Review Article Dietary Phytochemicals: Natural Swords...

Review ArticleDietary Phytochemicals Natural Swords CombatingInflammation and Oxidation-Mediated Degenerative Diseases

Md Asiful Islam1 Fahmida Alam1 Md Solayman2 Md Ibrahim Khalil12

Mohammad Amjad Kamal345 and Siew Hua Gan1

1Human Genome Centre School of Medical Sciences Universiti Sains Malaysia 16150 Kubang KerianKelantan Malaysia2Department of Biochemistry and Molecular Biology Jahangirnagar University Savar Dhaka 1342 Bangladesh3King Fahd Medical Research Center King Abdulaziz University PO Box 80216 Jeddah Saudi Arabia4Enzymoics 7 Peterlee Place Hebersham NSW 2770 Australia5Novel Global Community Educational Foundation 7 Peterlee Place Hebersham NSW 2770 Australia

Correspondence should be addressed to Md Asiful Islam ayoncx70yahoocom and Siew Hua Gan shganusmmy

Received 13 May 2016 Revised 8 July 2016 Accepted 22 August 2016

Academic Editor Yolanda de Pablo

Copyright copy 2016 Md Asiful Islam et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Cumulatively degenerative disease is one of the most fatal groups of diseases and it contributes to the mortality and poor quality oflife in the world while increasing the economic burden of the sufferers Oxidative stress and inflammation are the major pathogeniccauses of degenerative diseases such as rheumatoid arthritis (RA) diabetes mellitus (DM) and cardiovascular disease (CVD)Although a number of synthetic medications are used to treat these diseases none of the current regimens are completely safePhytochemicals (polyphenols carotenoids anthocyanins alkaloids glycosides saponins and terpenes) from natural productssuch as dietary fruits vegetables and spices are potential sources of alternative medications to attenuate the oxidative stress andinflammation associated with degenerative diseases Based on in vitro in vivo and clinical trials some of these active compoundshave shown good promise for development into novel agents for treating RA DM and CVD by targeting oxidative stress andinflammation In this review phytochemicals from natural products with the potential of ameliorating degenerative diseaseinvolving the bone metabolism and the heart are described

1 Introduction

Degenerative diseases occur due to the continuous deteriora-tion of cells and tissues that ultimately affects major organsBoth oxidative stress and inflammation are considered majorrole players in the pathogenesis of chronic degenerative dis-eases including cardiovascular diseases (CVDs) [1] diabetesmellitus (DM) [2] and rheumatoid arthritis (RA) [3] Allchronic degenerative diseases exert an immense impact onthe global health economy [4ndash6] Currently although severalsynthetic regimens are used to attenuate oxidative stress andinflammation-mediated degenerative diseases none are freefrom side effects when utilized in the treatment of CVDs [7]DM [8] or RA [9]

Over the last two decades tremendous experimentaladvancements have been made in the use of natural productsagainst different types of degenerative diseases targetingoxidative stress and inflammation [10] Many studies havealso demonstrated that phytochemicals are important ther-apeutic agents targeting oxidative stress and inflammationwhich are the major culprits in the pathogenesis of chronicdegenerative diseases [11 12] Some of these phytochemicalsare good candidates for future drug discovery and develop-ment to treat degenerative diseases [13ndash16]

In this review we discussed the pathogenesis of CVDsDM and RA which involve the heart metabolism andthe joints respectively and we discussed the use of phyto-chemicals (which are synthesized by fruits vegetables and

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 5137431 25 pageshttpdxdoiorg10115520165137431

2 Oxidative Medicine and Cellular Longevity

spices) in attenuating the oxidative stress and inflammationassociated with these chronic diseases

2 Methodology

ThePubMed database was systematically searched to retrieveevidence of potential dietary natural products (fruits vegeta-bles and spices) and their active substances (antioxidantspolyphenols carotenoids anthocyanins alkaloids glyco-sides saponins and terpenes) for use against CVDs DMand RA by attenuating oxidative stress and inflammation (seeAppendix) To retrieve clinical and experimental evidences ofdietary phytochemicals associated with CVDs DM and RAonly papers published in English between January 2000 andMarch 2016 were considered

3 Cardiovascular Diseases

CVDs are a group of diseases associated with complicationsof the heart and blood vessels most are associated withcoronary heart disease Major risk factors of CVDs includehypertension (HTN) hypercholesterolemia diabetes obe-sity inflammation smoking consumption of alcohol lack ofexercise and a familial history of heart diseases [17 18]

CVD is believed to be themajor contributor to worldwidemortality and morbidity in both developed and developingcountries In 2012 it was estimated that 175 million peopledied from CVDs which represents 31 of all global deathsAmong these deaths it was estimated that 74 million weredue to coronary heart disease It has also been predicted thatby 2030 over 28 million people will die from CVDs [19]Based on theAmericanHeart Association Report (2016) 856million American adults were afflicted with CVDs and thisnumber is anticipated to rise and add a greater economicburden to the overall health care system [4]

31 Pathogenesis Thepathogenesis of CVDs ismultifactorialresulting from the interplay of genetic and environmentalfactors However atherosclerosis which occurs due to theaccumulation of atherosclerotic plaques within the walls ofthe arteries (Figure 1) is believed to be the major precursorof CVDs

Plaque formation is initiated by endothelial damage and isfollowed by the adherence of circulating monocytes and sub-sequent exposure to homocysteine inflammation increasedplatelet aggregation and higher levels of oxidized low densitylipoprotein (LDL-ox) and reactive oxygen species (ROS)[20] In addition increased serum lipids such as triglyc-erides (TG) and cholesterol (C) increased plasma fibrinogenand coagulation factors abnormal glucose metabolism andhypertension play crucial roles in the pathogenesis of CVDs[21] Adherent monocytes differentiate into macrophageswhich ingest LDL-ox and transform into large foam cellsappearing as a fatty streak

Additionally although intact endothelium can preventsmooth muscle proliferation by releasing nitric oxide (NO)when the endothelium is damaged smooth muscle prolif-eration and migration are observed from the tunica mediainto the tunica intima in response to damaged endothelial

cell-secreted cytokinesThis activity induces the formation ofa fibrous capsule covering the fatty streak Due to calcificationin the smooth muscle cells and on the unstable fatty streakplaque hardening occurs which further blocks the coronaryarteries [22 23]

Further genetic alterations can adversely promote thedevelopment of CVDs Some examples include mutations orallelic variations of the renin-angiotensin pathway endothe-lial NO synthase coagulation factors and fibrinogen whichcan lead to the development of atherosclerosis [24] In addi-tion diets that are high in saturated fat trans-fats and saltdiets that are low in fruits vegetables and fish smoking theconsumption of tobacco and insufficient physical activity arecardiovascular risk factors [25 26] High density lipoprotein(HDL) levels are negatively correlated with CVDs there-fore the consumption of fiber-rich diets including fruitsand vegetables the control of high blood pressure properregulation of lipid and lipoprotein metabolism decreasedplatelet aggregation and increased antioxidant status shouldlimit the progress of CVDs

32 The Role of Dietary Phytochemicals Although there areseveral synthetic regimens available for treating CVDs noneare free of side effects and limitations (Table 1) Over the lasttwo decades researchers confirmed that the consumption ofregular fresh fruits vegetables and spices has the potential tolower CVD risks by attenuating oxidative stress and inflam-matory mediators Here we discuss some of the potentialexperimental and clinical evidence (Table 2) in favor oftreating CVDs by supplementation with fruits vegetablesand spices

321 Fruits A population-based prospective cohort studyfrom nine areas in Japan (77891 male and female subjectsaged 45ndash74 years) suggested that fruit consumption protectsagainst the risk of CVDs [27] A meta-analysis by Wanget al [28] provided evidence that a higher consumption offruits and vegetables correlated with a lower risk of all-causemortality predominantly cardiovascular mortality A cross-sectional study on Hispanic (119899 = 445) and non-Hispanicwhite elders (119899 = 154) found that the high-frequencyconsumption of fruits and vegetables lowered plasma C-reactive protein (CRP) and homocysteine concentrationsconsequently reducing inflammation which is consideredthe major risk factor of CVDs [29] Recently (2016) a studyon a Chinese population (512891 adults ranging from 30 to79 years old) from 10 diverse localities also revealed that ahigh level of fruit consumptionwas associatedwith decreasedHTN and blood glucose levels which significantly decreasethe risks of CVDs [30] Another study by vanrsquot Veer et al [31]on a Dutch population reported that cardiovascular deathscould be reduced by 16 (approximately 8000 deaths peryear) ranging from 6 to 22 through high intake of fruitsand vegetables A number of randomized controlled trialshave also been conducted in previous years (Table 2) wherefruits vegetables and spices have proven beneficial for CVDmanagement

Apple is one of the most commonly consumed fruits andits polyphenolic extract has a significant effect on decreasing

Oxidative Medicine and Cellular Longevity 3

Endothelial dysfunction

Macrophage recruitment

Adipokines

VCAM-1

InflammationLiver inflammation

Vascular adipose tissues

Obesity

ROS

Artery

Plaque

Cardiovascular disease

IL-1 TNF-120572 IL-6

darr HDL uarr CRP uarr LDL

uarr NF-120581B

Overnutrition physical inactivity

acids

JNK IKK

Inflammatory cytokines

Insulin resistance

IRS

120573-cellInsulin receptor

Insulin

Inflammatory genes

Diabetes mellitus

Inflammatorycytokines

120573-cell dysfunction

ROS

Mitochondria

Adipocyteuarr Glucose

uarr

AP-1 NF-120581B

NucleusFree fatty

Bone

Inflamed synovial membrane

Thinning of cartilage

Synovial fluid

Bone erosionuarr ROS uarr TNF-120572 IL-1120573IL-2 IL-4 IL-6 IL-8

IFN-120574 uarr MMPs uarr COX-2

(a) Cardiovascular disease

(b) Diabetes mellitus

(c) Rheumatoid arthritis

Figure 1 Inflammation and oxidative stress-mediated pathogenesis of (a) cardiovascular disease (b) diabetes mellitus and (c) rheumatoidarthritis

the serum total-C and LDL-C levels in healthy individualswith relatively high body mass index (BMI) which conse-quently limits CVD risk [32] Another study showed that theconsumption of banana decreased the oxidative modificationof LDL plasma lipids and lipoproteins and thus ultimatelyaids in protection from atherogenesis due to its antioxi-dant properties [33] In addition berry fruits (blueberriesstrawberries and cranberries) can also reduce cardiovascularrisk factors such as lipid peroxidation inflammation andthe control of HTN due to the presence of high levels ofanthocyanins and ellagitannins in their skin and flesh [34ndash36] In addition for being good sources of polyphenolsberries are rich in micronutrients such as folate 120572-carotene120573-carotene potassium vitamin C and vitamin E whichexhibit noteworthy antioxidant activities [37]

Several studies have shown that citrus fruits such asmandarins lemons oranges and grapefruits contain high

quantities of flavanones (eg naringin and hesperidin) thatimprove significant vascular functions and the lipid profilein patients with coronary artery diseases [38ndash40] The deli-cious pomegranate fruit and its juice and peel extracts haveantihypertensive antiatherosclerotic antioxidant and anti-inflammatory effects due to the presence of polyphenoliccompounds including anthocyanins catechins and tanninswhich contribute to the attenuation of CVD risk factors [4142]

The consumption of polyphenol-rich peach and plumjuice showed preventive effects against risk factors for car-diometabolic disorders This protection was largely achievedby decreasing the expression of plasma proatherogenicand proinflammatory molecules intercellular cell adhesionmolecule-1 (ICAM-1) monocyte chemotactic protein-1 andnuclear factor kappa B (NF-120581B) and by decreasing foamcell adherence to aortic arches In addition the ingestion


Table1Mechanism

ofactio

nandsid

eeffectso

fsom

esyntheticregimensu

sedin

thetreatmento

fCVDD

Mand

RA

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

Cardiovascular

diseases

1Aspirin

(Easprin)

(i)Inhibitin

gthep

rodu

ctionof

TXA2by

inactiv

ationof

COX-

1andCO

X-2enzymes

(i)Stom

achbleeding

(ii)R

iskof

hemorrhagicstr

okeuarr

(iii)Gastriculcers

(iv)S

tomachup

set

(v)H

eartbu

rn(vi)Nausea

(vii)

Epigastricdistress

(viii)D

yspepsia

(ix)Th

rombo

cytopenia

(x)F

ibrin

olyticactiv

ityuarr

2Quinapril

(Accup

ril)

(i)Inhibitin

gAC

Ewhich

catalyzesthe

form

ationof

angiotensin

II(a

stron

gvasoconstrictor)

(i)Dizziness

(ii)L

ightheadedness

(iii)Tiredn

ess

(iv)D

rycoug

h(v)N

ausea

(vi)Vo

miting

(vii)

Blurredvisio

n(viii)C

hestpain

(ix)C

onfusio

n(x)S

weatin

g

3Digoxin

(Lanoxin)

(i)Inhibitin

gtheN

a-K-AT

Pase

mem

branep

umpresulting

inan

increase

inintracellularsod

ium

(i)Dizziness

(ii)F

ainting

(iii)Fastpo

unding

orirr

egular

heartbeato

rpu

lse(iv

)Slowheartbeat

(v)N

ausea

(vi)Vo

miting

(vii)

Headache

(viii)L

osso

fapp

etite

(ix)D

iarrhea

4Amlodipine

(Norvasc)

(i)Decreasingarteria

lsmoo

thmuscle

contractilityand

vasoconstrictio

nby

inhibitin

gtheinfl

uxof

calcium

ions

throug

hcalcium

channels

(i)Dizziness

(ii)L

ightheadedness

(iii)Sw

ellin

ganklesfe

et(iv

)Flushing

(v)F

atigue

(vi)Palpitatio

ns(vii)

Edem

a(viii)T

ightnessin

thec

hest

(ix)W

heezing


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

5Isosorbide

dinitrate

(Dilatrate-SR

)

(i)Itisconvertedinto

NOwhich

activ

ates

thee

nzym

eguanylate

cyclasethatstim

ulates

thes

ynthesisof

cGMPwhich

then

activ

ates

aserieso

fprotein

kinase-dependent

phosph

orylations

inthe

smoo

thmuscle

cells

eventuallyresulting

invasodilatio

n

(i)Headache

(ii)D

izziness

(iii)Lightheadedn

ess

(iv)N

ausea

(v)F

lushing

(vi)Unu

sualbleeding

(vii)

Bruisin

g(viii)R

apid

heartrate

(ix)D

ifficulty

with

breathing

Diabetesm

ellitu

s

1Metform

in(G

lucoph

age)

(i)Ac

tivatingAMPK

toinhibith

epaticglucosep

rodu

ction

(ii)IncreasingAMPK

activ

ityin

skeletalmuscle

forg

lucose

uptake

byGLU

T4deploymenttothep

lasm

amem

brane

(i)Lacticacidosis

(ii)D

yspepsia

(iii)Nausea

(iv)D

iarrhea

(v)V

omiting

(vi)Weakn

ess

2Pioglitazon

e(A

ctos)

(i)Ac

tivatingPP

AR120574

receptorstomod

ulatethe

insulin

-sensitive

genestranscriptio

nforthe

redu

ctionof

insulin

resistance

(i)Weightg

ain

(ii)R

iskof

bladderc

ancer

(iii)Sore

throat

(iv)M

uscle

pain

(v)T

ooth

prob

lems

(vi)May

causeh

eartfailu

re(vii)

Fluidretention

(viii)P

eripheraledema

3Glib

encla

mide

(DiaBe

ta)

(i)Bind

ingandinhibitin

gtheA

TP-sensitivep

otassiu

mchannels

SUR1

receptor

onthep

ancreatic

cellsurfa

cew

hich

causes

mem

braned

epolarizationandop

ensthe

calcium

channelsfor

insulin

exocytosis

(i)Nausea

(ii)V

omiting

(iii)Diarrhea

(iv)Increased

appetite

(v)H

eartbu

rn(vi)Stom

achfulln

ess

(vii)

Weightg

ain

(viii)H

ypoglycemia

4Ac

arbo

se(Precose)

(i)Re

versiblybind

ingto

pancreatic120572-amylasea

ndintestinal

120572-glucosid

ehydrolasestoinhibitthe

hydrolysisof

complex

carboh

ydratestoglucose

(i)Diarrhea

(ii)G

as(iii)Upsetsto

mach

(iv)C

onstipatio

n(v)S

tomachpain

(vi)Nausea

(vii)

Lossof

appetite

(viii)Jaund

ice


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

5Hum

aninsulin

(Hum

ulin

R)

(i)Bind

ingto

theIRandstimulatingthed

ownstre

amsig

nalin

gmolecules

which

regu

latesthe

GLU

4andPK

Cactiv

ity

(i)Pain

(ii)M

ilditching

(iii)Re

dness

(iv)S

wellin

gattheinjectio

nsite

(v)M

ildweightg

ain

(vi)Hypoglycemia

Rheumatoidarthritis

1Metho

trexate

(Trexall)

(i)Inhibitin

gdihydrofolater

eductase

which

isinvolved

inpu

rine

metabolism

(ii)Inh

ibiting

T-cellactiv

ation

(iii)Selectively

downregulatingBcells

(iv)Inh

ibiting

methyltransfe

rase

activ

ityw

hich

leadsto

deactiv

ationof

immun

esystem

enzymea

ctivities

(i)Nausea

(ii)B

lood

yvomiting

(iii)Stom

achpain

(iv)D

rowsin

ess

(v)D

izziness

(vi)Blacktarrysto

ols

(vii)

Soresinthem

outh

orlip

s(viii)B

lurred

visio

n(ix

)Con

fusio

n(x)C

onvulsion

s

2Hydroxychloroqu

ine

(Quineprox)

(i)Inhibitin

gstimulationof

theT

LR-9

(ii)Inh

ibiting

thep

rodu

ctionof

rheumatoidfactor

(i)Nausea

(ii)S

tomachcram

ps(iii)Lo

ssof

appetite

(iv)D

iarrhea

(v)D

izziness

(vi)Headache

(vii)

Con

vulsion

s(viii)W

eakn

ess

(ix)S

orethroat

(x)F

ever

(xi)Unu

sualbleeding

(xii)

Bruisin

g


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

3Sulfasalazine

(Azulfidine)

(i)Inhibitin

gNF-120581Bandexertin

ganti-inflammatoryandor

immun

omod

ulatoryactiv

ities

(i)Stom

achup

set

(ii)N

ausea

(iii)Vo

miting

(iv)L

osso

fapp

etite

(v)H

eadache

(vi)Dizziness

(vii)

Unu

sualtiredness

(viii)F

ever

(ix)S

orethroat

(x)S

kinrash

oritching

(xi)Bleeding

gums

(xii)

Darkurine

4Leflu

nomide

(Arava)

(i)Inhibitin

gmito

chon

drialenzym

edihydroorotate

dehydrogenasea

ndthus

inhibitin

gther

eprodu

ctionof

rapidly

dividing

cellsespecially

autoim

mun

elym

phocytes

(i)Diarrhea

(ii)N

ausea

(iii)Dizziness

(iv)S

kinrash

(v)A

lopecia

(vi)ASTuarr

(vii)

ALTuarr

(viii)B

lood

yor

cloud

yurine

(ix)C

ough

(x)H

eadache

(xi)Vo

miting

(xii)

Sore

throat

5Certolizum

ab(C

imzia)

(i)Bind

ingandneutralizingthea

ctivity

ofTN

F120572(ii)Inh

ibiting

ther

elease

ofIL-1120573fro

mmon

ocytes

(i)Fever

(ii)C

ough

(iii)Sore

throat

(iv)R

unny

nose

(v)F

requ

entu

rinationwith

burningsensation

(vi)Jointp

ain

(vii)

Body

aches

(viii)H

eadache

(ix)L

osso

fvoice

(x)E

arcongestio

nAMPK

AMP-activ

ated

proteinkinaseG

LUT4

glucose

transporter4

SUR1sulfonylureareceptor

1IRinsulin

receptorP

KCprotein

kinase

CPP

AR120574

peroxiso

mep

roliferator-activated

receptor

gammaAT

Padenosinetripho

sphateT

XA2thrombo

xane

A2CO

Xcyclo

oxygenaseAST

aspartate

aminotransferaseA

LTalanine

aminotransferaseA

CEang

iotensin

convertin

genzymeNOn

itricoxidecG

MP

cyclic

guanosine3101584051015840-m

onop

hosphate


Table2Ev

idence

ofclinicaltria

lswith

naturalprodu

ctsa

ttenu

atingoxidatives

tressandinflammationin

patie

ntsw

ithCV

DD

Mand

RA

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

Cardiovascular

disease(CV

D)

1Ra

ndom

ized

controlled

crossovertria

l

30(F=24

M=6)473plusmn136

Con

trolapplespinachand

apple+

spinach

Health

ycontrol

4weeks

Alltre

atmentsshow

edhigh

erflo

w-m

ediateddilatation

(FMD)(119901lt005)a

ndlower

pulse

pressure

(119901lt005)a

ndapplea

ndspinachresultedin

lower

systo

licbloo

dpressure

(119901lt005)

2012

[49]

2Dou

ble-blind

rand

omized

crossovertria

lM=30526plusmn55

Twolyop

hilized

apples

(40g

)po

lyph

enol-richand

polyph

enol-poo

rproviding

respectiv

ely143g

and021g

polyph

enolsp

erday

Hypercholesterolemic

6weeks

FMDdidno

tdiffer

betweenthe

polyph

enol-richandthe

polyph

enol-poo

rapp

lesneith

erdidtheo

ther

cardiovascular

diseaser

iskfactors(plasma

lipidsho

mocysteineand

antio

xidant

capacity)

2010

[50]

3

Openprospective

rand

omized

crossover

controlledfeeding

trial

40(F=21

M=19)

28plusmn11

Rawtomatoeskg

(70g

)35g

oftomatosaucekg35gof

tomato

saucew

ithrefin

edoliveo

ilkg

and025

gof

sugarsolvedin

waterkg

Health

ycontrol

12days

Tomatosaucee

nrichedwith

refin

edoliveo

ilcanregu

late

lipid

profi

leandsoluble

inflammatorybiom

arkersbette

rthan

rawtomatoeso

rtom

ato

sauces

2016

[51]

4Dou

ble-blind

controlled

rand

omized

trial

F=79

56plusmn4

Genisteinfro

msoybeans

(54m

gday)estrogenprogestin

therapy(1mgday)

estro

genprogestin

combined

with

norethisteron

eacetate

(05mgday)

Health

ypo

stmenop

ausal

wom

en1y

ear

Genisteintherapyim

proved

endo

thelium

functio

nsim

ilarto

estro

genprogestin

regimen

2003

[52]

5Dou

ble-blinded

placebo-controlled

crossovertria

l

93(F=51

M=42)

25ndash6

5Quercetinday

from

fruitsand

vegetables

ources

(150

mg)

Overw

eighto

bese

6weeks

Redu

cedSB

Pandplasma

oxidized

LDLlevelw

itha

high

-CVDris

kph

enotype

2009

[53]

6

Dou

ble-blinded

rand

omized

placebo-controlled

crossovertria

l

M=31

35ndash51

Antho

cyaninsfrom

fruitsand

vegetables

ources

(640

mgday)

Prehypertensive

4weeks

HDL-Candbloo

dglucosew

ere

significantly

high

eraft

eranthocyaninversus

placebo

treatment(119901=0043and

119901=0024resp)

2013

[54]

7

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

105

20ndash6

0One

350m

gwho

rtleberryextract

capsulee

very

8ho

urs

Hyperlip

idem

ic2mon

ths

Lowered

total-C

(119901lt0001)

TG(119901=0002)andLD

L-C

(119901=0002)b

utincreased

HDL-Clevels(119901lt0001)

comparedwith

thep

lacebo

grou

patthee

ndpo

int

2014

[55]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

8

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

50ge1845plusmn2mgof

anthocyaninfro

mVa

ccinium

arctostaphylos

Lfruit

extract

Hyperlip

idem

ic4weeks

Sign

ificantlyredu

cedtotal-C

(119901lt0001)LD

L-C(119901=0004)

TG(119901lt0001)andMDA

(119901=0013)com

paredto

placebo

2014

[56]

9

Rand

omized

controlled

investigator

blinded

parallel-g

roup

trial

NCT

00421499

44(F=24

M=20)

56ndash73

Darkchocolate(63g

day)

containing

30mgof

polyph

enols

Stage-1h

ypertensive

18weeks

Redu

cedmean(SD)S

BPby

29

(16)m

mHg(119901lt0001)a

ndDBP

by19

(10)m

mHg

(119901lt0001)

2007

[57]

10

Rand

omized

placebo-controlled

single-blind

crossovertria

lNCT

00538083

45(F=35

M=10)

30ndash75

Inph

ase1solid

dark

chocolate

bar(containing

22gcocoa

powder)or

acocoa-fr

eeplacebo

barIn

phase2

sug

ar-fr

eecocoa

(con

taining22

gcocoap

owder)

sugaredcocoa(

containing

22g

cocoap

owder)ora

placebo

Health

ycontrol

1week

Thea

cuteingestionof

both

solid

dark

chocolatea

ndliq

uid

cocoaimproved

endo

thelial

functio

nandlowered

bloo

dpressure

inoverweightadu

lts

2008

[58]

Diabetesm

ellitu

s(DM)

11Openlabel

rand

omized

clinicaltria

l60

35ndash55

Standard

metform

intherapy

with

turm

eric(2g)

supp

lements

Standard

metform

intre

atment

4weeks

Turm

ericadministered

grou

psig

nificantly

(119901lt005)reduced

thelipid

peroxidatio

nMDA

inflammatorymarkerCR

PHbA

1cand

fastingbloo

dglucoselevels

andenhanced

the

totalantioxidant

status

2015

[59]

12

Rand

omized

doub

le-blin

dcontrolledclinical

trial

7030ndash70

Powderedrhizom

eofginger

(160

0mg)

Wheatflo

urplacebo

(160

0mg)

12weeks

Gingersignificantly

redu

cedthe

fastingplasmag

lucoseH

bA1c

insulin

trig

lycerid

etotal

cholesterolCR

PandPG

E2

2014

[60]

13Ra

ndom

ized

triple-blin

dcontrolledtrial

M=35

60plusmn11

Capsuleo

f350

mgof

RES

enric

hedgrapee

xtract(G

E)

350m

gof

capsules

containing

either

maltodextrin

(placebo

)orR

ESlackingGE

12mon

ths

RESenric

hedGE

downregulated

the

proinfl

ammatorycytokines

expressio

nviainvolving

the

inflammation-related

miRsin

circulatingim

mun

ecells

2013

[61]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

14Ra

ndom

ized

doub

le-blin

dcontrolledtrial

36(F=23

M=13)515plusmn100

FDSbeverage

of2cups

(50g

ofFD

Sisequivalent

to500g

offre

shstr

awberries)

Placebopo

wderw

ithstr

awberryflavor

6weeks

FDSsig

nificantly

(119901lt005)

decreasedtheC

RPlevelsand

lipid

peroxidatio

n(m

ainly

MDA)a

ndincreasedthetotal

antio

xidant

status

2013

[62]

15Ra

ndom

ized

doub

le-blin

dcontrolledtrial

6438ndash6

5Gingersup

plem

entatio

nPlacebo

8weeks

Gingersup

plem

entatio

nsig

nificantly

redu

cedthe

TNF-120572C

RPand

IL-6

levels

2013

[63]

16Ra

ndom

ized

doub

le-blin

dclinicaltria

l81

18ndash6

0BS

Pat10gday(119899=27)B

SPat

5gday

(119899=29)

Placebo

4weeks

BSPsig

nificantly

decreasedthe

MDAO

SIand

oxidized

low

density

lipop

rotein

cholesterol

andincreasedtheT

AC

2011[64]

17Dou

ble-blinded

rand

omized

crossovertria

l

32(M=16

F=16)618plusmn64

GSE

(600

mgday)

Placebo

4weeks

GSE

significantly

improved

the

inflammatorymarkers(m

ainly

CRP)glycemiaand

oxidative

stress

2009

[65]

Rheumatoidarthritis(RA)

18Ra

ndom

ized

single-blindpilot

study

45(F=38

M=7)478plusmn86

Curcum

in(500

mg)

and

diclo

fenacs

odium

(50m

g)alon

eor

incombinatio

n

Diclofenacs

odium

(anti-infl

ammatory

drug)

8weeks

Curcum

inalon

eprovedto

bethem

osteffective(119901lt005)

andsafestto

attenu

ateR

Acomplications

2012

[66]

19

Rand

omized

doub

le-blin

dplacebo-controlled

crossoverstudy

20(F=19

M=1)521plusmn103

Quercetin

(166

mgcapsule)+

vitamin

C(133

mgcapsule)

120572-lipo

icacid

(300

mgcapsule)

Placebo

6weeks

Nosig

nificantd

ifference

was

foun

dam

ongthe

proinfl

ammatorycytokines

however

quercetin

tend

edto

redu

ceVA

Sof

RA

2009

[67]

20

Rand

omized

doub

le-blin

dplacebo-controlled

study

105

55ndash75

Polyph

enolic-richolivee

xtract

Placebo

8weeks

Sign

ificant

(119901lt001)d

ecrease

ofplasmah

omocysteinelevel

(respo

nsibleforc

ardiovascular

complications

inRA

)and

notabler

eductio

nof

CRPwere

observed

2007

[68]

FfemaleMm

aleRA

rheum

atoidarthritis

VASvisualanalogue

scaleNR

notreported

CRP

C-reactiv

eprotein

RESresveratrolGE

grapeextractmiRsmicroRN

AsFD

Sfre

eze-driedstr

awberryMDA

malon

dialdehydeG

SEgrape

seed

extractBS

Pbroccolisproutsp

owderOSIoxidativ

estr

essind

exT

ACtotalantio

xidant

capacityP

GE2

prostagland

inE2

HbA

1cglycosylated

hemoglobin

CADcoron

ary

artery

diseaseLD

L-C

lowdensity

lipop

rotein

cholesterolHDL-C

high

density

lipop

rotein

cholesterolSB

Psysto

licbloo

dpressure


of peach and plum juice reduced angiotensin II levels inplasma and reduced the expression of its receptor Agtr1in cardiac tissues thus demonstrating the ability of peachand plum polyphenols to act as peroxisome proliferator-activated receptor-120574 (PPAR120574) agonists [43] An in vivo andex vivo experiment by Hong et al demonstrated that water-melon improved lipid profiles and antioxidant capacity anddecreased inflammation thus altering gene expression forlipid metabolism and consequently reducing the risk factorsfor CVDs [44]

322 Vegetables A group of widely consumed flavonoidspresent in vegetables exhibit some protective activities againstCVD progress [45] Sulfur-containing organic compounds(organosulfur) from garlic (Allium sativum) onion (Alliumcepa) and cruciferous vegetables such as broccoli cauli-flower cabbage and Brussels sprouts showed cardiopro-tective effects mediated by their antioxidant and anti-in-flammatory properties [46] Moreover experimental stud-ies on garlic suggested the blocking of platelet aggrega-tion through ADP and platelet-activating factor (PAF)inhibition [47] A key flavonoid from onion quercetin(3310158404101584057-pentahydroxyflavone) exerts antiatheroscleroticeffects and its metabolites which showed antioxidant andanti-inflammatory activities accumulate in the aorta tissue[48]

Upaganlawar et al [69] showed that lycopene a brightred carotene and carotenoid pigment in tomato considerablyreducedmyocardial infarction (MI) in isoproterenol-inducedrats because of its antioxidant activities A recent study (2015)also demonstrated that the supplementation of tomato withcorn oil improved diastolic function changed cardiacmiRNAexpression and attenuated both lipid hydroperoxidation andoxidative stress [70] Similarly tomato-based products suchas tomatoes tomato sauce and tomato juice had cardiovas-cular advantages due to the presence of dietary lycopene [71]

323 Spices Several studies have observed that the widelyused spice ginger (Zingiber officinale) helps in the treat-ment of CVDs Ginger exhibits anti-inflammatory as wellas antithrombotic properties by inhibiting the productionof NO inflammatory cytokines cyclooxygenase (COX) andlipoxygenase (LOX) and it shows no or very few side effectsunlike nonsteroidal anti-inflammatory drugs (NSAIDs) [7273] Ginger also displays antioxidant [74] antiplatelet [75]positive inotropic [76] hypotensive [77] and hypoglycemicand hypolipidemic effects [78] in in vitro and in vivo studiesand human clinical trials One of the most regularly con-sumed spices black pepper and its active principle (piperine)showed significant decreases in the levels of C free fattyacids phospholipids and triglycerides and an increase in theconcentration of high density lipoprotein cholesterol (HDL-C) thus reducing the risk of atherosclerosis [79 80] Anotherspice called saffron (Crocus sativus L) and its essential oil-likeconstituent safranal show remarkable cardioprotective effectsin isoproterenol-induced MI Wistar rats by maintainingthe redox status of the cell [81 82] Cinnamon is anotherspice that is abundantly found in Bangladesh India ChinaSri Lanka Egypt and Australia the leaves and barks of

cinnamon are used widely in food or to yield essential oilsand they show cardioprotective effects [83]

324 Miscellaneous A meta-analysis reported that the con-sumption of 1 cupday of green tea could decrease by 10the chance of developing coronary artery disease due tothe presence of polyphenols such as catechins epicatechin3-gallate (ECG) and epigallocatechin (EGC) and therebyprevent CVD however no significant relationship was foundbetween black tea polyphenols and cardioprotective effects[84]

Chocolate cocoa and cocoa products provide a sub-stantial quantity of dietary polyphenols There is numerousevidence from in vivo and ex vivo experiments as wellas clinical studies showing the roles of these products inprotecting against the risk factors of CVDs A cross-sectionalstudy by Buijsse et al [85] showed that the consumption ofcocoa-containing foods was inversely related to the bloodpressure and 15-year cardiovascular mortality Several meta-analyses have also established that the consumption of cocoacould modulate multiple cardiovascular risk factors such asflow-mediated vascular dilatation activation of platelets [86]insulin resistance [87] and the blood C level [88]

Because CVD is a multifactorial disorder the consump-tion of fruits vegetables spices green tea red wine or otherpolyphenol-rich phytochemicals is expected to decrease therisk of CVD via multiple mechanisms to ensure a healthy life

4 Diabetes Mellitus

DM is a group of metabolic diseases that are caused byovernutrition (mainly high-fat diet) and a lack of physicalactivity [89] In healthy individuals active pancreatic 120573-cellssecrete insulin to reduce glucose levels in insulin-sensitiveliver muscle and adipose tissues [90] In type 1 diabetesmellitus (T1DM) defective insulin secretion occurs due todysfunctional pancreatic 120573-cells or a decrease in 120573-cell massover time whereas in type 2 diabetes mellitus (T2DM)insulin-stimulated glucose uptake in hepatic and adiposetissues is reduced due to insulin resistance [91] Over timeinsulin resistance tends to increase with age In contrast120573-cells that initially produce insulin in sufficient quantitieseventually produce insufficient quantities thereby leading tothe onset and progression of diabetes [92]

Worldwide DM is themost common endocrine disorderthe reported prevalence in 2013was 382million people whichis anticipated to increase to as many as 592 million by 2035[93] The majority (80) of DM patients are from low andmiddle income countries where the incidence of DM isexpected to increase in the next 22 years [93]

41 Pathogenesis Chronic low-grade inflammation and theactivation of the innate immune system are considered to beclosely involved in the pathogenesis of DM [94] Excessivelevels of nutrients (glucose and free fatty acids) initiatecellular stress in the pancreatic islets and insulin-sensitivetissues including adipose tissue leading to the activationof c-Jun N-terminal kinase (JNK) and NF-120581B (Figure 1)[95] The inflammatory signaling pathways regulate protein


phosphorylation and cellular transcriptional events therebyincreasing the adipocyte production of proinflammatorycytokines including tumor necrosis factor alpha (TNF-120572)interleukin (IL) 6 IL-1120573 leptin resistin and chemokinessuch as MCP-1 CC-chemokine ligand 2 (CCL2) CCL3and CXC-chemokine ligand 8 As a result immune cellssuch as monocytes are recruited to the adipose tissues thuscontributing to tissue inflammation The monocytes thatdifferentiate into macrophages produce several inflamma-tory cytokines further promoting local inflammation Inaddition the release of cytokines and chemokines from theadipose tissues into the circulation promotes inflammationin other tissues including the islets [95]

Both JNK and IKK120573NF-120581B play important roles ininflammation-induced insulin resistance JNK is a stresskinase that normally phosphorylates the c-Jun component ofthe AP-1 transcription factor and promotes insulin resistancethrough the phosphorylation of serine residues in insulinreceptor substrate 1 (IRS-1) [96] Insulin receptor signalingthat normally occurs through a tyrosine kinase cascade[90] is inhibited by counter-regulatory serinethreoninephosphorylation [97] IKK120573 is highly selective towards itsphysiological substrates the I120581B protein inhibitors of NF-120581B Phosphorylation by IKK120573 targets I120581B120572 for proteasomaldegradation which liberates NF-120581B for translocation intothe nucleus where it promotes the expression of numeroustarget genes whose products induce insulin resistance IKK120573causes insulin resistance through the transcriptional activa-tion of NF-120581B Therefore anti-inflammatory therapies havethe potential to decrease gene expression and improve insulinresistance

Increasing adiposity is reported to increase inflammatorygene expression in the liver [98] which further increasesthe production of cytokines and chemokines Immune cellsincluding monocytes and macrophages are recruited andoractivated which leads to local insulin resistance Alterna-tively the portal delivery of abdominal fat-derived cytokinesand lipids contributes to hepatic inflammationHowever NF-120581B is activated in hepatocytes causing the overproductionof cytokines including IL-6 TNF-120572 and IL-1120573 in fattyliver The proinflammatory cytokines then contribute to thedevelopment of insulin resistance in skeletalmuscle and othertissues [95]

Oxidative stress contributes to DM by modifying theenzyme systems impairing glutathionemetabolism and lipidperoxidation and reducing vitamin C levels [99] In fact aclose relationship exists between hyperglycemia and oxida-tive stress inDMHyperglycemia fuels glucose autooxidationNADPH oxidase activity oxidative phosphorylation proteinglycation and the polyol pathway which leads to ROSgeneration and oxidative stress (Figure 1) [100] ROS attackthe healthy cells by damaging the functional and structuralintegrity of the cells which consequently leads to manypathophysiological conditions [101]

42 The Role of Dietary Phytochemicals Several groups ofsynthetic drugs and insulin possess antioxidative and anti-inflammatory potential that can be used in the treatmentof DM Unfortunately none are free from adverse effects

(Table 1) Therefore the quest for alternative and safer treat-ment regimens for DM is ongoing In this review successfulclinical trials based on intervention with fruits vegetablesand spices are considered (Table 2) and in vivo and in vitroexperiments using the phytochemicals from these dietarysources that have exhibited potential to attenuate oxidativestress and inflammation for DM treatment are discussed

421 Fruits Numerous in vivo and in vitro experimentswith fruits fruit products and fruit-derived compoundshave been extensively conducted for DM management Theoral administration of naringin (4101584057-trihydroxyflavonone-7-rhamnoglucoside) at 50mgkgday is reported to reduceoxidative stress and increase fasting plasma insulin instreptozotocin- (STZ-) induced diabetic Sprague Dawleyrats Naringin is considered to be the main flavonoid ingrapefruit juice and it is thought to ameliorate oxidativestress through its antioxidant effects thereby improving ATPsynthesis in pancreatic 120573-cell mitochondria and amelioratingthe subsequent insulin secretion by 120573-cells [102] Anotherstudy also investigated the effect of naringin treatment (2550 and 100mgkgday) on diabetic Wistar albino malerats for 28 days Naringin significantly ameliorated 120573-celldysfunction insulin resistance and hyperglycemia reducedTNF-120572 IL-6 CRP and antioxidant enzyme activities andNF-120581B expression and increased adiponectin and PPAR120574expression Additionally naringin effectively rescued kidneycells 120573-cells and liver cells from further pathological modi-fications and oxidative damage [103]

Resveratrol a naturally occurring polyphenol found ingrapes and red wine has recently been shown to exert potentantidiabetic antioxidative and anti-inflammatory activitiesIn the liver and spleen of STZ-induced male Long-Evans rats(type 1 diabetic animal models) resveratrol treatment (01or 10mgkgday) for 7 days significantly reduced oxidativestress (including superoxide anion content protein carbonyllevel and manganese-superoxide dismutase expression) inhepatic and splenic tissues and it reduced hepatic inflamma-tion (NF-120581B and IL-1120573) and decreased the TNF-120572 and IL-6levels in diabetic spleen [104]

Phlorizin (PZ) is a predominant phenolic compound thatis found in apples Preexposure to docosahexaenoic acid esterof PZ (PZ-DHA) in inflammation-induced macrophages[stimulated by lipopolysaccharide (LPS)] was effective inreducing the TNF-120572 IL-6 and COX-2 protein levels com-pared with DHA Both PZ-DHA ester and DHA have thepotential to inhibit NF-120581B activation Therefore PZ-DHAester has the potential to be used in T2DM-associatedinflammation [105]

Diabetes mellitus is associated with the reduction ofglutathione levels thus indicating the critical role of oxidativestress in its pathogenesis In Ins-1E pancreatic 120573-cells pre-treatment with the flavonoid epicatechin (present in greentea grapes and cocoa) prevented tert-butyl hydroperoxide-induced cell damage ROS and p-JNK expression In addi-tion it restored insulin secretion which indicates the protec-tive potentiality of epicatechin against oxidative stress on 120573-cells [106]


Pomegranate (Punica granatum) fruit contains flavonoidssuch as flavonols anthocyanins ellagitannins gallotanninsand proanthocyanidins Pomegranate has been reported toprovide a beneficial effect in T2DM by decreasing the lipidperoxidation and oxidative stress by increasing some ofthe enzymesrsquo antioxidant activity decreasing the ROS andpreventing or activating PPAR120574 and NF-120581B [107]

Anthocyanins can alter tissue PPAR activity which fur-ther affectsmetabolism and inflammation In the Zucker fattyrat model of obesity and metabolic syndrome the effect ofwhole tart cherry powder (prepared from anthocyanin-richtart cherries) was evaluated after 90 daysrsquo treatment Theintake of tart cherry reduced retroperitoneal IL-6 and TNF-120572mRNAexpressionNF-120581B activity and plasma IL-6 andTNF-120572 levels and it increased retroperitoneal PPAR120572 and PPAR120574mRNA expression As a whole tart cherry consumptionreduced both systemic and local inflammation andmetabolicsyndrome which may reduce the risk of T2DM development[108]

Macrophage infiltration in adipose tissue due to increasedadiposity can lead to T2DM In an in vitro model ofinflammation in which the pathologic relationships betweenadipocytes and macrophages were mimicked anthocyanin-enriched fractions fromblackberry-blueberry beverageswerefound to inhibit the secretion of NO and TNF-120572 and thephosphorylation of NF-120581B p65 in LPS-induced macrophages[109]

T2DM is associated with chronic low-grade systemicinflammation accompanied by an increased production ofadipokines or cytokines by obese adipose tissue The treat-ment of diabetic dbdb mice with grapefruit (05 gkg) for sixweeks produced antihyperglycemic effects that were accom-panied by the reducedmRNA expression of proinflammatorygenes such as COX-2monocyte chemotactic protein-1 TNF-120572 and NF-120581B in the liver and epididymal adipose tissueHypermethylation at the CpG3 site of TNF120572 in adipose tissuewas also found which may contribute to a reduction of theinflammation associated with T2DM [110]

In pancreas liver and adipose tissue endoplasmic reticu-lum (ER) stress is an early event linked to T2DM pathogene-sis In the skeletal muscle of diabetic rats 500mgkg of grapeseed proanthocyanidin extract (GSPE) administration for 16weeks decreased the plasma glucose levels and insulin resis-tance restored the normal activities of antioxidant enzymesand ATPases and partially alleviated severe ER stress whichsuggests that GSPE could be a useful treatment strategyfor T2DM [111] A similar study on GSPE using humanadipocytes (SGBS) and macrophage-like (THP-1) cells foundreduced cytokine (IL-6 and MCP-1) gene expression after aninflammatory stimulus and enhanced the production of theanti-inflammatory adipokines adiponectin (APM1) and LEPwhich may prevent the low-grade inflammation of T2DM[112]

Milk fat globule epidermal growth factor-8 (MFG-E8)is highly involved in the inflammatory response In dia-betic dbdb mice the administration of grape seed pro-cyanidin B2 (a natural complex of polyphenol polymers)provided anti-inflammatory protection in pancreatic tissuesby downregulating MFG-E8 and attenuating the levels of the

proinflammatory cytokines IL-1120573 and NLRP3 [113] Becausethe dysfunction of pancreatic islets is one of the mainstays inT2DMpathogenesis protecting the pancreas from inflamma-tion may lead to potential therapeutic approaches

422 Vegetables There is abundant in vitro and in vivoevidence that vegetables have anti-inflammatory and antiox-idant potential for DM management In diabetic Wistarrats the immunomodulatory effects of a mycelial sub-merged culture and the broth of Grifola frondosa mush-rooms were explored on splenocytes and peripheral bloodcells Two weeks of intragastric administration of fermentedmycelia broth or their combination (1 gkgday) significantlydecreased the 2-hour postprandial blood glucose level theproduction of T-leukocyte-derived interferon gamma (IFN-120574) monocyte-derived IL-4 and IL-6 and T-splenocyte-derived IL-4 and this treatment significantly enhancedmacrophage-derived TNF-120572 production [114]

In STZ-induced diabetic rats the administration offermented carrot juice by Lactobacillus plantarum NCU116for five weeks positively regulated the blood glucose levelhormone and lipid metabolism reestablished the antiox-idant capacity restored the morphology of pancreas andkidney and upregulated the LDL receptor cholesterol 7120572-hydroxylase (CYP7A1) GLUT4 and PPAR120572 and PPAR120574mRNA expression [115]

Sulforaphane (SFN) is an isothiocyanate that is naturallyavailable in widely consumed vegetables particularly broc-coli In diabetic male C57BL6J mice sulforaphane (05mgkg) treatment for four months significantly inhibited car-diac lipid accumulation and improved cardiac inflammationoxidative stress and fibrosis by downregulating diabetes-induced PAI-1 TNF-120572 CTGF TGF-120573 3-NT and 4-HNEexpression SFN also upregulated nuclear factor (erythroid-derived 2-) like factor 2 (Nrf2) and its downstream genesNQO1 and HO-1 SFN decreased 4-HNE-LKB1 adducts andreversed the diabetes-induced inhibition of LKB1AMPK andits downstream targets including sirtuin 1 PGC-1120572 phos-phorylated acetyl-CoA carboxylase and carnitine palmitoyltransferase-1 These results suggest that the SFN treatmentof T2DM mice may attenuate the cardiac oxidative stress-induced inhibition of the LKB1AMPK signaling pathwaythereby preventing T2DM-induced lipotoxicity and car-diomyopathy [116]

Onion-derived quercetin derivatives have been regardedas the most important flavonoids for improving diabetic con-ditions in both in vivo and in vitro models In STZ-inducedmale Sprague Dawley rats eight days of treatment with onionpeel extract (1) significantly (119901 = 00148) improved glucosetolerance liver and skeletal muscle glycogen content (119901 lt00001 and 119901 = 00089 resp) and insulin receptor (119901 =00408) and GLUT4 (119901 = 00346) expression in muscletissuesTheoxidative stress-inducing activities such as super-oxide dismutase activity the formation of malondialdehydefree fatty acids in the plasma and IL-6 expression in hepaticprotein were significantly (119901 = 00393 00237 00148 and00025 resp) decreased [117]

Cordycepin (31015840-deoxyadenosine) is produced by a tradi-tional medicinal mushroom known as Cordyceps militaris


Although cordycepin has been shown to exert immunologicalstimulation and anti-infection and anticancer activities themolecular mechanisms of cordycepin in T2DM are unclearIn LPS-stimulated RAW 2647 cells cordycepin has beenfound to inhibit NO suppressNF-120581B activation and suppressthe protein expression of proinflammatory mediators thatfurther inhibit the production of proinflammatory cytokinessuch as IL-1120573 IL-6 and TNF-120572 Moreover an increasedconcentration of cordycepin decreased the T2DM-regulatinggenes such as 11120573-HSD1 and PPAR120574 as well as the expressionof costimulatorymolecules such as ICAM-1 and B7-1-2 [118]

The administration of MT-120572-glucan (isolated from Gri-fola frondosa mushroom fruit body) in a murine T2DMmodel significantly decreased the body weight fastingplasma glucose levels HbA1c TG cholesterol FAA NONO synthase inducible NO synthase and malondialdehydecontent in the liver MT-120572-glucan also significantly increasedthe serum insulin content and hepatic glycogen content andit reduced both the glutathione levels and the superoxidedismutase and glutathione peroxidase activity These resultssuggest that the hypoglycemic effects of MT-120572-glucan inT2DM mice might be connected to its protection of pancre-atic 120573-cells accomplished by decreasing oxidative stress andNO synthesis [119]

In an in vitro study cocoa (Theobroma cacao) extracthas shown dose-dependent inhibition of 120572-amylase 120572-glucosidase and angiotensin-1-converting enzyme activitiesand has also shown scavenging ability for several radicals[DPPH (1694plusmn134mgmL) NO (698plusmn0886mgmL) OH(372plusmn026mgmL) and ABTS (157plusmn 106mmolTEACsdotg)][120]

423 Spices A variety of spices also show potential formanaging DM by reducing inflammation and oxidativestress Turmeric (Curcuma longa) contains curcumin (apolyphenolic compound) as the active ingredient whichpossesses broad-spectrum biological actions such as anti-inflammatory antioxidant and antitumor activities In theinjured lungs of diabetic rats curcumin has been foundto reduce oxidative stress and inflammatory responses andinhibit prostaglandin E2 (PGE2) and NOS Further resultsrevealed that curcumin inhibited the activation of NF-120581Bwhich is a key player in inflammatory responses [121] Indbdb mice curcumin treatment for eight weeks increasedAMPK and PPAR120574 expression and diminished NF-120581B pro-tein levels [122] In T1DM patients the development ofskeletal muscle atrophy is associated with chronic inflamma-tion According to an in vivo study on STZ-induced T1DMC57BL6J mice curcumin at a dose of 1500mgkgday fortwo weeks ameliorated skeletal muscle atrophy by inhibitingNF-120581B activation inflammatory cytokine (TNF-120572 and IL-1120573)concentrations oxidative stress and protein ubiquitination[123] According to an in vitro study the treatment ofsolid lipid curcumin particle (SLCP) formulations (10 to50120583gmL) using LPS-stimulatedRAW2647 culturedmurinemacrophages significantly decreased the LPS-induced proin-flammatory mediators NO PGE2 and IL-6 by inhibitingthe activation of NF-120581B [124] In another study on STZ-induced diabetic Wistar-NIN rats treatment with 001

curcumin or 05 turmeric for a period of eight weekscontrolled the oxidative stress and restored normal antioxi-dant enzyme activities [125] Neuronal injury can be inducedby hyperglycemia-mediated oxidative stress due to diabetesCurcuminoids which are polyphenols of turmeric exhibitedprotective effects against oxidative stress in the brain of STZ-induced diabetic rats by restoring the normal level of lipidperoxidation and nitrite content and endogenous antioxidantmarker enzymes [126] In an in vitro study curcumin wasfound to attenuate insulin-induced oxidative stress in hepaticstellate cells by inducing the expression of glutamate-cysteineligase leading to the de novo synthesis of glutathione andthe suppression of insulin receptor expression [127] In anin vitro study pretreatment with a novel curcumin analogue(B06) at 5 120583Msignificantly reduced the high glucose-inducedoverexpression of inflammatory cytokines in macrophagesvia the inhibition of c-Jun N-terminal kinaseNF-120581B activa-tion [128]

Diabetic complications occur as a result of increased ROSdue to long-termhyperglycemiaHoney and ginger have beenshown to exhibit antioxidant activity by scavenging ROS InSTZ-induced Sprague Dawley rats the combined adminis-tration of honey (2 gkg body weight) and ginger (60mgkgbody weight) for three weeks significantly (119901 lt 005) re-duced the superoxide dismutase and catalase activities andthe malondialdehyde levels whereas the reduced glutathionelevel and the reduced glutathioneoxidized glutathione ratiowere significantly elevated (119901 lt 005) [129] In STZ-in-duced diabetic rats oral administration with the combinedextract of purple waxy corn and ginger at doses of 100 200and 300mgkg body weight for 21 days improved chronicconstriction at the right sciatic nerve by improving theoxidative stress status and the axon density in the lesion nerve[130] Ginger was also found to inhibit 120572-glucosidase and 120572-amylase enzymes which is useful for T2DM managementand inhibition of COX was observed which protects againstinflammation [131] The oral administration of ginger indiabetic rats was found to exert neuroprotective effects byincreasing antioxidant defense mechanisms and downregu-lating malondialdehyde (MDA) levels to the normal levelsin brain [132] In another similar study ginger administeredat a dose of 500mgkgday revealed a protective role ondiabetic brain accomplished by reducing oxidative stressapoptosis and inflammation in STZ-induced diabetic rats[133] According to another in vivo study the treatment ofSTZ-induced inbred male WistarNIN rats for one monthwith ginger powder (05 1 and 5) showed protectiveeffects against diabetes by modulating antioxidant enzymesand glutathione and downregulating lipid and protein oxi-dation [134] In nicotinamide and STZ-induced diabeticrats treatment with garlic bulb ginger rhizome turmericrhizome and their mixture (200mgkg body weight) for 28consecutive days significantly alleviated hyperglycemia anddyslipidemia increased insulin production enhanced GSHand decreased lipid peroxidation [135]

In diabetic patients diabetic encephalopathy is one ofthe more severe complications In diabetic encephalopathyrats saffron at 40 and 80mgkg significantly increased thebody weight and serum TNF-120572 levels and decreased the


blood glucose glycosylated proteins and advanced glycationend product (AGE) levels in serum Furthermore saffronsignificantly increased the glutathione content superoxidedismutase and catalase but remarkably decreased the cogni-tive deficit and serum TNF-120572 and it induced NOS activityin hippocampus tissue [136] In STZ-induced diabetic ratswith renal injury the administration of crocin an active con-stituent of saffron significantly decreased malondialdehyde(119901 lt 001) and xanthine oxidase (119901 lt 005) activities andelevated glutathione (119901 lt 005) levels thus amelioratingrenal injury [137] Safranal is one of the components ofthe saffron plant In high-fat diet (HFD) and STZ-inducedT2DM rats safranal treatment for a period of four weeksdecreased the oxidative stress caused by T2DM and reducedthe inflammation by reducing the TNF-120572 and IL-1120573 levels inthe plasma and pancreas tissue [138]

The protective effect of onion against oxidative stresswas evaluated in an in vivo study In STZ-induced malediabetic Wistar rats daily treatment with 1mL of Allium cepasolution (04 g Allium ceparat) increased the fasting serumhigh density lipoprotein levels and alleviated hyperglycemiaby decreasing superoxide dismutase activities [139] Anotherin vivo study also investigated the protective effects of onionagainst oxidative stress 12 weeks of onion intake suppressedthe diabetes-induced oxidative stressmore effectively in STZ-induced diabetic rats [140] In STZ-induced diabetic maleSprague Dawley rats supplementation with onion powder(7 ww) suppressed the glutathione peroxidase glutathionereductase and glutathione S-transferase activities from highto normal levels [141]

Mustard leaf (Brassica juncea) has been reported tostrongly inhibit the formation of AGE and free radical-mediated protein damage in in vitro studies According toan in vivo study with STZ-induced diabetic rats the oraladministration of the EtOAc fraction of mustard leaf at dosesof 50 and 200mgkg body weightday for 10 days reduced theserum levels of glucose and glycosylated protein as well as thesuperoxide and nitritenitrate levels which suggests that theEtOAc fraction of mustard leaf has the capacity to attenuatedamage caused by the oxidative stress involved in diabetesand its complications [142]

Sesame butter is a natural product produced by grind-ing sesame seeds and is thus free from any chemical ornonchemical additives In STZ-induced male albino Wistarrats oral treatment with sesame butter (125 gkg) for sixweeks significantly decreased the blood glucose high densitylipoprotein and malondialdehyde levels and increased thetotal antioxidant capacity [143] Sesame contains sesamina lignan that has been found to diminish the elevation ofmalondialdehyde and the reduction of superoxide dismutaseactivity induced by diabetes after seven weeks of treatment inmale diabetic rats [144]

Eugenol (EU) is an active principle of cloves (Syzygiumaromaticum) that can also be found in basil and cinnamonIn an in vitro study with SHSY5Y cells under experimen-tally induced hyperglycemic conditions the exposure ofcells to EU (5ndash10 120583M) improved cell viability reduced theglutathione (GSH) levels and significantly decreased theglucose-associated oxidative stress (by diminishing ROS and

peroxide levels) From the in vivo experiment on STZ-induced diabetic rats treatment with EU at a dose of10mgkg body weightday for six weeks diminished theoxidative marker levels GSH and total thiols and enhancedthe antioxidants activities [145] In high-fat-diet and STZ-induced T2DM rats the administration of clove bud pow-der (20ndash40 gkg) reduced the blood glucose level and 120572-glucosidase and liver enzyme (alanine aminotransferaseaspartate aminotransferase and alkaline phosphatase) activ-ities and elevated the antioxidant (glutathione ascorbic acidsuperoxide dismutase and catalase) levels [146]

Cumin (Cuminum cyminum) is widely used as a spicein many countries In STZ-induced diabetic rats treatmentwith a methanolic extract of C cyminum seeds for 28 dayseffectively controlled the oxidative stress inhibited AGEformation and improved the antioxidant status in the kidneyand pancreas [147]

5 Rheumatoid Arthritis

RA is an inflammatory systemic autoimmune disorderwith primary degenerating articular structures involving inparticular the cartilage (movable synovial joints of kneesshoulders and hands) and the bones (osteoarthritis andosteoporosis) as a result of pannus formation over the jointsurfaces (abnormal layer of fibrovascular or granulationtissues) [148 149] The symptoms include swelling warmthand redness of the joints with pain morning stiffness fatigueand limited functioning of the joints which can result in poorcoordination of the limbs and the deterioration of the posture[150 151]

RA is the most common inflammatory arthritis andaffects approximately 1 of the world population with morethan 3 million new patients being diagnosed yearly [152153] It has been reported that 80 of RA patients becomedisabled within 20 years of diagnosis and if left untreatedapproximately 20ndash30 of RA patients can be permanentlydisabled within 2-3 years of their first diagnosis [154 155] Inaddition women are three times more likely to be affectedthan men [156] According to a 2013 report one in everyfive adults (227) in the United States has been diagnosedwith arthritis [157] and the number of affected individualsis projected to increase to approximately 67 million by 2030[158] this is going to be an alarming health issue imposing agreat socioeconomic impact worldwide

51 Pathogenesis The pathogenesis of RA involves a com-plex interplay between genetic and environmental factorsleading to autoimmune inflammatory responses against theconnective and synovial tissues of the joints [3] In additionincreased ROS levels are actively involved in RA pathogenesis(Figure 1) [159 160] In typical physiological conditionsdifferent types of cytokines are actively present in synovialtissuesHowever in patients with RA immune cells includingT cells B cells and macrophages penetrate the affectedsynovial tissues and promote the overexpression releaseand activity of proinflammatory cytokines including TNF-120572 TNF-induced NF-120581B vascular endothelial growth factor(VEGF) IL-1 beta (IL-1120573) IL-6 IL-8 and IFN-120574 [3 161 162]


In response to these proinflammatory cytokines fibroblast-like synoviocytes (FLS) proliferate and produce large quan-tities of cytokines matrix metalloproteinases (MMPs) andCOX-2 which progressively degrade cartilage and lead tojoint destruction (Figure 1) [163 164]

Oxidative stress was recently shown to be involved inthe degeneration of cartilage due to the deregulation ofNrf2 or NFE2L2 [165] When Nrf2 is activated it bindsto antioxidant response elements (AREs) resulting in theincreased expression of antioxidative enzyme [eg Hemeoxygenase-1 (HO-1)] encoding genes [166 167] Thus bothoxidative stress and inflammatory processes are implicated inthe pathogenesis of RA

52 The Role of Dietary Phytochemicals Although syntheticregimens have been used to treat patients with RA side effectsare common and unavoidable (Table 1) Researchers havefound that the regular consumption of fresh fruits vegetablesand spices rich in important phytochemicals can attenuateoxidative stress and inflammation and relieve RA Accordingto some cohort studies on RA high consumption of fruitsand vegetables not only is inversely correlated with diseaseprogression but also exerts some protective effects against RA[168ndash170] Here we discuss some of the clinical (Table 2) andexperimental evidence of phytochemicals being successfullyused as alternative treatments against RA

521 Fruits and Vegetables Osteoclastogenesis (the processof destroying bone tissues by osteoclast cells) has beenobserved as a clinical phenomenon in patients with RA[171] Polyphenols extracted from dried plums can inhibitosteoclastogenesis by suppressing the activity of TNF-120572 andNO synthase and downregulating the transcription factor-nuclear factor for activated T cells (NFATc1) [172] Thereforepolyphenols have the potential to be used in RA treatment

Anthocyanins from cherry can reduce both oxidativestress (increase superoxide dismutase and decrease serummalondialdehyde) and inflammatory mediators (decrease inTNF-120572 levels) in an adjuvant-induced RA rat model (maleSprague Dawley) [173]

In 2015 resveratrol polyphenol found in red grape skinwas reported to confer a significant protective effect againstan aggressiveRA ratmodel [174] In the experiment the activ-ity of specific rheumatoid biomarkers [serum rheumatoidfactor (RF) MMP-3 and cartilage oligomeric matrix protein(COMP)] immunological biomarkers [IgG and antinuclearantibody (ANA)] immunomodulatory cytokines (TNF-120572)and oxidative stress biomarkers [myeloperoxidase (MPO)CRP and MDA] were significantly reduced by the anti-inflammatory and antioxidative activities of resveratrol

In an in vivo study with RA-induced DBA-1J male micemangiferin (a natural polyphenol found especially in man-goes) suppressed the expression of IL-1120573 IL-6 TNF-120572 andreceptor activator of NF-120581B ligand (RANKL) via the activa-tion of extracellular signal-regulated kinase 12 (ERK12) andthe inhibition of NF-120581B [175] Another study withmangiferindemonstrated protection against joint destruction in RAby exerting strong proapoptotic effects on human synovia-derived synoviocytes [176]

Recently Natarajan et al [177] showed the suitability ofusing intra-articular injections with polyphenols to protectagainst cartilage degradation in collagen-induced arthriticrats They injected a combination of different polyphenols(EGC gallate catechin tannic acid and quercetin) in RA-induced rats and observed significant (119901 lt 005) protectioneffect against cartilage degradation along with attenuatedinflammation

Kaempferol (found especially in grapefruits) was shownto inhibit synovial fibroblast proliferation by suppressinginflammatory cytokines (inhibiting IL-1120573) inhibiting thephosphorylation of ERK-12 p38 and JNK inhibiting theactivation of NF-120581B and reducing oxidative stress by inhibit-ing the production of MMPs COX-2 and PGE2 in RA-derived synovial fibroblasts [178] All of these cytokinestranscription factors cell signaling pathways and enzymesare established compounds in the pathogenesis of RA thatin combination destroy the articular bone and cartilage inpatients with RA [179 180]

An in vivo study on p-coumaric acid (a polyphenolpresent in grapes apples oranges spinach tomatoes pota-toes wheat oats and maize) confirmed its potent immuno-suppressive activity because it significantly (119901 lt 005) re-duced the expression of TNF-120572 in adjuvant-induced arthriticrats [181] In a collagen-induced RA rat model (femaleSprague Dawley) genistein (a polyphenol rich in soybeans)exerted anti-inflammatory activities it maintained a balancebetween the T helper cell-1 (Th1) andTh2 cells by significantlysuppressing IFN-120574 and augmenting the production of IL-4[182]

Pattison et al [183] reported that the modest intake ofbeta-cryptoxanthin (a natural carotenoid) via the daily con-sumption of a glass of freshly squeezed orange juice isinversely correlated with the risk of RA in humans Addition-ally arterial dysfunction is a common clinical manifestationin patientswithRA that leads to cardiovascular complications[184 185] Nevertheless daily vegetable consumption wassignificantly (119901 = 0002) associated with more favorablearterial function in patients with RA [186]

522 Spices An in vivo study [187] revealed the beneficialeffects of using a mixture of blended ginger which is richin pungent phenolic compounds (eg shogaols and gin-gerols) and turmeric which is rich in phenolic curcum-inoids (including curcumin bisdemethoxycurcumin anddemethoxycurcumin) against extra-articular complicationsof RA including hematological metabolic and cardiovas-cular complications in adjuvant-induced arthritic rats (maleWistar albino) Earlier the same group of researchers con-firmed that both ginger and turmeric could independentlyand significantly (119901 lt 005) protect against RA in adjuvant-induced arthritic male Wistar albino rats [188]

Cinnamon bark (Cinnamomum zeylanicum) one of themost common spices used in Indian Bangladeshi Burmeseand Sri Lankan dishes can confer some protective effectsagainst RA Rathi et al [189] observed a significantly (119901 lt0001) higher level of anti-inflammatory activities [inhibitionof cytokines (IL-2 IL-4 and IFN-120574) and reduction of TNF-120572 concentration] upon the treatment of RA animal models


(male Wistar rat and Swiss albino mice) with the polypheno-lic fractions of cinnamon bark

An in vitro study with FLS (derived from RA patients)demonstrated that curcumin is a potent anti-inflammatoryspice [190] that blocks the expression of IL-1120573 and IL-6 whichare believed to play crucial roles in RA pathogenesis [191]Elevated apoptosis within the joint is therapeutically useful[192] and curcumin has been found to increase the levels ofapoptosis in rheumatic FLS [190]

Methotrexate is an antirheumatic drug widely used totreat patients with RA [193] Vascular endothelial dysfunctionhas been reported as one of its most deleterious side effectsdue to its ability to increase oxidative stress and decreaseNO levels [194]The coadministration of curcumin with folicacid was found to abrogate methotrexate-induced vascularendothelial dysfunctions in male Wistar rats due to theattenuation of oxidative stress and the regulation of NOproduction [195]

Another recent in vivo study on male Sprague Dawleyrats [196] revealed that the administration of curcumincould decrease the expression of NF-120581B TNF-120572 and IL-1120573 in both synovial fluid and blood serum thus producingeffects similar to a standard antirheumatic regimen withmethotrexateTherefore it is anticipated that curcumin couldbe given as antirheumatic therapy for patients with RA eitheradministered alone or as an adjuvant with modern therapies

523 Miscellaneous Extra virgin olive oil (EVOO) is con-sumed all over the world especially in the Mediterraneancountries [197] In 2014 [198] a group of Spanish researchersobserved that polyphenolic extracts of EVOOare potent anti-inflammatory substances protecting against RA-associatedinflammation An in vivo experiment conducted witha group (119899 = 10) of collagen-induced RA mice (maleDBA-1J) confirmed that polyphenolic extracts of EVOOinhibit JNK (associated with the regulation of cytokinefunction T-cell differentiation and apoptosis) p38 [involvedin mitogen-activated protein kinase (MAPK) pathway reg-ulating cytokines and apoptosis] and signal transducerand activator of transcription-3 (STAT-3) and decrease thetranslocation of NF-120581B Interestingly the activation of JNKp38 and NF-120581B and the overexpression of STAT-3 activelycontribute to the pathogenesis of RA [180 199 200] There-fore EVOO is a potential natural source of polyphenols thatcan combat RA

A recent experiment in 2015 [201] with a green tea-derived polyphenolic compound called epigallocatechin-3-gallate (EGCG) demonstrated that EGCG significantly (119901 lt001) upregulates the expression of the Nrf-2 antioxidantpathway in mice (male DBA-1J) with RA Yoon et al [202]observed in FLS that gallic acid (a polyphenol found ingrapes tea gall nuts sumac and wine) reduced the expres-sion levels of proinflammatory cytokines (IL-1120573 and IL-6) andenzymes including MMP-9 and COX-2 which are involvedin the inflammation and oxidation-induced pathogenesis ofRA However the black tea-derived polyphenol theaflavin-331015840-digallate (TFDG) demonstrated some protective activityagainst osteoclast formation and osteoporosis via the inhibi-tion of MMP-2 and MMP-9 both of which are responsible

for the degradation of collagens and joint destruction in RApatients [203 204]

An in vivo study with cocoa-extracted polyphenolsreported the suppression of TNF-120572-induced VEGF expres-sion (involved in RA) via the inhibition of phosphoinositide3-kinase (PI3 K) and MAPK kinase-1 (MAP2K1) activi-ties Grape polyphenolic extracts have been confirmed tohave potent anti-inflammatory activity against RA-mediatedinflammation by attenuating the expression of TNF-120572 IL1120573IL-6 and IFN-120574 and they can reduce the ldquoarthritis scorerdquo inexperimental rats [205]

In LPS-stimulated macrophages the secretion of IL-6(found at elevated levels in patients with RA)was significantlyreduced (by at least 25) upon incubation with polyphenol-rich extracts of rooibos tea black pepper ginger allspice car-away bay leaves cinnamon licorice paprika clove nutmegand apples [206] In addition decreased TNF-120572 secretion(by at least 25) was observed upon incubation with chilipepper black pepper cinnamon bay leaf caraway licoricenutmeg and bilberry extracts containing high concentrationsof polyphenols [206]

6 Conclusion

Dietary phytochemicals are some of the most potentialnatural sources for developing novel drugs with improvedefficiency efficacy and safety Well-designed clinical trialsare warranted to address the safety issues and the con-current utility of synthetic drugs and natural compoundsin attenuating oxidative stress and inflammation-mediateddegenerative diseases such as RA DM and CVD In in vitroand in vivo or ex vivo experiments more emphasis shouldbe given to studies with active compounds extracted fromnatural mixtures of phytochemicals In addition it wouldbe interesting to conduct computational in silico analysesto determine compatible phytochemicals targeting the activesites of regulatory proteins associated with CVDs DM andRA to promote the development of safer and more effectivedrugs

Appendix

Search Strategy

To find appropriate literature the following terms were usedin combination with Boolean operators (AND and OR)

Search 1 (Fruits) (apple OR apricot OR applesauce ORavocado OR banana OR blackberries OR blueberries ORcantaloupe OR cherries OR dates OR dried fruits OR figsOR fruits OR fruit cocktail OR grapefruits OR grapes ORhoneydew OR melon OR kiwi OR mango OR oranges ORpapaya OR peaches OR pears OR pineapple OR plum ORraspberries OR strawberries OR watermelon)

Search 2 (Vegetables) (amaranth OR Chinese spinach ORartichoke OR artichoke hearts OR asparagus OR baby cornOR bamboo shoots OR bean sprouts OR beets OR Brusselssprouts OR Broccoli OR green cabbage OR Chinese cabbage


OR bok choy cabbage OR Italian beans OR green beans ORwax beans OR bean OR cabbage OR carrot OR cauliflowerOR celery OR cucumber OR chayote OR daikonOR eggplantOR garlic OR ginger OR hearts of palm OR jicama ORkohlrabiOR leeksORmushroomsORonionORokraORpeapods OR peppers OR radish OR pepper OR black pepper ORred chillsOR green chili OR rutabagaOR chicoryOR escaroleOR endive OR lettuce OR romaine OR arugula OR tomatoesOR Swiss chard OR spinach OR watercress OR turnip ORmustard OR collard OR sprouts OR radicchio OR peas ORturnips OR vegetables OR yard-long beans)

Search 3 (Spices) (adobo seasoning OR allspice OR aniseseed OR apple pie spice OR bay leaf OR cardamom seed ORcayenneOR chili peppersOR cinnamonOR clovesOR cuminOR curry powder OR fennel seed OR fenugreek seed ORfive spice OR garam masala OR garlic OR ginger OR herbseasoning OR mace OR mustard OR nutmeg OR onion ORpaprika OR peppercorns OR saffronOR sesameOR spice ORstar anise OR thyme leaf OR turmeric)

Search 4 (Phytochemicals) (antioxidants OR polyphenolsOR carotenoids OR anthocyanins OR alkaloids OR glyco-sides OR saponins OR terpenes)

Search 5 (Search 1 OR Search 2 OR Search 3 OR Search4)

Search 6 (DegenerativeDiseases and Factors) Cardiovasculardiseases OR diabetes OR rheumatoid arthritis OR inflam-mation OR proinflammatory markers OR inflammatory ORoxidative stress OR reactive oxygen species

Search 7 (Search 5) AND (Search 6)

Competing Interests

The authors declare that there are no competing interests

Authorsrsquo Contributions

Md Asiful Islam and Fahmida Alam are equal contributors

Acknowledgments

The authors would like to acknowledge the Universiti SainsMalaysia (USM) Vice-Chancellor Award (20152016) and theUSM Global Fellowship (20142015) awarded to Md AsifulIslam and Fahmida Alam respectively to pursue their PhDdegrees

References

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[2] A O Odegaard D R Jacobs O A Sanchez D C Goff AP Reiner and M D Gross ldquoOxidative stress inflammation

endothelial dysfunction and incidence of type 2 diabetesrdquoCardiovascular Diabetology vol 15 no 1 pp 1ndash12 2016

[3] I B McInnes and G Schett ldquoThe pathogenesis of rheumatoidarthritisrdquoTheNew England Journal of Medicine vol 365 no 23pp 2205ndash2219 2011

[4] D Mozaffarian E J Benjamin A S Go et al ldquoExecutive sum-mary heart disease and stroke statisticsmdash2016 update a reportfrom the American Heart Associationrdquo Circulation vol 133 no4 pp 447ndash454 2016

[5] J W Beulens D E Grobbee and B Nealb ldquoThe global burdenof diabetes and its complications an emerging pandemicrdquoEuropean Journal of Cardiovascular PreventionampRehabilitationvol 17 no 1 supplement pp s3ndashs8 2010

[6] B C Wang P Hsu W Furnback et al ldquoEstimating the eco-nomic burden of rheumatoid arthritis in Taiwan using thenational health insurance databaserdquo DrugsmdashReal World Out-comes vol 3 no 1 pp 107ndash114 2016

[7] P Alagona and T A Ahmad ldquoCardiovascular disease riskassessment and prevention current guidelines and limitationsrdquoMedical Clinics of NorthAmerica vol 99 no 4 pp 711ndash731 2015

[8] G R Kokil R N Veedu G A Ramm J B Prins and H SParekh ldquoType 2 diabetes mellitus limitations of conventionaltherapies and intervention with nucleic acid-based therapeu-ticsrdquo Chemical Reviews vol 115 no 11 pp 4719ndash4743 2015

[9] K Albrecht and U Muller-Ladner ldquoSide effects and manage-ment of side effects of methotrexate in rheumatoid arthritisrdquoClinical and Experimental Rheumatology vol 28 no 5 supple-ment 61 pp S95ndashS101 2010

[10] R Fischer and O Maier ldquoInterrelation of oxidative stressand inflammation in neurodegenerative disease role of TNFrdquoOxidative Medicine and Cellular Longevity vol 2015 Article ID610813 18 pages 2015

[11] B Uttara A V Singh P Zamboni and R T Mahajan ldquoOxida-tive stress and neurodegenerative diseases a review of upstreamand downstream antioxidant therapeutic optionsrdquo CurrentNeuropharmacology vol 7 no 1 pp 65ndash74 2009

[12] B B Aggarwal S Krishnan and S Guha InflammationLifestyle and Chronic Diseases The Silent Link CRC Press NewYork NY USA 2011

[13] E Ignatowicz and W Baer-Dubowska ldquoResveratrol a naturalchemopreventive agent against degenerative diseasesrdquo PolishJournal of Pharmacology and Pharmacy vol 53 no 6 pp 557ndash569 2001

[14] S Ojha A Kurdi B Sadek et al ldquoPhytochemicals as prototypesfor pharmaceutical leads towards drug development againstdiabetic cardiomyopathyrdquo Current Pharmaceutical Design vol22 no 20 pp 3058ndash3070 2016

[15] MA Islam F AlamM I Khalil TH Sasongko and SHGanldquoNatural products towards the discovery of potential futureantithrombotic drugsrdquo Current Pharmaceutical Design vol 22no 20 pp 2926ndash2946 2016

[16] F Alam M A Islam S H Gan and M I Khalil ldquoHoneya potential therapeutic agent for managing diabetic woundsrdquoEvidence-Based Complementary and Alternative Medicine vol2014 Article ID 169130 16 pages 2014

[17] M A Winkleby D E Jatulis E Frank and S P FortmannldquoSocioeconomic status and health how education income andoccupation contribute to risk factors for cardiovascular diseaserdquoAmerican Journal of Public Health vol 82 no 6 pp 816ndash8201992


[18] P W Franks R L Hanson W C Knowler M L SieversP H Bennett and H C Looker ldquoChildhood obesity othercardiovascular risk factors and premature deathrdquo The NewEngland Journal of Medicine vol 362 no 6 pp 485ndash493 2010

[19] World Health Organization ldquoAtlas of heart disease and stroke2015rdquo 2015 httpwwwwhointcardiovascular diseasesre-sourcesatlasen

[20] R B Singh S A Mengi Y-J Xu A S Arneja and N SDhalla ldquoPathogenesis of atherosclerosis a multifactorial pro-cessrdquo Experimental and Clinical Cardiology vol 7 no 1 pp 40ndash53 2002

[21] D Wood ldquoEstablished and emerging cardiovascular risk fac-torsrdquo American Heart Journal vol 141 supplement 2 pp S49ndashS57 2001

[22] N V Goncharov P V Avdonin A D Nadeev I L Zharkikhand R O Jenkins ldquoReactive oxygen species in pathogenesis ofatherosclerosisrdquo Current Pharmaceutical Design vol 21 no 9pp 1134ndash1146 2015

[23] K S McCully ldquoHomocysteine and the pathogenesis of athero-sclerosisrdquo Expert Review of Clinical Pharmacology vol 8 no 2pp 211ndash219 2015

[24] RAHegele ldquoThegenetic basis of atherosclerosisrdquo InternationalJournal of Clinical and Laboratory Research vol 27 no 1 pp 2ndash13 1997

[25] C S Booker and J I Mann ldquoTrans fatty acids and cardio-vascular health translation of the evidence baserdquo NutritionMetabolism and Cardiovascular Diseases vol 18 no 6 pp 448ndash456 2008

[26] C Chrysohoou D B Panagiotakos C Pitsavos et al ldquoTheassociations between smoking physical activity dietary habitsand plasma homocysteine levels in cardiovascular disease-freepeople the lsquoATTICArsquo studyrdquoVascular Medicine vol 9 no 2 pp117ndash123 2004

[27] R Takachi M Inoue J Ishihara et al ldquoFruit and vegetableintake and risk of total cancer and cardiovascular diseaseJapan Public Health Center-based Prospective studyrdquoAmericanJournal of Epidemiology vol 167 no 1 pp 59ndash70 2008

[28] XWang Y Ouyang J Liu et al ldquoFruit and vegetable consump-tion and mortality from all causes cardiovascular disease andcancer systematic review and dose-response meta-analysis ofprospective cohort studiesrdquo British Medical Journal vol 349Article ID g4490 pp 1ndash14 2014

[29] X Gao O I Bermudez and K L Tucker ldquoPlasma C-reactiveprotein and homocysteine concentrations are related to fre-quent fruit and vegetable intake in Hispanic and non-Hispanicwhite eldersrdquo Journal of Nutrition vol 134 no 4 pp 913ndash9182004

[30] H Du L Li D Bennett et al ldquoFresh fruit consumption andmajor cardiovascular disease in Chinardquo The New EnglandJournal of Medicine vol 374 no 14 pp 1332ndash1343 2016

[31] P vanrsquot Veer M C Jansen M Klerk and F J Kok ldquoFruitsand vegetables in the prevention of cancer and cardiovasculardiseaserdquo Public Health Nutrition vol 3 no 1 pp 103ndash107 2000

[32] Y Nagasako-Akazome T Kanda Y Ohtake H Shimasakiand T Kobayashi ldquoApple polyphenols influence cholesterolmetabolism in healthy subjects with relatively high body massindexrdquo Journal of Oleo Science vol 56 no 8 pp 417ndash428 2007

[33] X Yin J Quan and T Kanazawa ldquoBanana prevents plasmaoxidative stress in healthy individualsrdquo Plant Foods for HumanNutrition vol 63 no 2 pp 71ndash76 2008

[34] A Basu M Du M J Leyva et al ldquoBlueberries decreasecardiovascular risk factors in obese men and women withmetabolic syndromerdquo The Journal of Nutrition vol 140 no 9pp 1582ndash1587 2010

[35] A Basu M Rhone and T J Lyons ldquoBerries emerging impacton cardiovascular healthrdquo Nutrition Reviews vol 68 no 3 pp168ndash177 2010

[36] I Erlund R Koli G Alfthan et al ldquoFavorable effects of berryconsumption on platelet function blood pressure and HDLcholesterolrdquoThe American Journal of Clinical Nutrition vol 87no 2 pp 323ndash331 2008

[37] J Y Toh VMH Tan P C Y Lim S T Lim andM F F ChongldquoFlavonoids from fruit and vegetables a focus on cardiovascularrisk factorsrdquo Current Atherosclerosis Reports vol 15 no 12article 368 pp 1ndash7 2013

[38] C Morand C Dubray D Milenkovic et al ldquoHesperidincontributes to the vascular protective effects of orange juice arandomized crossover study in healthy volunteersrdquo AmericanJournal of Clinical Nutrition vol 93 no 1 pp 73ndash80 2011

[39] S Rizza R Muniyappa M Iantorno et al ldquoCitrus polyphenolhesperidin stimulates production of nitric oxide in endothe-lial cells while improving endothelial function and reducinginflammatory markers in patients with metabolic syndromerdquoThe Journal of Clinical Endocrinology ampMetabolism vol 96 no5 pp E782ndashE792 2011

[40] S Gorinstein A Caspi I Libman et al ldquoRed grapefruit pos-itively influences serum triglyceride level in patients sufferingfrom coronary atherosclerosis studies in vitro and in humansrdquoJournal of Agricultural and Food Chemistry vol 54 no 5 pp1887ndash1892 2006

[41] T Ismail P Sestili and S Akhtar ldquoPomegranate peel andfruit extracts a review of potential anti-inflammatory and anti-infective effectsrdquo Journal of Ethnopharmacology vol 143 no 2pp 397ndash405 2012

[42] C B Stowe ldquoThe effects of pomegranate juice consumptionon blood pressure and cardiovascular healthrdquo ComplementaryTherapies in Clinical Practice vol 17 no 2 pp 113ndash115 2011

[43] G Noratto H S D Martino S Simbo D Byrne and S UMertens-Talcott ldquoConsumption of polyphenol-rich peach andplum juice prevents risk factors for obesity-related metabolicdisorders and cardiovascular disease in Zucker ratsrdquo Journal ofNutritional Biochemistry vol 26 no 6 pp 633ndash641 2015

[44] M Y Hong N Hartig K Kaufman S Hooshmand AFigueroa and M Kern ldquoWatermelon consumption improvesinflammation and antioxidant capacity in rats fed an athero-genic dietrdquo Nutrition Research vol 35 no 3 pp 251ndash258 2015

[45] T CWallace ldquoAnthocyanins in cardiovascular diseaserdquoAdvan-ces in Nutrition vol 2 no 1 pp 1ndash7 2011

[46] M A Vazquez-Prieto and R M Miatello ldquoOrganosulfur com-pounds and cardiovascular diseaserdquo Molecular Aspects ofMedicine vol 31 no 6 pp 540ndash545 2010

[47] H S Chang O Yamato M Yamasaki and Y Maede ldquoModula-tory influence of sodium 2-propenyl thiosulfate from garlic oncyclooxygenase activity in canine platelets possible mechanismfor the anti-aggregatory effectrdquo Prostaglandins Leukotrienes andEssential Fatty Acids vol 72 no 5 pp 351ndash355 2005

[48] J Terao Y Kawai andKMurota ldquoVegetable flavonoids and car-diovascular diseaserdquo Asia Pacific Journal of Clinical Nutritionvol 17 supplement 1 pp 291ndash293 2008

[49] C P Bondonno X Yang K D Croft et al ldquoFlavonoid-richapples and nitrate-rich spinach augment nitric oxide status and


improve endothelial function in healthy men and women arandomized controlled trialrdquo Free Radical Biology amp Medicinevol 52 no 1 pp 95ndash102 2012

[50] S Auclair G Chironi D Milenkovic et al ldquoThe regularconsumption of a polyphenol-rich apple does not influenceendothelial function a randomised double-blind trial in hyper-cholesterolemic adultsrdquo European Journal of Clinical Nutritionvol 64 no 10 pp 1158ndash1165 2010

[51] P Valderas-Martinez G Chiva-Blanch R Casas et al ldquoTomatosauce enriched with olive oil exerts greater effects on cardiovas-cular disease risk factors than raw tomato and tomato sauce arandomized trialrdquo Nutrients vol 8 no 3 article 170 2016

[52] F Squadrito D Altavilla A Crisafulli et al ldquoEffect of genisteinon endothelial function in postmenopausal women a random-ized double-blind controlled studyrdquo The American Journal ofMedicine vol 114 no 6 pp 470ndash476 2003

[53] S Egert A Bosy-Westphal J Seiberl et al ldquoQuercetin reducessystolic blood pressure and plasma oxidised low-densitylipoprotein concentrations in overweight subjects with ahigh-cardiovascular disease risk phenotype a double-blindedplacebo-controlled cross-over studyrdquo British Journal of Nutri-tion vol 102 no 7 pp 1065ndash1074 2009

[54] S S Hassellund A Flaa S E Kjeldsen et al ldquoEffects ofanthocyanins on cardiovascular risk factors and inflammationin pre-hypertensive men a double-blind randomized placebo-controlled crossover studyrdquo Journal of Human Hypertensionvol 27 no 2 pp 100ndash106 2013

[55] S Kianbakht B Abasi and F Hashem Dabaghian ldquoImprovedlipid profile in hyperlipidemic patients taking Vaccinium arc-tostaphylos fruit hydroalcoholic extract a randomized double-blind placebo-controlled clinical trialrdquo Phytotherapy Researchvol 28 no 3 pp 432ndash436 2014

[56] R Soltani M Hakimi S Asgary SM GhanadianM Keshvariand N Sarrafzadegan ldquoEvaluation of the effects of Vacciniumarctostaphylos L fruit extract on serum lipids and hs-CRPlevels and oxidative stress in adult patients with hyperlipidemiaa randomized double-blind placebo-controlled clinical trialrdquoEvidence-Based Complementary and Alternative Medicine vol2014 Article ID 217451 6 pages 2014

[57] D Taubert R Roesen C Lehmann N Jung and E SchomigldquoEffects of low habitual cocoa intake on blood pressure andbioactive nitric oxide a randomized controlled trialrdquo TheJournal of the American Medical Association vol 298 no 1 pp49ndash60 2007

[58] Z Faridi V Y Njike S Dutta A Ali and D L Katz ldquoAcutedark chocolate and cocoa ingestion and endothelial function arandomized controlled crossover trialrdquoTheAmerican Journal ofClinical Nutrition vol 88 no 1 pp 58ndash63 2008

[59] N M K Selvi M G Sridhar R P Swaminathan and RSripradha ldquoEfficacy of turmeric as adjuvant therapy in type 2diabetic patientsrdquo Indian Journal of Clinical Biochemistry vol30 no 2 pp 180ndash186 2015

[60] T Arablou N Aryaeian M Valizadeh F Sharifi A Hosseiniand M Djalali ldquoThe effect of ginger consumption on glycemicstatus lipid profile and some inflammatory markers in patientswith type 2 diabetes mellitusrdquo International Journal of FoodSciences and Nutrition vol 65 no 4 pp 515ndash520 2014

[61] J Tome-Carneiro M Larrosa M J Yanez-Gascon et al ldquoOne-year supplementation with a grape extract containing resvera-trolmodulates inflammatory-relatedmicroRNAs and cytokines

expression in peripheral blood mononuclear cells of type 2 dia-betes and hypertensive patients with coronary artery diseaserdquoPharmacological Research vol 72 pp 69ndash82 2013

[62] S Moazen R Amani A Homayouni Rad H Shahbazian KAhmadi and M Taha Jalali ldquoEffects of freeze-dried strawberrysupplementation on metabolic biomarkers of atherosclerosisin subjects with type 2 diabetes a randomized double-blindcontrolled trialrdquo Annals of Nutrition and Metabolism vol 63no 3 pp 256ndash264 2013

[63] S Mahluji A Ostadrahimi M Mobasseri V E Attari andL Payahoo ldquoAnti-inflammatory effects of Zingiber officinale intype 2 diabetic patientsrdquoAdvanced Pharmaceutical Bulletin vol3 no 2 pp 273ndash276 2013

[64] Z Bahadoran P Mirmiran F Hosseinpanah M HedayatiS Hosseinpour-Niazi and F Azizi ldquoBroccoli sprouts reduceoxidative stress in type 2 diabetes a randomized double-blindclinical trialrdquo European Journal of Clinical Nutrition vol 65 no8 pp 972ndash977 2011

[65] P Kar D Laight H K Rooprai KM Shaw andM CummingsldquoEffects of grape seed extract in Type 2 diabetic subjects athigh cardiovascular risk a double blind randomized placebocontrolled trial examining metabolic markers vascular toneinflammation oxidative stress and insulin sensitivityrdquo DiabeticMedicine vol 26 no 5 pp 526ndash531 2009

[66] B Chandran and A Goel ldquoA randomized pilot study to assessthe efficacy and safety of curcumin in patients with activerheumatoid arthritisrdquo Phytotherapy Research vol 26 no 11 pp1719ndash1725 2012

[67] S-C Bae W-J Jung E-J Lee R Yu and M-K Sung ldquoEffectsof antioxidant supplements intervention on the level of plasmainflammatory molecules and disease severity of rheumatoidarthritis patientsrdquo Journal of the American College of Nutritionvol 28 no 1 pp 56ndash62 2009

[68] C M Bitler K Matt M Irving et al ldquoOlive extract supplementdecreases pain and improves daily activities in adults withosteoarthritis and decreases plasma homocysteine in those withrheumatoid arthritisrdquoNutrition Research vol 27 no 8 pp 470ndash477 2007

[69] A Upaganlawar V Patel and R Balaraman ldquoTomato lycopeneattenuates myocardial infarction induced by isoproterenolelectrocardiographic biochemical and anti-apoptotic studyrdquoAsian Pacific Journal of Tropical Biomedicine vol 2 no 5 pp345ndash351 2012

[70] B L B Pereira F C O Arruda P P Reis et al ldquoTomato(Lycopersicon esculentum) supplementation induces changes incardiac miRNA expression reduces oxidative stress and leftventricular mass and improves diastolic functionrdquo Nutrientsvol 7 no 11 pp 9640ndash9649 2015

[71] H D Sesso S Liu J M Gaziano and J E Buring ldquoDietarylycopene tomato-based food products and cardiovascular dis-ease in womenrdquo Journal of Nutrition vol 133 no 7 pp 2336ndash2341 2003

[72] R Grzanna L Lindmark and C G Frondoza ldquoGingermdashanherbal medicinal product with broad anti-inflammatory ac-tionsrdquo Journal of Medicinal Food vol 8 no 2 pp 125ndash132 2005

[73] MThomson K K Al-Qattan S M Al-SawanM A AlnaqeebI Khan andMAli ldquoTheuse of ginger (Zingiber officinaleRosc)as a potential anti-inflammatory and antithrombotic agentrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 67no 6 pp 475ndash478 2002

[74] R S Ahmed V Seth and B D Banerjee ldquoInfluence of dietaryginger (Zingiber officinales Rosc) on antioxidant defense system


in rat Comparison with ascorbic acidrdquo Indian Journal ofExperimental Biology vol 38 no 6 pp 604ndash606 2000

[75] A Bordia S K Verma and K C Srivastava ldquoEffect of ginger(Zingiber officinale Rosc) and fenugreek (Trigonella foenum-graecum L) on blood lipids blood sugar and platelet aggrega-tion in patients with coronary artery diseaserdquo ProstaglandinsLeukotrienes and Essential Fatty Acids vol 56 no 5 pp 379ndash384 1997

[76] M Kobayashi Y Ishida N Shoji and Y Ohizumi ldquoCardiotonicaction of [8]-gingerol an activator of the Ca++-pumpingadenosine triphosphatase of sarcoplasmic reticulum in guineapig atrial musclerdquo Journal of Pharmacology and ExperimentalTherapeutics vol 246 no 2 pp 667ndash673 1988

[77] M N Ghayur and A H Gilani ldquoGinger lowers blood pressurethrough blockade of voltage-dependent calcium channelsrdquoJournal of Cardiovascular Pharmacology vol 45 no 1 pp 74ndash80 2005

[78] B Fuhrman M Rosenblat T Hayek R Coleman and MAviram ldquoGinger extract consumption reduces plasma choles-terol inhibits LDL oxidation and attenuates development ofatherosclerosis in atherosclerotic apolipoprotein E-deficientmicerdquo Journal of Nutrition vol 130 no 5 pp 1124ndash1131 2000

[79] A S Wakade A S Shah M P Kulkarni and A R JuvekarldquoProtective effect of Piper longum L on oxidative stress inducedinjury and cellular abnormality in adriamycin induced car-diotoxicity in ratsrdquo Indian Journal of Experimental Biology vol46 no 7 pp 528ndash533 2008

[80] R S Vijayakumar D Surya R Senthilkumar and N NalinildquoHypolipidemic effect of black pepper (Piper nigrum Linn)in Rats fed high fat dietrdquo Journal of Clinical Biochemistry andNutrition vol 32 pp 31ndash42 2002

[81] S Joukar H Najafipour M Khaksari et al ldquoThe effect ofsaffron consumption on biochemical and histopathologicalheart indices of rats withmyocardial infarctionrdquoCardiovascularToxicology vol 10 no 1 pp 66ndash71 2010

[82] R Mehdizadeh M-R Parizadeh A-R Khooei S Mehri andH Hosseinzadeh ldquoCardioprotective effect of saffron extractand safranal in isoproterenol-induced myocardial infarction inwistar ratsrdquo Iranian Journal of BasicMedical Sciences vol 16 no1 pp 56ndash63 2013

[83] G K Jayaprakasha L J M Rao and K K Sakariah ldquoVolatileconstituents from Cinnamomum zeylanicum fruit stalks andtheir antioxidant activitiesrdquo Journal of Agricultural and FoodChemistry vol 51 no 15 pp 4344ndash4348 2003

[84] Z-M Wang B Zhou Y-S Wang et al ldquoBlack and green teaconsumption and the risk of coronary artery disease a meta-analysisrdquoTheAmerican Journal of Clinical Nutrition vol 93 no3 pp 506ndash515 2011

[85] B Buijsse E J M Feskens F J Kok and D KromhoutldquoCocoa intake blood pressure and cardiovascular mortalitythe Zutphen Elderly Studyrdquo Archives of Internal Medicine vol166 no 4 pp 411ndash417 2006

[86] L Hooper C Kay A Abdelhamid et al ldquoEffects of chocolatecocoa and flavan-3-ols on cardiovascular health a systematicreview and meta-analysis of randomized trialsrdquo AmericanJournal of Clinical Nutrition vol 95 no 3 pp 740ndash751 2012

[87] R Corti A J Flammer N K Hollenberg and T F LuscherldquoCocoa and cardiovascular healthrdquo Circulation vol 119 no 10pp 1433ndash1441 2009

[88] L Jia X Liu Y Y Bai et al ldquoShort-term effect of cocoa productconsumption on lipid profile a meta-analysis of randomized

controlled trialsrdquo The American Journal of Clinical Nutritionvol 92 no 1 pp 218ndash225 2010

[89] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 37 supplement 1 ppS81ndashS90 2013

[90] F Alam M A Islam M I Khalil and S H Gan ldquoMetaboliccontrol of type 2 diabetes by targeting the GLUT4 glucosetransporter intervention approachesrdquo Current PharmaceuticalDesign vol 22 no 20 pp 3034ndash3049 2016

[91] B B Kahn ldquoType 2 diabetes when insulin secretion fails tocompensate for insulin resistancerdquo Cell vol 92 no 5 pp 593ndash596 1998

[92] M Y Donath ldquoTargeting inflammation in the treatment of type2 diabetes time to startrdquoNature Reviews DrugDiscovery vol 13no 6 pp 465ndash476 2014

[93] L Guariguata D R Whiting I Hambleton J Beagley ULinnenkamp and J E Shaw ldquoGlobal estimates of diabetesprevalence for 2013 and projections for 2035rdquoDiabetes Researchand Clinical Practice vol 103 no 2 pp 137ndash149 2014

[94] J C Pickup ldquoInflammation and activated innate immunity inthe pathogenesis of type 2 diabetesrdquo Diabetes Care vol 27 no3 pp 813ndash823 2004

[95] S E Shoelson J Lee and A B Goldfine ldquoInflammation andinsulin resistancerdquoThe Journal of Clinical Investigation vol 116no 7 pp 1793ndash1801 2006

[96] E D Werner J Lee L Hansen M Yuan and S E ShoelsonldquoInsulin resistance due to phosphorylation of insulin receptorsubstrate-1 at serine 302rdquo The Journal of Biological Chemistryvol 279 no 34 pp 35298ndash35305 2004

[97] Y Zick ldquoSerThr phosphorylation of IRS proteins a molecularbasis for insulin resistancerdquo Science Signaling vol 2005 no 268article pe4 2005

[98] D Cai M Yuan D F Frantz et al ldquoLocal and systemic insulinresistance resulting from hepatic activation of IKK-120573 and NF-120581Brdquo Nature Medicine vol 11 no 2 pp 183ndash190 2005

[99] U Asmat K Abad and K Ismail ldquoDiabetes mellitus and oxida-tive stressmdasha concise reviewrdquo Saudi Pharmaceutical Journal2015

[100] M Solayman Y Ali F Alam et al ldquoPolyphenols potentialfuture arsenals in the treatment of diabetesrdquo Current Pharma-ceutical Design vol 22 no 5 pp 549ndash565 2016

[101] D J Betteridge ldquoWhat is oxidative stressrdquoMetabolism vol 49no 2 pp 3ndash8 2000

[102] A N Murunga D O Miruka C Driver F S Nkomo S ZCobongela and P M Owira ldquoGrapefruit derived flavonoidnaringin improves ketoacidosis and lipid peroxidation in type1 diabetes rat modelrdquo PLoS ONE vol 11 no 4 Article IDe0153241 pp 1ndash16 2016

[103] A K Sharma S Bharti S Ojha et al ldquoUp-regulation of PPAR120574heat shock protein-27 and-72 by naringin attenuates insulinresistance 120573-cell dysfunction hepatic steatosis and kidneydamage in a rat model of type 2 diabetesrdquo British Journal ofNutrition vol 106 no 11 pp 1713ndash1723 2011

[104] C-C Chang C-Y Chang J-P Huang and L-M Hung ldquoEffectof resveratrol on oxidative and inflammatory stress in liver andspleen of streptozotocin-induced type 1 diabetic ratsrdquo ChineseJournal of Physiology vol 55 no 3 pp 192ndash201 2012

[105] S Sekhon-Loodu Ziaullah and H P V Rupasinghe ldquoDocosa-hexaenoic acid ester of phloridzin inhibit lipopolysaccharide-induced inflammation in THP-1 differentiated macrophagesrdquoInternational Immunopharmacology vol 25 no 1 pp 199ndash2062015


[106] M A Martın E Fernandez-Millan S Ramos L Bravo andL Goya ldquoCocoa flavonoid epicatechin protects pancreatic betacell viability and function against oxidative stressrdquo MolecularNutrition amp Food Research vol 58 no 3 pp 447ndash456 2014

[107] S Banihani S Swedan and Z Alguraan ldquoPomegranate andtype 2 diabetesrdquo Nutrition Research vol 33 no 5 pp 341ndash3482013

[108] E M Seymour S K Lewis D E Urcuyo-Llanes et al ldquoRegulartart cherry intake alters abdominal adiposity adipose genetranscription and inflammation in obesity-prone rats fed a highfat dietrdquo Journal of Medicinal Food vol 12 no 5 pp 935ndash9422009

[109] D F Garcia-Diaz M H Johnson and E G de Mejia ldquoAntho-cyanins from fermented berry beverages inhibit inflammation-related adiposity response in vitrordquo Journal of Medicinal Foodvol 18 no 4 pp 489ndash496 2015

[110] A D de la Garza U Etxeberria S Palacios-Ortega et al ldquoMod-ulation of hyperglycemia and TNF120572-mediated inflammation byhelichrysum and grapefruit extracts in diabetic dbdb micerdquoFood amp Function vol 5 no 9 pp 2120ndash2128 2014

[111] Y Ding X Dai Y Jiang et al ldquoGrape seed proanthocyanidinextracts alleviate oxidative stress and ER stress in skeletal mus-cle of low-dose streptozotocin- and high-carbohydratehigh-fat diet-induced diabetic ratsrdquo Molecular Nutrition amp FoodResearch vol 57 no 2 pp 365ndash369 2013

[112] M R Chacon V Ceperuelo-Mallafre E Maymo-Masip et alldquoGrape-seed procyanidins modulate inflammation on humandifferentiated adipocytes in vitrordquo Cytokine vol 47 no 2 pp137ndash142 2009

[113] W Yin B Li X Li et al ldquoAnti-inflammatory effects of grapeseed procyanidin B2 on a diabetic pancreasrdquo Food amp Functionvol 6 no 9 pp 3065ndash3071 2015

[114] Y-H Chen C-H Lee T-H Hsu and H-C Lo ldquoSubmerged-culture mycelia and broth of the maitake medicinal mush-room Grifola frondosa (higher basidiomycetes) alleviate type 2diabetes-induced alterations in immunocytic functionrdquo Inter-national Journal of Medicinal Mushrooms vol 17 no 6 pp 541ndash556 2015

[115] C Li Q Ding S-P Nie Y-S Zhang T Xiong and M-Y XieldquoCarrot juice fermented with Lactobacillus plantarum NCU116ameliorates type 2 diabetes in ratsrdquo Journal of Agricultural andFood Chemistry vol 62 no 49 pp 11884ndash11891 2014

[116] Z Zhang S Wang S Zhou et al ldquoSulforaphane preventsthe development of cardiomyopathy in type 2 diabetic miceprobably by reversing oxidative stress-induced inhibition ofLKB1AMPK pathwayrdquo Journal of Molecular and Cellular Car-diology vol 77 pp 42ndash52 2014

[117] J Y Jung Y Lim M S Moon J Y Kim and O Kwon ldquoOnionpeel extracts ameliorate hyperglycemia and insulin resistance inhigh fat dietstreptozotocin-induced diabetic ratsrdquo Nutrition ampMetabolism vol 8 no 1 article 18 pp 1ndash8 2011

[118] S Shin S Lee J Kwon et al ldquoCordycepin suppresses expressionof diabetes regulating genes by inhibition of lipopolysaccharide-induced inflammation in macrophagesrdquo Immune Network vol9 no 3 pp 98ndash105 2009

[119] H Lei M Zhang Q Wang et al ldquoMT-120572-glucan from thefruit body of the maitake medicinal mushroom Grifola fron-dosa (higher Basidiomyetes) shows protective effects for hypo-glycemic pancreatic 120573-cellsrdquo International Journal of MedicinalMushrooms vol 15 no 4 pp 373ndash381 2013

[120] G Oboh A O Ademosun A O Ademiluyi O S OmojokunE E Nwanna and K O Longe ldquoIn vitro studies on the antiox-idant property and inhibition of 120572-amylase 120572-glucosidase andangiotensin I-converting enzyme by polyphenol-rich extractsfrom cocoa (Theobroma cacao) Beanrdquo Pathology Research Inter-national vol 2014 Article ID 549287 6 pages 2014

[121] F Zhang F YangH Zhao andYAn ldquoCurcumin alleviates lunginjury in diabetic rats by inhibiting nuclear factor-120581B pathwayrdquoClinical and Experimental Pharmacology andPhysiology vol 42no 9 pp 956ndash963 2015

[122] L M Jimenez-Flores S Lopez-Briones M H Macıas-Cervantes J Ramırez-Emiliano and V Perez-Vazquez ldquoAPPAR120574 NF-120581B and AMPK-dependent mechanism may beinvolved in the beneficial effects of curcumin in the diabeticdbdb mice liverrdquoMolecules vol 19 no 6 pp 8289ndash8302 2014

[123] T Ono S Takada S Kinugawa and H Tsutsui ldquoCurcuminameliorates skeletal muscle atrophy in type 1 diabetic mice byinhibiting protein ubiquitinationrdquoExperimental Physiology vol100 no 9 pp 1052ndash1063 2015

[124] P P Nahar A L Slitt and N P Seeram ldquoAnti-inflammatoryeffects of novel standardized solid lipid curcumin formulationsrdquoJournal of Medicinal Food vol 18 no 7 pp 786ndash792 2015

[125] P Suryanarayana A Satyanarayana N Balakrishna P UKumar and G B Reddy ldquoEffect of turmeric and curcuminon oxidative stress and antioxidant enzymes in streptozotocin-induced diabetic ratrdquoMedical ScienceMonitor vol 13 no 12 ppBR286ndashBR292 2007

[126] M Rastogi R P Ojha G V Rajamanickam A Agrawal AAggarwal andG PDubey ldquoCurcuminoidsmodulates oxidativedamage and mitochondrial dysfunction in diabetic rat brainrdquoFree Radical Research vol 42 no 11-12 pp 999ndash1005 2008

[127] J Lin S Zheng and A Chen ldquoCurcumin attenuates the effectsof insulin on stimulating hepatic stellate cell activation byinterrupting insulin signaling and attenuating oxidative stressrdquoLaboratory Investigation vol 89 no 12 pp 1397ndash1409 2009

[128] Y Pan G Zhu Y Wang et al ldquoAttenuation of high-glucose-induced inflammatory response by a novel curcumin derivativeB06 contributes to its protection from diabetic pathogenicchanges in rat kidney andheartrdquo Journal ofNutritional Biochem-istry vol 24 no 1 pp 146ndash155 2013

[129] N F Abdul Sani L K Belani C Pui Sin et al ldquoEffect of thecombination of gelam honey and ginger on oxidative stress andmetabolic profile in streptozotocin-induced diabetic sprague-dawley ratsrdquo BioMed Research International vol 2014 ArticleID 160695 9 pages 2014

[130] J Wattanathorn P Thiraphatthanavong S Muchimapura WThukhammee K Lertrat and B Suriharn ldquoThe combinedextract of Zingiber officinale and Zea mays (purple color)improves neuropathy oxidative stress and axon density instreptozotocin induced diabetic ratsrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2015 Article ID 30102911 pages 2015

[131] M Priya Rani K P Padmakumari B Sankarikutty O LijoCherian V M Nisha and K G Raghu ldquoInhibitory potentialof ginger extracts against enzymes linked to type 2 diabetesinflammation and induced oxidative stressrdquo International Jour-nal of Food Sciences and Nutrition vol 62 no 2 pp 106ndash1102011

[132] K R Shanmugam K Mallikarjuna N Kesireddy and KS Reddy ldquoNeuroprotective effect of ginger on anti-oxidantenzymes in streptozotocin-induced diabetic ratsrdquo Food andChemical Toxicology vol 49 no 4 pp 893ndash897 2011


[133] G El-Akabawy and W El-Kholy ldquoNeuroprotective effect ofginger in the brain of streptozotocin-induced diabetic ratsrdquoAnnals of Anatomy vol 196 no 2-3 pp 119ndash128 2014

[134] N Kota V V Panpatil R Kaleb B Varanasi and K PolasaldquoDose-dependent effect in the inhibition of oxidative stress andanticlastogenic potential of ginger in STZ induced diabetic ratsrdquoFood Chemistry vol 135 no 4 pp 2954ndash2959 2012

[135] H R Madkor S W Mansour and G Ramadan ldquoModulatoryeffects of garlic ginger turmeric and their mixture on hyper-glycaemia dyslipidaemia and oxidative stress in streptozotocin-nicotinamide diabetic ratsrdquo British Journal of Nutrition vol 105no 8 pp 1210ndash1217 2011

[136] S Samarghandian M Azimi-Nezhad and F Samini ldquoAme-liorative effect of saffron aqueous extract on hyperglycemiahyperlipidemia and oxidative stress on diabetic encephalopa-thy in streptozotocin induced experimental diabetes mellitusrdquoBioMed Research International vol 2014 Article ID 920857 12pages 2014

[137] E Altinoz Z Oner H Elbe Y Cigremis and Y TurkozldquoProtective effects of saffron (its active constituent crocin) onnephropathy in streptozotocin-induced diabetic ratsrdquo Humanamp Experimental Toxicology vol 34 no 2 pp 127ndash134 2015

[138] O Hazman and S Ovalı ldquoInvestigation of the anti-inflammatory effects of safranal on high-fat diet and multiplelow-dose streptozotocin induced type 2 diabetes rat modelrdquoInflammation vol 38 no 3 pp 1012ndash1019 2015

[139] K E Campos Y S Diniz A C Cataneo L A Faine M JQ F Alves and E L B Novelli ldquoHypoglycaemic and antiox-idant effects of onion Allium cepa dietary onion additionantioxidant activity and hypoglycaemic effects on diabetic ratsrdquoInternational Journal of Food Sciences and Nutrition vol 54 no3 pp 241ndash246 2003

[140] K Azuma Y Minami K Ippoushi and J Terao ldquoLower-ing effects of onion intake on oxidative stress biomarkersin streptozotocin-induced diabetic ratsrdquo Journal of ClinicalBiochemistry and Nutrition vol 40 no 2 pp 131ndash140 2007

[141] M Bang H-A Kim and Y-J Cho ldquoAlterations in the bloodglucose serum lipids and renal oxidative stress in diabetic ratsby supplementation of onion (Allium cepa Linn)rdquo NutritionResearch and Practice vol 3 no 3 pp 242ndash246 2009

[142] T Yokozawa H Y Kim E J Cho N Yamabe and J S ChoildquoProtective effects of mustard leaf (Brassica juncea) againstdiabetic oxidative stressrdquo Journal of Nutritional Science andVitaminology vol 49 no 2 pp 87ndash93 2003

[143] F HaidariMMohammadshahiM Zarei and Z Gorji ldquoEffectsof sesame butter (Ardeh) versus sesame oil on metabolic andoxidative stress markers in streptozotocin-induced diabeticratsrdquo Iranian Journal of Medical Sciences vol 41 no 2 pp 102ndash109 2016

[144] T Baluchnejadmojarad M Roghani M-R Jalali Nadoushan etal ldquoThe sesame lignan sesamin attenuates vascular dysfunctionin streptozotocin diabetic rats involvement of nitric oxide andoxidative stressrdquo European Journal of Pharmacology vol 698no 1ndash3 pp 316ndash321 2013

[145] S N PrasadM S Bharath andMuralidhara ldquoNeurorestorativeeffects of eugenol a spice bioactive evidence in cell modeland its efficacy as an intervention molecule to abrogate brainoxidative dysfunctions in the streptozotocin diabetic ratrdquo Neu-rochemistry International vol 95 pp 24ndash36 2016

[146] S A Adefegha G Oboh O M Adefegha A A BoligonandM LAthayde ldquoAntihyperglycemic hypolipidemic hepato-protective and antioxidative effects of dietary clove (Szyzgium

aromaticum) bud powder in a high-fat dietstreptozotocin-induced diabetes rat modelrdquo Journal of the Science of Food andAgriculture vol 94 no 13 pp 2726ndash2737 2014

[147] A G Jagtap and P B Patil ldquoAntihyperglycemic activity andinhibition of advanced glycation end product formation byCuminum cyminum in streptozotocin induced diabetic ratsrdquoFood and Chemical Toxicology vol 48 no 8-9 pp 2030ndash20362010

[148] M-C Boissier L Semerano S Challal N Saidenberg-Kerman-acrsquoh and G Falgarone ldquoRheumatoid arthritis from autoimmu-nity to synovitis and joint destructionrdquo Journal of Autoimmu-nity vol 39 no 3 pp 222ndash228 2012

[149] J S Smolen D Aletaha M Koeller M H Weisman and PEmery ldquoNew therapies for treatment of rheumatoid arthritisrdquoThe Lancet vol 370 no 9602 pp 1861ndash1874 2007

[150] S Shiozawa and K Tsumiyama ldquoPathogenesis of rheumatoidarthritis and c-FosAP-1rdquoCell Cycle vol 8 no 10 pp 1539ndash15432009

[151] H B Sun ldquoMechanical loading cartilage degradation andarthritisrdquo Annals of the New York Academy of Sciences vol 1211no 1 pp 37ndash50 2010

[152] D L Scott F Wolfe and T W J Huizinga ldquoRheumatoidarthritisrdquoThe Lancet vol 376 no 9746 pp 1094ndash1108 2010

[153] N Vivar and R F Van Vollenhoven ldquoAdvances in the treatmentof rheumatoid arthritisrdquo F1000Prime Reports vol 6 no 31 pp1ndash9 2014

[154] J A Rindfleisch and D Muller ldquoDiagnosis and management ofrheumatoid arthritisrdquoAmerican Family Physician vol 72 no 6pp 1037ndash1047 2005

[155] G Schmajuk A N Trivedi D H Solomon et al ldquoReceipt ofdisease-modifying antirheumatic drugs among patients withrheumatoid arthritis in medicare managed care plansrdquo TheJournal of the American Medical Association vol 305 no 5 pp480ndash486 2011

[156] K A Theis C G Helmick and J M Hootman ldquoArthritisburden and impact are greater among US women than menintervention opportunitiesrdquo Journal of Womenrsquos Health vol 16no 4 pp 441ndash453 2007

[157] K E Barbour C G Helmick K A Theis et al ldquoPrevalenceof doctor-diagnosed arthritis and arthritis-attributable activitylimitationmdashUnited Statesrdquo Morbidity and Mortality WeeklyReport vol 62 no 44 pp 869ndash873 2013

[158] J M Hootman and C G Helmick ldquoProjections of US preva-lence of arthritis and associated activity limitationsrdquo Arthritisamp Rheumatism vol 54 no 1 pp 226ndash229 2006

[159] C AHitchon andH S El-Gabalawy ldquoOxidation in rheumatoidarthritisrdquo Arthritis Research amp Therapy vol 6 no 6 pp 265ndash278 2004

[160] J Fay D Varoga C J Wruck B Kurz M B Goldring and TPufe ldquoReactive oxygen species induce expression of vascularendothelial growth factor in chondrocytes and human articularcartilage explantsrdquo Arthritis Research amp Therapy vol 8 articleR189 2006

[161] I B McInnes and G Schett ldquoCytokines in the pathogenesis ofrheumatoid arthritisrdquoNature Reviews Immunology vol 7 no 6pp 429ndash442 2007

[162] S-A Yoo S-K Kwok and W-U Kim ldquoProinflammatory roleof vascular endothelial growth factor in the pathogenesis ofrheumatoid arthritis prospects for therapeutic interventionrdquoMediators of Inflammation vol 2008 Article ID 129873 6 pages2008


[163] L C Huber O Distler I Tarner R E Gay S Gay and TPap ldquoSynovial fibroblasts key players in rheumatoid arthritisrdquoRheumatology vol 45 no 6 pp 669ndash675 2006

[164] I Meinecke E Rutkauskaite S Gay and T Pap ldquoThe role ofsynovial fibroblasts in mediating joint destruction in rheuma-toid arthritisrdquo Current Pharmaceutical Design vol 11 no 5 pp563ndash568 2005

[165] C J Wruck A Fragoulis A Gurzynski et al ldquoRole of oxidativestress in rheumatoid arthritis insights from the Nrf2-knockoutmicerdquo Annals of the Rheumatic Diseases vol 70 no 5 pp 844ndash850 2011

[166] C J Wruck M E Gotz T Herdegen D Varoga L-OBrandenburg and T Pufe ldquoKavalactones protect neural cellsagainst amyloid 120573 peptide-induced neurotoxicity via extracel-lular signal-regulated kinase 12-dependent nuclear factor ery-throid 2-related factor 2 activationrdquo Molecular Pharmacologyvol 73 no 6 pp 1785ndash1795 2008

[167] A K Jaiswal ldquoNrf2 signaling in coordinated activation ofantioxidant gene expressionrdquo Free Radical Biology amp Medicinevol 36 no 10 pp 1199ndash1207 2004

[168] D J Pattison A J Silman N J Goodson et al ldquoVitamin C andthe risk of developing inflammatory polyarthritis prospectivenested case-control studyrdquo Annals of the Rheumatic Diseasesvol 63 no 7 pp 843ndash847 2004

[169] J R Cerhan K G Saag L A Merlino T R Mikuls and L ACriswell ldquoAntioxidant micronutrients and risk of rheumatoidarthritis in a cohort of older womenrdquo American Journal ofEpidemiology vol 157 no 4 pp 345ndash354 2003

[170] D J Pattison D P M Symmons M Lunt et al ldquoDietaryrisk factors for the development of inflammatory polyarthritisevidence for a role of high level of red meat consumptionrdquoArthritis amp Rheumatism vol 50 no 12 pp 3804ndash3812 2004

[171] N Udagawa S Kotake N Kamatani N Takahashi and TSuda ldquoThe molecular mechanism of osteoclastogenesis inrheumatoid arthritisrdquo Arthritis Research vol 4 no 5 pp 281ndash289 2002

[172] S Y Bu M Lerner B J Stoecker et al ldquoDried plum polyphe-nols inhibit osteoclastogenesis by downregulating NFATc1 andinflammatory mediatorsrdquo Calcified Tissue International vol 82no 6 pp 475ndash488 2008

[173] Y-H He J Zhou Y-S Wang et al ldquoAntiminusinflammatory andantiminusoxidative effects of cherries on Freundrsquos adjuvantminusinducedarthritis in ratsrdquo Scandinavian Journal of Rheumatology vol 35no 5 pp 356ndash358 2006

[174] MG FWahba B A SMessiha andAAAbo-Saif ldquoProtectiveeffects of fenofibrate and resveratrol in an aggressive model ofrheumatoid arthritis in ratsrdquo Pharmaceutical Biology vol 54no 9 pp 1705ndash1715 2015

[175] M Tsubaki T Takeda T Kino et al ldquoMangiferin suppressesCIA by suppressing the expression of TNF-120572 IL-6 IL-1120573and RANKL through inhibiting the activation of NF-120581B andERK12rdquo American Journal of Translational Research vol 7 no8 pp 1371ndash1381 2015

[176] P Luczkiewicz A Kokotkiewicz A Dampc and M Luczkiew-icz ldquoMangiferin a promising therapeutic agent for rheumatoidarthritis treatmentrdquoMedical Hypotheses vol 83 no 5 pp 570ndash574 2014

[177] V Natarajan B Madhan and M L Tiku ldquoIntra-articularinjections of polyphenols protect articular cartilage frominflammation-induced degradation suggesting a potential rolein cartilage therapeuticsrdquo PLoS ONE vol 10 no 6 Article IDe0127165 20 pages 2015

[178] H-Y Yoon E-G Lee H Lee et al ldquoKaempferol inhibitsIL-1120573-induced proliferation of rheumatoid arthritis synovialfibroblasts and the production of COX-2 PGE2 and MMPsrdquoInternational Journal of Molecular Medicine vol 32 no 4 pp971ndash977 2013

[179] M Comalada D Camuesco S Sierra et al ldquoIn vivo quercitrinanti-inflammatory effect involves release of quercetin whichinhibits inflammation through down-regulation of the NF-120581Bpathwayrdquo European Journal of Immunology vol 35 no 2 pp584ndash592 2005

[180] G Schett M Tohidast-Akrad J S Smolen et al ldquoActivationdifferential localization and regulation of the stress-activatedprotein kinases extracellular signal-regulated kinase c-Jun N-terminal kinase and p38 mitogen-activated protein kinase insynovial tissue and cells in rheumatoid arthritisrdquo Arthritis ampRheumatism vol 43 no 11 pp 2501ndash2512 2000

[181] S J Pragasam V Venkatesan and M Rasool ldquoImmunomod-ulatory and anti-inflammatory effect of p-coumaric acid acommon dietary polyphenol on experimental inflammation inratsrdquo Inflammation vol 36 no 1 pp 169ndash176 2013

[182] J Wang Q Zhang S Jin D He S Zhao and S Liu ldquoGenisteinmodulate immune responses in collagen-induced rheumatoidarthritis modelrdquoMaturitas vol 59 no 4 pp 405ndash412 2008

[183] D J Pattison D P M Symmons M Lunt et al ldquoDietary 120573-cryptoxanthin and inflammatory polyarthritis results from apopulation-based prospective studyrdquo The American Journal ofClinical Nutrition vol 82 no 2 pp 451ndash455 2005

[184] I Avalos C P Chung A Oeser et al ldquoIncreased augmentationindex in rheumatoid arthritis and its relationship to coronaryartery atherosclerosisrdquoThe Journal of Rheumatology vol 34 no12 pp 2388ndash2394 2007

[185] A Cypiene A Laucevicius A Venalis et al ldquoNon-invasiveassessment of arterial stiffness indices by applanation tonome-try and pulsewave analysis in patients with rheumatoid arthritistreated with TNF-120572 blocker remicade (infliximab)rdquo ProceedingsWestern Pharmacology Society vol 50 pp 119ndash122 2007

[186] M A Crilly and G McNeill ldquoArterial dysfunction in patientswith rheumatoid arthritis and the consumption of daily fruitsand daily vegetablesrdquoEuropean Journal of Clinical Nutrition vol66 no 3 pp 345ndash352 2012

[187] G Ramadan and O El-Menshawy ldquoProtective effects of ginger-turmeric rhizomes mixture on joint inflammation atheroge-nesis kidney dysfunction and other complications in a ratmodel of human rheumatoid arthritisrdquo International Journal ofRheumatic Diseases vol 16 no 2 pp 219ndash229 2013

[188] G Ramadan M A Al-Kahtani and W M El-Sayed ldquoAnti-inflammatory and anti-oxidant properties of Curcuma longa(turmeric) versus Zingiber officinale (ginger) rhizomes in ratadjuvant-induced arthritisrdquo Inflammation vol 34 no 4 pp291ndash301 2011

[189] B Rathi S Bodhankar V Mohan and P Thakurdesai ldquoAme-liorative effects of a polyphenolic fraction of Cinnamomumzeylanicum L bark in animal models of inflammation andarthritisrdquo Scientia Pharmaceutica vol 81 no 2 pp 567ndash5892013

[190] BKloesch T Becker EDietersdorferHKiener andG SteinerldquoAnti-inflammatory and apoptotic effects of the polyphenolcurcumin on human fibroblast-like synoviocytesrdquo InternationalImmunopharmacology vol 15 no 2 pp 400ndash405 2013

[191] R Woodrick and E M Ruderman ldquoAnti-interleukin-6 therapyin rheumatoid arthritisrdquo Bulletin of the NYU Hospital for JointDiseases vol 68 no 3 pp 211ndash217 2010


[192] H Liu and R M Pope ldquoThe role of apoptosis in rheumatoidarthritisrdquo Current Opinion in Pharmacology vol 3 no 3 pp317ndash322 2003

[193] A Soultati G Mountzios C Avgerinou et al ldquoEndothelialvascular toxicity from chemotherapeutic agents preclinicalevidence and clinical implicationsrdquo Cancer Treatment Reviewsvol 38 no 5 pp 473ndash483 2012

[194] L Zeng Z Yan S Ding K Xu and L Wang ldquoEndothelialinjury an intriguing effect of methotrexate and cyclophos-phamide during hematopoietic stem cell transplantation inmicerdquo Transplantation Proceedings vol 40 no 8 pp 2670ndash2673 2008

[195] H Sankrityayan and A S Majumdar ldquoCurcumin and folic acidabrogated methotrexate induced vascular endothelial dysfunc-tionrdquoCanadian Journal of Physiology andPharmacology vol 94no 1 pp 89ndash96 2015

[196] Z Zheng Y Sun Z LiuM Zhang C Li andH Cai ldquoThe effectof curcumin and its nanoformulation on adjuvant-inducedarthritis in ratsrdquo Drug Design Development and Therapy vol9 pp 4931ndash4942 2015

[197] C Delgado and J-X Guinard ldquoHow do consumer hedonicratings for extra virgin olive oil relate to quality ratings byexperts and descriptive analysis ratingsrdquo Food Quality andPreference vol 22 no 2 pp 213ndash225 2011

[198] M A Rosillo M J Alcaraz M Sanchez-Hidalgo J G Fer-nandez-Bolanos C Alarcon-de-la-Lastra and M L FerrandizldquoAnti-inflammatory and joint protective effects of extra-virginolive-oil polyphenol extract in experimental arthritisrdquo Journalof Nutritional Biochemistry vol 25 no 12 pp 1275ndash1281 2014

[199] J Morel and F Berenbaum ldquoSignal transduction pathways newtargets for treating rheumatoid arthritisrdquo Joint Bone Spine vol71 no 6 pp 503ndash510 2004

[200] Z Han D L Boyle A M Manning and G S Firestein ldquoAP-1 and NF-120581B regulation in rheumatoid arthritis and murinecollagen-induced arthritisrdquo Autoimmunity vol 28 no 4 pp197ndash208 1998

[201] S-Y Min M Yan S B Kim et al ldquoGreen tea epigallocatechin-3-gallate suppresses autoimmune arthritis through indoleam-ine-23-dioxygenase expressing dendritic cells and the nuclearfactor erythroid 2-like 2 antioxidant pathwayrdquo Journal ofInflammation vol 12 no 1 article 53 15 pages 2015

[202] C-H Yoon S-J Chung S-W Lee Y-B Park S-K Lee andM-C Park ldquoGallic acid a natural polyphenolic acid inducesapoptosis and inhibits proinflammatory gene expressions inrheumatoid arthritis fibroblast-like synoviocytesrdquo Joint BoneSpine vol 80 no 3 pp 274ndash279 2013

[203] Y Oka S Iwai H Amano et al ldquoTea polyphenols inhibit ratosteoclast formation and differentiationrdquo Journal of Pharmaco-logical Sciences vol 118 no 1 pp 55ndash64 2012

[204] P S Burrage K S Mix and C E Brinckerhoff ldquoMatrixmetalloproteinases role in arthritisrdquo Frontiers in Bioscience vol11 no 1 pp 529ndash543 2006

[205] M D Mossalayi J Rambert E Renouf M Micouleau andJ M Merillon ldquoGrape polyphenols and propolis mixtureinhibits inflammatory mediator release from human leuko-cytes and reduces clinical scores in experimental arthritisrdquoPhytomedicine vol 21 no 3 pp 290ndash297 2014

[206] M Mueller S Hobiger and A Jungbauer ldquoAnti-inflammatoryactivity of extracts from fruits herbs and spicesrdquo Food Chem-istry vol 122 no 4 pp 987ndash996 2010

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


spices) in attenuating the oxidative stress and inflammationassociated with these chronic diseases

2 Methodology

ThePubMed database was systematically searched to retrieveevidence of potential dietary natural products (fruits vegeta-bles and spices) and their active substances (antioxidantspolyphenols carotenoids anthocyanins alkaloids glyco-sides saponins and terpenes) for use against CVDs DMand RA by attenuating oxidative stress and inflammation (seeAppendix) To retrieve clinical and experimental evidences ofdietary phytochemicals associated with CVDs DM and RAonly papers published in English between January 2000 andMarch 2016 were considered

3 Cardiovascular Diseases

CVDs are a group of diseases associated with complicationsof the heart and blood vessels most are associated withcoronary heart disease Major risk factors of CVDs includehypertension (HTN) hypercholesterolemia diabetes obe-sity inflammation smoking consumption of alcohol lack ofexercise and a familial history of heart diseases [17 18]

CVD is believed to be themajor contributor to worldwidemortality and morbidity in both developed and developingcountries In 2012 it was estimated that 175 million peopledied from CVDs which represents 31 of all global deathsAmong these deaths it was estimated that 74 million weredue to coronary heart disease It has also been predicted thatby 2030 over 28 million people will die from CVDs [19]Based on theAmericanHeart Association Report (2016) 856million American adults were afflicted with CVDs and thisnumber is anticipated to rise and add a greater economicburden to the overall health care system [4]

31 Pathogenesis Thepathogenesis of CVDs ismultifactorialresulting from the interplay of genetic and environmentalfactors However atherosclerosis which occurs due to theaccumulation of atherosclerotic plaques within the walls ofthe arteries (Figure 1) is believed to be the major precursorof CVDs

Plaque formation is initiated by endothelial damage and isfollowed by the adherence of circulating monocytes and sub-sequent exposure to homocysteine inflammation increasedplatelet aggregation and higher levels of oxidized low densitylipoprotein (LDL-ox) and reactive oxygen species (ROS)[20] In addition increased serum lipids such as triglyc-erides (TG) and cholesterol (C) increased plasma fibrinogenand coagulation factors abnormal glucose metabolism andhypertension play crucial roles in the pathogenesis of CVDs[21] Adherent monocytes differentiate into macrophageswhich ingest LDL-ox and transform into large foam cellsappearing as a fatty streak

Additionally although intact endothelium can preventsmooth muscle proliferation by releasing nitric oxide (NO)when the endothelium is damaged smooth muscle prolif-eration and migration are observed from the tunica mediainto the tunica intima in response to damaged endothelial

cell-secreted cytokinesThis activity induces the formation ofa fibrous capsule covering the fatty streak Due to calcificationin the smooth muscle cells and on the unstable fatty streakplaque hardening occurs which further blocks the coronaryarteries [22 23]

Further genetic alterations can adversely promote thedevelopment of CVDs Some examples include mutations orallelic variations of the renin-angiotensin pathway endothe-lial NO synthase coagulation factors and fibrinogen whichcan lead to the development of atherosclerosis [24] In addi-tion diets that are high in saturated fat trans-fats and saltdiets that are low in fruits vegetables and fish smoking theconsumption of tobacco and insufficient physical activity arecardiovascular risk factors [25 26] High density lipoprotein(HDL) levels are negatively correlated with CVDs there-fore the consumption of fiber-rich diets including fruitsand vegetables the control of high blood pressure properregulation of lipid and lipoprotein metabolism decreasedplatelet aggregation and increased antioxidant status shouldlimit the progress of CVDs

32 The Role of Dietary Phytochemicals Although there areseveral synthetic regimens available for treating CVDs noneare free of side effects and limitations (Table 1) Over the lasttwo decades researchers confirmed that the consumption ofregular fresh fruits vegetables and spices has the potential tolower CVD risks by attenuating oxidative stress and inflam-matory mediators Here we discuss some of the potentialexperimental and clinical evidence (Table 2) in favor oftreating CVDs by supplementation with fruits vegetablesand spices

321 Fruits A population-based prospective cohort studyfrom nine areas in Japan (77891 male and female subjectsaged 45ndash74 years) suggested that fruit consumption protectsagainst the risk of CVDs [27] A meta-analysis by Wanget al [28] provided evidence that a higher consumption offruits and vegetables correlated with a lower risk of all-causemortality predominantly cardiovascular mortality A cross-sectional study on Hispanic (119899 = 445) and non-Hispanicwhite elders (119899 = 154) found that the high-frequencyconsumption of fruits and vegetables lowered plasma C-reactive protein (CRP) and homocysteine concentrationsconsequently reducing inflammation which is consideredthe major risk factor of CVDs [29] Recently (2016) a studyon a Chinese population (512891 adults ranging from 30 to79 years old) from 10 diverse localities also revealed that ahigh level of fruit consumptionwas associatedwith decreasedHTN and blood glucose levels which significantly decreasethe risks of CVDs [30] Another study by vanrsquot Veer et al [31]on a Dutch population reported that cardiovascular deathscould be reduced by 16 (approximately 8000 deaths peryear) ranging from 6 to 22 through high intake of fruitsand vegetables A number of randomized controlled trialshave also been conducted in previous years (Table 2) wherefruits vegetables and spices have proven beneficial for CVDmanagement

Apple is one of the most commonly consumed fruits andits polyphenolic extract has a significant effect on decreasing




Adipokines

VCAM-1



Obesity

ROS

Artery

Plaque


IL-1 TNF-120572 IL-6


uarr NF-120581B


acids

JNK IKK


Insulin resistance

IRS


Insulin

Inflammatory genes

Diabetes mellitus



ROS

Mitochondria


uarr

AP-1 NF-120581B

NucleusFree fatty

Bone



Synovial fluid












Table1Mechanism

ofactio

nandsid

eeffectso

fsom

esyntheticregimensu

sedin

thetreatmento

fCVDD

Mand

RA

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

Cardiovascular

diseases

1Aspirin

(Easprin)

(i)Inhibitin

gthep

rodu

ctionof

TXA2by

inactiv

ationof

COX-

1andCO

X-2enzymes

(i)Stom

achbleeding

(ii)R

iskof

hemorrhagicstr

okeuarr

(iii)Gastriculcers

(iv)S

tomachup

set

(v)H

eartbu

rn(vi)Nausea

(vii)

Epigastricdistress

(viii)D

yspepsia

(ix)Th

rombo

cytopenia

(x)F

ibrin

olyticactiv

ityuarr

2Quinapril

(Accup

ril)

(i)Inhibitin

gAC

Ewhich

catalyzesthe

form

ationof

angiotensin

II(a

stron

gvasoconstrictor)

(i)Dizziness

(ii)L

ightheadedness

(iii)Tiredn

ess

(iv)D

rycoug

h(v)N

ausea

(vi)Vo

miting

(vii)

Blurredvisio

n(viii)C

hestpain

(ix)C

onfusio

n(x)S

weatin

g

3Digoxin

(Lanoxin)

(i)Inhibitin

gtheN

a-K-AT

Pase

mem

branep

umpresulting

inan

increase

inintracellularsod

ium

(i)Dizziness

(ii)F

ainting

(iii)Fastpo

unding

orirr

egular

heartbeato

rpu

lse(iv

)Slowheartbeat

(v)N

ausea

(vi)Vo

miting

(vii)

Headache

(viii)L

osso

fapp

etite

(ix)D

iarrhea

4Amlodipine

(Norvasc)


lsmoo

thmuscle

contractilityand

vasoconstrictio

nby

inhibitin

gtheinfl

uxof

calcium

ions

throug

hcalcium

channels

(i)Dizziness

(ii)L

ightheadedness

(iii)Sw

ellin

ganklesfe

et(iv

)Flushing

(v)F

atigue

(vi)Palpitatio

ns(vii)

Edem

a(viii)T

ightnessin

thec

hest

(ix)W

heezing


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

5Isosorbide

dinitrate

(Dilatrate-SR

)


NOwhich

activ

ates

thee

nzym

eguanylate

cyclasethatstim

ulates

thes

ynthesisof

cGMPwhich

then

activ

ates

aserieso

fprotein

kinase-dependent

phosph

orylations

inthe

smoo

thmuscle

cells

eventuallyresulting

invasodilatio

n

(i)Headache

(ii)D

izziness

(iii)Lightheadedn

ess

(iv)N

ausea

(v)F

lushing

(vi)Unu

sualbleeding

(vii)

Bruisin

g(viii)R

apid

heartrate

(ix)D

ifficulty

with

breathing

Diabetesm

ellitu

s

1Metform

in(G

lucoph

age)

(i)Ac

tivatingAMPK

toinhibith

epaticglucosep

rodu

ction

(ii)IncreasingAMPK

activ

ityin

skeletalmuscle

forg

lucose

uptake

byGLU

T4deploymenttothep

lasm

amem

brane

(i)Lacticacidosis

(ii)D

yspepsia

(iii)Nausea

(iv)D

iarrhea

(v)V

omiting

(vi)Weakn

ess

2Pioglitazon

e(A

ctos)

(i)Ac

tivatingPP

AR120574

receptorstomod

ulatethe

insulin

-sensitive

genestranscriptio

nforthe

redu

ctionof

insulin

resistance

(i)Weightg

ain

(ii)R

iskof

bladderc

ancer

(iii)Sore

throat

(iv)M

uscle

pain

(v)T

ooth

prob

lems

(vi)May

causeh

eartfailu

re(vii)

Fluidretention

(viii)P

eripheraledema

3Glib

encla

mide

(DiaBe

ta)

(i)Bind

ingandinhibitin

gtheA

TP-sensitivep

otassiu

mchannels

SUR1

receptor

onthep

ancreatic

cellsurfa

cew

hich

causes

mem

braned

epolarizationandop

ensthe

calcium

channelsfor

insulin

exocytosis

(i)Nausea

(ii)V

omiting

(iii)Diarrhea

(iv)Increased

appetite

(v)H

eartbu

rn(vi)Stom

achfulln

ess

(vii)

Weightg

ain

(viii)H

ypoglycemia

4Ac

arbo

se(Precose)

(i)Re

versiblybind

ingto


ndintestinal

120572-glucosid


hydrolysisof

complex

carboh

ydratestoglucose

(i)Diarrhea

(ii)G

as(iii)Upsetsto

mach

(iv)C

onstipatio

n(v)S

tomachpain

(vi)Nausea

(vii)

Lossof

appetite

(viii)Jaund

ice


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

5Hum

aninsulin

(Hum

ulin

R)

(i)Bind

ingto


ownstre

amsig

nalin

gmolecules

which

regu

latesthe

GLU

4andPK

Cactiv

ity

(i)Pain

(ii)M

ilditching

(iii)Re

dness

(iv)S

wellin

gattheinjectio

nsite

(v)M

ildweightg

ain

(vi)Hypoglycemia

Rheumatoidarthritis

1Metho

trexate

(Trexall)

(i)Inhibitin

gdihydrofolater

eductase

which

isinvolved

inpu

rine

metabolism

(ii)Inh

ibiting

T-cellactiv

ation

(iii)Selectively


(iv)Inh

ibiting

methyltransfe

rase

activ

ityw

hich

leadsto

deactiv

ationof

immun

esystem

enzymea

ctivities

(i)Nausea

(ii)B

lood

yvomiting

(iii)Stom

achpain

(iv)D

rowsin

ess

(v)D

izziness

(vi)Blacktarrysto

ols

(vii)

Soresinthem

outh

orlip

s(viii)B

lurred

visio

n(ix

)Con

fusio

n(x)C

onvulsion

s

2Hydroxychloroqu

ine

(Quineprox)

(i)Inhibitin

gstimulationof

theT

LR-9

(ii)Inh

ibiting

thep

rodu

ctionof

rheumatoidfactor

(i)Nausea

(ii)S

tomachcram

ps(iii)Lo

ssof

appetite

(iv)D

iarrhea

(v)D

izziness

(vi)Headache

(vii)

Con

vulsion

s(viii)W

eakn

ess

(ix)S

orethroat

(x)F

ever

(xi)Unu

sualbleeding

(xii)

Bruisin

g


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

3Sulfasalazine

(Azulfidine)

(i)Inhibitin



immun

omod

ulatoryactiv

ities

(i)Stom

achup

set

(ii)N

ausea

(iii)Vo

miting

(iv)L

osso

fapp

etite

(v)H

eadache

(vi)Dizziness

(vii)

Unu

sualtiredness

(viii)F

ever

(ix)S

orethroat

(x)S

kinrash

oritching

(xi)Bleeding

gums

(xii)

Darkurine

4Leflu

nomide

(Arava)

(i)Inhibitin

gmito

chon

drialenzym

edihydroorotate

dehydrogenasea

ndthus

inhibitin

gther

eprodu

ctionof

rapidly

dividing

cellsespecially

autoim

mun

elym

phocytes

(i)Diarrhea

(ii)N

ausea

(iii)Dizziness

(iv)S

kinrash

(v)A

lopecia

(vi)ASTuarr

(vii)

ALTuarr

(viii)B

lood

yor

cloud

yurine

(ix)C

ough

(x)H

eadache

(xi)Vo

miting

(xii)

Sore

throat

5Certolizum

ab(C

imzia)

(i)Bind


ctivity

ofTN

F120572(ii)Inh

ibiting

ther

elease

ofIL-1120573fro

mmon

ocytes

(i)Fever

(ii)C

ough

(iii)Sore

throat

(iv)R

unny

nose

(v)F

requ

entu

rinationwith

burningsensation

(vi)Jointp

ain

(vii)

Body

aches

(viii)H

eadache

(ix)L

osso

fvoice

(x)E

arcongestio

nAMPK

AMP-activ

ated

proteinkinaseG

LUT4

glucose

transporter4


1IRinsulin

receptorP

KCprotein

kinase

CPP

AR120574

peroxiso

mep


receptor

gammaAT

Padenosinetripho

sphateT

XA2thrombo

xane

A2CO

Xcyclo

oxygenaseAST

aspartate

aminotransferaseA

LTalanine

aminotransferaseA

CEang

iotensin

convertin

genzymeNOn

itricoxidecG

MP

cyclic

guanosine3101584051015840-m

onop

hosphate


Table2Ev

idence

ofclinicaltria

lswith

naturalprodu

ctsa

ttenu

atingoxidatives


patie

ntsw

ithCV

DD

Mand

RA

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

Cardiovascular

disease(CV

D)

1Ra

ndom

ized

controlled

crossovertria

l

30(F=24

M=6)473plusmn136

Con

trolapplespinachand

apple+

spinach

Health

ycontrol

4weeks

Alltre

atmentsshow

edhigh

erflo

w-m

ediateddilatation

(FMD)(119901lt005)a

ndlower

pulse

pressure

(119901lt005)a

ndapplea

ndspinachresultedin

lower

systo

licbloo

dpressure

(119901lt005)

2012

[49]

2Dou

ble-blind

rand

omized

crossovertria

lM=30526plusmn55

Twolyop

hilized

apples

(40g

)po

lyph

enol-richand

polyph

enol-poo

rproviding

respectiv

ely143g

and021g

polyph

enolsp

erday


6weeks

FMDdidno

tdiffer

betweenthe

polyph

enol-richandthe

polyph

enol-poo

rapp

lesneith

erdidtheo

ther

cardiovascular

diseaser

iskfactors(plasma

lipidsho

mocysteineand

antio

xidant

capacity)

2010

[50]

3

Openprospective

rand

omized

crossover

controlledfeeding

trial

40(F=21

M=19)

28plusmn11

Rawtomatoeskg

(70g

)35g


tomato

saucew

ithrefin

edoliveo

ilkg

and025

gof

sugarsolvedin

waterkg

Health

ycontrol

12days

Tomatosaucee

nrichedwith

refin

edoliveo

ilcanregu

late

lipid

profi

leandsoluble

inflammatorybiom

arkersbette

rthan

rawtomatoeso

rtom

ato

sauces

2016

[51]

4Dou

ble-blind

controlled

rand

omized

trial

F=79

56plusmn4

Genisteinfro

msoybeans

(54m


therapy(1mgday)

estro

genprogestin

combined

with

norethisteron

eacetate

(05mgday)

Health

ypo

stmenop

ausal

wom

en1y

ear

Genisteintherapyim

proved

endo

thelium

functio

nsim

ilarto

estro

genprogestin

regimen

2003

[52]

5Dou

ble-blinded

placebo-controlled

crossovertria

l

93(F=51

M=42)

25ndash6

5Quercetinday

from

fruitsand

vegetables

ources

(150

mg)

Overw

eighto

bese

6weeks

Redu

cedSB

Pandplasma

oxidized

LDLlevelw

itha

high

-CVDris

kph

enotype

2009

[53]

6

Dou

ble-blinded

rand

omized

placebo-controlled

crossovertria

l

M=31

35ndash51

Antho

cyaninsfrom

fruitsand

vegetables

ources

(640

mgday)

Prehypertensive

4weeks

HDL-Candbloo

dglucosew

ere

significantly

high

eraft

eranthocyaninversus

placebo


119901=0024resp)

2013

[54]

7

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

105

20ndash6

0One

350m

gwho

rtleberryextract

capsulee

very

8ho

urs

Hyperlip

idem

ic2mon

ths

Lowered

total-C

(119901lt0001)

TG(119901=0002)andLD

L-C

(119901=0002)b

utincreased


comparedwith

thep

lacebo

grou

patthee

ndpo

int

2014

[55]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

8

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

50ge1845plusmn2mgof

anthocyaninfro

mVa

ccinium

arctostaphylos

Lfruit

extract

Hyperlip

idem

ic4weeks

Sign

ificantlyredu

cedtotal-C

(119901lt0001)LD

L-C(119901=0004)


(119901=0013)com

paredto

placebo

2014

[56]

9

Rand

omized

controlled

investigator

blinded

parallel-g

roup

trial

NCT

00421499

44(F=24

M=20)

56ndash73

Darkchocolate(63g

day)

containing

30mgof

polyph

enols

Stage-1h

ypertensive

18weeks

Redu

cedmean(SD)S

BPby

29

(16)m

mHg(119901lt0001)a

ndDBP

by19

(10)m

mHg

(119901lt0001)

2007

[57]

10

Rand

omized

placebo-controlled

single-blind

crossovertria

lNCT

00538083

45(F=35

M=10)

30ndash75

Inph

ase1solid

dark

chocolate

bar(containing

22gcocoa

powder)or

acocoa-fr

eeplacebo

barIn

phase2

sug

ar-fr

eecocoa

(con

taining22

gcocoap

owder)

sugaredcocoa(

containing

22g

cocoap

owder)ora

placebo

Health

ycontrol

1week

Thea

cuteingestionof

both

solid

dark

chocolatea

ndliq

uid

cocoaimproved

endo

thelial

functio

nandlowered

bloo

dpressure

inoverweightadu

lts

2008

[58]

Diabetesm

ellitu

s(DM)

11Openlabel

rand

omized

clinicaltria

l60

35ndash55

Standard

metform

intherapy

with

turm

eric(2g)

supp

lements

Standard

metform

intre

atment

4weeks

Turm

ericadministered

grou

psig

nificantly


thelipid

peroxidatio

nMDA


PHbA

1cand

fastingbloo

dglucoselevels

andenhanced

the

totalantioxidant

status

2015

[59]

12

Rand

omized

doub

le-blin

dcontrolledclinical

trial

7030ndash70

Powderedrhizom

eofginger

(160

0mg)

Wheatflo

urplacebo

(160

0mg)

12weeks

Gingersignificantly

redu

cedthe

fastingplasmag

lucoseH

bA1c

insulin

trig

lycerid

etotal

cholesterolCR

PandPG

E2

2014

[60]

13Ra

ndom

ized

triple-blin

dcontrolledtrial

M=35

60plusmn11

Capsuleo

f350

mgof

RES

enric

hedgrapee

xtract(G

E)

350m

gof

capsules

containing

either

maltodextrin

(placebo

)orR

ESlackingGE

12mon

ths

RESenric

hedGE

downregulated

the

proinfl

ammatorycytokines

expressio

nviainvolving

the


miRsin

circulatingim

mun

ecells

2013

[61]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

14Ra

ndom

ized

doub

le-blin

dcontrolledtrial

36(F=23

M=13)515plusmn100

FDSbeverage

of2cups

(50g

ofFD

Sisequivalent

to500g

offre

shstr

awberries)

Placebopo

wderw

ithstr

awberryflavor

6weeks

FDSsig

nificantly

(119901lt005)

decreasedtheC

RPlevelsand

lipid

peroxidatio

n(m

ainly

MDA)a

ndincreasedthetotal

antio

xidant

status

2013

[62]

15Ra

ndom

ized

doub

le-blin

dcontrolledtrial

6438ndash6

5Gingersup

plem

entatio

nPlacebo

8weeks

Gingersup

plem

entatio

nsig

nificantly

redu

cedthe

TNF-120572C

RPand

IL-6

levels

2013

[63]

16Ra

ndom

ized

doub

le-blin

dclinicaltria

l81

18ndash6

0BS

Pat10gday(119899=27)B

SPat

5gday

(119899=29)

Placebo

4weeks

BSPsig

nificantly

decreasedthe

MDAO

SIand

oxidized

low

density

lipop

rotein

cholesterol

andincreasedtheT

AC

2011[64]

17Dou

ble-blinded

rand

omized

crossovertria

l

32(M=16

F=16)618plusmn64

GSE

(600

mgday)

Placebo

4weeks

GSE

significantly

improved

the


ainly

CRP)glycemiaand

oxidative

stress

2009

[65]


18Ra

ndom

ized

single-blindpilot

study

45(F=38

M=7)478plusmn86

Curcum

in(500

mg)

and

diclo

fenacs

odium

(50m

g)alon

eor

incombinatio

n

Diclofenacs

odium

(anti-infl

ammatory

drug)

8weeks

Curcum

inalon

eprovedto

bethem


andsafestto

attenu

ateR

Acomplications

2012

[66]

19

Rand

omized

doub

le-blin

dplacebo-controlled

crossoverstudy

20(F=19

M=1)521plusmn103

Quercetin

(166

mgcapsule)+

vitamin

C(133

mgcapsule)

120572-lipo

icacid

(300

mgcapsule)

Placebo

6weeks

Nosig

nificantd

ifference

was

foun

dam

ongthe

proinfl

ammatorycytokines

however

quercetin

tend

edto

redu

ceVA

Sof

RA

2009

[67]

20

Rand

omized

doub

le-blin

dplacebo-controlled

study

105

55ndash75

Polyph

enolic-richolivee

xtract

Placebo

8weeks

Sign

ificant

(119901lt001)d

ecrease

ofplasmah

omocysteinelevel

(respo

nsibleforc

ardiovascular

complications

inRA

)and

notabler

eductio

nof

CRPwere

observed

2007

[68]

FfemaleMm

aleRA

rheum

atoidarthritis

VASvisualanalogue

scaleNR

notreported

CRP

C-reactiv

eprotein

RESresveratrolGE


AsFD

Sfre

eze-driedstr

awberryMDA

malon

dialdehydeG

SEgrape

seed

extractBS

Pbroccolisproutsp

owderOSIoxidativ

estr

essind

exT

ACtotalantio

xidant

capacityP

GE2

prostagland

inE2

HbA

1cglycosylated

hemoglobin

CADcoron

ary

artery

diseaseLD

L-C

lowdensity

lipop

rotein

cholesterolHDL-C

high

density

lipop

rotein

cholesterolSB

Psysto

licbloo

dpressure










4 Diabetes Mellitus








































































6 Conclusion


Appendix

Search Strategy











Competing Interests




Acknowledgments


References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Adipokines

VCAM-1



Obesity

ROS

Artery

Plaque


IL-1 TNF-120572 IL-6


uarr NF-120581B


acids

JNK IKK


Insulin resistance

IRS


Insulin

Inflammatory genes

Diabetes mellitus



ROS

Mitochondria


uarr

AP-1 NF-120581B

NucleusFree fatty

Bone



Synovial fluid












Table1Mechanism

ofactio

nandsid

eeffectso

fsom

esyntheticregimensu

sedin

thetreatmento

fCVDD

Mand

RA

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

Cardiovascular

diseases

1Aspirin

(Easprin)

(i)Inhibitin

gthep

rodu

ctionof

TXA2by

inactiv

ationof

COX-

1andCO

X-2enzymes

(i)Stom

achbleeding

(ii)R

iskof

hemorrhagicstr

okeuarr

(iii)Gastriculcers

(iv)S

tomachup

set

(v)H

eartbu

rn(vi)Nausea

(vii)

Epigastricdistress

(viii)D

yspepsia

(ix)Th

rombo

cytopenia

(x)F

ibrin

olyticactiv

ityuarr

2Quinapril

(Accup

ril)

(i)Inhibitin

gAC

Ewhich

catalyzesthe

form

ationof

angiotensin

II(a

stron

gvasoconstrictor)

(i)Dizziness

(ii)L

ightheadedness

(iii)Tiredn

ess

(iv)D

rycoug

h(v)N

ausea

(vi)Vo

miting

(vii)

Blurredvisio

n(viii)C

hestpain

(ix)C

onfusio

n(x)S

weatin

g

3Digoxin

(Lanoxin)

(i)Inhibitin

gtheN

a-K-AT

Pase

mem

branep

umpresulting

inan

increase

inintracellularsod

ium

(i)Dizziness

(ii)F

ainting

(iii)Fastpo

unding

orirr

egular

heartbeato

rpu

lse(iv

)Slowheartbeat

(v)N

ausea

(vi)Vo

miting

(vii)

Headache

(viii)L

osso

fapp

etite

(ix)D

iarrhea

4Amlodipine

(Norvasc)


lsmoo

thmuscle

contractilityand

vasoconstrictio

nby

inhibitin

gtheinfl

uxof

calcium

ions

throug

hcalcium

channels

(i)Dizziness

(ii)L

ightheadedness

(iii)Sw

ellin

ganklesfe

et(iv

)Flushing

(v)F

atigue

(vi)Palpitatio

ns(vii)

Edem

a(viii)T

ightnessin

thec

hest

(ix)W

heezing


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

5Isosorbide

dinitrate

(Dilatrate-SR

)


NOwhich

activ

ates

thee

nzym

eguanylate

cyclasethatstim

ulates

thes

ynthesisof

cGMPwhich

then

activ

ates

aserieso

fprotein

kinase-dependent

phosph

orylations

inthe

smoo

thmuscle

cells

eventuallyresulting

invasodilatio

n

(i)Headache

(ii)D

izziness

(iii)Lightheadedn

ess

(iv)N

ausea

(v)F

lushing

(vi)Unu

sualbleeding

(vii)

Bruisin

g(viii)R

apid

heartrate

(ix)D

ifficulty

with

breathing

Diabetesm

ellitu

s

1Metform

in(G

lucoph

age)

(i)Ac

tivatingAMPK

toinhibith

epaticglucosep

rodu

ction

(ii)IncreasingAMPK

activ

ityin

skeletalmuscle

forg

lucose

uptake

byGLU

T4deploymenttothep

lasm

amem

brane

(i)Lacticacidosis

(ii)D

yspepsia

(iii)Nausea

(iv)D

iarrhea

(v)V

omiting

(vi)Weakn

ess

2Pioglitazon

e(A

ctos)

(i)Ac

tivatingPP

AR120574

receptorstomod

ulatethe

insulin

-sensitive

genestranscriptio

nforthe

redu

ctionof

insulin

resistance

(i)Weightg

ain

(ii)R

iskof

bladderc

ancer

(iii)Sore

throat

(iv)M

uscle

pain

(v)T

ooth

prob

lems

(vi)May

causeh

eartfailu

re(vii)

Fluidretention

(viii)P

eripheraledema

3Glib

encla

mide

(DiaBe

ta)

(i)Bind

ingandinhibitin

gtheA

TP-sensitivep

otassiu

mchannels

SUR1

receptor

onthep

ancreatic

cellsurfa

cew

hich

causes

mem

braned

epolarizationandop

ensthe

calcium

channelsfor

insulin

exocytosis

(i)Nausea

(ii)V

omiting

(iii)Diarrhea

(iv)Increased

appetite

(v)H

eartbu

rn(vi)Stom

achfulln

ess

(vii)

Weightg

ain

(viii)H

ypoglycemia

4Ac

arbo

se(Precose)

(i)Re

versiblybind

ingto


ndintestinal

120572-glucosid


hydrolysisof

complex

carboh

ydratestoglucose

(i)Diarrhea

(ii)G

as(iii)Upsetsto

mach

(iv)C

onstipatio

n(v)S

tomachpain

(vi)Nausea

(vii)

Lossof

appetite

(viii)Jaund

ice


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

5Hum

aninsulin

(Hum

ulin

R)

(i)Bind

ingto


ownstre

amsig

nalin

gmolecules

which

regu

latesthe

GLU

4andPK

Cactiv

ity

(i)Pain

(ii)M

ilditching

(iii)Re

dness

(iv)S

wellin

gattheinjectio

nsite

(v)M

ildweightg

ain

(vi)Hypoglycemia

Rheumatoidarthritis

1Metho

trexate

(Trexall)

(i)Inhibitin

gdihydrofolater

eductase

which

isinvolved

inpu

rine

metabolism

(ii)Inh

ibiting

T-cellactiv

ation

(iii)Selectively


(iv)Inh

ibiting

methyltransfe

rase

activ

ityw

hich

leadsto

deactiv

ationof

immun

esystem

enzymea

ctivities

(i)Nausea

(ii)B

lood

yvomiting

(iii)Stom

achpain

(iv)D

rowsin

ess

(v)D

izziness

(vi)Blacktarrysto

ols

(vii)

Soresinthem

outh

orlip

s(viii)B

lurred

visio

n(ix

)Con

fusio

n(x)C

onvulsion

s

2Hydroxychloroqu

ine

(Quineprox)

(i)Inhibitin

gstimulationof

theT

LR-9

(ii)Inh

ibiting

thep

rodu

ctionof

rheumatoidfactor

(i)Nausea

(ii)S

tomachcram

ps(iii)Lo

ssof

appetite

(iv)D

iarrhea

(v)D

izziness

(vi)Headache

(vii)

Con

vulsion

s(viii)W

eakn

ess

(ix)S

orethroat

(x)F

ever

(xi)Unu

sualbleeding

(xii)

Bruisin

g


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

3Sulfasalazine

(Azulfidine)

(i)Inhibitin



immun

omod

ulatoryactiv

ities

(i)Stom

achup

set

(ii)N

ausea

(iii)Vo

miting

(iv)L

osso

fapp

etite

(v)H

eadache

(vi)Dizziness

(vii)

Unu

sualtiredness

(viii)F

ever

(ix)S

orethroat

(x)S

kinrash

oritching

(xi)Bleeding

gums

(xii)

Darkurine

4Leflu

nomide

(Arava)

(i)Inhibitin

gmito

chon

drialenzym

edihydroorotate

dehydrogenasea

ndthus

inhibitin

gther

eprodu

ctionof

rapidly

dividing

cellsespecially

autoim

mun

elym

phocytes

(i)Diarrhea

(ii)N

ausea

(iii)Dizziness

(iv)S

kinrash

(v)A

lopecia

(vi)ASTuarr

(vii)

ALTuarr

(viii)B

lood

yor

cloud

yurine

(ix)C

ough

(x)H

eadache

(xi)Vo

miting

(xii)

Sore

throat

5Certolizum

ab(C

imzia)

(i)Bind


ctivity

ofTN

F120572(ii)Inh

ibiting

ther

elease

ofIL-1120573fro

mmon

ocytes

(i)Fever

(ii)C

ough

(iii)Sore

throat

(iv)R

unny

nose

(v)F

requ

entu

rinationwith

burningsensation

(vi)Jointp

ain

(vii)

Body

aches

(viii)H

eadache

(ix)L

osso

fvoice

(x)E

arcongestio

nAMPK

AMP-activ

ated

proteinkinaseG

LUT4

glucose

transporter4


1IRinsulin

receptorP

KCprotein

kinase

CPP

AR120574

peroxiso

mep


receptor

gammaAT

Padenosinetripho

sphateT

XA2thrombo

xane

A2CO

Xcyclo

oxygenaseAST

aspartate

aminotransferaseA

LTalanine

aminotransferaseA

CEang

iotensin

convertin

genzymeNOn

itricoxidecG

MP

cyclic

guanosine3101584051015840-m

onop

hosphate


Table2Ev

idence

ofclinicaltria

lswith

naturalprodu

ctsa

ttenu

atingoxidatives


patie

ntsw

ithCV

DD

Mand

RA

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

Cardiovascular

disease(CV

D)

1Ra

ndom

ized

controlled

crossovertria

l

30(F=24

M=6)473plusmn136

Con

trolapplespinachand

apple+

spinach

Health

ycontrol

4weeks

Alltre

atmentsshow

edhigh

erflo

w-m

ediateddilatation

(FMD)(119901lt005)a

ndlower

pulse

pressure

(119901lt005)a

ndapplea

ndspinachresultedin

lower

systo

licbloo

dpressure

(119901lt005)

2012

[49]

2Dou

ble-blind

rand

omized

crossovertria

lM=30526plusmn55

Twolyop

hilized

apples

(40g

)po

lyph

enol-richand

polyph

enol-poo

rproviding

respectiv

ely143g

and021g

polyph

enolsp

erday


6weeks

FMDdidno

tdiffer

betweenthe

polyph

enol-richandthe

polyph

enol-poo

rapp

lesneith

erdidtheo

ther

cardiovascular

diseaser

iskfactors(plasma

lipidsho

mocysteineand

antio

xidant

capacity)

2010

[50]

3

Openprospective

rand

omized

crossover

controlledfeeding

trial

40(F=21

M=19)

28plusmn11

Rawtomatoeskg

(70g

)35g


tomato

saucew

ithrefin

edoliveo

ilkg

and025

gof

sugarsolvedin

waterkg

Health

ycontrol

12days

Tomatosaucee

nrichedwith

refin

edoliveo

ilcanregu

late

lipid

profi

leandsoluble

inflammatorybiom

arkersbette

rthan

rawtomatoeso

rtom

ato

sauces

2016

[51]

4Dou

ble-blind

controlled

rand

omized

trial

F=79

56plusmn4

Genisteinfro

msoybeans

(54m


therapy(1mgday)

estro

genprogestin

combined

with

norethisteron

eacetate

(05mgday)

Health

ypo

stmenop

ausal

wom

en1y

ear

Genisteintherapyim

proved

endo

thelium

functio

nsim

ilarto

estro

genprogestin

regimen

2003

[52]

5Dou

ble-blinded

placebo-controlled

crossovertria

l

93(F=51

M=42)

25ndash6

5Quercetinday

from

fruitsand

vegetables

ources

(150

mg)

Overw

eighto

bese

6weeks

Redu

cedSB

Pandplasma

oxidized

LDLlevelw

itha

high

-CVDris

kph

enotype

2009

[53]

6

Dou

ble-blinded

rand

omized

placebo-controlled

crossovertria

l

M=31

35ndash51

Antho

cyaninsfrom

fruitsand

vegetables

ources

(640

mgday)

Prehypertensive

4weeks

HDL-Candbloo

dglucosew

ere

significantly

high

eraft

eranthocyaninversus

placebo


119901=0024resp)

2013

[54]

7

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

105

20ndash6

0One

350m

gwho

rtleberryextract

capsulee

very

8ho

urs

Hyperlip

idem

ic2mon

ths

Lowered

total-C

(119901lt0001)

TG(119901=0002)andLD

L-C

(119901=0002)b

utincreased


comparedwith

thep

lacebo

grou

patthee

ndpo

int

2014

[55]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

8

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

50ge1845plusmn2mgof

anthocyaninfro

mVa

ccinium

arctostaphylos

Lfruit

extract

Hyperlip

idem

ic4weeks

Sign

ificantlyredu

cedtotal-C

(119901lt0001)LD

L-C(119901=0004)


(119901=0013)com

paredto

placebo

2014

[56]

9

Rand

omized

controlled

investigator

blinded

parallel-g

roup

trial

NCT

00421499

44(F=24

M=20)

56ndash73

Darkchocolate(63g

day)

containing

30mgof

polyph

enols

Stage-1h

ypertensive

18weeks

Redu

cedmean(SD)S

BPby

29

(16)m

mHg(119901lt0001)a

ndDBP

by19

(10)m

mHg

(119901lt0001)

2007

[57]

10

Rand

omized

placebo-controlled

single-blind

crossovertria

lNCT

00538083

45(F=35

M=10)

30ndash75

Inph

ase1solid

dark

chocolate

bar(containing

22gcocoa

powder)or

acocoa-fr

eeplacebo

barIn

phase2

sug

ar-fr

eecocoa

(con

taining22

gcocoap

owder)

sugaredcocoa(

containing

22g

cocoap

owder)ora

placebo

Health

ycontrol

1week

Thea

cuteingestionof

both

solid

dark

chocolatea

ndliq

uid

cocoaimproved

endo

thelial

functio

nandlowered

bloo

dpressure

inoverweightadu

lts

2008

[58]

Diabetesm

ellitu

s(DM)

11Openlabel

rand

omized

clinicaltria

l60

35ndash55

Standard

metform

intherapy

with

turm

eric(2g)

supp

lements

Standard

metform

intre

atment

4weeks

Turm

ericadministered

grou

psig

nificantly


thelipid

peroxidatio

nMDA


PHbA

1cand

fastingbloo

dglucoselevels

andenhanced

the

totalantioxidant

status

2015

[59]

12

Rand

omized

doub

le-blin

dcontrolledclinical

trial

7030ndash70

Powderedrhizom

eofginger

(160

0mg)

Wheatflo

urplacebo

(160

0mg)

12weeks

Gingersignificantly

redu

cedthe

fastingplasmag

lucoseH

bA1c

insulin

trig

lycerid

etotal

cholesterolCR

PandPG

E2

2014

[60]

13Ra

ndom

ized

triple-blin

dcontrolledtrial

M=35

60plusmn11

Capsuleo

f350

mgof

RES

enric

hedgrapee

xtract(G

E)

350m

gof

capsules

containing

either

maltodextrin

(placebo

)orR

ESlackingGE

12mon

ths

RESenric

hedGE

downregulated

the

proinfl

ammatorycytokines

expressio

nviainvolving

the


miRsin

circulatingim

mun

ecells

2013

[61]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

14Ra

ndom

ized

doub

le-blin

dcontrolledtrial

36(F=23

M=13)515plusmn100

FDSbeverage

of2cups

(50g

ofFD

Sisequivalent

to500g

offre

shstr

awberries)

Placebopo

wderw

ithstr

awberryflavor

6weeks

FDSsig

nificantly

(119901lt005)

decreasedtheC

RPlevelsand

lipid

peroxidatio

n(m

ainly

MDA)a

ndincreasedthetotal

antio

xidant

status

2013

[62]

15Ra

ndom

ized

doub

le-blin

dcontrolledtrial

6438ndash6

5Gingersup

plem

entatio

nPlacebo

8weeks

Gingersup

plem

entatio

nsig

nificantly

redu

cedthe

TNF-120572C

RPand

IL-6

levels

2013

[63]

16Ra

ndom

ized

doub

le-blin

dclinicaltria

l81

18ndash6

0BS

Pat10gday(119899=27)B

SPat

5gday

(119899=29)

Placebo

4weeks

BSPsig

nificantly

decreasedthe

MDAO

SIand

oxidized

low

density

lipop

rotein

cholesterol

andincreasedtheT

AC

2011[64]

17Dou

ble-blinded

rand

omized

crossovertria

l

32(M=16

F=16)618plusmn64

GSE

(600

mgday)

Placebo

4weeks

GSE

significantly

improved

the


ainly

CRP)glycemiaand

oxidative

stress

2009

[65]


18Ra

ndom

ized

single-blindpilot

study

45(F=38

M=7)478plusmn86

Curcum

in(500

mg)

and

diclo

fenacs

odium

(50m

g)alon

eor

incombinatio

n

Diclofenacs

odium

(anti-infl

ammatory

drug)

8weeks

Curcum

inalon

eprovedto

bethem


andsafestto

attenu

ateR

Acomplications

2012

[66]

19

Rand

omized

doub

le-blin

dplacebo-controlled

crossoverstudy

20(F=19

M=1)521plusmn103

Quercetin

(166

mgcapsule)+

vitamin

C(133

mgcapsule)

120572-lipo

icacid

(300

mgcapsule)

Placebo

6weeks

Nosig

nificantd

ifference

was

foun

dam

ongthe

proinfl

ammatorycytokines

however

quercetin

tend

edto

redu

ceVA

Sof

RA

2009

[67]

20

Rand

omized

doub

le-blin

dplacebo-controlled

study

105

55ndash75

Polyph

enolic-richolivee

xtract

Placebo

8weeks

Sign

ificant

(119901lt001)d

ecrease

ofplasmah

omocysteinelevel

(respo

nsibleforc

ardiovascular

complications

inRA

)and

notabler

eductio

nof

CRPwere

observed

2007

[68]

FfemaleMm

aleRA

rheum

atoidarthritis

VASvisualanalogue

scaleNR

notreported

CRP

C-reactiv

eprotein

RESresveratrolGE


AsFD

Sfre

eze-driedstr

awberryMDA

malon

dialdehydeG

SEgrape

seed

extractBS

Pbroccolisproutsp

owderOSIoxidativ

estr

essind

exT

ACtotalantio

xidant

capacityP

GE2

prostagland

inE2

HbA

1cglycosylated

hemoglobin

CADcoron

ary

artery

diseaseLD

L-C

lowdensity

lipop

rotein

cholesterolHDL-C

high

density

lipop

rotein

cholesterolSB

Psysto

licbloo

dpressure










4 Diabetes Mellitus








































































6 Conclusion


Appendix

Search Strategy











Competing Interests




Acknowledgments


References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table1Mechanism

ofactio

nandsid

eeffectso

fsom

esyntheticregimensu

sedin

thetreatmento

fCVDD

Mand

RA

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

Cardiovascular

diseases

1Aspirin

(Easprin)

(i)Inhibitin

gthep

rodu

ctionof

TXA2by

inactiv

ationof

COX-

1andCO

X-2enzymes

(i)Stom

achbleeding

(ii)R

iskof

hemorrhagicstr

okeuarr

(iii)Gastriculcers

(iv)S

tomachup

set

(v)H

eartbu

rn(vi)Nausea

(vii)

Epigastricdistress

(viii)D

yspepsia

(ix)Th

rombo

cytopenia

(x)F

ibrin

olyticactiv

ityuarr

2Quinapril

(Accup

ril)

(i)Inhibitin

gAC

Ewhich

catalyzesthe

form

ationof

angiotensin

II(a

stron

gvasoconstrictor)

(i)Dizziness

(ii)L

ightheadedness

(iii)Tiredn

ess

(iv)D

rycoug

h(v)N

ausea

(vi)Vo

miting

(vii)

Blurredvisio

n(viii)C

hestpain

(ix)C

onfusio

n(x)S

weatin

g

3Digoxin

(Lanoxin)

(i)Inhibitin

gtheN

a-K-AT

Pase

mem

branep

umpresulting

inan

increase

inintracellularsod

ium

(i)Dizziness

(ii)F

ainting

(iii)Fastpo

unding

orirr

egular

heartbeato

rpu

lse(iv

)Slowheartbeat

(v)N

ausea

(vi)Vo

miting

(vii)

Headache

(viii)L

osso

fapp

etite

(ix)D

iarrhea

4Amlodipine

(Norvasc)


lsmoo

thmuscle

contractilityand

vasoconstrictio

nby

inhibitin

gtheinfl

uxof

calcium

ions

throug

hcalcium

channels

(i)Dizziness

(ii)L

ightheadedness

(iii)Sw

ellin

ganklesfe

et(iv

)Flushing

(v)F

atigue

(vi)Palpitatio

ns(vii)

Edem

a(viii)T

ightnessin

thec

hest

(ix)W

heezing


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

5Isosorbide

dinitrate

(Dilatrate-SR

)


NOwhich

activ

ates

thee

nzym

eguanylate

cyclasethatstim

ulates

thes

ynthesisof

cGMPwhich

then

activ

ates

aserieso

fprotein

kinase-dependent

phosph

orylations

inthe

smoo

thmuscle

cells

eventuallyresulting

invasodilatio

n

(i)Headache

(ii)D

izziness

(iii)Lightheadedn

ess

(iv)N

ausea

(v)F

lushing

(vi)Unu

sualbleeding

(vii)

Bruisin

g(viii)R

apid

heartrate

(ix)D

ifficulty

with

breathing

Diabetesm

ellitu

s

1Metform

in(G

lucoph

age)

(i)Ac

tivatingAMPK

toinhibith

epaticglucosep

rodu

ction

(ii)IncreasingAMPK

activ

ityin

skeletalmuscle

forg

lucose

uptake

byGLU

T4deploymenttothep

lasm

amem

brane

(i)Lacticacidosis

(ii)D

yspepsia

(iii)Nausea

(iv)D

iarrhea

(v)V

omiting

(vi)Weakn

ess

2Pioglitazon

e(A

ctos)

(i)Ac

tivatingPP

AR120574

receptorstomod

ulatethe

insulin

-sensitive

genestranscriptio

nforthe

redu

ctionof

insulin

resistance

(i)Weightg

ain

(ii)R

iskof

bladderc

ancer

(iii)Sore

throat

(iv)M

uscle

pain

(v)T

ooth

prob

lems

(vi)May

causeh

eartfailu

re(vii)

Fluidretention

(viii)P

eripheraledema

3Glib

encla

mide

(DiaBe

ta)

(i)Bind

ingandinhibitin

gtheA

TP-sensitivep

otassiu

mchannels

SUR1

receptor

onthep

ancreatic

cellsurfa

cew

hich

causes

mem

braned

epolarizationandop

ensthe

calcium

channelsfor

insulin

exocytosis

(i)Nausea

(ii)V

omiting

(iii)Diarrhea

(iv)Increased

appetite

(v)H

eartbu

rn(vi)Stom

achfulln

ess

(vii)

Weightg

ain

(viii)H

ypoglycemia

4Ac

arbo

se(Precose)

(i)Re

versiblybind

ingto


ndintestinal

120572-glucosid


hydrolysisof

complex

carboh

ydratestoglucose

(i)Diarrhea

(ii)G

as(iii)Upsetsto

mach

(iv)C

onstipatio

n(v)S

tomachpain

(vi)Nausea

(vii)

Lossof

appetite

(viii)Jaund

ice


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

5Hum

aninsulin

(Hum

ulin

R)

(i)Bind

ingto


ownstre

amsig

nalin

gmolecules

which

regu

latesthe

GLU

4andPK

Cactiv

ity

(i)Pain

(ii)M

ilditching

(iii)Re

dness

(iv)S

wellin

gattheinjectio

nsite

(v)M

ildweightg

ain

(vi)Hypoglycemia

Rheumatoidarthritis

1Metho

trexate

(Trexall)

(i)Inhibitin

gdihydrofolater

eductase

which

isinvolved

inpu

rine

metabolism

(ii)Inh

ibiting

T-cellactiv

ation

(iii)Selectively


(iv)Inh

ibiting

methyltransfe

rase

activ

ityw

hich

leadsto

deactiv

ationof

immun

esystem

enzymea

ctivities

(i)Nausea

(ii)B

lood

yvomiting

(iii)Stom

achpain

(iv)D

rowsin

ess

(v)D

izziness

(vi)Blacktarrysto

ols

(vii)

Soresinthem

outh

orlip

s(viii)B

lurred

visio

n(ix

)Con

fusio

n(x)C

onvulsion

s

2Hydroxychloroqu

ine

(Quineprox)

(i)Inhibitin

gstimulationof

theT

LR-9

(ii)Inh

ibiting

thep

rodu

ctionof

rheumatoidfactor

(i)Nausea

(ii)S

tomachcram

ps(iii)Lo

ssof

appetite

(iv)D

iarrhea

(v)D

izziness

(vi)Headache

(vii)

Con

vulsion

s(viii)W

eakn

ess

(ix)S

orethroat

(x)F

ever

(xi)Unu

sualbleeding

(xii)

Bruisin

g


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

3Sulfasalazine

(Azulfidine)

(i)Inhibitin



immun

omod

ulatoryactiv

ities

(i)Stom

achup

set

(ii)N

ausea

(iii)Vo

miting

(iv)L

osso

fapp

etite

(v)H

eadache

(vi)Dizziness

(vii)

Unu

sualtiredness

(viii)F

ever

(ix)S

orethroat

(x)S

kinrash

oritching

(xi)Bleeding

gums

(xii)

Darkurine

4Leflu

nomide

(Arava)

(i)Inhibitin

gmito

chon

drialenzym

edihydroorotate

dehydrogenasea

ndthus

inhibitin

gther

eprodu

ctionof

rapidly

dividing

cellsespecially

autoim

mun

elym

phocytes

(i)Diarrhea

(ii)N

ausea

(iii)Dizziness

(iv)S

kinrash

(v)A

lopecia

(vi)ASTuarr

(vii)

ALTuarr

(viii)B

lood

yor

cloud

yurine

(ix)C

ough

(x)H

eadache

(xi)Vo

miting

(xii)

Sore

throat

5Certolizum

ab(C

imzia)

(i)Bind


ctivity

ofTN

F120572(ii)Inh

ibiting

ther

elease

ofIL-1120573fro

mmon

ocytes

(i)Fever

(ii)C

ough

(iii)Sore

throat

(iv)R

unny

nose

(v)F

requ

entu

rinationwith

burningsensation

(vi)Jointp

ain

(vii)

Body

aches

(viii)H

eadache

(ix)L

osso

fvoice

(x)E

arcongestio

nAMPK

AMP-activ

ated

proteinkinaseG

LUT4

glucose

transporter4


1IRinsulin

receptorP

KCprotein

kinase

CPP

AR120574

peroxiso

mep


receptor

gammaAT

Padenosinetripho

sphateT

XA2thrombo

xane

A2CO

Xcyclo

oxygenaseAST

aspartate

aminotransferaseA

LTalanine

aminotransferaseA

CEang

iotensin

convertin

genzymeNOn

itricoxidecG

MP

cyclic

guanosine3101584051015840-m

onop

hosphate


Table2Ev

idence

ofclinicaltria

lswith

naturalprodu

ctsa

ttenu

atingoxidatives


patie

ntsw

ithCV

DD

Mand

RA

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

Cardiovascular

disease(CV

D)

1Ra

ndom

ized

controlled

crossovertria

l

30(F=24

M=6)473plusmn136

Con

trolapplespinachand

apple+

spinach

Health

ycontrol

4weeks

Alltre

atmentsshow

edhigh

erflo

w-m

ediateddilatation

(FMD)(119901lt005)a

ndlower

pulse

pressure

(119901lt005)a

ndapplea

ndspinachresultedin

lower

systo

licbloo

dpressure

(119901lt005)

2012

[49]

2Dou

ble-blind

rand

omized

crossovertria

lM=30526plusmn55

Twolyop

hilized

apples

(40g

)po

lyph

enol-richand

polyph

enol-poo

rproviding

respectiv

ely143g

and021g

polyph

enolsp

erday


6weeks

FMDdidno

tdiffer

betweenthe

polyph

enol-richandthe

polyph

enol-poo

rapp

lesneith

erdidtheo

ther

cardiovascular

diseaser

iskfactors(plasma

lipidsho

mocysteineand

antio

xidant

capacity)

2010

[50]

3

Openprospective

rand

omized

crossover

controlledfeeding

trial

40(F=21

M=19)

28plusmn11

Rawtomatoeskg

(70g

)35g


tomato

saucew

ithrefin

edoliveo

ilkg

and025

gof

sugarsolvedin

waterkg

Health

ycontrol

12days

Tomatosaucee

nrichedwith

refin

edoliveo

ilcanregu

late

lipid

profi

leandsoluble

inflammatorybiom

arkersbette

rthan

rawtomatoeso

rtom

ato

sauces

2016

[51]

4Dou

ble-blind

controlled

rand

omized

trial

F=79

56plusmn4

Genisteinfro

msoybeans

(54m


therapy(1mgday)

estro

genprogestin

combined

with

norethisteron

eacetate

(05mgday)

Health

ypo

stmenop

ausal

wom

en1y

ear

Genisteintherapyim

proved

endo

thelium

functio

nsim

ilarto

estro

genprogestin

regimen

2003

[52]

5Dou

ble-blinded

placebo-controlled

crossovertria

l

93(F=51

M=42)

25ndash6

5Quercetinday

from

fruitsand

vegetables

ources

(150

mg)

Overw

eighto

bese

6weeks

Redu

cedSB

Pandplasma

oxidized

LDLlevelw

itha

high

-CVDris

kph

enotype

2009

[53]

6

Dou

ble-blinded

rand

omized

placebo-controlled

crossovertria

l

M=31

35ndash51

Antho

cyaninsfrom

fruitsand

vegetables

ources

(640

mgday)

Prehypertensive

4weeks

HDL-Candbloo

dglucosew

ere

significantly

high

eraft

eranthocyaninversus

placebo


119901=0024resp)

2013

[54]

7

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

105

20ndash6

0One

350m

gwho

rtleberryextract

capsulee

very

8ho

urs

Hyperlip

idem

ic2mon

ths

Lowered

total-C

(119901lt0001)

TG(119901=0002)andLD

L-C

(119901=0002)b

utincreased


comparedwith

thep

lacebo

grou

patthee

ndpo

int

2014

[55]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

8

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

50ge1845plusmn2mgof

anthocyaninfro

mVa

ccinium

arctostaphylos

Lfruit

extract

Hyperlip

idem

ic4weeks

Sign

ificantlyredu

cedtotal-C

(119901lt0001)LD

L-C(119901=0004)


(119901=0013)com

paredto

placebo

2014

[56]

9

Rand

omized

controlled

investigator

blinded

parallel-g

roup

trial

NCT

00421499

44(F=24

M=20)

56ndash73

Darkchocolate(63g

day)

containing

30mgof

polyph

enols

Stage-1h

ypertensive

18weeks

Redu

cedmean(SD)S

BPby

29

(16)m

mHg(119901lt0001)a

ndDBP

by19

(10)m

mHg

(119901lt0001)

2007

[57]

10

Rand

omized

placebo-controlled

single-blind

crossovertria

lNCT

00538083

45(F=35

M=10)

30ndash75

Inph

ase1solid

dark

chocolate

bar(containing

22gcocoa

powder)or

acocoa-fr

eeplacebo

barIn

phase2

sug

ar-fr

eecocoa

(con

taining22

gcocoap

owder)

sugaredcocoa(

containing

22g

cocoap

owder)ora

placebo

Health

ycontrol

1week

Thea

cuteingestionof

both

solid

dark

chocolatea

ndliq

uid

cocoaimproved

endo

thelial

functio

nandlowered

bloo

dpressure

inoverweightadu

lts

2008

[58]

Diabetesm

ellitu

s(DM)

11Openlabel

rand

omized

clinicaltria

l60

35ndash55

Standard

metform

intherapy

with

turm

eric(2g)

supp

lements

Standard

metform

intre

atment

4weeks

Turm

ericadministered

grou

psig

nificantly


thelipid

peroxidatio

nMDA


PHbA

1cand

fastingbloo

dglucoselevels

andenhanced

the

totalantioxidant

status

2015

[59]

12

Rand

omized

doub

le-blin

dcontrolledclinical

trial

7030ndash70

Powderedrhizom

eofginger

(160

0mg)

Wheatflo

urplacebo

(160

0mg)

12weeks

Gingersignificantly

redu

cedthe

fastingplasmag

lucoseH

bA1c

insulin

trig

lycerid

etotal

cholesterolCR

PandPG

E2

2014

[60]

13Ra

ndom

ized

triple-blin

dcontrolledtrial

M=35

60plusmn11

Capsuleo

f350

mgof

RES

enric

hedgrapee

xtract(G

E)

350m

gof

capsules

containing

either

maltodextrin

(placebo

)orR

ESlackingGE

12mon

ths

RESenric

hedGE

downregulated

the

proinfl

ammatorycytokines

expressio

nviainvolving

the


miRsin

circulatingim

mun

ecells

2013

[61]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

14Ra

ndom

ized

doub

le-blin

dcontrolledtrial

36(F=23

M=13)515plusmn100

FDSbeverage

of2cups

(50g

ofFD

Sisequivalent

to500g

offre

shstr

awberries)

Placebopo

wderw

ithstr

awberryflavor

6weeks

FDSsig

nificantly

(119901lt005)

decreasedtheC

RPlevelsand

lipid

peroxidatio

n(m

ainly

MDA)a

ndincreasedthetotal

antio

xidant

status

2013

[62]

15Ra

ndom

ized

doub

le-blin

dcontrolledtrial

6438ndash6

5Gingersup

plem

entatio

nPlacebo

8weeks

Gingersup

plem

entatio

nsig

nificantly

redu

cedthe

TNF-120572C

RPand

IL-6

levels

2013

[63]

16Ra

ndom

ized

doub

le-blin

dclinicaltria

l81

18ndash6

0BS

Pat10gday(119899=27)B

SPat

5gday

(119899=29)

Placebo

4weeks

BSPsig

nificantly

decreasedthe

MDAO

SIand

oxidized

low

density

lipop

rotein

cholesterol

andincreasedtheT

AC

2011[64]

17Dou

ble-blinded

rand

omized

crossovertria

l

32(M=16

F=16)618plusmn64

GSE

(600

mgday)

Placebo

4weeks

GSE

significantly

improved

the


ainly

CRP)glycemiaand

oxidative

stress

2009

[65]


18Ra

ndom

ized

single-blindpilot

study

45(F=38

M=7)478plusmn86

Curcum

in(500

mg)

and

diclo

fenacs

odium

(50m

g)alon

eor

incombinatio

n

Diclofenacs

odium

(anti-infl

ammatory

drug)

8weeks

Curcum

inalon

eprovedto

bethem


andsafestto

attenu

ateR

Acomplications

2012

[66]

19

Rand

omized

doub

le-blin

dplacebo-controlled

crossoverstudy

20(F=19

M=1)521plusmn103

Quercetin

(166

mgcapsule)+

vitamin

C(133

mgcapsule)

120572-lipo

icacid

(300

mgcapsule)

Placebo

6weeks

Nosig

nificantd

ifference

was

foun

dam

ongthe

proinfl

ammatorycytokines

however

quercetin

tend

edto

redu

ceVA

Sof

RA

2009

[67]

20

Rand

omized

doub

le-blin

dplacebo-controlled

study

105

55ndash75

Polyph

enolic-richolivee

xtract

Placebo

8weeks

Sign

ificant

(119901lt001)d

ecrease

ofplasmah

omocysteinelevel

(respo

nsibleforc

ardiovascular

complications

inRA

)and

notabler

eductio

nof

CRPwere

observed

2007

[68]

FfemaleMm

aleRA

rheum

atoidarthritis

VASvisualanalogue

scaleNR

notreported

CRP

C-reactiv

eprotein

RESresveratrolGE


AsFD

Sfre

eze-driedstr

awberryMDA

malon

dialdehydeG

SEgrape

seed

extractBS

Pbroccolisproutsp

owderOSIoxidativ

estr

essind

exT

ACtotalantio

xidant

capacityP

GE2

prostagland

inE2

HbA

1cglycosylated

hemoglobin

CADcoron

ary

artery

diseaseLD

L-C

lowdensity

lipop

rotein

cholesterolHDL-C

high

density

lipop

rotein

cholesterolSB

Psysto

licbloo

dpressure










4 Diabetes Mellitus








































































6 Conclusion


Appendix

Search Strategy











Competing Interests




Acknowledgments


References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

5Isosorbide

dinitrate

(Dilatrate-SR

)


NOwhich

activ

ates

thee

nzym

eguanylate

cyclasethatstim

ulates

thes

ynthesisof

cGMPwhich

then

activ

ates

aserieso

fprotein

kinase-dependent

phosph

orylations

inthe

smoo

thmuscle

cells

eventuallyresulting

invasodilatio

n

(i)Headache

(ii)D

izziness

(iii)Lightheadedn

ess

(iv)N

ausea

(v)F

lushing

(vi)Unu

sualbleeding

(vii)

Bruisin

g(viii)R

apid

heartrate

(ix)D

ifficulty

with

breathing

Diabetesm

ellitu

s

1Metform

in(G

lucoph

age)

(i)Ac

tivatingAMPK

toinhibith

epaticglucosep

rodu

ction

(ii)IncreasingAMPK

activ

ityin

skeletalmuscle

forg

lucose

uptake

byGLU

T4deploymenttothep

lasm

amem

brane

(i)Lacticacidosis

(ii)D

yspepsia

(iii)Nausea

(iv)D

iarrhea

(v)V

omiting

(vi)Weakn

ess

2Pioglitazon

e(A

ctos)

(i)Ac

tivatingPP

AR120574

receptorstomod

ulatethe

insulin

-sensitive

genestranscriptio

nforthe

redu

ctionof

insulin

resistance

(i)Weightg

ain

(ii)R

iskof

bladderc

ancer

(iii)Sore

throat

(iv)M

uscle

pain

(v)T

ooth

prob

lems

(vi)May

causeh

eartfailu

re(vii)

Fluidretention

(viii)P

eripheraledema

3Glib

encla

mide

(DiaBe

ta)

(i)Bind

ingandinhibitin

gtheA

TP-sensitivep

otassiu

mchannels

SUR1

receptor

onthep

ancreatic

cellsurfa

cew

hich

causes

mem

braned

epolarizationandop

ensthe

calcium

channelsfor

insulin

exocytosis

(i)Nausea

(ii)V

omiting

(iii)Diarrhea

(iv)Increased

appetite

(v)H

eartbu

rn(vi)Stom

achfulln

ess

(vii)

Weightg

ain

(viii)H

ypoglycemia

4Ac

arbo

se(Precose)

(i)Re

versiblybind

ingto


ndintestinal

120572-glucosid


hydrolysisof

complex

carboh

ydratestoglucose

(i)Diarrhea

(ii)G

as(iii)Upsetsto

mach

(iv)C

onstipatio

n(v)S

tomachpain

(vi)Nausea

(vii)

Lossof

appetite

(viii)Jaund

ice


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

5Hum

aninsulin

(Hum

ulin

R)

(i)Bind

ingto


ownstre

amsig

nalin

gmolecules

which

regu

latesthe

GLU

4andPK

Cactiv

ity

(i)Pain

(ii)M

ilditching

(iii)Re

dness

(iv)S

wellin

gattheinjectio

nsite

(v)M

ildweightg

ain

(vi)Hypoglycemia

Rheumatoidarthritis

1Metho

trexate

(Trexall)

(i)Inhibitin

gdihydrofolater

eductase

which

isinvolved

inpu

rine

metabolism

(ii)Inh

ibiting

T-cellactiv

ation

(iii)Selectively


(iv)Inh

ibiting

methyltransfe

rase

activ

ityw

hich

leadsto

deactiv

ationof

immun

esystem

enzymea

ctivities

(i)Nausea

(ii)B

lood

yvomiting

(iii)Stom

achpain

(iv)D

rowsin

ess

(v)D

izziness

(vi)Blacktarrysto

ols

(vii)

Soresinthem

outh

orlip

s(viii)B

lurred

visio

n(ix

)Con

fusio

n(x)C

onvulsion

s

2Hydroxychloroqu

ine

(Quineprox)

(i)Inhibitin

gstimulationof

theT

LR-9

(ii)Inh

ibiting

thep

rodu

ctionof

rheumatoidfactor

(i)Nausea

(ii)S

tomachcram

ps(iii)Lo

ssof

appetite

(iv)D

iarrhea

(v)D

izziness

(vi)Headache

(vii)

Con

vulsion

s(viii)W

eakn

ess

(ix)S

orethroat

(x)F

ever

(xi)Unu

sualbleeding

(xii)

Bruisin

g


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

3Sulfasalazine

(Azulfidine)

(i)Inhibitin



immun

omod

ulatoryactiv

ities

(i)Stom

achup

set

(ii)N

ausea

(iii)Vo

miting

(iv)L

osso

fapp

etite

(v)H

eadache

(vi)Dizziness

(vii)

Unu

sualtiredness

(viii)F

ever

(ix)S

orethroat

(x)S

kinrash

oritching

(xi)Bleeding

gums

(xii)

Darkurine

4Leflu

nomide

(Arava)

(i)Inhibitin

gmito

chon

drialenzym

edihydroorotate

dehydrogenasea

ndthus

inhibitin

gther

eprodu

ctionof

rapidly

dividing

cellsespecially

autoim

mun

elym

phocytes

(i)Diarrhea

(ii)N

ausea

(iii)Dizziness

(iv)S

kinrash

(v)A

lopecia

(vi)ASTuarr

(vii)

ALTuarr

(viii)B

lood

yor

cloud

yurine

(ix)C

ough

(x)H

eadache

(xi)Vo

miting

(xii)

Sore

throat

5Certolizum

ab(C

imzia)

(i)Bind


ctivity

ofTN

F120572(ii)Inh

ibiting

ther

elease

ofIL-1120573fro

mmon

ocytes

(i)Fever

(ii)C

ough

(iii)Sore

throat

(iv)R

unny

nose

(v)F

requ

entu

rinationwith

burningsensation

(vi)Jointp

ain

(vii)

Body

aches

(viii)H

eadache

(ix)L

osso

fvoice

(x)E

arcongestio

nAMPK

AMP-activ

ated

proteinkinaseG

LUT4

glucose

transporter4


1IRinsulin

receptorP

KCprotein

kinase

CPP

AR120574

peroxiso

mep


receptor

gammaAT

Padenosinetripho

sphateT

XA2thrombo

xane

A2CO

Xcyclo

oxygenaseAST

aspartate

aminotransferaseA

LTalanine

aminotransferaseA

CEang

iotensin

convertin

genzymeNOn

itricoxidecG

MP

cyclic

guanosine3101584051015840-m

onop

hosphate


Table2Ev

idence

ofclinicaltria

lswith

naturalprodu

ctsa

ttenu

atingoxidatives


patie

ntsw

ithCV

DD

Mand

RA

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

Cardiovascular

disease(CV

D)

1Ra

ndom

ized

controlled

crossovertria

l

30(F=24

M=6)473plusmn136

Con

trolapplespinachand

apple+

spinach

Health

ycontrol

4weeks

Alltre

atmentsshow

edhigh

erflo

w-m

ediateddilatation

(FMD)(119901lt005)a

ndlower

pulse

pressure

(119901lt005)a

ndapplea

ndspinachresultedin

lower

systo

licbloo

dpressure

(119901lt005)

2012

[49]

2Dou

ble-blind

rand

omized

crossovertria

lM=30526plusmn55

Twolyop

hilized

apples

(40g

)po

lyph

enol-richand

polyph

enol-poo

rproviding

respectiv

ely143g

and021g

polyph

enolsp

erday


6weeks

FMDdidno

tdiffer

betweenthe

polyph

enol-richandthe

polyph

enol-poo

rapp

lesneith

erdidtheo

ther

cardiovascular

diseaser

iskfactors(plasma

lipidsho

mocysteineand

antio

xidant

capacity)

2010

[50]

3

Openprospective

rand

omized

crossover

controlledfeeding

trial

40(F=21

M=19)

28plusmn11

Rawtomatoeskg

(70g

)35g


tomato

saucew

ithrefin

edoliveo

ilkg

and025

gof

sugarsolvedin

waterkg

Health

ycontrol

12days

Tomatosaucee

nrichedwith

refin

edoliveo

ilcanregu

late

lipid

profi

leandsoluble

inflammatorybiom

arkersbette

rthan

rawtomatoeso

rtom

ato

sauces

2016

[51]

4Dou

ble-blind

controlled

rand

omized

trial

F=79

56plusmn4

Genisteinfro

msoybeans

(54m


therapy(1mgday)

estro

genprogestin

combined

with

norethisteron

eacetate

(05mgday)

Health

ypo

stmenop

ausal

wom

en1y

ear

Genisteintherapyim

proved

endo

thelium

functio

nsim

ilarto

estro

genprogestin

regimen

2003

[52]

5Dou

ble-blinded

placebo-controlled

crossovertria

l

93(F=51

M=42)

25ndash6

5Quercetinday

from

fruitsand

vegetables

ources

(150

mg)

Overw

eighto

bese

6weeks

Redu

cedSB

Pandplasma

oxidized

LDLlevelw

itha

high

-CVDris

kph

enotype

2009

[53]

6

Dou

ble-blinded

rand

omized

placebo-controlled

crossovertria

l

M=31

35ndash51

Antho

cyaninsfrom

fruitsand

vegetables

ources

(640

mgday)

Prehypertensive

4weeks

HDL-Candbloo

dglucosew

ere

significantly

high

eraft

eranthocyaninversus

placebo


119901=0024resp)

2013

[54]

7

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

105

20ndash6

0One

350m

gwho

rtleberryextract

capsulee

very

8ho

urs

Hyperlip

idem

ic2mon

ths

Lowered

total-C

(119901lt0001)

TG(119901=0002)andLD

L-C

(119901=0002)b

utincreased


comparedwith

thep

lacebo

grou

patthee

ndpo

int

2014

[55]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

8

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

50ge1845plusmn2mgof

anthocyaninfro

mVa

ccinium

arctostaphylos

Lfruit

extract

Hyperlip

idem

ic4weeks

Sign

ificantlyredu

cedtotal-C

(119901lt0001)LD

L-C(119901=0004)


(119901=0013)com

paredto

placebo

2014

[56]

9

Rand

omized

controlled

investigator

blinded

parallel-g

roup

trial

NCT

00421499

44(F=24

M=20)

56ndash73

Darkchocolate(63g

day)

containing

30mgof

polyph

enols

Stage-1h

ypertensive

18weeks

Redu

cedmean(SD)S

BPby

29

(16)m

mHg(119901lt0001)a

ndDBP

by19

(10)m

mHg

(119901lt0001)

2007

[57]

10

Rand

omized

placebo-controlled

single-blind

crossovertria

lNCT

00538083

45(F=35

M=10)

30ndash75

Inph

ase1solid

dark

chocolate

bar(containing

22gcocoa

powder)or

acocoa-fr

eeplacebo

barIn

phase2

sug

ar-fr

eecocoa

(con

taining22

gcocoap

owder)

sugaredcocoa(

containing

22g

cocoap

owder)ora

placebo

Health

ycontrol

1week

Thea

cuteingestionof

both

solid

dark

chocolatea

ndliq

uid

cocoaimproved

endo

thelial

functio

nandlowered

bloo

dpressure

inoverweightadu

lts

2008

[58]

Diabetesm

ellitu

s(DM)

11Openlabel

rand

omized

clinicaltria

l60

35ndash55

Standard

metform

intherapy

with

turm

eric(2g)

supp

lements

Standard

metform

intre

atment

4weeks

Turm

ericadministered

grou

psig

nificantly


thelipid

peroxidatio

nMDA


PHbA

1cand

fastingbloo

dglucoselevels

andenhanced

the

totalantioxidant

status

2015

[59]

12

Rand

omized

doub

le-blin

dcontrolledclinical

trial

7030ndash70

Powderedrhizom

eofginger

(160

0mg)

Wheatflo

urplacebo

(160

0mg)

12weeks

Gingersignificantly

redu

cedthe

fastingplasmag

lucoseH

bA1c

insulin

trig

lycerid

etotal

cholesterolCR

PandPG

E2

2014

[60]

13Ra

ndom

ized

triple-blin

dcontrolledtrial

M=35

60plusmn11

Capsuleo

f350

mgof

RES

enric

hedgrapee

xtract(G

E)

350m

gof

capsules

containing

either

maltodextrin

(placebo

)orR

ESlackingGE

12mon

ths

RESenric

hedGE

downregulated

the

proinfl

ammatorycytokines

expressio

nviainvolving

the


miRsin

circulatingim

mun

ecells

2013

[61]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

14Ra

ndom

ized

doub

le-blin

dcontrolledtrial

36(F=23

M=13)515plusmn100

FDSbeverage

of2cups

(50g

ofFD

Sisequivalent

to500g

offre

shstr

awberries)

Placebopo

wderw

ithstr

awberryflavor

6weeks

FDSsig

nificantly

(119901lt005)

decreasedtheC

RPlevelsand

lipid

peroxidatio

n(m

ainly

MDA)a

ndincreasedthetotal

antio

xidant

status

2013

[62]

15Ra

ndom

ized

doub

le-blin

dcontrolledtrial

6438ndash6

5Gingersup

plem

entatio

nPlacebo

8weeks

Gingersup

plem

entatio

nsig

nificantly

redu

cedthe

TNF-120572C

RPand

IL-6

levels

2013

[63]

16Ra

ndom

ized

doub

le-blin

dclinicaltria

l81

18ndash6

0BS

Pat10gday(119899=27)B

SPat

5gday

(119899=29)

Placebo

4weeks

BSPsig

nificantly

decreasedthe

MDAO

SIand

oxidized

low

density

lipop

rotein

cholesterol

andincreasedtheT

AC

2011[64]

17Dou

ble-blinded

rand

omized

crossovertria

l

32(M=16

F=16)618plusmn64

GSE

(600

mgday)

Placebo

4weeks

GSE

significantly

improved

the


ainly

CRP)glycemiaand

oxidative

stress

2009

[65]


18Ra

ndom

ized

single-blindpilot

study

45(F=38

M=7)478plusmn86

Curcum

in(500

mg)

and

diclo

fenacs

odium

(50m

g)alon

eor

incombinatio

n

Diclofenacs

odium

(anti-infl

ammatory

drug)

8weeks

Curcum

inalon

eprovedto

bethem


andsafestto

attenu

ateR

Acomplications

2012

[66]

19

Rand

omized

doub

le-blin

dplacebo-controlled

crossoverstudy

20(F=19

M=1)521plusmn103

Quercetin

(166

mgcapsule)+

vitamin

C(133

mgcapsule)

120572-lipo

icacid

(300

mgcapsule)

Placebo

6weeks

Nosig

nificantd

ifference

was

foun

dam

ongthe

proinfl

ammatorycytokines

however

quercetin

tend

edto

redu

ceVA

Sof

RA

2009

[67]

20

Rand

omized

doub

le-blin

dplacebo-controlled

study

105

55ndash75

Polyph

enolic-richolivee

xtract

Placebo

8weeks

Sign

ificant

(119901lt001)d

ecrease

ofplasmah

omocysteinelevel

(respo

nsibleforc

ardiovascular

complications

inRA

)and

notabler

eductio

nof

CRPwere

observed

2007

[68]

FfemaleMm

aleRA

rheum

atoidarthritis

VASvisualanalogue

scaleNR

notreported

CRP

C-reactiv

eprotein

RESresveratrolGE


AsFD

Sfre

eze-driedstr

awberryMDA

malon

dialdehydeG

SEgrape

seed

extractBS

Pbroccolisproutsp

owderOSIoxidativ

estr

essind

exT

ACtotalantio

xidant

capacityP

GE2

prostagland

inE2

HbA

1cglycosylated

hemoglobin

CADcoron

ary

artery

diseaseLD

L-C

lowdensity

lipop

rotein

cholesterolHDL-C

high

density

lipop

rotein

cholesterolSB

Psysto

licbloo

dpressure










4 Diabetes Mellitus








































































6 Conclusion


Appendix

Search Strategy











Competing Interests




Acknowledgments


References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

5Hum

aninsulin

(Hum

ulin

R)

(i)Bind

ingto


ownstre

amsig

nalin

gmolecules

which

regu

latesthe

GLU

4andPK

Cactiv

ity

(i)Pain

(ii)M

ilditching

(iii)Re

dness

(iv)S

wellin

gattheinjectio

nsite

(v)M

ildweightg

ain

(vi)Hypoglycemia

Rheumatoidarthritis

1Metho

trexate

(Trexall)

(i)Inhibitin

gdihydrofolater

eductase

which

isinvolved

inpu

rine

metabolism

(ii)Inh

ibiting

T-cellactiv

ation

(iii)Selectively


(iv)Inh

ibiting

methyltransfe

rase

activ

ityw

hich

leadsto

deactiv

ationof

immun

esystem

enzymea

ctivities

(i)Nausea

(ii)B

lood

yvomiting

(iii)Stom

achpain

(iv)D

rowsin

ess

(v)D

izziness

(vi)Blacktarrysto

ols

(vii)

Soresinthem

outh

orlip

s(viii)B

lurred

visio

n(ix

)Con

fusio

n(x)C

onvulsion

s

2Hydroxychloroqu

ine

(Quineprox)

(i)Inhibitin

gstimulationof

theT

LR-9

(ii)Inh

ibiting

thep

rodu

ctionof

rheumatoidfactor

(i)Nausea

(ii)S

tomachcram

ps(iii)Lo

ssof

appetite

(iv)D

iarrhea

(v)D

izziness

(vi)Headache

(vii)

Con

vulsion

s(viii)W

eakn

ess

(ix)S

orethroat

(x)F

ever

(xi)Unu

sualbleeding

(xii)

Bruisin

g


Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

3Sulfasalazine

(Azulfidine)

(i)Inhibitin



immun

omod

ulatoryactiv

ities

(i)Stom

achup

set

(ii)N

ausea

(iii)Vo

miting

(iv)L

osso

fapp

etite

(v)H

eadache

(vi)Dizziness

(vii)

Unu

sualtiredness

(viii)F

ever

(ix)S

orethroat

(x)S

kinrash

oritching

(xi)Bleeding

gums

(xii)

Darkurine

4Leflu

nomide

(Arava)

(i)Inhibitin

gmito

chon

drialenzym

edihydroorotate

dehydrogenasea

ndthus

inhibitin

gther

eprodu

ctionof

rapidly

dividing

cellsespecially

autoim

mun

elym

phocytes

(i)Diarrhea

(ii)N

ausea

(iii)Dizziness

(iv)S

kinrash

(v)A

lopecia

(vi)ASTuarr

(vii)

ALTuarr

(viii)B

lood

yor

cloud

yurine

(ix)C

ough

(x)H

eadache

(xi)Vo

miting

(xii)

Sore

throat

5Certolizum

ab(C

imzia)

(i)Bind


ctivity

ofTN

F120572(ii)Inh

ibiting

ther

elease

ofIL-1120573fro

mmon

ocytes

(i)Fever

(ii)C

ough

(iii)Sore

throat

(iv)R

unny

nose

(v)F

requ

entu

rinationwith

burningsensation

(vi)Jointp

ain

(vii)

Body

aches

(viii)H

eadache

(ix)L

osso

fvoice

(x)E

arcongestio

nAMPK

AMP-activ

ated

proteinkinaseG

LUT4

glucose

transporter4


1IRinsulin

receptorP

KCprotein

kinase

CPP

AR120574

peroxiso

mep


receptor

gammaAT

Padenosinetripho

sphateT

XA2thrombo

xane

A2CO

Xcyclo

oxygenaseAST

aspartate

aminotransferaseA

LTalanine

aminotransferaseA

CEang

iotensin

convertin

genzymeNOn

itricoxidecG

MP

cyclic

guanosine3101584051015840-m

onop

hosphate


Table2Ev

idence

ofclinicaltria

lswith

naturalprodu

ctsa

ttenu

atingoxidatives


patie

ntsw

ithCV

DD

Mand

RA

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

Cardiovascular

disease(CV

D)

1Ra

ndom

ized

controlled

crossovertria

l

30(F=24

M=6)473plusmn136

Con

trolapplespinachand

apple+

spinach

Health

ycontrol

4weeks

Alltre

atmentsshow

edhigh

erflo

w-m

ediateddilatation

(FMD)(119901lt005)a

ndlower

pulse

pressure

(119901lt005)a

ndapplea

ndspinachresultedin

lower

systo

licbloo

dpressure

(119901lt005)

2012

[49]

2Dou

ble-blind

rand

omized

crossovertria

lM=30526plusmn55

Twolyop

hilized

apples

(40g

)po

lyph

enol-richand

polyph

enol-poo

rproviding

respectiv

ely143g

and021g

polyph

enolsp

erday


6weeks

FMDdidno

tdiffer

betweenthe

polyph

enol-richandthe

polyph

enol-poo

rapp

lesneith

erdidtheo

ther

cardiovascular

diseaser

iskfactors(plasma

lipidsho

mocysteineand

antio

xidant

capacity)

2010

[50]

3

Openprospective

rand

omized

crossover

controlledfeeding

trial

40(F=21

M=19)

28plusmn11

Rawtomatoeskg

(70g

)35g


tomato

saucew

ithrefin

edoliveo

ilkg

and025

gof

sugarsolvedin

waterkg

Health

ycontrol

12days

Tomatosaucee

nrichedwith

refin

edoliveo

ilcanregu

late

lipid

profi

leandsoluble

inflammatorybiom

arkersbette

rthan

rawtomatoeso

rtom

ato

sauces

2016

[51]

4Dou

ble-blind

controlled

rand

omized

trial

F=79

56plusmn4

Genisteinfro

msoybeans

(54m


therapy(1mgday)

estro

genprogestin

combined

with

norethisteron

eacetate

(05mgday)

Health

ypo

stmenop

ausal

wom

en1y

ear

Genisteintherapyim

proved

endo

thelium

functio

nsim

ilarto

estro

genprogestin

regimen

2003

[52]

5Dou

ble-blinded

placebo-controlled

crossovertria

l

93(F=51

M=42)

25ndash6

5Quercetinday

from

fruitsand

vegetables

ources

(150

mg)

Overw

eighto

bese

6weeks

Redu

cedSB

Pandplasma

oxidized

LDLlevelw

itha

high

-CVDris

kph

enotype

2009

[53]

6

Dou

ble-blinded

rand

omized

placebo-controlled

crossovertria

l

M=31

35ndash51

Antho

cyaninsfrom

fruitsand

vegetables

ources

(640

mgday)

Prehypertensive

4weeks

HDL-Candbloo

dglucosew

ere

significantly

high

eraft

eranthocyaninversus

placebo


119901=0024resp)

2013

[54]

7

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

105

20ndash6

0One

350m

gwho

rtleberryextract

capsulee

very

8ho

urs

Hyperlip

idem

ic2mon

ths

Lowered

total-C

(119901lt0001)

TG(119901=0002)andLD

L-C

(119901=0002)b

utincreased


comparedwith

thep

lacebo

grou

patthee

ndpo

int

2014

[55]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

8

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

50ge1845plusmn2mgof

anthocyaninfro

mVa

ccinium

arctostaphylos

Lfruit

extract

Hyperlip

idem

ic4weeks

Sign

ificantlyredu

cedtotal-C

(119901lt0001)LD

L-C(119901=0004)


(119901=0013)com

paredto

placebo

2014

[56]

9

Rand

omized

controlled

investigator

blinded

parallel-g

roup

trial

NCT

00421499

44(F=24

M=20)

56ndash73

Darkchocolate(63g

day)

containing

30mgof

polyph

enols

Stage-1h

ypertensive

18weeks

Redu

cedmean(SD)S

BPby

29

(16)m

mHg(119901lt0001)a

ndDBP

by19

(10)m

mHg

(119901lt0001)

2007

[57]

10

Rand

omized

placebo-controlled

single-blind

crossovertria

lNCT

00538083

45(F=35

M=10)

30ndash75

Inph

ase1solid

dark

chocolate

bar(containing

22gcocoa

powder)or

acocoa-fr

eeplacebo

barIn

phase2

sug

ar-fr

eecocoa

(con

taining22

gcocoap

owder)

sugaredcocoa(

containing

22g

cocoap

owder)ora

placebo

Health

ycontrol

1week

Thea

cuteingestionof

both

solid

dark

chocolatea

ndliq

uid

cocoaimproved

endo

thelial

functio

nandlowered

bloo

dpressure

inoverweightadu

lts

2008

[58]

Diabetesm

ellitu

s(DM)

11Openlabel

rand

omized

clinicaltria

l60

35ndash55

Standard

metform

intherapy

with

turm

eric(2g)

supp

lements

Standard

metform

intre

atment

4weeks

Turm

ericadministered

grou

psig

nificantly


thelipid

peroxidatio

nMDA


PHbA

1cand

fastingbloo

dglucoselevels

andenhanced

the

totalantioxidant

status

2015

[59]

12

Rand

omized

doub

le-blin

dcontrolledclinical

trial

7030ndash70

Powderedrhizom

eofginger

(160

0mg)

Wheatflo

urplacebo

(160

0mg)

12weeks

Gingersignificantly

redu

cedthe

fastingplasmag

lucoseH

bA1c

insulin

trig

lycerid

etotal

cholesterolCR

PandPG

E2

2014

[60]

13Ra

ndom

ized

triple-blin

dcontrolledtrial

M=35

60plusmn11

Capsuleo

f350

mgof

RES

enric

hedgrapee

xtract(G

E)

350m

gof

capsules

containing

either

maltodextrin

(placebo

)orR

ESlackingGE

12mon

ths

RESenric

hedGE

downregulated

the

proinfl

ammatorycytokines

expressio

nviainvolving

the


miRsin

circulatingim

mun

ecells

2013

[61]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

14Ra

ndom

ized

doub

le-blin

dcontrolledtrial

36(F=23

M=13)515plusmn100

FDSbeverage

of2cups

(50g

ofFD

Sisequivalent

to500g

offre

shstr

awberries)

Placebopo

wderw

ithstr

awberryflavor

6weeks

FDSsig

nificantly

(119901lt005)

decreasedtheC

RPlevelsand

lipid

peroxidatio

n(m

ainly

MDA)a

ndincreasedthetotal

antio

xidant

status

2013

[62]

15Ra

ndom

ized

doub

le-blin

dcontrolledtrial

6438ndash6

5Gingersup

plem

entatio

nPlacebo

8weeks

Gingersup

plem

entatio

nsig

nificantly

redu

cedthe

TNF-120572C

RPand

IL-6

levels

2013

[63]

16Ra

ndom

ized

doub

le-blin

dclinicaltria

l81

18ndash6

0BS

Pat10gday(119899=27)B

SPat

5gday

(119899=29)

Placebo

4weeks

BSPsig

nificantly

decreasedthe

MDAO

SIand

oxidized

low

density

lipop

rotein

cholesterol

andincreasedtheT

AC

2011[64]

17Dou

ble-blinded

rand

omized

crossovertria

l

32(M=16

F=16)618plusmn64

GSE

(600

mgday)

Placebo

4weeks

GSE

significantly

improved

the


ainly

CRP)glycemiaand

oxidative

stress

2009

[65]


18Ra

ndom

ized

single-blindpilot

study

45(F=38

M=7)478plusmn86

Curcum

in(500

mg)

and

diclo

fenacs

odium

(50m

g)alon

eor

incombinatio

n

Diclofenacs

odium

(anti-infl

ammatory

drug)

8weeks

Curcum

inalon

eprovedto

bethem


andsafestto

attenu

ateR

Acomplications

2012

[66]

19

Rand

omized

doub

le-blin

dplacebo-controlled

crossoverstudy

20(F=19

M=1)521plusmn103

Quercetin

(166

mgcapsule)+

vitamin

C(133

mgcapsule)

120572-lipo

icacid

(300

mgcapsule)

Placebo

6weeks

Nosig

nificantd

ifference

was

foun

dam

ongthe

proinfl

ammatorycytokines

however

quercetin

tend

edto

redu

ceVA

Sof

RA

2009

[67]

20

Rand

omized

doub

le-blin

dplacebo-controlled

study

105

55ndash75

Polyph

enolic-richolivee

xtract

Placebo

8weeks

Sign

ificant

(119901lt001)d

ecrease

ofplasmah

omocysteinelevel

(respo

nsibleforc

ardiovascular

complications

inRA

)and

notabler

eductio

nof

CRPwere

observed

2007

[68]

FfemaleMm

aleRA

rheum

atoidarthritis

VASvisualanalogue

scaleNR

notreported

CRP

C-reactiv

eprotein

RESresveratrolGE


AsFD

Sfre

eze-driedstr

awberryMDA

malon

dialdehydeG

SEgrape

seed

extractBS

Pbroccolisproutsp

owderOSIoxidativ

estr

essind

exT

ACtotalantio

xidant

capacityP

GE2

prostagland

inE2

HbA

1cglycosylated

hemoglobin

CADcoron

ary

artery

diseaseLD

L-C

lowdensity

lipop

rotein

cholesterolHDL-C

high

density

lipop

rotein

cholesterolSB

Psysto

licbloo

dpressure










4 Diabetes Mellitus








































































6 Conclusion


Appendix

Search Strategy











Competing Interests




Acknowledgments


References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table1Con

tinued

Num

ber

Drugs

(brand

names)

Mechanism

Side

effects

Structure

3Sulfasalazine

(Azulfidine)

(i)Inhibitin



immun

omod

ulatoryactiv

ities

(i)Stom

achup

set

(ii)N

ausea

(iii)Vo

miting

(iv)L

osso

fapp

etite

(v)H

eadache

(vi)Dizziness

(vii)

Unu

sualtiredness

(viii)F

ever

(ix)S

orethroat

(x)S

kinrash

oritching

(xi)Bleeding

gums

(xii)

Darkurine

4Leflu

nomide

(Arava)

(i)Inhibitin

gmito

chon

drialenzym

edihydroorotate

dehydrogenasea

ndthus

inhibitin

gther

eprodu

ctionof

rapidly

dividing

cellsespecially

autoim

mun

elym

phocytes

(i)Diarrhea

(ii)N

ausea

(iii)Dizziness

(iv)S

kinrash

(v)A

lopecia

(vi)ASTuarr

(vii)

ALTuarr

(viii)B

lood

yor

cloud

yurine

(ix)C

ough

(x)H

eadache

(xi)Vo

miting

(xii)

Sore

throat

5Certolizum

ab(C

imzia)

(i)Bind


ctivity

ofTN

F120572(ii)Inh

ibiting

ther

elease

ofIL-1120573fro

mmon

ocytes

(i)Fever

(ii)C

ough

(iii)Sore

throat

(iv)R

unny

nose

(v)F

requ

entu

rinationwith

burningsensation

(vi)Jointp

ain

(vii)

Body

aches

(viii)H

eadache

(ix)L

osso

fvoice

(x)E

arcongestio

nAMPK

AMP-activ

ated

proteinkinaseG

LUT4

glucose

transporter4


1IRinsulin

receptorP

KCprotein

kinase

CPP

AR120574

peroxiso

mep


receptor

gammaAT

Padenosinetripho

sphateT

XA2thrombo

xane

A2CO

Xcyclo

oxygenaseAST

aspartate

aminotransferaseA

LTalanine

aminotransferaseA

CEang

iotensin

convertin

genzymeNOn

itricoxidecG

MP

cyclic

guanosine3101584051015840-m

onop

hosphate


Table2Ev

idence

ofclinicaltria

lswith

naturalprodu

ctsa

ttenu

atingoxidatives


patie

ntsw

ithCV

DD

Mand

RA

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

Cardiovascular

disease(CV

D)

1Ra

ndom

ized

controlled

crossovertria

l

30(F=24

M=6)473plusmn136

Con

trolapplespinachand

apple+

spinach

Health

ycontrol

4weeks

Alltre

atmentsshow

edhigh

erflo

w-m

ediateddilatation

(FMD)(119901lt005)a

ndlower

pulse

pressure

(119901lt005)a

ndapplea

ndspinachresultedin

lower

systo

licbloo

dpressure

(119901lt005)

2012

[49]

2Dou

ble-blind

rand

omized

crossovertria

lM=30526plusmn55

Twolyop

hilized

apples

(40g

)po

lyph

enol-richand

polyph

enol-poo

rproviding

respectiv

ely143g

and021g

polyph

enolsp

erday


6weeks

FMDdidno

tdiffer

betweenthe

polyph

enol-richandthe

polyph

enol-poo

rapp

lesneith

erdidtheo

ther

cardiovascular

diseaser

iskfactors(plasma

lipidsho

mocysteineand

antio

xidant

capacity)

2010

[50]

3

Openprospective

rand

omized

crossover

controlledfeeding

trial

40(F=21

M=19)

28plusmn11

Rawtomatoeskg

(70g

)35g


tomato

saucew

ithrefin

edoliveo

ilkg

and025

gof

sugarsolvedin

waterkg

Health

ycontrol

12days

Tomatosaucee

nrichedwith

refin

edoliveo

ilcanregu

late

lipid

profi

leandsoluble

inflammatorybiom

arkersbette

rthan

rawtomatoeso

rtom

ato

sauces

2016

[51]

4Dou

ble-blind

controlled

rand

omized

trial

F=79

56plusmn4

Genisteinfro

msoybeans

(54m


therapy(1mgday)

estro

genprogestin

combined

with

norethisteron

eacetate

(05mgday)

Health

ypo

stmenop

ausal

wom

en1y

ear

Genisteintherapyim

proved

endo

thelium

functio

nsim

ilarto

estro

genprogestin

regimen

2003

[52]

5Dou

ble-blinded

placebo-controlled

crossovertria

l

93(F=51

M=42)

25ndash6

5Quercetinday

from

fruitsand

vegetables

ources

(150

mg)

Overw

eighto

bese

6weeks

Redu

cedSB

Pandplasma

oxidized

LDLlevelw

itha

high

-CVDris

kph

enotype

2009

[53]

6

Dou

ble-blinded

rand

omized

placebo-controlled

crossovertria

l

M=31

35ndash51

Antho

cyaninsfrom

fruitsand

vegetables

ources

(640

mgday)

Prehypertensive

4weeks

HDL-Candbloo

dglucosew

ere

significantly

high

eraft

eranthocyaninversus

placebo


119901=0024resp)

2013

[54]

7

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

105

20ndash6

0One

350m

gwho

rtleberryextract

capsulee

very

8ho

urs

Hyperlip

idem

ic2mon

ths

Lowered

total-C

(119901lt0001)

TG(119901=0002)andLD

L-C

(119901=0002)b

utincreased


comparedwith

thep

lacebo

grou

patthee

ndpo

int

2014

[55]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

8

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

50ge1845plusmn2mgof

anthocyaninfro

mVa

ccinium

arctostaphylos

Lfruit

extract

Hyperlip

idem

ic4weeks

Sign

ificantlyredu

cedtotal-C

(119901lt0001)LD

L-C(119901=0004)


(119901=0013)com

paredto

placebo

2014

[56]

9

Rand

omized

controlled

investigator

blinded

parallel-g

roup

trial

NCT

00421499

44(F=24

M=20)

56ndash73

Darkchocolate(63g

day)

containing

30mgof

polyph

enols

Stage-1h

ypertensive

18weeks

Redu

cedmean(SD)S

BPby

29

(16)m

mHg(119901lt0001)a

ndDBP

by19

(10)m

mHg

(119901lt0001)

2007

[57]

10

Rand

omized

placebo-controlled

single-blind

crossovertria

lNCT

00538083

45(F=35

M=10)

30ndash75

Inph

ase1solid

dark

chocolate

bar(containing

22gcocoa

powder)or

acocoa-fr

eeplacebo

barIn

phase2

sug

ar-fr

eecocoa

(con

taining22

gcocoap

owder)

sugaredcocoa(

containing

22g

cocoap

owder)ora

placebo

Health

ycontrol

1week

Thea

cuteingestionof

both

solid

dark

chocolatea

ndliq

uid

cocoaimproved

endo

thelial

functio

nandlowered

bloo

dpressure

inoverweightadu

lts

2008

[58]

Diabetesm

ellitu

s(DM)

11Openlabel

rand

omized

clinicaltria

l60

35ndash55

Standard

metform

intherapy

with

turm

eric(2g)

supp

lements

Standard

metform

intre

atment

4weeks

Turm

ericadministered

grou

psig

nificantly


thelipid

peroxidatio

nMDA


PHbA

1cand

fastingbloo

dglucoselevels

andenhanced

the

totalantioxidant

status

2015

[59]

12

Rand

omized

doub

le-blin

dcontrolledclinical

trial

7030ndash70

Powderedrhizom

eofginger

(160

0mg)

Wheatflo

urplacebo

(160

0mg)

12weeks

Gingersignificantly

redu

cedthe

fastingplasmag

lucoseH

bA1c

insulin

trig

lycerid

etotal

cholesterolCR

PandPG

E2

2014

[60]

13Ra

ndom

ized

triple-blin

dcontrolledtrial

M=35

60plusmn11

Capsuleo

f350

mgof

RES

enric

hedgrapee

xtract(G

E)

350m

gof

capsules

containing

either

maltodextrin

(placebo

)orR

ESlackingGE

12mon

ths

RESenric

hedGE

downregulated

the

proinfl

ammatorycytokines

expressio

nviainvolving

the


miRsin

circulatingim

mun

ecells

2013

[61]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

14Ra

ndom

ized

doub

le-blin

dcontrolledtrial

36(F=23

M=13)515plusmn100

FDSbeverage

of2cups

(50g

ofFD

Sisequivalent

to500g

offre

shstr

awberries)

Placebopo

wderw

ithstr

awberryflavor

6weeks

FDSsig

nificantly

(119901lt005)

decreasedtheC

RPlevelsand

lipid

peroxidatio

n(m

ainly

MDA)a

ndincreasedthetotal

antio

xidant

status

2013

[62]

15Ra

ndom

ized

doub

le-blin

dcontrolledtrial

6438ndash6

5Gingersup

plem

entatio

nPlacebo

8weeks

Gingersup

plem

entatio

nsig

nificantly

redu

cedthe

TNF-120572C

RPand

IL-6

levels

2013

[63]

16Ra

ndom

ized

doub

le-blin

dclinicaltria

l81

18ndash6

0BS

Pat10gday(119899=27)B

SPat

5gday

(119899=29)

Placebo

4weeks

BSPsig

nificantly

decreasedthe

MDAO

SIand

oxidized

low

density

lipop

rotein

cholesterol

andincreasedtheT

AC

2011[64]

17Dou

ble-blinded

rand

omized

crossovertria

l

32(M=16

F=16)618plusmn64

GSE

(600

mgday)

Placebo

4weeks

GSE

significantly

improved

the


ainly

CRP)glycemiaand

oxidative

stress

2009

[65]


18Ra

ndom

ized

single-blindpilot

study

45(F=38

M=7)478plusmn86

Curcum

in(500

mg)

and

diclo

fenacs

odium

(50m

g)alon

eor

incombinatio

n

Diclofenacs

odium

(anti-infl

ammatory

drug)

8weeks

Curcum

inalon

eprovedto

bethem


andsafestto

attenu

ateR

Acomplications

2012

[66]

19

Rand

omized

doub

le-blin

dplacebo-controlled

crossoverstudy

20(F=19

M=1)521plusmn103

Quercetin

(166

mgcapsule)+

vitamin

C(133

mgcapsule)

120572-lipo

icacid

(300

mgcapsule)

Placebo

6weeks

Nosig

nificantd

ifference

was

foun

dam

ongthe

proinfl

ammatorycytokines

however

quercetin

tend

edto

redu

ceVA

Sof

RA

2009

[67]

20

Rand

omized

doub

le-blin

dplacebo-controlled

study

105

55ndash75

Polyph

enolic-richolivee

xtract

Placebo

8weeks

Sign

ificant

(119901lt001)d

ecrease

ofplasmah

omocysteinelevel

(respo

nsibleforc

ardiovascular

complications

inRA

)and

notabler

eductio

nof

CRPwere

observed

2007

[68]

FfemaleMm

aleRA

rheum

atoidarthritis

VASvisualanalogue

scaleNR

notreported

CRP

C-reactiv

eprotein

RESresveratrolGE


AsFD

Sfre

eze-driedstr

awberryMDA

malon

dialdehydeG

SEgrape

seed

extractBS

Pbroccolisproutsp

owderOSIoxidativ

estr

essind

exT

ACtotalantio

xidant

capacityP

GE2

prostagland

inE2

HbA

1cglycosylated

hemoglobin

CADcoron

ary

artery

diseaseLD

L-C

lowdensity

lipop

rotein

cholesterolHDL-C

high

density

lipop

rotein

cholesterolSB

Psysto

licbloo

dpressure










4 Diabetes Mellitus








































































6 Conclusion


Appendix

Search Strategy











Competing Interests




Acknowledgments


References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table2Ev

idence

ofclinicaltria

lswith

naturalprodu

ctsa

ttenu

atingoxidatives


patie

ntsw

ithCV

DD

Mand

RA

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

Cardiovascular

disease(CV

D)

1Ra

ndom

ized

controlled

crossovertria

l

30(F=24

M=6)473plusmn136

Con

trolapplespinachand

apple+

spinach

Health

ycontrol

4weeks

Alltre

atmentsshow

edhigh

erflo

w-m

ediateddilatation

(FMD)(119901lt005)a

ndlower

pulse

pressure

(119901lt005)a

ndapplea

ndspinachresultedin

lower

systo

licbloo

dpressure

(119901lt005)

2012

[49]

2Dou

ble-blind

rand

omized

crossovertria

lM=30526plusmn55

Twolyop

hilized

apples

(40g

)po

lyph

enol-richand

polyph

enol-poo

rproviding

respectiv

ely143g

and021g

polyph

enolsp

erday


6weeks

FMDdidno

tdiffer

betweenthe

polyph

enol-richandthe

polyph

enol-poo

rapp

lesneith

erdidtheo

ther

cardiovascular

diseaser

iskfactors(plasma

lipidsho

mocysteineand

antio

xidant

capacity)

2010

[50]

3

Openprospective

rand

omized

crossover

controlledfeeding

trial

40(F=21

M=19)

28plusmn11

Rawtomatoeskg

(70g

)35g


tomato

saucew

ithrefin

edoliveo

ilkg

and025

gof

sugarsolvedin

waterkg

Health

ycontrol

12days

Tomatosaucee

nrichedwith

refin

edoliveo

ilcanregu

late

lipid

profi

leandsoluble

inflammatorybiom

arkersbette

rthan

rawtomatoeso

rtom

ato

sauces

2016

[51]

4Dou

ble-blind

controlled

rand

omized

trial

F=79

56plusmn4

Genisteinfro

msoybeans

(54m


therapy(1mgday)

estro

genprogestin

combined

with

norethisteron

eacetate

(05mgday)

Health

ypo

stmenop

ausal

wom

en1y

ear

Genisteintherapyim

proved

endo

thelium

functio

nsim

ilarto

estro

genprogestin

regimen

2003

[52]

5Dou

ble-blinded

placebo-controlled

crossovertria

l

93(F=51

M=42)

25ndash6

5Quercetinday

from

fruitsand

vegetables

ources

(150

mg)

Overw

eighto

bese

6weeks

Redu

cedSB

Pandplasma

oxidized

LDLlevelw

itha

high

-CVDris

kph

enotype

2009

[53]

6

Dou

ble-blinded

rand

omized

placebo-controlled

crossovertria

l

M=31

35ndash51

Antho

cyaninsfrom

fruitsand

vegetables

ources

(640

mgday)

Prehypertensive

4weeks

HDL-Candbloo

dglucosew

ere

significantly

high

eraft

eranthocyaninversus

placebo


119901=0024resp)

2013

[54]

7

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

105

20ndash6

0One

350m

gwho

rtleberryextract

capsulee

very

8ho

urs

Hyperlip

idem

ic2mon

ths

Lowered

total-C

(119901lt0001)

TG(119901=0002)andLD

L-C

(119901=0002)b

utincreased


comparedwith

thep

lacebo

grou

patthee

ndpo

int

2014

[55]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

8

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

50ge1845plusmn2mgof

anthocyaninfro

mVa

ccinium

arctostaphylos

Lfruit

extract

Hyperlip

idem

ic4weeks

Sign

ificantlyredu

cedtotal-C

(119901lt0001)LD

L-C(119901=0004)


(119901=0013)com

paredto

placebo

2014

[56]

9

Rand

omized

controlled

investigator

blinded

parallel-g

roup

trial

NCT

00421499

44(F=24

M=20)

56ndash73

Darkchocolate(63g

day)

containing

30mgof

polyph

enols

Stage-1h

ypertensive

18weeks

Redu

cedmean(SD)S

BPby

29

(16)m

mHg(119901lt0001)a

ndDBP

by19

(10)m

mHg

(119901lt0001)

2007

[57]

10

Rand

omized

placebo-controlled

single-blind

crossovertria

lNCT

00538083

45(F=35

M=10)

30ndash75

Inph

ase1solid

dark

chocolate

bar(containing

22gcocoa

powder)or

acocoa-fr

eeplacebo

barIn

phase2

sug

ar-fr

eecocoa

(con

taining22

gcocoap

owder)

sugaredcocoa(

containing

22g

cocoap

owder)ora

placebo

Health

ycontrol

1week

Thea

cuteingestionof

both

solid

dark

chocolatea

ndliq

uid

cocoaimproved

endo

thelial

functio

nandlowered

bloo

dpressure

inoverweightadu

lts

2008

[58]

Diabetesm

ellitu

s(DM)

11Openlabel

rand

omized

clinicaltria

l60

35ndash55

Standard

metform

intherapy

with

turm

eric(2g)

supp

lements

Standard

metform

intre

atment

4weeks

Turm

ericadministered

grou

psig

nificantly


thelipid

peroxidatio

nMDA


PHbA

1cand

fastingbloo

dglucoselevels

andenhanced

the

totalantioxidant

status

2015

[59]

12

Rand

omized

doub

le-blin

dcontrolledclinical

trial

7030ndash70

Powderedrhizom

eofginger

(160

0mg)

Wheatflo

urplacebo

(160

0mg)

12weeks

Gingersignificantly

redu

cedthe

fastingplasmag

lucoseH

bA1c

insulin

trig

lycerid

etotal

cholesterolCR

PandPG

E2

2014

[60]

13Ra

ndom

ized

triple-blin

dcontrolledtrial

M=35

60plusmn11

Capsuleo

f350

mgof

RES

enric

hedgrapee

xtract(G

E)

350m

gof

capsules

containing

either

maltodextrin

(placebo

)orR

ESlackingGE

12mon

ths

RESenric

hedGE

downregulated

the

proinfl

ammatorycytokines

expressio

nviainvolving

the


miRsin

circulatingim

mun

ecells

2013

[61]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

14Ra

ndom

ized

doub

le-blin

dcontrolledtrial

36(F=23

M=13)515plusmn100

FDSbeverage

of2cups

(50g

ofFD

Sisequivalent

to500g

offre

shstr

awberries)

Placebopo

wderw

ithstr

awberryflavor

6weeks

FDSsig

nificantly

(119901lt005)

decreasedtheC

RPlevelsand

lipid

peroxidatio

n(m

ainly

MDA)a

ndincreasedthetotal

antio

xidant

status

2013

[62]

15Ra

ndom

ized

doub

le-blin

dcontrolledtrial

6438ndash6

5Gingersup

plem

entatio

nPlacebo

8weeks

Gingersup

plem

entatio

nsig

nificantly

redu

cedthe

TNF-120572C

RPand

IL-6

levels

2013

[63]

16Ra

ndom

ized

doub

le-blin

dclinicaltria

l81

18ndash6

0BS

Pat10gday(119899=27)B

SPat

5gday

(119899=29)

Placebo

4weeks

BSPsig

nificantly

decreasedthe

MDAO

SIand

oxidized

low

density

lipop

rotein

cholesterol

andincreasedtheT

AC

2011[64]

17Dou

ble-blinded

rand

omized

crossovertria

l

32(M=16

F=16)618plusmn64

GSE

(600

mgday)

Placebo

4weeks

GSE

significantly

improved

the


ainly

CRP)glycemiaand

oxidative

stress

2009

[65]


18Ra

ndom

ized

single-blindpilot

study

45(F=38

M=7)478plusmn86

Curcum

in(500

mg)

and

diclo

fenacs

odium

(50m

g)alon

eor

incombinatio

n

Diclofenacs

odium

(anti-infl

ammatory

drug)

8weeks

Curcum

inalon

eprovedto

bethem


andsafestto

attenu

ateR

Acomplications

2012

[66]

19

Rand

omized

doub

le-blin

dplacebo-controlled

crossoverstudy

20(F=19

M=1)521plusmn103

Quercetin

(166

mgcapsule)+

vitamin

C(133

mgcapsule)

120572-lipo

icacid

(300

mgcapsule)

Placebo

6weeks

Nosig

nificantd

ifference

was

foun

dam

ongthe

proinfl

ammatorycytokines

however

quercetin

tend

edto

redu

ceVA

Sof

RA

2009

[67]

20

Rand

omized

doub

le-blin

dplacebo-controlled

study

105

55ndash75

Polyph

enolic-richolivee

xtract

Placebo

8weeks

Sign

ificant

(119901lt001)d

ecrease

ofplasmah

omocysteinelevel

(respo

nsibleforc

ardiovascular

complications

inRA

)and

notabler

eductio

nof

CRPwere

observed

2007

[68]

FfemaleMm

aleRA

rheum

atoidarthritis

VASvisualanalogue

scaleNR

notreported

CRP

C-reactiv

eprotein

RESresveratrolGE


AsFD

Sfre

eze-driedstr

awberryMDA

malon

dialdehydeG

SEgrape

seed

extractBS

Pbroccolisproutsp

owderOSIoxidativ

estr

essind

exT

ACtotalantio

xidant

capacityP

GE2

prostagland

inE2

HbA

1cglycosylated

hemoglobin

CADcoron

ary

artery

diseaseLD

L-C

lowdensity

lipop

rotein

cholesterolHDL-C

high

density

lipop

rotein

cholesterolSB

Psysto

licbloo

dpressure










4 Diabetes Mellitus








































































6 Conclusion


Appendix

Search Strategy











Competing Interests




Acknowledgments


References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

8

Rand

omized

doub

le-blin

dplacebo-controlled

clinicaltria

l

50ge1845plusmn2mgof

anthocyaninfro

mVa

ccinium

arctostaphylos

Lfruit

extract

Hyperlip

idem

ic4weeks

Sign

ificantlyredu

cedtotal-C

(119901lt0001)LD

L-C(119901=0004)


(119901=0013)com

paredto

placebo

2014

[56]

9

Rand

omized

controlled

investigator

blinded

parallel-g

roup

trial

NCT

00421499

44(F=24

M=20)

56ndash73

Darkchocolate(63g

day)

containing

30mgof

polyph

enols

Stage-1h

ypertensive

18weeks

Redu

cedmean(SD)S

BPby

29

(16)m

mHg(119901lt0001)a

ndDBP

by19

(10)m

mHg

(119901lt0001)

2007

[57]

10

Rand

omized

placebo-controlled

single-blind

crossovertria

lNCT

00538083

45(F=35

M=10)

30ndash75

Inph

ase1solid

dark

chocolate

bar(containing

22gcocoa

powder)or

acocoa-fr

eeplacebo

barIn

phase2

sug

ar-fr

eecocoa

(con

taining22

gcocoap

owder)

sugaredcocoa(

containing

22g

cocoap

owder)ora

placebo

Health

ycontrol

1week

Thea

cuteingestionof

both

solid

dark

chocolatea

ndliq

uid

cocoaimproved

endo

thelial

functio

nandlowered

bloo

dpressure

inoverweightadu

lts

2008

[58]

Diabetesm

ellitu

s(DM)

11Openlabel

rand

omized

clinicaltria

l60

35ndash55

Standard

metform

intherapy

with

turm

eric(2g)

supp

lements

Standard

metform

intre

atment

4weeks

Turm

ericadministered

grou

psig

nificantly


thelipid

peroxidatio

nMDA


PHbA

1cand

fastingbloo

dglucoselevels

andenhanced

the

totalantioxidant

status

2015

[59]

12

Rand

omized

doub

le-blin

dcontrolledclinical

trial

7030ndash70

Powderedrhizom

eofginger

(160

0mg)

Wheatflo

urplacebo

(160

0mg)

12weeks

Gingersignificantly

redu

cedthe

fastingplasmag

lucoseH

bA1c

insulin

trig

lycerid

etotal

cholesterolCR

PandPG

E2

2014

[60]

13Ra

ndom

ized

triple-blin

dcontrolledtrial

M=35

60plusmn11

Capsuleo

f350

mgof

RES

enric

hedgrapee

xtract(G

E)

350m

gof

capsules

containing

either

maltodextrin

(placebo

)orR

ESlackingGE

12mon

ths

RESenric

hedGE

downregulated

the

proinfl

ammatorycytokines

expressio

nviainvolving

the


miRsin

circulatingim

mun

ecells

2013

[61]


Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

14Ra

ndom

ized

doub

le-blin

dcontrolledtrial

36(F=23

M=13)515plusmn100

FDSbeverage

of2cups

(50g

ofFD

Sisequivalent

to500g

offre

shstr

awberries)

Placebopo

wderw

ithstr

awberryflavor

6weeks

FDSsig

nificantly

(119901lt005)

decreasedtheC

RPlevelsand

lipid

peroxidatio

n(m

ainly

MDA)a

ndincreasedthetotal

antio

xidant

status

2013

[62]

15Ra

ndom

ized

doub

le-blin

dcontrolledtrial

6438ndash6

5Gingersup

plem

entatio

nPlacebo

8weeks

Gingersup

plem

entatio

nsig

nificantly

redu

cedthe

TNF-120572C

RPand

IL-6

levels

2013

[63]

16Ra

ndom

ized

doub

le-blin

dclinicaltria

l81

18ndash6

0BS

Pat10gday(119899=27)B

SPat

5gday

(119899=29)

Placebo

4weeks

BSPsig

nificantly

decreasedthe

MDAO

SIand

oxidized

low

density

lipop

rotein

cholesterol

andincreasedtheT

AC

2011[64]

17Dou

ble-blinded

rand

omized

crossovertria

l

32(M=16

F=16)618plusmn64

GSE

(600

mgday)

Placebo

4weeks

GSE

significantly

improved

the


ainly

CRP)glycemiaand

oxidative

stress

2009

[65]


18Ra

ndom

ized

single-blindpilot

study

45(F=38

M=7)478plusmn86

Curcum

in(500

mg)

and

diclo

fenacs

odium

(50m

g)alon

eor

incombinatio

n

Diclofenacs

odium

(anti-infl

ammatory

drug)

8weeks

Curcum

inalon

eprovedto

bethem


andsafestto

attenu

ateR

Acomplications

2012

[66]

19

Rand

omized

doub

le-blin

dplacebo-controlled

crossoverstudy

20(F=19

M=1)521plusmn103

Quercetin

(166

mgcapsule)+

vitamin

C(133

mgcapsule)

120572-lipo

icacid

(300

mgcapsule)

Placebo

6weeks

Nosig

nificantd

ifference

was

foun

dam

ongthe

proinfl

ammatorycytokines

however

quercetin

tend

edto

redu

ceVA

Sof

RA

2009

[67]

20

Rand

omized

doub

le-blin

dplacebo-controlled

study

105

55ndash75

Polyph

enolic-richolivee

xtract

Placebo

8weeks

Sign

ificant

(119901lt001)d

ecrease

ofplasmah

omocysteinelevel

(respo

nsibleforc

ardiovascular

complications

inRA

)and

notabler

eductio

nof

CRPwere

observed

2007

[68]

FfemaleMm

aleRA

rheum

atoidarthritis

VASvisualanalogue

scaleNR

notreported

CRP

C-reactiv

eprotein

RESresveratrolGE


AsFD

Sfre

eze-driedstr

awberryMDA

malon

dialdehydeG

SEgrape

seed

extractBS

Pbroccolisproutsp

owderOSIoxidativ

estr

essind

exT

ACtotalantio

xidant

capacityP

GE2

prostagland

inE2

HbA

1cglycosylated

hemoglobin

CADcoron

ary

artery

diseaseLD

L-C

lowdensity

lipop

rotein

cholesterolHDL-C

high

density

lipop

rotein

cholesterolSB

Psysto

licbloo

dpressure










4 Diabetes Mellitus








































































6 Conclusion


Appendix

Search Strategy











Competing Interests




Acknowledgments


References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table2Con

tinued

Num

ber

Type

ofstu

dyNum

bero

fparticipants

Age

(years)

Interventio

nCom

paris

oncon

trol

Perio

dof

interventio

nOutcomes

Year

[references]

14Ra

ndom

ized

doub

le-blin

dcontrolledtrial

36(F=23

M=13)515plusmn100

FDSbeverage

of2cups

(50g

ofFD

Sisequivalent

to500g

offre

shstr

awberries)

Placebopo

wderw

ithstr

awberryflavor

6weeks

FDSsig

nificantly

(119901lt005)

decreasedtheC

RPlevelsand

lipid

peroxidatio

n(m

ainly

MDA)a

ndincreasedthetotal

antio

xidant

status

2013

[62]

15Ra

ndom

ized

doub

le-blin

dcontrolledtrial

6438ndash6

5Gingersup

plem

entatio

nPlacebo

8weeks

Gingersup

plem

entatio

nsig

nificantly

redu

cedthe

TNF-120572C

RPand

IL-6

levels

2013

[63]

16Ra

ndom

ized

doub

le-blin

dclinicaltria

l81

18ndash6

0BS

Pat10gday(119899=27)B

SPat

5gday

(119899=29)

Placebo

4weeks

BSPsig

nificantly

decreasedthe

MDAO

SIand

oxidized

low

density

lipop

rotein

cholesterol

andincreasedtheT

AC

2011[64]

17Dou

ble-blinded

rand

omized

crossovertria

l

32(M=16

F=16)618plusmn64

GSE

(600

mgday)

Placebo

4weeks

GSE

significantly

improved

the


ainly

CRP)glycemiaand

oxidative

stress

2009

[65]


18Ra

ndom

ized

single-blindpilot

study

45(F=38

M=7)478plusmn86

Curcum

in(500

mg)

and

diclo

fenacs

odium

(50m

g)alon

eor

incombinatio

n

Diclofenacs

odium

(anti-infl

ammatory

drug)

8weeks

Curcum

inalon

eprovedto

bethem


andsafestto

attenu

ateR

Acomplications

2012

[66]

19

Rand

omized

doub

le-blin

dplacebo-controlled

crossoverstudy

20(F=19

M=1)521plusmn103

Quercetin

(166

mgcapsule)+

vitamin

C(133

mgcapsule)

120572-lipo

icacid

(300

mgcapsule)

Placebo

6weeks

Nosig

nificantd

ifference

was

foun

dam

ongthe

proinfl

ammatorycytokines

however

quercetin

tend

edto

redu

ceVA

Sof

RA

2009

[67]

20

Rand

omized

doub

le-blin

dplacebo-controlled

study

105

55ndash75

Polyph

enolic-richolivee

xtract

Placebo

8weeks

Sign

ificant

(119901lt001)d

ecrease

ofplasmah

omocysteinelevel

(respo

nsibleforc

ardiovascular

complications

inRA

)and

notabler

eductio

nof

CRPwere

observed

2007

[68]

FfemaleMm

aleRA

rheum

atoidarthritis

VASvisualanalogue

scaleNR

notreported

CRP

C-reactiv

eprotein

RESresveratrolGE


AsFD

Sfre

eze-driedstr

awberryMDA

malon

dialdehydeG

SEgrape

seed

extractBS

Pbroccolisproutsp

owderOSIoxidativ

estr

essind

exT

ACtotalantio

xidant

capacityP

GE2

prostagland

inE2

HbA

1cglycosylated

hemoglobin

CADcoron

ary

artery

diseaseLD

L-C

lowdensity

lipop

rotein

cholesterolHDL-C

high

density

lipop

rotein

cholesterolSB

Psysto

licbloo

dpressure










4 Diabetes Mellitus








































































6 Conclusion


Appendix

Search Strategy











Competing Interests




Acknowledgments


References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























4 Diabetes Mellitus








































































6 Conclusion


Appendix

Search Strategy











Competing Interests




Acknowledgments


References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















































































6 Conclusion


Appendix

Search Strategy











Competing Interests




Acknowledgments


References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























Competing Interests




Acknowledgments


References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article Dietary Phytochemicals: Natural Swords...

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