MManson ldquoInvolvement of Nrf2 p38 B-Raf and nuclear factor-120581B but not phosphatidylinositol 3-kinase in induction ofhemeoxygenase-1 by dietary polyphenolsrdquo Molecular Pharma-cology vol 69 no 3 pp 1033ndash1040 2006

[36] I Rodrıguez-Ramiro S Ramos L Bravo L Goya and MA Martın ldquoProcyanidin B2 induces Nrf2 translocation andglutathione S-transferase P1 expression via ERKs and p38-MAPK pathways and protect human colonic cells againstoxidative stressrdquo European Journal of Nutrition vol 51 no 7 pp881ndash892 2012

[37] G E Mann D J Rowlands F Y L Li P de Winter and RC M Siow ldquoActivation of endothelial nitric oxide synthase bydietary isoflavones role of NO in Nrf2-mediated antioxidantgene expressionrdquo Cardiovascular Research vol 75 no 2 pp261ndash274 2007

[38] T W Kensler N Wakabayashi and S Biswal ldquoCell survivalresponses to environmental stresses via the Keap1-Nrf2-AREpathwayrdquo Annual Review of Pharmacology and Toxicology vol47 pp 89ndash116 2007

[39] K Mahn C Borras G A Knock et al ldquoDietary soy isoflavoneinduced increases in antioxidant and eNOS gene expressionlead to improved endothelial function and reduced bloodpressure in vivordquo The FASEB Journal vol 19 no 12 pp 1755ndash1757 2005

[40] P Nestel A Fujii and L Zhang ldquoAn isoflavone metabolitereduces arterial stiffness and blood pressure in overweight menand postmenopausal womenrdquoAtherosclerosis vol 192 no 1 pp184ndash189 2007

[41] K C Das and C W White ldquoRedox systems of the cell possiblelinks and implicationsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 99 pp 9617ndash96182002

[42] S Davinelli N Sapere D Zella R Bracale M Intrieri and GScapagnini ldquoPleiotropic protective effects of phytochemicals inAlzheimerrsquos diseaserdquoOxidativeMedicine andCellular Longevityvol 2012 Article ID 386527 11 pages 2012

[43] G P Lim T Chu F Yang W Beech S A Frautschy and G MCole ldquoThe curry spice curcumin reduces oxidative damage andamyloid pathology in an Alzheimer transgenic mouserdquo Journalof Neuroscience vol 21 no 21 pp 8370ndash8377 2001

[44] D A Dickinson K E Iles H Zhang V Blank and H JForman ldquoCurcumin alters EpRE and AP-1 binding complexesand elevates glutamate-cysteine ligase gene expressionrdquo TheFASEB Journal vol 17 no 3 pp 473ndash475 2003

[45] H Liu L EHarrell S Shenvi THagen andR-M Liu ldquoGenderdifferences in glutathione metabolism in Alzheimerrsquos diseaserdquoJournal of Neuroscience Research vol 79 no 6 pp 861ndash8672005

[46] L-C Lin M-N Wang T-Y Tseng J-S Sung and T-H Tsai ldquoPharmacokinetics of (-)-epigallocatechin-3-gallatein conscious and freely moving rats and its brain regionaldistributionrdquo Journal of Agricultural and Food Chemistry vol55 no 4 pp 1517ndash1524 2007

[47] J A Baur K J Pearson N L Price et al ldquoResveratrol improveshealth and survival of mice on a high-calorie dietrdquo Nature vol444 no 7117 pp 337ndash342 2006

[48] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006

[49] D Kim M D Nguyen M M Dobbin et al ldquoSIRT1 deacetylaseprotects against neurodegeneration in models for Alzheimerrsquosdisease and amyotrophic lateral sclerosisrdquo The EMBO Journalvol 26 no 13 pp 3169ndash3179 2007

[50] Y A Kim S-Y Lim S-H Rhee et al ldquoResveratrol inhibitsinducible nitric oxide synthase and cyclooxygenase-2 expres-sion in 120573-amyloid-treated C6 glioma cellsrdquo International Jour-nal of Molecular Medicine vol 17 no 6 pp 1069ndash1075 2006

[51] L Drsquoevoli F Morroni G Lombardi-Boccia et al ldquoRed chicory(Cichorium intybus L cultivar) as a potential source of antioxi-dant anthocyanins for intestinal healthrdquoOxidativeMedicine andCellular Longevity vol 2013 Article ID 704310 8 pages 2013

[52] M-J Bak V L Truong H-S Kang M Jun and W-S JeongldquoAnti-inflammatory effect of procyanidins from wild grape(Vitis amurensis) seeds in LPS-induced RAW 2647 cellsrdquoOxidative Medicine and Cellular Longevity vol 2013 Article ID409321 11 pages 2013

[53] J Terao ldquoDietary flavonoids as antioxidantsrdquo Forum of Nutri-tion vol 61 pp 87ndash94 2009

[54] M Aviram M Rosenblat D Gaitini et al ldquoPomegranate juiceconsumption for 3 years by patients with carotid artery stenosisreduces common carotid intima-media thickness blood pres-sure and LDL oxidationrdquo Clinical Nutrition vol 23 no 3 pp423ndash433 2004

[55] R Korhonen A Lahti H Kankaanranta and E MoilanenldquoNitric oxide production and signaling in inflammationrdquo Cur-rent Drug Targets Inflammation and Allergy vol 4 no 4 pp471ndash479 2005

[56] Y Shan R Zhao W Geng et al ldquoProtective effect ofsulforaphane on human vascular endothelial cells againstlipopolysaccharide-induced inflammatory damagerdquoCardiovas-cular Toxicology vol 10 no 2 pp 139ndash145 2010

[57] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo Journal of BiologicalChemistry vol 276 no 34 pp 32008ndash32015 2001

[58] A Prawan C L L Saw T O Khor et al ldquoAnti-NF-120581B and anti-inflammatory activities of synthetic isothiocyanates effect of


chemical structures and cellular signalingrdquo Chemico-BiologicalInteractions vol 179 no 2-3 pp 202ndash211 2009

[59] A E Wagner A M Terschluesen and G Rimbach ldquoHealthpromoting effects of brassica-derived phytochemicals fromchemopreventive and anti-inflammatory activities to epigeneticregulationrdquo Oxidative Medicine and Cellular Longevity vol2013 Article ID 964539 12 pages 2013

[60] A E Wagner O Will C Sturm S Lipinski P Rosenstiel andG Rimbach ldquoDSS-induced acute colitis in C57BL6 mice ismitigated by sulforaphane pre-treatmentrdquo Journal of NutritionalBiochemistry vol 24 no 12 pp 2085ndash2091 2013

[61] Y-L Lin S-H Tsai S-Y Lin-Shiau and C-T Ho ldquoTheaflavin-33rsquo-digallate from black tea blocks the nitric oxide synthaseby down-regulating the activation of NF-120581B in macrophagesrdquoEuropean Journal of Pharmacology vol 367 no 2-3 pp 379ndash388 1999

[62] B-T Chen W-X Li R-R He et al ldquoAnti-inflammatory effectsof a polyphenols-rich extract from tea (Camellia sinensis)flowers in acute and chronic mice modelsrdquo Oxidative Medicineand Cellular Longevity vol 2012 Article ID 537923 7 pages2012

[63] C Santangelo R Varı B Scazzocchio R di Benedetto CFilesi and RMasella ldquoPolyphenols intracellular signalling andinflammationrdquo Annali dellrsquoIstituto Superiore di Sanita vol 43no 4 pp 394ndash405 2007

[64] C L Leger M A Carbonneau F Michel et al ldquoA thromboxaneeffect of a hydroxytyrosol-rich olive oil wastewater extract inpatients with uncomplicated type 1 diabetesrdquo European Journalof Clinical Nutrition vol 59 no 5 pp 727ndash730 2005

[65] M C Maiuri D De Stefano P Di Meglio et al ldquoHydrox-ytyrosol a phenolic compound from virgin olive oil pre-vents macrophage activationrdquo Naunyn-Schmiedebergrsquos Archivesof Pharmacology vol 371 no 6 pp 457ndash465 2005

[66] D Ichikawa A Matsui M Imai Y Sonoda and T KasaharaldquoEffect of various catechins on the IL-12p40 production bymurine peritoneal macrophages and a macrophage cell lineJ7741rdquo Biological and Pharmaceutical Bulletin vol 27 no 9 pp1353ndash1358 2004

[67] B B Aggarwal and K B Harikumar ldquoPotential therapeuticeffects of curcumin the anti-inflammatory agent against neu-rodegenerative cardiovascular pulmonary metabolic autoim-mune and neoplastic diseasesrdquo International Journal of Bio-chemistry and Cell Biology vol 41 no 1 pp 40ndash59 2009

[68] A Nemmar D Subramaniyan and B H Ali ldquoProtective effectof curcumin on pulmonary and cardiovascular effects inducedby repeated exposure to diesel exhaust particles in micerdquo PLoSONE vol 7 no 6 Article ID e39554 2012

[69] R A Pauwels J C Kips R A Peleman and M E vander Straeten ldquoThe effect of endotoxin inhalation on airwayresponsiveness and cellular influx in ratsrdquo American Review ofRespiratory Disease vol 141 no 3 pp 540ndash545 1990

[70] B L Graf I Raskin W T Cefalu and D M Ribnicky ldquoPlant-derived therapeutics for the treatment of metabolic syndromerdquoCurrent Opinion in Investigational Drugs vol 11 no 10 pp 1107ndash1115 2010

[71] A Garcıa-Lafuente E Guillamon A Villares M A Rostagnoand J A Martınez ldquoFlavonoids as anti-inflammatory agentsimplications in cancer and cardiovascular diseaserdquo Inflamma-tion Research vol 58 no 9 pp 537ndash552 2009

[72] Y V Bobryshev S M Cherian S J Inder and R S A LordldquoNeovascular expression of VE-cadherin in human atheroscle-rotic arteries and its relation to intimal inflammationrdquo Cardio-vascular Research vol 43 no 4 pp 1003ndash1017 1999

[73] J-J Dugoua D Seely D Perri et al ldquoFrom type 2 diabetesto antioxidant activity a systematic review of the safety andefficacy of common and cassia cinnamon barkrdquo CanadianJournal of Physiology and Pharmacology vol 85 no 9 pp 837ndash847 2007

[74] A Z Kalea K Clark D A Schuschke and D J Klimis-ZacasldquoVascular reactivity is affected by dietary consumption of wildblueberries in the sprague-dawley ratrdquo Journal of MedicinalFood vol 12 no 1 pp 21ndash28 2009

[75] A Z Kalea K Clark D A Schuschke A S Kristo and DJ Klimis-Zacas ldquoDietary enrichment with wild blueberries(Vaccinium angustifolium) affects the vascular reactivity in theaorta of young spontaneously hypertensive ratsrdquo Journal ofNutritional Biochemistry vol 21 no 1 pp 14ndash22 2010

[76] N Peng J T Clark J Prasain H Kim C R White and J MWyss ldquoAntihypertensive and cognitive effects of grape polyphe-nols in estrogen-depleted female spontaneously hypertensiveratsrdquo The American Journal of PhysiologymdashRegulatory Integra-tive and Comparative Physiology vol 289 no 3 pp R771ndashR7752005

[77] A Termentzi P Alexiou V J Demopoulos and E KokkalouldquoThe aldose reductase inhibitory capacity of Sorbus domesticafruit extracts depends on their phenolic content and may beuseful for the control of diabetic complicationsrdquo Pharmazie vol63 no 9 pp 693ndash696 2008

[78] C Veeresham A R Rao and K Asres ldquoAldose reductaseinhibitors of plant originrdquo Phytotherapy Research vol 28 no3 pp 317ndash333 2014

[79] D Govorko S Logendra Y Wang et al ldquoPolyphenolic com-pounds from Artemisia dracunculus L inhibit PEPCK geneexpression and gluconeogenesis in an H4IIE hepatoma celllinerdquo The American Journal of PhysiologymdashEndocrinology andMetabolism vol 293 no 6 pp E1503ndashE1510 2007

[80] S K Banerjee and S KMaulik ldquoEffect of garlic on cardiovascu-lar disorders a reviewrdquo Nutrition Journal vol 1 article 4 2002

[81] Y-Y Yeh and L Liu ldquoCholesterol-lowering effect of garlicextracts and organosulfur compounds human and animalstudiesrdquo Journal of Nutrition vol 131 no 3 pp 989Sndash993S 2001

[82] C D Gardner L M Chatterjee and J J Carlson ldquoThe effectof a garlic preparation on plasma lipid levels in moderatelyhypercholesterolemic adultsrdquo Atherosclerosis vol 154 no 1 pp213ndash220 2001

[83] R Gebhardt and H Beck ldquoDifferential inhibitory effects ofgarlic-derived organosulfur compounds on cholesterol biosyn-thesis in primary rat hepatocyte culturesrdquo Lipids vol 31 no 12pp 1269ndash1276 1996

[84] A Sendl G Elbl B Steinke K Redl W Breu and H Wag-ner ldquoComparative pharmacological investigations of Alliumursinum and Allium sativumrdquo Planta Medica vol 58 no 1 pp1ndash7 1992

[85] K Rahman andGM Lowe ldquoGarlic and cardiovascular diseasea critical reviewrdquo Journal of Nutrition vol 136 no 3 pp 736Sndash740S 2006

[86] O Weingartner M Bohm and U Laufs ldquoControversial roleof plant sterol esters in the management of hypercholestero-laemiardquo European Heart Journal vol 30 no 4 pp 404ndash4092009


[87] A Berger P J H Jones and S S Abumweis ldquoPlant sterolsfactors affecting their efficacy and safety as functional foodingredientsrdquo Lipids in Health and Disease vol 3 article 5 2004

[88] S Pelletier S Kundrat and CMHasler ldquoEffects of a functionalfoods nutrition education program with cardiac rehabilitationpatientsrdquo Journal of Cardiopulmonary Rehabilitation vol 23 no5 pp 334ndash340 2003

[89] J Plat and R P Mensink ldquoIncreased intestinal ABCA1 expres-sion contributes to the decrease in cholesterol absorption afterplant stanol consumptionrdquo The FASEB Journal vol 16 no 10pp 1248ndash1253 2002

[90] P K Prabhakar and M Doble ldquoSynergistic effect of phyto-chemicals in combination with hypoglycemic drugs on glucoseuptake in myotubesrdquo Phytomedicine vol 16 no 12 pp 1119ndash1126 2009

[91] P K Prabhakar and M Doble ldquoInteraction of phytochemicalswith hypoglycemic drugs on glucose uptake in L6 myotubesrdquoPhytomedicine vol 18 no 4 pp 285ndash291 2011

[92] M Gonzalez-Castejon and A Rodriguez-Casado ldquoDietaryphytochemicals and their potential effects on obesity a reviewrdquoPharmacological Research vol 64 no 5 pp 438ndash455 2011

[93] M Lagouge C Argmann Z Gerhart-Hines et al ldquoResver-atrol improves mitochondrial function and protects againstmetabolic disease by activating SIRT1 and PGC-1120572rdquo Cell vol127 no 6 pp 1109ndash1122 2006

[94] K-Y Chyu S M Babbidge X Zhao et al ldquoDifferential effectsof green tea-derived catechin on developing versus establishedatherosclerosis in apolipoprotein E-null micerdquo Circulation vol109 no 20 pp 2448ndash2453 2004

[95] C-H Kim and S-K Moon ldquoEpigallocatechin-3-gallate causesthe p21WAF1-mediated G

1-phase arrest of cell cycle and

inhibits matrix metalloproteinase-9 expression in TNF-120572-induced vascular smoothmuscle cellsrdquoArchives of Biochemistryand Biophysics vol 435 no 2 pp 264ndash272 2005

[96] X W Cheng M Kuzuya S Kanda et al ldquoEpigallocatechin-3-gallate binding to MMP-2 inhibits gelatinolytic activity withoutinfluencing the attachment to extracellular matrix proteins butenhances MMP-2 binding to TIMP-2rdquo Archives of Biochemistryand Biophysics vol 415 no 1 pp 126ndash132 2003

[97] X W Cheng M Kuzuya T Sasaki et al ldquoGreen tea catechinsinhibit neointimal hyperplasia in a rat carotid arterial injurymodel by TIMP-2 overexpressionrdquo Cardiovascular Researchvol 62 no 3 pp 594ndash602 2004

[98] J El Bedoui M-H Oak P Anglard and V B Schini-KerthldquoCatechins prevent vascular smooth muscle cell invasion byinhibiting MT1-MMP activity andMMP-2 expressionrdquo Cardio-vascular Research vol 67 no 2 pp 317ndash325 2005

[99] N Khan F Afaq M Saleem N Ahmad and H MukhtarldquoTargetingmultiple signaling pathways by green tea polyphenol(minus)-epigallocatechin-3-gallaterdquo Cancer Research vol 66 no 5pp 2500ndash2505 2006

[100] R Kesavan U R Potunuru B Nastasijevic T Avaneesh GJoksic andM Dixit ldquoInhibition of vascular smooth muscle cellproliferation by Gentiana lutea root extractsrdquo PLoS ONE vol 8no 4 Article ID e61393 2013

[101] U P Rani R Kesavan R Ganugula et al ldquoEllagic acid inhibitsPDGF-BB-induced vascular smooth muscle cell proliferationand prevents atheroma formation in streptozotocin-induceddiabetic ratsrdquo Journal of Nutritional Biochemistry vol 24 no11 pp 1830ndash1839 2013

[102] A Ouhtit R L Gaur M Abdraboh et al ldquoSimultaneousinhibition of cell-cycle proliferation survival metastatic path-ways and induction of apoptosis in breast cancer cells by aphytochemical super-cocktail genes that underpin its mode ofactionrdquo Journal of Cancer vol 4 no 9 pp 703ndash715 2013

[103] J Duo G-G Ying G-W Wang and L Zhang ldquoQuercetininhibits human breast cancer cell proliferation and inducesapoptosis via Bcl-2 and Bax regulationrdquo Molecular MedicineReports vol 5 no 6 pp 1453ndash1456 2012

[104] A Murakami H Ashida and J Terao ldquoMultitargeted cancerprevention by quercetinrdquoCancer Letters vol 269 no 2 pp 315ndash325 2008

[105] J Kowshik H Giri T K Kishore et al ldquoEllagic acid inhibitsVEGFVEGFR2 PI3KAkt and MAPK signaling cascades inthe hamster cheek pouch carcinogenesis modelrdquo Anti-CancerAgents in Medicinal Chemistry vol 14 no 9 pp 1249ndash12602014

[106] S Lodhi R S Pawar A P Jain and A K Singhai ldquoWoundhealing potential of Tephrosia purpurea (Linn) Pers in ratsrdquoJournal of Ethnopharmacology vol 108 no 2 pp 204ndash210 2006

[107] JWKimA RM RAmin andDM Shin ldquoChemopreventionof head and neck cancer with green tea polyphenolsrdquo CancerPrevention Research vol 3 no 8 pp 900ndash909 2010

[108] J Kowshik A B Baba H Giri et al ldquoAstaxanthin inhibitsJAKSTAT-3 signaling to abrogate cell proliferation invasionand angiogenesis in a hamstermodel of oral cancerrdquo PLoS ONEvol 9 no 10 Article ID e109114 2014

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table1Classifi

catio

nof

phytochemicals(adaptedfro

mGon

zalez-Ca

stejonandRo

driguez-Ca

sado

[3692107])

Dietary

phytochemicals

Functio

nald

erivatives

Sources

Therapeutic

seffect

Polyph

enols

Phenolicacid

Curcum

inoids

Flavon

oids

Chalcones

Stilb

enes

Lign

ans

Isofl

avon

oids

Caffeicacid

Ferulic

acid

Chlorogenica

cid

Curcum

inFlavon

olsFlavanon

esAntho

cyanins

Flavanon

oles

Phloriz

inRe

sveratol

Sesamin

Pino

resin

olGenistein

Daidzein

Coff

eebeanssoybeans

Turm

eric

Teafruits(citrusapp

legrapes)

Vegetables

Tomatoestea

Grapesredwine

Who

legrainslegum

es

Soya

Antioxidativ

eeffect

(1)C

urcuminresveratro

lteap

olypheno

landiso

thiocyanatesuarrthep

hase

IIdetoxifyingandantio

xidant

enzymes

likeH

O-1G

STby

mod

ulationtranscrip

tionfactor

Nrf2

[2024]

(2)C

urcumin

protectsagainstn

euronaldegenerationbydarrRO

SneutralizingNOindu

cedfre

eradicalsCu

rcum

inuarr

intracellularG

SHpo

olby

triggerin

gspecifictranscriptio

nfactors(eg

TP

AE

pRE)

[4445]

(3)IsoflavonestargeteNOSandredo

xsensitive

gene

expressio

nandregulatev

ascularreactivity

[3740

](4)A

gedratsfedsoyproteindietric

hin

geniste

inanddaidzeinw

hich

interactwith

estro

genreceptorsuarreN

OS

andantio

xidant

enzymes

expressio

n[39]

(5)R

esveratro

lanthocyanin

blocking

activ

ationof

NF-kB

MAPK

and

PGE2

protectneuron

aldisorder

[5152]

Anti-infl

ammatoryeffect

(1)P

rocyanidinsdarr

expressio

nof

iNOSandCO

X-2inhibitinfl

ammatoryph

enom

enon

Procyanidinsa

lsosig

nificantlydarrexpressio

nof

TNF-120572andIL-1120573by

blocking

NF-kB

activ

ityviadarr

ofMAPK

andP3

8pathways[52]

(2)T

eaandor

redwinep

olypheno

linh

ibitexpressio

nof

COX-

2LO

Xandexertanti-infl

ammatoryeffect

Similarly

kaem

pferola

flavono

idric

hin

fruits

vegetables

(broccoli)darrredu

ceinflammationby

inhibitin

gthe

generatio

nof

PGE2

[64ndash

66]

(3)O

ralsup

plem

entatio

nof

curcum

in(45m

gkg)inmalem

icedarr

stemicinflammationby

blocking

ther

eleaseo

fTN

F-120572andCR

P[68]

(4)C

innamon

bark

extract(contentT

APP

)protectsfrom

AHRor

asthmab

yredu

cing

inflammatorymediators

likeIL-4andIL-13[69]

(5)C

innamon

bark

extractp

rotectsa

gainstsyste

micinflammationin

rheumatoidarthritisby

redu

cing

CRPand

stimulatingautoim

mun

esystem

bydarrexpressio

nof

manyinflammatorymediators(prosta

glandinE2

NO)inRA

rats[69]

Metabolism

regu

lation

(1)A

ntho

cyanin

andmyrtillin

ofblueberryextractsho

whypo

glycem

iceffectinhu

mansSupp

lementatio

nof

3blueberryenric

heddietfor8

weeks

andor

05

GSE

-sup

plem

enteddietsig

nificantly

redu

cedthea

rterialblood

pressure

inSH

Rsviae

ndotheliu

mmediatedstimulationof

NOmetabolism

andactiv

ationof

COX-

indu

ced

prod

uct[7475]

(2)T

APPthe

mainactiv

ecom

ponent

ofCinn

amon

extractsig

nificantlydarrtheb

lood

HbA

1cleveland

improves

the

insulin

signalin

gin

diabeticanim

alstu

dy[73]

(3)P

heno

liccompo

undsn

amely

chlorogenicacid

andferulic

acidand

aplant

alkaloidberberin

earec

onsid

ered

aspo

tent

antid

iabetic

agentas

thesep

hytochem

icalse

nhance

theu

ptakeo

f2DGin

time-

anddo

se-dependent

mannera

ndsig

nificantly

upregulatethe

expressio

nof

GLU

T4andPP

AR-120574andPK

13Kexpressio

n[9091]

Antiproliferativee

ffect

(1)T

eapo

lyph

enolse

xertantip

roliferativee

ffectsb

yinteractingwith

MMPsyste

mTea

polyph

enoldarrSM

Cproliferatio

nby

blocking

cyclinD1and

CyclinEandby

inhibitin

gthec

ellgrowth

markersPC

NA[9495]

(2)R

esveratro

luarrapop

tosis

byup

regulationof

tumor

supp

ressor

genesp

21Cip1W

AF1p53the

proapo

ptotic

proteinBa

xexpressio

nuarrcaspasea

poptoticsig

nals

anddarrantiapo

ptoticproteins

Bcl-2

Bcl-

XLand

survivin

expressio

n[103104]

(3)P

olypheno

ls(resveratro

lgeniste

incurcuminC

-phycocyaninand

quercetin

)inh

ibitproliferatio

nandmotility

ofcells

bysupp

ressionof

celladhesio

nmoleculeC

D44

expressio

n[102]

(4)E

llagica

cidiso

vitexindarrSM

Cproliferatio

nmight

bebydarrRO

Sgeneratio

nanddarrof

ERK1

2andiN

OS

expressio

n[101]

Antiang

iogenice

ffect

(1)E

llagica

cidsig

nificantlydarrangiogenesisin

hamste

rbuccalpun

chbydarrPI3K

Akt

andMAPK

andVEG

Fsig

nalin

gpathwayssupp

ressingHDAC

6andhypo

xia-indu

cibleH

IF-1120572respon

ses[105]

(2)T

ephrociapurpurea

richin

flavono

idsw

asfoun

dto

exertw

ound

healingeffectb

ysig

nificantuarr

ofangiogenesis

orbloo

dvessels

form

ation

fibroblastcells

andgeneratio

nof

collagenfib

res[106]

(3)A

staxanthin(non

-provitamin

Acaroteno

id)p

redo

minantly

distr

ibuted

inmicroalgaefung

iplants

andsea

food

sinhibitstumor

progressionby

regulatingST

AT3JAK-

2[108]


Table1Con

tinued

Dietary

phytochemicals

Functio

nald

erivatives

Sources

Therapeutic

seffect

Terpenoids

Caroteno

ids

Sesquiterpenes

Lycopene

Lutein

Carotene

Acyclic

compo

und(Farnesol

Nerolidol)

Cyclicc

ompo

und(A

bscisic

acid)


Fruits

vegetables

Antioxidativ

eeffectcon

sumptionof

lycopene

(richin

tomatospinachetc)


xidant

enzymes

SODG

SH-PxGR

andGSH

anddarrlevelsof

MDAin

hypertensiv


levelsin

postm

enop

ausalw

omen

andprotectsfro

mcardiovascular

disorder

Anti-infl


eleaseo



activ

ationand

indu

cesa

nti-infl


ibition

oflip

idperoxidatio

nby

thec

ombinatio

nof

ascorbicacid

and120572-to

coph

erolisthec

omplem

entary

tothea

nti-infl

ammatoryeffecto

flycop

ene

Organosulfur

Allicin

Allylsulfid

eGarliconion

Metabolism

regu

lation

(1)Invivo

antid

iabetic

effecto

fgarlic

iswelld

ocum

entedin


ainactiv

ecompo

nent)ind

uces


insulin

orits

releasefrom

boun

dinsulin

[8081]

(2)G

arlic

andgarlicp

rotein

dietsig

nificantlydarrserum


eandLD


mediatedinhibitio

nof


(3)G

amma-glutam

ylcyste

ines

compo

nent

ofgarlicdarr

bloo

dpressure

byinhibitin

gangiotensin

-con

vertingenzyme

[148085]

Phytosterols

SterolStano

lsCa

mpesta

nols

Diosgenin

Fenu

greekwild

yam

Metabolicregulation











2O2)








2O2








































VEG

Fdarr

P13

Aktdarr

MAP

Kdarr


CD-44 darr

HbA1 darr

Plasma glucose

regulation

ROS darr


Anti-inflammation

Metabolic disorder

Antiangio

genesi

s

Antiproliferation

Antioxidation

HO-1 uarr

IL-1120573 IL-6) darr

AP-1 darr

NF-120581B

darr

NF-120581B

darrNF-120581B









Acknowledgments


References
























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table1Con

tinued

Dietary

phytochemicals

Functio

nald

erivatives

Sources

Therapeutic

seffect

Terpenoids

Caroteno

ids

Sesquiterpenes

Lycopene

Lutein

Carotene

Acyclic

compo

und(Farnesol

Nerolidol)

Cyclicc

ompo

und(A

bscisic

acid)


Fruits

vegetables

Antioxidativ

eeffectcon

sumptionof

lycopene

(richin

tomatospinachetc)


xidant

enzymes

SODG

SH-PxGR

andGSH

anddarrlevelsof

MDAin

hypertensiv


levelsin

postm

enop

ausalw

omen

andprotectsfro

mcardiovascular

disorder

Anti-infl


eleaseo



activ

ationand

indu

cesa

nti-infl


ibition

oflip

idperoxidatio

nby

thec

ombinatio

nof

ascorbicacid

and120572-to

coph

erolisthec

omplem

entary

tothea

nti-infl

ammatoryeffecto

flycop

ene

Organosulfur

Allicin

Allylsulfid

eGarliconion

Metabolism

regu

lation

(1)Invivo

antid

iabetic

effecto

fgarlic

iswelld

ocum

entedin


ainactiv

ecompo

nent)ind

uces


insulin

orits

releasefrom

boun

dinsulin

[8081]

(2)G

arlic

andgarlicp

rotein

dietsig

nificantlydarrserum


eandLD


mediatedinhibitio

nof


(3)G

amma-glutam

ylcyste

ines

compo

nent

ofgarlicdarr

bloo

dpressure

byinhibitin

gangiotensin

-con

vertingenzyme

[148085]

Phytosterols

SterolStano

lsCa

mpesta

nols

Diosgenin

Fenu

greekwild

yam

Metabolicregulation











2O2)








2O2








































VEG

Fdarr

P13

Aktdarr

MAP

Kdarr


CD-44 darr

HbA1 darr

Plasma glucose

regulation

ROS darr


Anti-inflammation

Metabolic disorder

Antiangio

genesi

s

Antiproliferation

Antioxidation

HO-1 uarr

IL-1120573 IL-6) darr

AP-1 darr

NF-120581B

darr

NF-120581B

darrNF-120581B









Acknowledgments


References
























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























2O2)








2O2








































VEG

Fdarr

P13

Aktdarr

MAP

Kdarr


CD-44 darr

HbA1 darr

Plasma glucose

regulation

ROS darr


Anti-inflammation

Metabolic disorder

Antiangio

genesi

s

Antiproliferation

Antioxidation

HO-1 uarr

IL-1120573 IL-6) darr

AP-1 darr

NF-120581B

darr

NF-120581B

darrNF-120581B









Acknowledgments


References
























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















2O2








































VEG

Fdarr

P13

Aktdarr

MAP

Kdarr


CD-44 darr

HbA1 darr

Plasma glucose

regulation

ROS darr


Anti-inflammation

Metabolic disorder

Antiangio

genesi

s

Antiproliferation

Antioxidation

HO-1 uarr

IL-1120573 IL-6) darr

AP-1 darr

NF-120581B

darr

NF-120581B

darrNF-120581B









Acknowledgments


References
























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































VEG

Fdarr

P13

Aktdarr

MAP

Kdarr


CD-44 darr

HbA1 darr

Plasma glucose

regulation

ROS darr


Anti-inflammation

Metabolic disorder

Antiangio

genesi

s

Antiproliferation

Antioxidation

HO-1 uarr

IL-1120573 IL-6) darr

AP-1 darr

NF-120581B

darr

NF-120581B

darrNF-120581B









Acknowledgments


References
























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Acknowledgments


References
























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of











































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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