review article phytochemical compounds and...

Review ArticlePhytochemical Compounds and Protection fromCardiovascular Diseases A State of the Art

Beniamino Pagliaro1 Caterina Santolamazza1

Francesca Simonelli1 and Speranza Rubattu12

1Department of Clinical and Molecular Medicine School of Medicine and Psychology Saint Andrea HospitalSapienza University of Rome 00189 Rome Italy2IRCCS Neuromed 86077 Pozzilli Italy

Correspondence should be addressed to Speranza Rubattu rubattusperanzaneuromedit

Received 18 March 2015 Accepted 14 June 2015

Academic Editor Umberto Benedetto

Copyright copy 2015 Beniamino Pagliaro 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

Cardiovascular diseases represent a worldwide relevant socioeconomical problem Cardiovascular disease prevention relies alsoon lifestyle changes including dietary habits The cardioprotective effects of several foods and dietary supplements in bothanimal models and in humans have been explored It was found that beneficial effects are mainly dependent on antioxidantand anti-inflammatory properties also involving modulation of mitochondrial function Resveratrol is one of the most studiedphytochemical compounds and it is provided with several benefits in cardiovascular diseases as well as in other pathologicalconditions (such as cancer) Other relevant compounds are Brassica oleracea curcumin and berberine and they all exert beneficialeffects in several diseases In the attempt to provide a comprehensive reference tool for both researchers and clinicians wesummarized in the present paper the existing literature on both preclinical and clinical cardioprotective effects of each mentionedphytochemical We structured the discussion of each compound by analyzing first its cellular molecular targets of actionsubsequently focusing on results from applications in both ex vivo and in vivo models finally discussing the relevance of thecompound in the context of human diseases

1 Introduction

Cardiovascular diseases (CVDs) still remain the primarycause of death worldwide according to the World HealthOrganization and American Heart Association statistics [1]Different approaches have been proposed to reduce the highglobal incidence of CVDs and to improve human healthTheconsumption of functional foods or dietary supplements forlowering the risk of CVDs has gained attention over the lastfew years from both scientific and clinical communities [2 3]Several antioxidant compounds can be found in vegetables(eg vitamins and phenolic compounds) They are partlyresponsible for the health benefits by scavenging reactiveoxygen radicals (ROS) and by inhibiting cellular damageat different levels Although the literature contains severalreview articles describing either general health benefits ofphytochemical supplements or the cardioprotective effects of

a single phytochemical compound no comprehensive reviewarticle has been so far reported focusing on both preclinicaland clinical cardiovascular beneficial effects of the mostknown compounds (resveratrol Brassica oleracea curcuminand berberine)

In the present paper we attempted to fill up this literaturegap In order to reach our goal we discussed each phytochem-ical compound by analyzing its molecular targets of actiondiscussing all existing in vitro ex vivo and in vivo data relatedto its cardiovascular beneficial properties finally highlightingthe evidence available in human CVDs

2 Resveratrol

Resveratrol (3541015840-trihydroxy-trans-stilbene) is a naturalpolyphenolic compound that exists in Polygonum cuspi-datum grapes peanuts and berries as well as in their

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 918069 17 pageshttpdxdoiorg1011552015918069

2 BioMed Research International

AMPK

Resveratrol

Brassica Curcumin

Berberine

SIRT1

ROS Inflammation

Heart Vasculature Brain Kidney

(i) Hypertension(ii) Hypertrophy(iii) Ischemic damage(iv) Drug toxicity(v) Heart failure

(i) EC damage(ii) Platelet activation(iii) VSMC proliferation

(iv) Atherosclerosis

(i) Ischemic damage(ii) BBB disruption(iii) Stroke

(i) Hypertensive and ischemic damage(tubular glomerular and vascular) and migration

PPAR120574PPAR120572NF-120581B TNF-120572

Figure 1 Schematic representation of beneficial effects exerted in the cardiovascular system by resveratrol Brassica oleracea curcumin andberberine The AMPKSIRT-1PPAR120572120574molecular pathway underlying most of the effects of all vegetable compounds is illustrated AMPK51015840-adenosine monophosphate-activated protein kinase SIRT-1 silent mating type information regulation-1 PPAR peroxisome proliferator-activated receptor ROS reactive oxygen species NF-120581B nuclear factor-120581B TNF-120572 tumor necrosis factor-120572 EC endothelial cell VSMCvascular smooth muscle cell BBB blood brain barrier

manufactured products especially red wine [4] It exists inboth cis- and trans-configurations of which trans-resveratrolis the principal biologically active form [5] Interestinglyred wine (therefore resveratrol) was supposed to be one ofthe factors responsible for the ldquoFrench Paradoxrdquo togetherwith several lifestyle and dietary factors The term is usedto describe the low incidence of CVDs in French populationdespite its high intake of saturated fats However the mediandaily dose of resveratrol to be protective is estimated tobe 20mgkgday whereas its concentration in red wine isroughly 198ndash713mgL [6] Therefore the assumption of ahigh quantity of red wine per day would be needed for aman to obtain a protective dose of resveratrol causing serioushealth problems [7 8] However an inverse associationbetween moderate alcohol consumption (30ndash50 grday) andCVDs has been assessed in several epidemiological studiesThe physiological mechanism of the protective effect ofalcohol seems to be at least in part related to its effect inreducing platelet action

21 Molecular Targets and Properties Resveratrol inter-acts with multiple targets in cardio- and cerebrovascular

diseases age-related diseases cancer and so forth [9 10]Themain molecular mechanism mediating resveratrol biologicaleffects is the 51015840-adenosine monophosphate-activated proteinkinase (AMPK)silent mating type information regulation-1(SIRT-1) pathway (Figure 1) [11 12] The precise mechanismthrough which resveratrol activates SIRT-1 is not completelyunderstood [13] Other minor pathways mediate some of theresveratrol effects and they will be briefly mentioned below

The most important properties of resveratrol are con-nected with oxidative stress vascular inflammation andplatelet aggregation In fact resveratrol upregulates theendogenous antioxidant systems such as superoxide dismu-tase (SOD) enzymes in endothelial cells (ECs) and in cardiacmyoblasts and it reduces ROS production [14 15] Moreoverit reduces arachidonic acid and prostaglandin E2 synthesisIt inhibits phospholipase A2 and ciclooxygenase-2 activityit antagonizes the function of the most important moleculesinvolved in inflammation such as nuclear factor-120581B (NF-120581B) tumor necrosis factor-120572 (TNF-120572) interleukin-6 (IL-6)inducible nitric oxide synthase (iNOS) activity and mono-cyte chemotactic protein-1 (MCP-1) [16ndash19] Resveratrol alsoprevents platelet activation by modulating platelet adhesion

BioMed Research International 3

secretion and activation signaling ROS production andapoptosis and by enhancing nitric oxide (NO) production[20ndash22] Furthermore several studies demonstrated thatresveratrol inhibits protein kinase C (PKC) activation andintracellular calcium release thus blocking phosphoinositidemetabolism upstream platelet activation signaling [23]

22 Hypertension Preclinical Studies The ldquoantihyperten-siverdquo effect of resveratrol is thought to be mediated byboth endothelium-dependent and endothelium-independentmechanisms [24 25] by inhibition of vascular smoothmusclecell (VSMC) contractility by reduction of vasoconstrictormolecules expression (angiotensin (Ang) II and endothe-lin (ET)-1) and by inhibition of strain-induced ET-1 geneexpression through the extracellular-signal regulated kinase(ERK) 12 pathway [11 26 27] Finally its effect on the sym-pathetic nervous system (SNS) can also contribute to bloodpressure (BP) lowering [28] The antihypertensive effectof resveratrol (administered at the dose of 10ndash320mgkgbody weightday) has been demonstrated although withsome controversial results in several hypertensive animalmodels including spontaneously hypertensive (SHR) twokidney one-clip hypertensive partially nephrectomized anddeoxycorticosterone acetate- (DOCA-) salt hypertensive ratmodels and in the Ang II-infused mouse [11 29ndash32] Con-troversies appear mainly related to the specific model understudy In particular resveratrol wasmore effective in loweringBP in animals with either diabetes or metabolic syndromein which variable doses of resveratrol (20mgkgday) wereadministered [33]

Along with the antihypertensive effect an improve-ment of endothelial function was described being largelyattributable to endothelial NO synthase (eNOS) activation[34 35] This effect can certainly contribute to protectingvasculature from hypertensive damage [36]

221 Hypertension Clinical Studies Scarce information isavailable regarding the antihypertensive effect of resveratrolin humans A recent meta-analysis has shown that treatmentwith ge150mgday of resveratrol considered as a very lowdose decreases systolic BP (SBP) without affecting diastolicBP (DBP) [37] Interestingly doses of 125ndash100 120583L of resvera-trol were shown to enhance Acetylcholine-mediated vasore-laxation in blood vessels from patients with hypertensionand dyslipidemia but not in vessels from healthy subjects[38] Although resveratrol supplementation did not exert anyeffect on BP in healthy obese adults and in patients withmetabolic syndrome it significantly improved flow-mediateddilatation (FMD) in these subjects [37 39] Similar resultswere obtained in patientswith previousmyocardial infarction(MI) receiving 10mg of resveratrol daily for 3 months [40]However the duration of these clinical trials was too shortin order to assess the long-term consequences of the dietaryintervention

No clinical trials are available yet exploring the BPlowering effect of resveratrol in hypertensive patients

23 Atherosclerosis and Dyslipidemia Preclinical StudiesResveratrol acts at the very early stages of atherosclerosis

by increasing the hepatic uptake of low-density lipoprotein(LDL) through an AMPK independent mechanism and byreducing the expression of intercellular adhesion molecule-1(ICAM-1) and of vascular cell adhesion molecule-1 (VCAM-1) on endothelium [41 42] Additional in vitro studiesdemonstrated that resveratrol likely via the phosphatidyli-nositol 31015840-kinase (PI3K)protein kinase B (PKB or Akt) path-way bluntsMCP-1 and chemokine receptor type 2 expressioninmonocytes [43 44] Also it reduces foam cell formation byupregulating the expression of cholesterol transporters and bydownregulating the uptake of oxidized LDL (Ox-LDL) [45]The anti-inflammatory and antioxidant properties of resver-atrol may be responsible for inhibition of LDL oxidation ofmacrophagemigration and transformation into foam cells aswell as of VSMCs migration and proliferation [46 47]

Several in vivo studies have shown the hypocholestero-lemic effect of a standard dose of resveratrol (20mgkgday)[48 49] In the apolipoprotein (APO) Eminusminus mice resvera-trol downregulated the hepatic 3-hydroxy 3-methylglutarylcoenzyme A (HMG-CoA) reductase enzyme a key enzymeinvolved in cholesterol biosynthesis thus reducing totaland LDL cholesterol and increasing high-density lipoprotein(HDL) cholesterol [50] In the high fat fed mice resvera-trol increased liver expression of cholesterol 7120572-hydroxylase(CYP7A1) which led to increased bile acid synthesis andsecretion thus lowering the plasma level of total and LDLcholesterol [51]

231 Atherosclerosis and Dyslipidemia Clinical Studies Ameta-analysis evaluating the benefits of resveratrol supple-mentation on plasma lipids revealed no significant effecton any of the lipid parameters (eg total LDL and HD-cholesterol and triglycerides) independently of the doseduration of the study and cardiovascular risk of the consid-ered population [52] However few single studies includedin this meta-analysis reported that a relatively low dose ofresveratrol treatment (250mg per day for 3 months) led to asignificant decrease of total cholesterol total and ox-LDL andApoB levels in patients with type 2 diabetes mellitus (T2DM)coronary artery disease (CAD) hyperlipidemia and othercardiovascular risk factors [53] Similarly total cholesteroland triglyceride levels were reduced by a very low dose ofresveratrol (20mgper day for 2 months) in patients withstable angina [54]

24 Obesity and T2DM Preclinical Studies Resveratrolreduced lipid accumulation both in vivo and in vitro byinhibiting lipogenesis increasing apoptosis and promotinglipolysis [55ndash57] In Sprague-Dawley rats the body fat-lowering effect of 30mg resveratrolkg body weightday wasmediated at least in part by reduction in fatty acid uptakefrom circulating triacylglycerols as well as by a de novolipogenesis in adipose tissue [58] In addition it modulatedinsulin signaling pathway and improved insulin sensitivityin adipose and muscle tissue as well as glucose uptake andinsulin secretion [59 60] In humanmuscle cells derived fromT2DM patients resveratrol may improve glucose utilizationand resistance to hyperglycemia by inhibiting phosphoryla-tion of Insulin Receptor Substrate-1 [61]


In vivo resveratrol restores vascular function throughantioxidant anti-inflammatory and antiapoptotic proper-ties as it was observed treating rats with very low doses(075mgkgthree times a day) [62] At a standard dose of20mgkgday it improved cardiac function in both type 1 andtype 2 DM [63ndash65]

241 Obesity and T2DM Clinical Studies Resveratrol atthe standard dosage of 500mg three times a day improvedinsulin sensitivity in both obese and metabolic syndromepatients [66 67] However other studies failed to confirmthese findings [68 69] Anti-inflammatory effects of resver-atrol were reported in several clinical studies performed inpatientswith high cardiovascular risk profile [54 70] Admin-istration of resveratrol using different chemical formulae atseveral dosages was associatedwith decreased oxidative stressin patients with metabolic syndrome [71]

25 Ischemic Heart Disease Preclinical Studies Resveratrolprotects against ischemic heart disease through multiplemechanisms The mechanisms underlying the precondi-tioning effect of resveratrol (05mgkgday) appear to bemainly mediated by NO and the antioxidant enzyme hemeoxygenase-1 (HO-1) [72]

In vitro studies showed that resveratrol upregulatedvascular endothelial growth factor (VEGF) expression incardiomyocytes and in ECs through an increased oxidative-stress related proteins Thioredoxin-1 (Trx-1) and HO-1expression [73] It also protected cardiac tissue fromcell deaththroughmultiple mechanisms including antiapoptotic effectsand autophagy [74 75]

Pretreatment of rats with resveratrol resulted in cardio-protection when the isolated heart was subjected to 30minglobal ischemia followed by 2 hr reperfusion or followingpermanent left anterior descending coronary artery (LAD)occlusion [76] Resveratrol can potentiate regeneration ofinfarctedmyocardium in a LAD occlusion rat model by stim-ulating neovascularization and cardiac stem cells [76 77]Interestingly pretreatment with resveratrol largely restoredthe altered microRNAs expression in the ischemic heart [78]

The protective effects of resveratrol in the ischemicmyocardium were confirmed in vivo [72 79] An interestingstudy conducted by Kanamori et al suggested that onlyhigh dose (50mgkgday) of resveratrol may be an effectivetreatment for ischemic heart failure (HF) by preventingnecrotic area expansion and by improving cardiac func-tion Authors tested two doses of resveratrol (5mgkg and50mgkg) demonstrating the dose-dependent effect of thiscompound [80]

251 Ischemic Heart Disease Clinical Studies Few clinicaltrials investigated the effects of both standard and low dosesof resveratrol in stable angina acute coronary syndromesand previous MI with positive results [40 54 70] Additionalstudies suggested that resveratrol may be cardioprotectivethrough increase of adiponectin and reduction of thrombo-genic plasminogen activator inhibitor type 1 (PAI-1) [81 82]

26 Cardiac Hypertrophy and Heart Failure Preclinical Stud-ies Resveratrol was shown to prevent cardiac hypertrophyand dysfunction through reduction of oxidative stress inhi-bition of hypertrophic gene expression and increase of Ca2+handling [83] The antihypertrophic effect of resveratrol maybe BP independent For instance low doses of resvera-trol (25mgkgday) prevented cardiac hypertrophy withoutreducing BP in SHR and Dahl-salt sensitive rats [84 85]The cardioprotective properties were demonstrated in severalanimal models including pressure-overload volume over-load SHR doxorubicin-induced cardiotoxicity myocardi-tis MI and ischemia-reperfusion (IR) injury [15 84 86ndash90] Recently Sung et al demonstrated that high doses ofresveratrol (320mgkgday) promote beneficial remodelingand improve both diastolic function and cardiac energymetabolism in a mice model of pressure-overload HF thusincreasing animal survival [91]

261 Cardiac Hypertrophy andHeart Failure Clinical StudiesIn one study performed in patients with HF of ischemicorigin treatment with resveratrol significantly improveddiastolic function and induced a modest increase of systolicperformance despite the low dose administered (10mg ofresveratrol capsuleday) [40]

27 Cerebrovascular Disease Preclinical Studies The previ-ously described beneficial vascular properties of resveratrolcan also explain protection from ischemic stroke [92] Invitro resveratrol promoted angiogenesis in cerebral ECs andprevented impairment of eNOS-dependent vasorelaxation ofcerebral arterioles in diabetes [93 94] It also reduced infarctsize in a rat model of focal cerebral ischemia and preservedblood brain barrier function by interfering with occludin andzonula occludens- (ZO-)1 tight junctions [92 95 96] Thestroke protective effects of resveratrol were also attributed toits specific neuroprotective properties [97 98]

271 Cerebrovascular Disease Clinical Studies There are noclinical studies investigating the protective effects of resvera-trol in stroke patients Interestingly a single dose (250mg)of trans-resveratrol increased cerebral blood flow during amental stress (cognitive tasks) in healthy adult subjects [99]

28 Other Cardiovascular Diseases Preclinical Studies Res-veratrol protected from doxorubicin-induced cardiotoxicityin a variety of animal models through the above discussedmechanisms [100ndash102] However there is scarce informa-tion on the cardioprotective effects of resveratrol in cancerpatients treated with either doxorubicin or other cardiotoxicchemotherapeutic agents

Few studies suggested an antiarrhythmic property Infact resveratrol caused a significant antiarrhythmic effectin three models of arrhythmia aconitine-induced ouabain-induced and coronary ligation-induced arrhythmias [103]Furthermore chronic oral low-dose resveratrol treatment(5mgkgday for 4 weeks starting one week before MI)significantly suppressed MI-induced ventricular tachycardiaand ventricular fibrillation [104] Recently Baczko et al


designed and characterized a multifunctional resveratrol-derived small molecule compound 1 targeting a numberof key pathways involved in atrial fibrillation (AF) able toreduce the average and total AF duration in a model ofinducible AF in conscious dogs [105]

3 Brassica oleraceaBrassica oleracea (BO) is a commonly used phytochemicalThe species include broccoli cauliflowers Brussel sproutsand kale BO is highly enriched with bioactive moleculeswhose effects on health have been partly explored [106ndash108]It is known that the content of vitamin C varies significantlybetween the different subspecies ofBrassicaThese differencesmainly depend on genotype and also on industrial storingprocessing and domestic cooking that reduce the final levelsof available antioxidant compounds [109]

BO in particular broccoli sprouts is rich in glucosi-nolates they are large molecules composed by a 120573-D-thioglucose group a sulphonated oxime group and an amino-acidic side chain [110] Sulforaphane is the active metaboliteof glucoraphanin and is produced after hydrolyzation bymyrosinase enzyme [111] Cooking the vegetables partiallydenatures myrosinase however when glucoraphanin reachesthe intestinal floramyrosinase-producing bacteria release theactive metabolite that is then absorbed [112] After absorp-tion sulforaphane is partly conjugatedwith glutathione in theliver forming sulforaphane-glutathione After reaching thekidneys where it becomes sulforaphane-N-acetylcysteine itis finally excreted in the urine [113] Other active compoundsof Brassica plants are anthocyanins carotenoids vitaminC tocopherol folic acid and minerals We will focus ourdiscussion on sulforaphane and anthocyanins as the maincomponents of BO

31 Molecular Targets and Properties Molecular targetsof BO include NF-120581B nuclear factor-2 (Nrf2) mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase(JNK) AktPKB and AMPKSIRT-1peroxisome prolifera-tor-activated receptor-120572 (PPAR120572)uncoupling protein-2(UCP2) [114ndash117] By interacting with these molecularsignaling pathways BOplays antioxidant anti-inflammatoryand antithrombotic effects

32 Preclinical Studies Broccoli sprouts exert several cardio-vascular beneficial effects [106 107]

With regard to glucosinolates sulforaphane has beenproven to be the most beneficial In vitro it inducedexpression of detoxification enzymes the so called ldquoARErdquotargets (Antioxidant Response Elements nicotinamide ade-nine dinucleotide (NADH) quinone reductase HO-1 andglutathione transferase) and several nuclear factors such asNrf2 involved in ROS elimination and xenobiotic excretion[114] Sulforaphane suppressed the expression of MAPK p38in ECs through activation of Nrf2 thus leading to reductionof VCAM-1 synthesis [118] By reducing ROS sulforaphanelowered ox-LDL level in blood [119] In a study conductedin rats fed for 14 weeks with 200mgday of dried broccolisprouts a significant increase in glutathione content wasobserved along with increased glutathione reductase and

peroxidase (GPx) activities in both heart and kidneys [120]Interestingly administration of broccoli sprouts in pregnantfemale stroke prone-SHR (SHRSP) decreased oxidative stressand BP levels compared to females fed with control diet Fur-thermore offspring of females maintained on broccoli dietduring pregnancy had also lower BP and tissue inflammationin adulthood regardless of diet [121]

Anthocyanins are known to promote optimal plateletfunction and antithrombotic effects [122] These compoundscan act on different types of cells involved in atherosclerosisdevelopment In fact they exert a protective effect towardTNF-120572 induced MCP-1 secretion in primary human ECs[123] Anthocyanins prevented the expression of VEGFstimulated by platelet derived growth factor (PDGF) AB inVSMCs and byMAPK p38 and c-JNK inhibition [115] More-over anthocyanins extract induced endothelium-dependentrelaxation in porcine coronary arteries [124] Increasedcardiac glutathione concentrations in rats receiving long-term administration of anthocyanins contributed to theantioxidant effects [125] The protective effect on heart alsodepends on reduction of hypertrophy-associated increasedphosphorylation of PKC and on activation of AktPKB[116] Moreover anthocyanins prevented CD40-activatedproinflammatory signaling in ECs by regulating cholesteroldistribution [126] They also inhibit the activation of NF-120581B and lipopolysaccharides induced NO biosynthesis inmacrophages [127]

Broccoli sprouts protect frommyocardial oxidative dam-age and cell death in ischemiareperfusion (IR) rat modelsIn particular anthocyanins decreased the extent of cell deathin cultured cardiomyocytes and reduced infarct size byinhibiting signal transducer and activator of transcription1 (STAT1) stimulation [106 128] Notably BO improveddiabetic nephropathy in rats [107] and prevented renal dam-age in salt-loaded SHRSP independently from SBP throughAMPKSIRT1PPAR120572UCP2 axis activation [117] In factselective inhibition of PPAR120572 antagonized the nephroprotec-tive effects of BO sprouts consistently with previous evidenceon the role of cyanidin as PPAR120572 agonist [129]

33 Clinical Studies The beneficial effects in humans wereenhanced when broccoli supplements were combined withfresh broccoli sprouts administration in healthy subjects whoconsumed either 68 gr of broccoli sprouts or 6 Brocco-Maxpills (about 3 gr of freeze-dried broccoli sprouts in 6 pills)for 7 days [130 131] In a small clinical trial conducted in6 men and 6 women all smokers eating 100 gr of broccolisprouts daily for 7 days a significant reduction of both totaland LDL cholesterol along with urinary 8-isoprostanes andother markers of oxidative stress was observed [119] Theadministration of 150mLday kale juice for 12 weeks in 32men with hypercholesterolemia significantly reduced plasmaLDL cholesterol and increased both HDL cholesterol andGPx activity thus lowering CAD risk [108] In additionbroccoli sprouts supplement could play favorable effects onlipid profiles and OX-LDLLDL cholesterol ratio in T2DM[132] Recently anthocyanins intake (84ndash236mgday) wasshown to associate with lower arterial stiffness and central BPin women [133]


Results from human trials are controversial In factCurtis et al showed no effect on markers of CVDs (includ-ing inflammatory biomarkers platelet reactivity lipids andglucose) on liver and kidney function as well as on anthro-pometric parameters BP and heart rate following 12-weekintervention with 500mgday cyanidin in postmenopausalwomen [134]

4 Curcumin

Curcumin (diferuloylmethane) is a naturally occurring phe-nolic compound isolated as a yellow pigment from spiceturmeric (Curcuma Longa) This compound has receivedattention due to its various biological and pharmacologi-cal activities Its therapeutic effects have been extensivelyinvestigated particularly in the treatment of cancer andinflammatory diseases [135]

There is growing evidence that curcumin has a potentialrole in protection from several CVDs [135 136]

41 Molecular Targets and Properties Curcumin interactswith different molecular targets such as Janus Kinase 2(JAK2)STAT3 AMPKUCP2 AktNrf2 ERK MAPK p38JNK ICAM-1 MCP-1 and IL-8 [137ndash141] As a consequenceit exerts anti-inflammatory antiplatelet and antioxidantproperties [141ndash144] Concerning the latter a single doseof 15mgkg of curcumin appears to decrease levels ofxanthine oxidase superoxide anion lipid peroxides andmyeloperoxidase and to increase levels of SOD catalase GPxand glutathione-S-transferase (GST) [145] Moreover thisphytochemical reduces level of eNOS and iNOS through theactivation of NF-120581B and protein-1 (AP-1) [146] Curcumin isalso a potent inducer of HO-1 in ECs through activation ofARE in several cardiovascular cells exposed to curcumin 5ndash15 120583M [147] Moreover curcumin appears to attenuate mito-chondrial alterations and respiratory cellular dysfunction[148]

42 Preclinical Studies Curcumin plays a protective role onendothelium by inducing HO-1 in bovine aortic ECs [147] Itexerts antiproliferative and antiapoptotic effects on VSMCsexposed to 1ndash25 120583M of curcumin thus attenuating carotidartery neointima formation [149ndash151] It plays a relevant roleon calcium homeostasis in both skeletal muscle and cardiacsarcoplasmic reticulum [152]

The role of curcumin in CVDs has been investigated inseveral animal models For instance 166mg curcuminkgshowed a hypolipidemic effect and protection from aorticfatty streak development [153 154] The cardioprotective roleof curcumin was shown in myocardial ischemia rat models[145 155] In IR models curcumin reduced collagen syn-thesis and fibrosis and significantly improved left ventricularend-diastolic volume stroke volume and ejection fraction[156] In addition it reduced MI size and depressed lactatedehydrogenase release in the coronary blood flow throughactivation of JAK2STAT3 [137]These beneficial effects couldbe related to a decrease of proinflammatory cytokines and ofcardiomyocyte apoptosis [157]

In two different HF models 50mg curcuminkgdayameliorated systolic function and prevented myocardialhypertrophy by inhibiting p300-HAT (histone acetyltrans-ferases) [158] Additionally a larger amount of curcumin(200mgkgday) showed a protective role in adriamycin-induced cardiac damage [159] and it also prevented car-diovascular complications in diabetes [146] In fact itreduced high glucose-induced overexpression of inflamma-tory cytokines inmacrophages [144] A beneficial role towardmyocardial injury was reported in renal IR injury rat models[160]

Finally a standard dose of curcumin (25ndash50mgkgday)protected against cerebral ischemic insult [161] as well asaging-related cerebrovascular dysfunction via AMPKUCP2pathway It protected neurons against ischemic injurythrough AktNrf2 pathway [138 139] In different strokemodels curcumin not only decreased oxidative stress butalso attenuated reperfusion injury by preventing neutrophiladhesion to the cerebrovascular microcirculation [162 163]

43 Clinical Studies Controversial results exist with regard tothe effect of curcumin on plasma lipids in healthy subjects Infact in healthy volunteers a dosage of 500mg curcumindaydecreased both serum lipid peroxides and total cholesteroland increased HDL cholesterol [164] Hypolipidemic effectswere also observed in patients affected by atherosclerosisacute coronary syndrome and T2DM Moreover the effectof curcumin administration on lipid profile was evaluatedin acute coronary syndrome (ACS) patients at escalatingdoses (low dose 3 times 15mgday moderate dose 3 times30mgday high dose 3 times 60mgday) Unexpectedly thisstudy showed that the low dose of curcumin was associatedwith higher reduction of total HDL and LDL cholesterollevels [165 166] On the other hand a meta-analysis failed toshow protective effects of curcumin on both cholesterol andtriglycerides in a heterogeneous population [167] Curcuminadministration and aerobic exercise training increased FMDin postmenopausal women [168] Interestingly curcuminmay improve the blood compatibility of rapamycin-elutingstents through its antiplatelet properties [169]

5 Berberine

Berberine (BBR) an alkaloid isolated from Hydrastis canad-ensis the Chinese herb Huanglian and many other plantssuch as the Berberidaceae and Ranunculaceae families has along history in traditional Chinese medicine BBR is presentin roots rhizomes and stem bulk of the plants Various phar-macological actions including antibiotic immunostimulantantitumor and antimotility properties have been describedfor BBR [170 171]

Recent studies have indicated that BBR may be alsoeffective in treating chronicmultifactorial diseases includingdiabetes hyperlipidemia heart diseases cancer neurologicaldisorders and inflammatory diseases [172 173]

51 Molecular Targets and Properties Molecularmechanismsmediating antioxidant effects appear to be mainly related


to upregulation of both SOD and UCP2 and to down-regulation of NADPH oxidase expression [174 175] withparticular regard to NADPH oxidase 24 subunits [175] BBRadministration activates Nrf2 pathway which is crucial forantioxidant and anti-inflammatory activities [176] BBR couldsuppress inflammation by blocking the MAPK pathwaysin a AMPK-dependent manner by inhibiting the NF-120581Bsignaling pathway and the Rho GTPase pathway and byattenuating transcription activity of AP-1 which is possiblymediated by PPAR120572 activation [177ndash179]

52 Preclinical Evidences In vitro studies demonstratedthe role of BBR in counteracting endothelial progenitorcells (EPCs) dysfunction In fact BBR improved the pro-liferative ability of EPCs impaired by TNF-120572 via activa-tion of PI3KAkteNOS signaling pathway [180] More-over BBR induced endothelium-dependent vasorelaxationand enhanced endothelium-independent VSMC dilatationthrough a partial reduction of oxidative stress [181]

In VSMCs isolated from thoracic aorta of Sprague-Dawley rats BBR inhibited Ang II- and heparin bindingepidermal growth factor- (HB-EGF-) induced VSMC prolif-eration and migration In vivo results showed a reduction ofneointima formation after balloon injury thus lowering riskof restenosis [182] Zimetti et al demonstrated a double pro-tective effect of BBR on cholesterol homeostasis underlyingfoam cells formation and on the inflammatory phenotype inmouse and human macrophages [183]

BBR affected glucose metabolism by increasing insulinsecretion stimulating glycolysis suppressing adipogene-sis and increasing glucokinase activity and both glucosetransporter-4 (GLUT-4) and glucagon-like peptide (GLP-1)levels in glucose-consuming tissues [184]

Furthermore BBR was shown to have lipid-loweringproperties in animals as well as in hyperlipidemic patientsthrough mechanisms different from those of statins involv-ing activation of ERK pathway and increase of LDLRexpression on the hepatocytes surface [185] Interestinglycontrasting results were reported with regard to modulationof the gene encoding proprotein convertase subtilisin kexin9 (PCSK9) a natural inhibitor of LDLR In HepG2 cells20120583M BBR downregulated the transcription of the gene[186] whereas 400mg BBRkgday significantly reducedbody weight and improved lipid profile by increasing thePCSK9 expression levels through Sterol Regulatory Element-Binding Proteins activation in the high fat diet (HFD) ratmodel [187]

BBR at the dosage of 100mgkgday plays positiveinotropic antiarrhythmic and vasodilator properties relatedto the cardiovascular system [188 189] The antiarrhythmiceffects are due at least in part to preferential blockade ofthe components of the delayed rectifying potassium currentI(Kr) and I(Ks) and to increased effective refractory periodof Purkinje fibers [190 191]

The beneficial effects of BBR were demonstrated in sev-eral animalmodels such as SHRHFD rats pressure-overloadHF and myocardial ischemia [187 192ndash194] Notably 50Sprague-Dawley rats were treated with BBR (30 or 60mgkg)demonstrating that BBR had cardioprotective effects against

acute ischemic myocardial injury in a dose-dependent man-ner [194] BBR counteracted several pathological features ofhypertension including suppression of endoplasmic reticu-lum stress inhibition of ROS accumulation and attenuationof endothelium-dependent contractions in SHR [195] Theantihypertensive effect of BBR derivative 6-protoberberine(PTB-6) was shown in conscious SHR and Wistar-Kyoto(WKY) rats and it was mediated by reduced SNS activitythrough a negative inotropic and chronotropic effect [192]

A recent in vivo study reported that BBR can preventcardiac hypertrophy and attenuate cardiomyocyte apoptosisin the transverse aortic contraction treated rat model [193]

In a rat model of MI BBR administration significantlyenhanced autophagic activity attenuated adverse left ven-tricular remodelling and preserved left ventricular systolicfunction Interestingly low-dose BBR (10mgkg per day)was associated with greater improvement in cardiac functioncompared with high-dose BBR (50mgkg per day) [196]In diabetic rat models BBR protected the heart against IRinjury improved cardiac function and reduced myocardialapoptosis via activation of AMPK and PI3KAkt and eNOSsignaling [197] In addition cardioprotective effects of BBRin myocardial ischemia are due to its antioxidant and anti-inflammatory properties [194]

Chronic administration of BBR significantly reducedoxidative stress and vascular inflammation and suppressedatherogenesis in ApoEminusminus mice by AMPK-dependent UCP2expression [174]

In a middle cerebral artery occlusion (MCAO) modelBBR improved neurological outcome and reduced IR-induced cerebral infarction 48 hrs after MCAO The protec-tive effect of BBR was confirmed in vitro [198]

53 Clinical Evidences BBR has shown good safety resultsin human studies [199] A randomized clinical trial testedits effects in 156 patients with chronic congestive HF TheBBR-treated group (12ndash2 grday) showed significantly greaterincreases in left ventricular ejection fraction and exercisecapacity significant improvements on the dyspnea-fatigueindex and decreased rates of ventricular premature com-plexes and long-term mortality [200]

Treatment of 100 arrhythmic patients with BBR resultedin a gt89 reduction in premature beating in the majorityof patients and gt50 reduction in the remaining patients[201] These results were independently reproduced [202]A recent meta-analysis including 11 randomized controlledstudies (874 Chinese participants affected by hyperlipidemiaT2DM or both diseases) has shown a significant reductionin total cholesterol triglycerides and LDL cholesterol levelsand a small but significant increase in HDL cholesterol [203]

In T2DM patients high-dose BBR administration (100ndash200mgkgday) was associated with a significant reductionin glycated hemoglobin fasting plasma insulin postprandialglucose and fasting plasma glucose [204]

BBR beneficial effects were also observed in hypercholes-terolemic European patients [205]

A recent meta-analysis emphasized the role of BBR inthe treatment of hypertension In fact BBR associated with


Table1Preclin

icaleffectsof

vegetablec

ompo

unds

Vegetable

Preclin

icaleffects

Reference

Resveratrol

(i)Upregulates

thea

ntioxida

ntsystem

andredu

cesR

OSprod

uctio

n[14

15]

(ii)Inh

ibits

vascular

infla

mmationandpreventsplateletactiv

ation

[16ndash

22]

(iii)Lo

wersB

Pin

anim

alsw

itheither

diabetes

ormetabolicsynd

rome

[33]

(iv)Inh

ibits

very

early

stageso

fatherosclerosis

[4142]

(v)R

educes

lipid

accumulationby

inhibitin

glip

ogenesis

increasin

gapop

tosisand

prom

otinglip

olysis

[55ndash57]

(vi)Protectsagainstischemicheartd

isease

[72]

(vii)

Protectscardiactissue

from

celldeaththou

ghapop

tosis

andautoph

agy

[7475]

(viii)P

otentiatesregenerationof

infarctedmyocardium

[7677]

(ix)P

reventsc

ardiac

hypertroph

yanddysfu

nctio

n[83]

(x)P

romotes

angiog

enesisin

cerebralEC

sand

preventsim

pairm

ento

feNOS-depend

entvasorelaxationof

cerebralarterio

les

[9394]

(xi)Protectsfro

mdo

xorubicin-indu

cedcardiotoxicity

[100ndash102]

(xii)

Antiarrhy

thmiceff

ects

[103]

Brassicaoleracea

(i)Indu

cese

xpressionof

detoxific

ationenzymes

(ARE

targets)

[114]

(ii)L

owerso

x-LD

Lbloo

dlevels

[119]

(iii)Decreases

oxidatives

tressa

ndBP

levelsin

pregnant

femaleS

HRS

P[121]

(iv)P

romotes

optim

alplateletfunctio

nandan

tithrom

botic

effects

[122]

(v)A

ctso

ndifferent

typeso

fcellsinvolved

inatherosclerosis

developm

ent

[123]

(vi)Re

gulates

cholesterold

istrib

ution

[126]

(vii)

Protectsfro

mmyocardialoxida

tived

amagea

ndcelldeathin

ischemia-reperfusio

nratm

odels

[106128]

(viii)N

ephrop

rotectivee

ffects

[129]

Curcum

in

(i)Protectiv

eroleo

nendo

thelium

byindu

cing

HO-1

[147]

(ii)A

ntiproliferativea

ndan

tiapo

ptoticeffectson

VSMCs

atte

nuatingne

ointim

aformation

[149ndash

151]

(iii)Hyp

olipidem

iceffectand

protectio

nfro

maorticfatty

streak

developm

ent

[153154]

(iv)R

educes

collagensynthesis

andfib

rosis

andim

proves

leftventriculare

nd-diastolicvolumestroke

volumean

dejectio

nfractio

n[156]

(v)R

educes

MIsize

[137]

(vi)Protectsfro

mad

riam

ycin-in

ducedcardiotoxicity

[159]

(vii)

Protectsfro

mcerebralisc

hemicinsult

[138139]

Berberine

(i)Im

proves

thep

roliferativea

bilityo

fEPC

s[180]

(ii)Ind

uces

endo

thelial-d

ependent

vasorelaxatio

nandenhances

endo

thelium-in

depend

entV

SMCdilatatio

n[181]

(iii)InhibitsVS

MCproliferatio

nandmigratio

nandredu

cesn

eointim

aformation

[182]

(iv)L

ipid-lo

wering

prop

ertie

s[185]

(v)P

ositive

inotropican

tiarrhy

thmicand

vasodilatorp

roperties

[188189]

(vi)Antihyp

ertensivee

ffectsinSH

R[19

5](vii)

Preventscardiach

ypertrop

hyandattenu

ates

cardiomyocyteapop

tosis

[193]

(viii)A

ttenu

ates

adverseleft

ventricularr

emod

elingan

dpreservesleft

ventriculars

ystolic

functio

nin

ratm

odelof

MI

[196]

ROSreactiv

eoxygen

speciesBP

blood

pressureeNOSendo

thelialn

itricoxidesin

thaseARE

Antioxidant

Respon

seElem

ents

ox-LDL

oxidized

low-densitylip

oproteinSHRS

Pstr

okepron

espon

taneou

slyhypertensiv

eratsHO-1hem

eoxygenase-1E

Csend

othelialcells

VSMC

vascular

smoo

thmuscularc

ells

MImyocardialinfarction

EPCs

end

othelialprogenitorc

ells


Table2Clinicaleffectsof

vegetablec

ompo

unds

Vegetable

Clinicaleffects

Reference

Resveratrol

(i)Decreases

SBPwith

outaffectingDBP

[37]

(ii)E

nhancesA

ch-m

ediatedvasorelaxatio

nin

hypertensiv

eand

dyslipidemicpts

[38]

(iii)Im

proves

FMDin

ptsw

itheither

metabolicsynd

romeo

rpreviou

sMI

[3940

](iv

)Decreases

totalcho

lesterolan

dtotaland

ox-LDL

triglyceridesandAp

oBlevelsin

ptsw

ithT2

DMC

ADhyperlip

idem

iaand

otherC

Vris

kfactors

[5354]

(v)Improves

insulin

sensitivity

inbo

thob

esea

ndmetabolicsynd

romep

ts[6667]

(vi)Im

proves

significantly

diastolic

functio

nandmod

estly

systolicfunctio

nin

ptsw

ithprevious

MI

[40]

Brassicaoleracea

(i)Re

ducestotalL

DLcholesteroland

markers

ofoxidatives

tressinsm

okersa

ndhypercho

leste

rolemicpts

[108119]

(ii)Improves

lipid

profi

lesa

ndox-LDLLD

Lcholesterolratio

inT2

DM

pts

[132]

(iii)Lo

wersa

rterialstiff

nessandcentralB

Pin

wom

en[133]

Curcum

in(i)

Decreases

both

totaland

LDLcholesteroland

increasesH

DLcholesterolinhealthysubjectsandin

ACSpts

[164

165]

(ii)Increases

FMDin

postm

enop

ausalw

omen

[168]

Berberine

(i)Increasesb

othLV

EFandexercise

capa

city

anddecreasesrates

ofventricularp

rematurec

omplexes

andlong

-term

mortalityin

HFpts

[199]

(ii)R

educes

totalcho

lesteroltriglyceridesand

LDLcholesterollevels

andmod

estly

increasesH

DLcholesterolinhyperlipidemicandT2

DM

pts

[203205]

(iii)Re

ducesg

lycatedhemog

lobin

fastingplasmainsulinp

ostprand

ialglucoseand

fastingplasmag

lucose

inT2

DM

pts

[204

](iv

)Low

ersS

BPandDBP

inhypertensiv

eT2

DMand

hyperlipidemicpts

[206]

SBP

systo

licbloo

dpressureD

BPdiasto

licbloo

dpressureA

chA

cetylch

olineFM

Dflow

-mediateddilationMImyocardialinfarctionox-LDLoxidized

low-densitylip

oproteinH

DLhigh

-densitylip

oprotein

Apoapolipop

roteinT

2DMtype2

diabetes

mellitusC

ADcoron

aryartery

diseaseCV

cardiovascularAC

Sacutec

oron

arysynd

romeLV

EFleft

ventric

ular

ejectio

nfractio

nHFheartfailurepts

patie

nts


lifestyle intervention tended to lower the level of BP morethan lifestyle intervention alone or than placebo [206]

6 Conclusions

Preclinical studies revealed several beneficial cardiovascu-lar effects of resveratrol Brassica oleracea curcumin andberberine The benefits appeared to be mainly dependent onantioxidant anti-inflammatory and antithrombotic proper-ties In fact the excellent results of both in vitro and in vivostudies induced researchers and clinicians to test the effectsof phytochemicals in humans However evidences obtainedfrom the few available clinical trials on the protective effectsof these compounds in several CVDs are still controversialA main limitation of current clinical studies relies on theirheterogeneity and on small samples size Furthermore basedon the literature discussed in the present paper some confu-sion arises about the precise dose of each compound exertingmore pronounced beneficial effects In particular whereas theuse of a very high dose is associated with the most protectiveeffects for few phytochemicals the lowest dose turns out tobe themost effective for other compoundsThis phenomenonappears to be related to different animal models as well as tothe specific disease under consideration Therefore there is aneed for additional larger and well controlled human studies

Altogether the lack of a clear beneficial role in humansthe wide variety of in vitro ex vivo and in vivo experimentalevidences that are summarized in Tables 1 and 2 suggests thatresveratrol Brassica oleracea curcumin and berberine mayreveal very useful preventive andor therapeutic tools for thetreatment of CVDs as a valid support to medical therapies

Conflict of Interests

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

Acknowledgments

The present work was supported by a grant (Ricerca Cor-rente) from the Italian Ministry of Health to SperanzaRubattu and by the 5permil grant to Speranza Rubattu

References

[1] D Mozaffarian E J Benjamin A S Go et al ldquoExecutivesummary heart disease and stroke statistics-2015 update areport from the American Heart Associationrdquo Circulation vol131 no 4 pp 434ndash441 2015

[2] Y Qin F Shu Y Zeng et al ldquoDaidzein supplementationdecreases serum triglyceride and uric acid concentrations inhypercholesterolemic adults with the effect on triglyceridesbeing greater in those with the GA compared with the GGgenotype of ESR-120573 RsaIrdquo Journal of Nutrition vol 144 no 1 pp49ndash54 2014

[3] E Chan C Y-K Wong C-W Wan et al ldquoEvaluation of anti-oxidant capacity of root of Scutellaria baicalensis Georgi incomparison with roots of Polygonum multiflorum Thunb and

Panax ginseng CA Meyerrdquo The American Journal of ChineseMedicine vol 38 no 4 pp 815ndash827 2010

[4] J Burns T Yokota H Ashihara M E J Lean and A CrozierldquoPlant foods and herbal sources of resveratrolrdquo Journal ofAgricultural and Food Chemistry vol 50 no 11 pp 3337ndash33402002

[5] D Mikulski R Gorniak and M Molski ldquoA theoretical studyof the structure-radical scavenging activity of trans-resveratrolanalogues and cis-resveratrol in gas phase and water environ-mentrdquo European Journal of Medicinal Chemistry vol 45 no 3pp 1015ndash1027 2010

[6] D K Das S Mukherjee and D Ray ldquoResveratrol and red winehealthy heart and longevityrdquo Heart Failure Reviews vol 15 no5 pp 467ndash477 2010

[7] S Renaud andM de Lorgeril ldquoWine alcohol platelets and theFrench paradox for coronary heart diseaserdquoTheLancet vol 339no 8808 pp 1523ndash1526 1992

[8] C-H Cottart V Nivet-Antoine and J-L Beaudeux ldquoReview ofrecent data on themetabolism biological effects and toxicity ofresveratrol in humansrdquoMolecular Nutrition and Food Researchvol 58 no 1 pp 7ndash21 2014

[9] H Yun S Park M-J Kim et al ldquoAMP-activated proteinkinase mediates the antioxidant effects of resveratrol throughregulation of the transcription factor FoxO1rdquo FEBS Journal vol281 no 19 pp 4421ndash4438 2014

[10] S M Saud W Li N L Morris et al ldquoResveratrol preventstumorigenesis in mouse model of Kras activated sporadiccolorectal cancer by suppressing oncogenic Kras expressionrdquoCarcinogenesis vol 35 no 12 pp 2778ndash2786 2014

[11] X Cao T Luo X Luo and Z Tang ldquoResveratrol pre-vents AngII-induced hypertension via AMPK activation andRhoAROCK suppression in micerdquoHypertension Research vol37 no 9 pp 803ndash810 2014

[12] M J Zarzuelo R Lopez-Sepulveda M Sanchez et al ldquoSIRT1inhibits NADPH oxidase activation and protects endothelialfunction in the rat aorta implications for vascular agingrdquoBiochemical Pharmacology vol 85 no 9 pp 1288ndash1296 2013

[13] M Pacholec J E Bleasdale B Chrunyk et al ldquoSRT1720SRT2183 SRT1460 and resveratrol are not direct activators ofSIRT1rdquo The Journal of Biological Chemistry vol 285 no 11 pp8340ndash8351 2010

[14] G Spanier H Xu N Xia et al ldquoResveratrol reduces endothelialoxidative stress by modulating the gene expression of superox-ide dismutase 1 (SOD1) glutathione peroxidase 1 (GPx1) andNADPH oxidase subunit (Nox4)rdquo Journal of Physiology andPharmacology vol 60 supplement 4 pp 111ndash116 2009

[15] M Tanno A Kuno T Yano et al ldquoInduction of manganesesuperoxide dismutase by nuclear translocation and activationof SIRT1 promotes cell survival in chronic heart failurerdquo TheJournal of Biological Chemistry vol 285 no 11 pp 8375ndash83822010

[16] J J Moreno ldquoResveratrol modulates arachidonic acid releaseprostaglandin synthesis and 3T6 fibroblast growthrdquo Journal ofPharmacology and ExperimentalTherapeutics vol 294 no 1 pp333ndash338 2000

[17] J K Kundu Y K Shin S H Kim and Y-J Surh ldquoResveratrolinhibits phorbol ester-induced expression of COX-2 and acti-vation of NF-120581B in mouse skin by blocking I120581B kinase activityrdquoCarcinogenesis vol 27 no 7 pp 1465ndash1474 2006

[18] L Yang J Zhang C Yan et al ldquoSIRT1 regulates CD40expression induced byTNF-120572 viaNF-120581Bpathway in endothelial


cellsrdquo Cellular Physiology and Biochemistry vol 30 no 5 pp1287ndash1298 2012

[19] J P Cullen D Morrow Y Jin et al ldquoResveratrol a polyphe-nolic phytostilbene inhibits endothelial monocyte chemotacticprotein-1 synthesis and secretionrdquo Journal of Vascular Researchvol 44 no 1 pp 75ndash84 2007

[20] C C Wu C I Wu W Y Wang and Y C Wu ldquoLowconcentrations of resveratrol potentiate the antiplatelet effect ofprostaglandinsrdquo PlantaMedica vol 73 no 5 pp 439ndash443 2007

[21] K H Lin G Hsiao C M Shih D S Chou and J RSheu ldquoMechanisms of resveratrol-induced platelet apoptosisrdquoCardiovascular Research vol 83 no 3 pp 575ndash585 2009

[22] M Y Shen G Hsiao C L Liu et al ldquoInhibitory mechanisms ofresveratrol in platelet activation pivotal roles of p38MAPK andNOcyclic GMPrdquo British Journal of Haematology vol 139 no 3pp 475ndash485 2007

[23] B Olas B Wachowicz H Holmsen and M H FukamildquoResveratrol inhibits polyphosphoinositide metabolism in acti-vated plateletsrdquo Biochimica et Biophysica ActamdashBiomembranesvol 1714 no 2 pp 125ndash133 2005

[24] J W E Rush J Quadrilatero A S Levy and R J FordldquoChronic resveratrol enhances endothelium-dependent relax-ation but does not alter eNOS levels in aorta of spontaneouslyhypertensive ratsrdquo Experimental Biology and Medicine vol 232no 6 pp 814ndash822 2007

[25] A Novakovic L Gojkovic-Bukarica M Peric et al ldquoThemechanism of endothelium-independent relaxation induced bythe wine polyphenol resveratrol in human internal mammaryarteryrdquo Journal of Pharmacological Sciences vol 101 no 1 pp85ndash90 2006

[26] J Zou Z Wang Y Huang K Cao and J Wu ldquoEffect of redwine and wine polyphenol resveratrol on endothelial functionin hypercholesterolemic rabbitsrdquo International Journal ofMolec-ular Medicine vol 11 no 3 pp 317ndash320 2003

[27] J-C Liu J-J Chen P Chan C-F Cheng and T-H ChengldquoInhibition of cyclic strain-induced endothelin-1 gene expres-sion by resveratrolrdquo Hypertension vol 42 no 6 pp 1198ndash12052003

[28] H-J Ma Y-K Cao Y-X Liu R Wang and Y-M WuldquoMicroinjection of resveratrol into rostral ventrolateral medulladecreases sympathetic vasomotor tone through nitric oxide andintracellular Ca2+ in anesthetizedmale ratsrdquoActa Pharmacolog-ica Sinica vol 29 no 8 pp 906ndash912 2008

[29] S R Bhatt M F Lokhandwala and A A Banday ldquoResver-atrol prevents endothelial nitric oxide synthase uncouplingand attenuates development of hypertension in spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 667no 1ndash3 pp 258ndash264 2011

[30] H Z Toklu O Sehirli M Ersahin et al ldquoResveratrol improvescardiovascular function and reduces oxidative organ damagein the renal cardiovascular and cerebral tissues of two-kidneyone-clip hypertensive ratsrdquo Journal of Pharmacy and Pharma-cology vol 62 no 12 pp 1784ndash1793 2010

[31] Z Liu Y Song X Zhang et al ldquoEffects of trans-resveratrol onhypertension-induced cardiac hypertrophy using the partiallynephrectomized rat modelrdquoClinical and Experimental Pharma-cology and Physiology vol 32 no 12 pp 1049ndash1054 2005

[32] V Chan A Fenning A Iyer A Hoey and L Brown ldquoResvera-trol improves cardiovascular function in DOCA-salt hyperten-sive ratsrdquo Current Pharmaceutical Biotechnology vol 12 no 3pp 429ndash436 2011

[33] M-C Aubin C Lajoie R Clement H Gosselin A Calderoneand L P Perrault ldquoFemale rats fed a high-fat diet wereassociated with vascular dysfunction and cardiac fibrosis in theabsence of overt obesity and hyperlipidemia therapeutic poten-tial of resveratrolrdquo Journal of Pharmacology and ExperimentalTherapeutics vol 325 no 3 pp 961ndash968 2008

[34] U Forstermann and H Li ldquoTherapeutic effect of enhancingendothelial nitric oxide synthase (eNOS) expression and pre-venting eNOS uncouplingrdquo British Journal of Pharmacologyvol 164 no 2 pp 213ndash223 2011

[35] I Mattagajasingh C-S Kim A Naqvi et al ldquoSIRT1 pro-motes endothelium-dependent vascular relaxation by acti-vating endothelial nitric oxide synthaserdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 104 no 37 pp 14855ndash14860 2007

[36] H Li and U Forstermann ldquoNitric oxide in the pathogenesis ofvascular diseaserdquo Journal of Pathology vol 190 no 3 pp 244ndash254 2000

[37] Y Liu W Ma P Zhang S He and D Huang ldquoEffect ofresveratrol on blood pressure a meta-analysis of randomizedcontrolled trialsrdquo Clinical Nutrition vol 34 no 1 pp 27ndash342015

[38] A Carrizzo A Puca A Damato et al ldquoResveratrol improvesvascular function in patients with hypertension and dyslipi-demia by modulating NO metabolismrdquo Hypertension vol 62no 2 pp 359ndash366 2013

[39] RH XWongNM Berry AMCoates et al ldquoChronic resver-atrol consumption improves brachial flow-mediated dilatationin healthy obese adultsrdquo Journal of Hypertension vol 31 no 9pp 1819ndash1827 2013

[40] K Magyar R Halmosi A Palfi et al ldquoCardioprotectionby resveratrol a human clinical trial in patients with stablecoronary artery diseaserdquo Clinical Hemorheology and Microcir-culation vol 50 no 3 pp 179ndash187 2012

[41] T Yashiro M Nanmoku M Shimizu J Inoue and R SatoldquoResveratrol increases the expression and activity of the lowdensity lipoprotein receptor in hepatocytes by the proteolyticactivation of the sterol regulatory element-binding proteinsrdquoAtherosclerosis vol 220 no 2 pp 369ndash374 2012

[42] J Xiao J Song V Hodara et al ldquoProtective effects of resveratrolon TNF-120572-induced endothelial cytotoxicity in baboon femoralarterial endothelial cellsrdquo Journal of Diabetes Research vol 2013Article ID 185172 9 pages 2013

[43] D-W Park K Baek J-R Kim et al ldquoResveratrol inhibits foamcell formation via NADPH oxidase 1-mediated reactive oxygenspecies andmonocyte chemotactic protein-1rdquoExperimental andMolecular Medicine vol 41 no 3 pp 171ndash179 2009

[44] J P Cullen DMorrow Y Jin et al ldquoResveratrol inhibits expres-sion and binding activity of themonocyte chemotactic protein-1receptor CCR2 on THP-1 monocytesrdquo Atherosclerosis vol 195no 1 pp e125ndashe133 2007

[45] I Voloshyna OHaiM J Littlefield S Carsons andA B ReissldquoResveratrol mediates anti-atherogenic effects on cholesterolflux in human macrophages and endothelium via PPARgammaand adenosinerdquo European Journal of Pharmacology vol 698 no1ndash3 pp 299ndash309 2013

[46] A Csiszar D Sosnowska M Wang E G Lakatta W ESonntag and Z Ungvari ldquoAge-associated proinflammatorysecretory phenotype in vascular smooth muscle cells from thenon-human primate macaca mulatta reversal by resveratroltreatmentrdquo Journals of GerontologymdashSeries A Biological Sci-ences and Medical Sciences vol 67 no 8 pp 811ndash820 2012


[47] L Li P Gao H Zhang et al ldquoSIRT1 inhibits angiotensinII-induced vascular smooth muscle cell hypertrophyrdquo ActaBiochimica et Biophysica Sinica vol 43 no 2 pp 103ndash109 2011

[48] A Y Gocmen D Burgucu and S Gumuslu ldquoEffect ofresveratrol on platelet activation in hypercholesterolemic ratsCD40-CD40l system as a potential targetrdquo Applied PhysiologyNutrition and Metabolism vol 36 no 3 pp 323ndash330 2011

[49] Z Wang J Zou K Cao T-C Hsieh Y Huang and J MWu ldquoDealcoholized red wine containing known amounts ofresveratrol suppresses atherosclerosis in hypercholesterolemicrabbits without affecting plasma lipid levelsrdquo InternationalJournal of Molecular Medicine vol 16 no 4 pp 533ndash540 2005

[50] G-M Do E-Y Kwon H-J Kim et al ldquoLong-term effectsof resveratrol supplementation on suppression of atherogeniclesion formation and cholesterol synthesis in apo E-deficientmicerdquo Biochemical and Biophysical Research Communicationsvol 374 no 1 pp 55ndash59 2008

[51] Q Chen E Wang L Ma and P Zhai ldquoDietary resveratrolincreases the expression of hepatic 7-hydroxylase and ame-liorates hypercholesterolemia in high-fat fed C57BL6J micerdquoLipids in Health and Disease vol 11 article 56 2012

[52] A Sahebkar ldquoEffects of resveratrol supplementation on plasmalipids a systematic review and meta-analysis of randomizedcontrolled trialsrdquoNutrition Reviews vol 71 no 12 pp 822ndash8352013

[53] J K Bhatt S Thomas and M J Nanjan ldquoResveratrol sup-plementation improves glycemic control in type 2 diabetesmellitusrdquo Nutrition Research vol 32 no 7 pp 537ndash541 2012

[54] C Militaru I Donoiu A Craciun I D Scorei A M Bulearcaand R I Scorei ldquoOral resveratrol and calcium fructoboratesupplementation in subjects with stable angina pectoris effectson lipid profiles inflammation markers and quality of liferdquoNutrition vol 29 no 1 pp 178ndash183 2013

[55] S Chen Z Li W Li Z Shan and W Zhu ldquoResveratrolinhibits cell differentiation in 3T3-L1 adipocytes via activationofAMPKrdquoCanadian Journal of PhysiologyampPharmacology vol89 no 11 pp 793ndash799 2011

[56] I Mader M Wabitsch K-M Debatin P Fischer-Posovszkyand S Fulda ldquoIdentification of a novel proapoptotic functionof resveratrol in fat cells SIRT1-independent sensitization toTRAIL-induced apoptosisrdquo The FASEB Journal vol 24 no 6pp 1997ndash2009 2010

[57] A Lasa M Schweiger P Kotzbeck et al ldquoResveratrol regulateslipolysis via adipose triglyceride lipaserdquo Journal of NutritionalBiochemistry vol 23 no 4 pp 379ndash384 2012

[58] G Alberdi V M Rodrıguez J Miranda et al ldquoChanges inwhite adipose tissue metabolism induced by resveratrol in ratsrdquoNutrition amp Metabolism vol 8 no 1 p 29 2011

[59] S Koren and I G Fantus ldquoInhibition of the protein tyrosinephosphatase PTP1B potential therapy for obesity insulin resis-tance and type-2 diabetes mellitusrdquo Best Practice and Researchin Clinical Endocrinology andMetabolism vol 21 no 4 pp 621ndash640 2007

[60] S M Grundy I J Benjamin G L Burke et al ldquoDiabetes andcardiovascular disease a statement for healthcare professionalsfrom the AmericanHeart AssociationrdquoCirculation vol 100 no10 pp 1134ndash1146 1999

[61] S Frojdo C Durand L Molin et al ldquoPhosphoinositide 3-kinase as a novel functional target for the regulation of theinsulin signaling pathway by SIRT1rdquo Molecular and CellularEndocrinology vol 335 no 2 pp 166ndash176 2011

[62] Y-H Jing K-H Chen S-H Yang P-C Kuo and J-K ChenldquoResveratrol ameliorates vasculopathy in STZ-induced dia-betic rats role of AGE-RAGE signallingrdquo DiabetesMetabolismResearch and Reviews vol 26 no 3 pp 212ndash222 2010

[63] M Thirunavukkarasu S V Penumathsa S Koneru et alldquoResveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes role of nitric oxide thioredoxin and hemeoxygenaserdquo Free Radical Biology andMedicine vol 43 no 5 pp720ndash729 2007

[64] M Sulaiman M J Matta N R Sunderesan M P Gupta MPeriasamy and M Gupta ldquoResveratrol an activator of SIRT1upregulates sarcoplasmic calciumATPase and improves cardiacfunction in diabetic cardiomyopathyrdquo The American Journal ofPhysiologymdashHeart and Circulatory Physiology vol 298 no 3pp H833ndashH843 2010

[65] H Zhang B Morgan B J Potter et al ldquoResveratrol improvesleft ventricular diastolic relaxation in type 2 diabetes by inhibit-ing oxidativenitrative stress in vivo demonstration with mag-netic resonance imagingrdquoTheAmerican Journal of PhysiologymdashHeart and Circulatory Physiology vol 299 no 4 pp H985ndashH994 2010

[66] J P Crandall V Oram G Trandafirescu et al ldquoPilot studyof resveratrol in older adults with impaired glucose tolerancerdquoJournals of GerontologymdashSeries A Biological Sciences and Med-ical Sciences vol 67 no 12 pp 1307ndash1312 2012

[67] M Mendez-del Villar M Gonzalez-Ortiz E Martınez-Abundis K G Perez-Rubio and R Lizarraga-Valdez ldquoEffectof resveratrol administration on metabolic syndrome insulinsensitivity and insulin secretionrdquo Metabolic Syndrome andRelated Disorders vol 12 no 10 pp 497ndash501 2014

[68] V S Chachay G A Macdonald J H Martin et al ldquoResveratroldoes not benefit patients with nonalcoholic fatty liver diseaserdquoClinical Gastroenterology and Hepatology vol 12 no 12 pp2092ndash2103e6 2014

[69] S Dash C Xiao C Morgantini L Szeto and G F LewisldquoHigh-dose resveratrol treatment for 2 weeks inhibits intestinaland hepatic lipoprotein production in overweightobese menrdquoArteriosclerosis Thrombosis and Vascular Biology vol 33 no12 pp 2895ndash2901 2013

[70] J Tome-Carneiro M Gonzalvez M Larrosa et al ldquoGraperesveratrol increases serum adiponectin and downregulatesinflammatory genes in peripheral blood mononuclear cellsa triple-blind placebo-controlled one-year clinical trial inpatients with stable coronary artery diseaserdquo CardiovascularDrugs andTherapy vol 27 no 1 pp 37ndash48 2013

[71] D De Groote K van Belleghem J Devire W Van BrusselA Mukaneza and L Amininejad ldquoEffect of the intake ofresveratrol resveratrol phosphate and catechin-rich grape seedextract on markers of oxidative stress and gene expression inadult obese subjectsrdquo Annals of Nutrition and Metabolism vol61 no 1 pp 15ndash24 2012

[72] L-M Hung M-J Su and J-K Chen ldquoResveratrol protectsmyocardial ischemia-reperfusion injury through both NO-dependent and NO-independent mechanismsrdquo Free RadicalBiology and Medicine vol 36 no 6 pp 774ndash781 2004

[73] X-B Wang J Huang J-G Zou et al ldquoEffects of resveratrol onnumber and activity of endothelial progenitor cells fromhumanperipheral bloodrdquo Clinical and Experimental Pharmacology andPhysiology vol 34 no 11 pp 1109ndash1115 2007

[74] C-J Chen W Yu Y-C Fu X Wang J-L Li and W WangldquoResveratrol protects cardiomyocytes from hypoxia-inducedapoptosis through the SIRT1-FoxO1 pathwayrdquo Biochemical and


Biophysical Research Communications vol 378 no 3 pp 389ndash393 2009

[75] N Gurusamy I Lekli S Mukherjee et al ldquoCardioprotectionby resveratrol a novel mechanism via autophagy involving themTORC2 pathwayrdquo Cardiovascular Research vol 86 no 1 pp103ndash112 2010

[76] S Kaga L Zhan M Matsumoto and N Maulik ldquoResveratrolenhances neovascularization in the infarcted rat myocardiumthrough the induction of thioredoxin-1 heme oxygenase-1 andvascular endothelial growth factorrdquo Journal of Molecular andCellular Cardiology vol 39 no 5 pp 813ndash822 2005

[77] N Gurusamy D Ray I Lekli and D K Das ldquoRed wineantioxidant resveratrol-modified cardiac stem cells regener-ate infarcted myocardiumrdquo Journal of Cellular and MolecularMedicine vol 14 no 9 pp 2235ndash2239 2010

[78] PMukhopadhyay SMukherjee K Ahsan A Bagchi P Pacherand D K Das ldquoRestoration of altered MicroRNA expression inthe ischemic heart with resveratrolrdquo PLoS ONE vol 5 no 12Article ID e15705 2010

[79] M Shalwala S-G Zhu A Das F N Salloum L Xi and RC Kukreja ldquoSirtuin 1 (SIRT1) activation mediates sildenafilinduced delayed cardioprotection against ischemia-reperfusioninjury in micerdquo PLoS ONE vol 9 no 1 Article ID e86977 2014

[80] H Kanamori G Takemura K Goto et al ldquoResveratrol reversesremodeling in hearts with large old myocardial infarctionsthrough enhanced autophagy-activating AMP kinase pathwayrdquoAmerican Journal of Pathology vol 182 no 3 pp 701ndash713 2013

[81] A Barseghian D Gawande and M Bajaj ldquoAdiponectin andvulnerable atherosclerotic plaquesrdquo Journal of the AmericanCollege of Cardiology vol 57 no 7 pp 761ndash770 2011

[82] H Maruyoshi S Kojima T Funahashi et al ldquoAdiponectinis inversely related to plasminogen activator inhibitor type1 in patients with stable exertional anginardquo Thrombosis andHaemostasis vol 91 no 5 pp 1026ndash1030 2004

[83] B N Zordoky I M Robertson and J R Dyck ldquoPreclinicaland clinical evidence for the role of resveratrol in the treatmentof cardiovascular diseasesrdquo Biochimica et Biophysica Acta vol1852 no 6 pp 1155ndash1177 2014

[84] S JThandapilly PWojciechowski J Behbahani et al ldquoResvera-trol prevents the development of pathological cardiac hypertro-phy and contractile dysfunction in the SHR without loweringblood pressurerdquo American Journal of Hypertension vol 23 no2 pp 192ndash196 2010

[85] S Rimbaud M Ruiz J Piquereau et al ldquoResveratrol improvessurvival hemodynamics and energetics in a rat model ofhypertension leading to heart failurerdquo PLoS ONE vol 6 no 10Article ID e26391 2011

[86] PWojciechowski D Juric X L Louis et al ldquoResveratrol arrestsand regresses the development of pressure overload- but notvolume overload-induced cardiac hypertrophy in ratsrdquo Journalof Nutrition vol 140 no 5 pp 962ndash968 2010

[87] P Ferroni D Della-Morte R Palmirotta et al ldquoPlatinum-basedcompounds and risk for cardiovascular toxicity in the elderlyrole of the antioxidants in chemopreventionrdquo RejuvenationResearch vol 14 no 3 pp 293ndash308 2011

[88] X S Gu Z B Wang Z Ye et al ldquoResveratrol an activatorof SIRT1 upregulates AMPK and improves cardiac function inheart failurerdquoGenetics andMolecular Research vol 13 no 1 pp323ndash335 2014

[89] Y Yoshida T Shioi and T Izumi ldquoResveratrol amelioratesexperimental autoimmune myocarditisrdquo Circulation Journalvol 71 no 3 pp 397ndash404 2007

[90] W Xuan B Wu C Chen et al ldquoResveratrol improves myocar-dial ischemia and ischemic heart failure inmice by antagonizingthe detrimental effects of fractalkinerdquo Critical Care Medicinevol 40 no 11 pp 3026ndash3033 2012

[91] MM Sung S K Das J Levasseur et al ldquoResveratrol treatmentof mice with pressure-overload-induced heart failure improvesdiastolic function and cardiac energy metabolismrdquo CirculationHeart Failure vol 8 no 1 pp 128ndash137 2015

[92] D Clark U I Tuor R Thompson et al ldquoProtection againstrecurrent stroke with resveratrol endothelial protectionrdquo PLoSONE vol 7 no 10 Article ID e47792 2012

[93] F Simao A S Pagnussat J H Seo et al ldquoPro-angiogenic effectsof resveratrol in brain endothelial cells nitric oxide-mediatedregulation of vascular endothelial growth factor and metallo-proteinasesrdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 884ndash895 2012

[94] D M Arrick H Sun K P Patel and W G Mayhan ldquoChronicresveratrol treatment restores vascular responsiveness of cere-bral arterioles in type 1 diabetic ratsrdquo The American Journal ofPhysiologymdashHeart andCirculatory Physiology vol 301 no 3 ppH696ndashH703 2011

[95] S S Huang M C Tsai C L Chih L M Hung and S KTsai ldquoResveratrol reduction of infarct size in Long-Evans ratssubjected to focal cerebral ischemiardquo Life Sciences vol 69 no 9pp 1057ndash1065 2001

[96] H-C Chang Y-T Tai Y-G Cherng et al ldquoResveratrol attenu-ates high-fat diet-induced disruption of the blood-brain barrierand protects brain neurons from apoptotic insultsrdquo Journal ofAgricultural and Food Chemistry vol 62 no 15 pp 3466ndash34752014

[97] J Ren C Fan N Chen J Huang and Q Yang ldquoResveratrolpretreatment attenuates cerebral ischemic injury by upregulat-ing expression of transcription factor Nrf2 and HO-1 in RatsrdquoNeurochemical Research vol 36 no 12 pp 2352ndash2362 2011

[98] DDella-Morte K R Dave R A DeFazio Y C Bao A P Ravaland M A Perez-Pinzon ldquoResveratrol pretreatment protects ratbrain from cerebral ischemic damage via a sirtuin 1-uncouplingprotein 2 pathwayrdquo Neuroscience vol 159 no 3 pp 993ndash10022009

[99] E L Wightman J L Reay C F Haskell G WilliamsonT P Dew and D O Kennedy ldquoEffects of resveratrol aloneor in combination with piperine on cerebral blood flowparameters and cognitive performance in human subjectsa randomised double-blind placebo-controlled cross-overinvestigationrdquo British Journal of Nutrition vol 112 no 2 pp203ndash213 2014

[100] M H Arafa N S Mohammad H H Atteia and H R Abd-Elaziz ldquoProtective effect of resveratrol against doxorubicin-induced cardiac toxicity and fibrosis in male experimental ratsrdquoJournal of Physiology and Biochemistry vol 70 no 3 pp 701ndash711 2014

[101] G-Y Wang Y-M Wang L-N Zhang et al ldquoEffect of resver-atrol on heart function of rats with adriamycin-induced heartfailurerdquo Zhongguo Zhong Yao Za Zhi vol 32 no 15 pp 1563ndash1565 2007

[102] SWang P Song andM-H Zou ldquoInhibition of AMP-activatedprotein kinase 120572 (AMPK120572) by doxorubicin accentuates geno-toxic stress and cell death in mouse embryonic fibroblasts andcardiomyocytes role of p53 and SIRT1rdquoThe Journal of BiologicalChemistry vol 287 no 11 pp 8001ndash8012 2012


[103] Y Zhang Y Liu T Wang et al ldquoResveratrol a natural ingre-dient of grape skin antiarrhythmic efficacy and ionic mecha-nismsrdquo Biochemical and Biophysical Research Communicationsvol 340 no 4 pp 1192ndash1199 2006

[104] Y R Chen F F Yi X Y Li et al ldquoResveratrol attenuatesventricular arrhythmias and improves the long-term survivalin rats with myocardial infarctionrdquo Cardiovascular Drugs andTherapy vol 22 no 6 pp 479ndash485 2008

[105] I Baczko D Liknes W Yang et al ldquoCharacterization of a novelmultifunctional resveratrol derivative for the treatment of atrialfibrillationrdquo British Journal of Pharmacology vol 171 no 1 pp92ndash106 2014

[106] M Akhlaghi and B Bandy ldquoDietary broccoli sprouts protectagainst myocardial oxidative damage and cell death duringischemia-reperfusionrdquo Plant Foods for Human Nutrition vol65 no 3 pp 193ndash199 2010

[107] H A H Kataya and A A Hamza ldquoRed cabbage (Brassicaoleracea) ameliorates diabetic nephropathy in ratsrdquo Evidence-Based Complementary and Alternative Medicine vol 5 no 3pp 281ndash287 2008

[108] S Y Kim S Yoon S M Kwon K S Park and Y C Lee-Kim ldquoKale Juice improves coronary artery disease risk factorsin hypercholesterolemic menrdquo Biomedical and EnvironmentalSciences vol 21 no 2 pp 91ndash97 2008

[109] R Domınguez-Perles P Mena C Garcıa-Viguera and D AMoreno ldquoBrassica foods as a dietary source of vitamin C areviewrdquo Critical Reviews in Food Science and Nutrition vol 54no 8 pp 1076ndash1091 2014

[110] RMithen R Bennett and JMarquez ldquoGlucosinolate biochem-ical diversity and innovation in the Brassicalesrdquo Phytochemistryvol 71 no 17-18 pp 2074ndash2086 2010

[111] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013

[112] C C Conaway S M Getahun L L Liebes et al ldquoDispositionof glucosinolates and sulforaphane in humans after ingestion ofsteamed and fresh broccolirdquo Nutrition and Cancer vol 38 no2 pp 168ndash178 2000

[113] M Vermeulen H JM van Rooijen andWH J Vaes ldquoAnalysisof isothiocyanate mercapturic acids in urine a biomarker forcruciferous vegetable intakerdquo Journal of Agricultural and FoodChemistry vol 51 no 12 pp 3554ndash3559 2003

[114] S A Ritz J Wan and D Diaz-Sanchez ldquoSulforaphane-stimulated phase II enzyme induction inhibits cytokine produc-tion by airway epithelial cells stimulatedwith diesel extractrdquoTheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 292 no 1 pp L33ndashL39 2007

[115] M-H Oak J E Bedoui S V F Madeira K Chalupsky and VB Schini-Kerth ldquoDelphinidin and cyanidin inhibit PDGFAB-induced VEGF release in vascular smooth muscle cells bypreventing activation of p38 MAPK and JNKrdquo British Journalof Pharmacology vol 149 no 3 pp 283ndash290 2006

[116] A Palfi E Bartha L Copf et al ldquoAlcohol-free red wineinhibits isoproterenol-induced cardiac remodeling in rats bythe regulation of Akt1 and protein kinase C 120572120573 IIrdquo Journal ofNutritional Biochemistry vol 20 no 6 pp 418ndash425 2009

[117] S Rubattu S di Castro M Cotugno et al ldquoProtective effects ofBrassica oleracea sprouts extract toward renal damage in high-salt-fed SHRSP role of AMPKPPAR120572UCP2 axisrdquo Journal ofHypertension vol 33 no 7 pp 1465ndash1479 2015

[118] M Zakkar K van der Heiden L A Luong et al ldquoActivationof Nrf2 in endothelial cells protects arteries from exhibiting a

proinflammatory staterdquo Arteriosclerosis Thrombosis and Vas-cular Biology vol 29 no 11 pp 1851ndash1857 2009

[119] M Murashima S Watanabe X-G Zhuo M Uehara andA Kurashige ldquoPhase 1 study of multiple biomarkers formetabolism and oxidative stress after one-week intake of broc-coli sproutsrdquo BioFactors vol 22 no 1ndash4 pp 271ndash275 2004

[120] L Wu M H N Ashraf M Facci et al ldquoDietary approach toattenuate oxidative stress hypertension and inflammation inthe cardiovascular systemrdquo Proceedings of the National Academyof Sciences of the United States of America vol 101 no 18 pp7094ndash7099 2004

[121] M H Noyan-Ashraf L Wu R Wang and B H J JuurlinkldquoDietary approaches to positively influence fetal determinantsof adult healthrdquo The FASEB Journal vol 20 no 2 pp 371ndash3732006

[122] A R Rechner and C Kroner ldquoAnthocyanins and colonicmetabolites of dietary polyphenols inhibit platelet functionrdquoThrombosis Research vol 116 no 4 pp 327ndash334 2005

[123] M Garcia-Alonso A-M Minihane G Rimbach J C Rivas-Gonzalo and S de Pascual-Teresa ldquoRed wine anthocyanins arerapidly absorbed in humans and affect monocyte chemoattrac-tant protein 1 levels and antioxidant capacity of plasmardquo Journalof Nutritional Biochemistry vol 20 no 7 pp 521ndash529 2009

[124] D R Bell andKGochenaur ldquoDirect vasoactive and vasoprotec-tive properties of anthocyanin-rich extractsrdquo Journal of AppliedPhysiology vol 100 no 4 pp 1164ndash1170 2006

[125] M-C Toufektsian M de Lorgeril N Nagy et al ldquoChronicdietary intake of plant-derived anthocyanins protects the ratheart against ischemia-reperfusion injuryrdquo Journal of Nutritionvol 138 no 4 pp 747ndash752 2008

[126] M Xia W Ling H Zhu et al ldquoAnthocyanin prevents CD40-activated proinflammatory signaling in endothelial cells by reg-ulating cholesterol distributionrdquo Arteriosclerosis Thrombosisand Vascular Biology vol 27 no 3 pp 519ndash524 2007

[127] M Hamalainen R Nieminen P Vuorela M Heinonen and EMoilanen ldquoAnti-inflammatory effects of flavonoids genisteinkaempferol quercetin and daidzein inhibit STAT-1 and NF-120581B activations whereas flavone isorhamnetin naringenin andpelargonidin inhibit only NF-120581B activation along with theirinhibitory effect on iNOS expression and NO production inactivated macrophagesrdquo Mediators of Inflammation vol 2007Article ID 45673 10 pages 2007

[128] T M Scarabelli S Mariotto S Abdel-Azeim et al ldquoTargetingSTAT1 by myricetin and delphinidin provides efficient protec-tion of the heart from ischemiareperfusion-induced injuryrdquoFEBS Letters vol 583 no 3 pp 531ndash541 2009

[129] Y Jia J-Y Kim H-J Jun et al ldquoCyanidin is an agonistic ligandfor peroxisome proliferator-activated receptor-alpha reducinghepatic lipidrdquo Biochimica et Biophysica ActamdashMolecular andCell Biology of Lipids vol 1831 no 4 pp 698ndash708 2013

[130] J D Clarke K Riedl D Bella S J Schwartz J F Stevensand E Ho ldquoComparison of isothiocyanate metabolite levelsand histone deacetylase activity in human subjects consumingbroccoli sprouts or broccoli supplementrdquo Journal of Agriculturaland Food Chemistry vol 59 no 20 pp 10955ndash10963 2011

[131] J M Cramer and E H Jeffery ldquoSulforaphane absorptionand excretion following ingestion of a semi-purified broccolipowder rich in glucoraphanin and broccoli sprouts in healthymenrdquo Nutrition and Cancer vol 63 no 2 pp 196ndash201 2011

[132] Z Bahadoran P Mirmiran F Hosseinpanah A Rajab GAsghari and F Azizi ldquoBroccoli sprouts powder could improve


serum triglyceride and oxidized LDLLDL-cholesterol ratio intype 2 diabetic patients a randomized double-blind placebo-controlled clinical trialrdquoDiabetes Research and Clinical Practicevol 96 no 3 pp 348ndash354 2012

[133] A Jennings A A Welch S J Fairweather-Tait et al ldquoHigheranthocyanin intake is associated with lower arterial stiffnessand central blood pressure in womenrdquo The American Journalof Clinical Nutrition vol 96 no 4 pp 781ndash788 2012

[134] P J Curtis P A Kroon W J Hollands et al ldquoCardiovasculardisease risk biomarkers and liver and kidney function are notaltered in postmenopausal women after ingesting an elderberryextract rich in anthocyanins for 12 weeksrdquo Journal of Nutritionvol 139 no 12 pp 2266ndash2271 2009

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

[136] W Wongcharoen and A Phrommintikul ldquoThe protective roleof curcumin in cardiovascular diseasesrdquo International Journalof Cardiology vol 133 no 2 pp 145ndash151 2009

[137] W Duan Y Yang J Yan et al ldquoThe effects of curcuminpost-treatment against myocardial ischemia and reperfusionby activation of the JAK2STAT3 signaling pathwayrdquo BasicResearch in Cardiology vol 107 no 3 article 263 2012

[138] Y Pu H Zhang P Wang et al ldquoDietary curcumin amelio-rates aging-related cerebrovascular dysfunction through theampkuncoupling protein 2 pathwayrdquo Cellular Physiology andBiochemistry vol 32 no 5 pp 1167ndash1177 2013

[139] J Wu Q Li X Wang et al ldquoNeuroprotection by curcuminin ischemic brain injury involves the AktNrf2 pathwayrdquo PLoSONE vol 8 no 3 Article ID e59843 2013

[140] Z-H Deng J Liao J-Y Zhang et al ldquoLocalized leptin releasemay be an importantmechanism of curcumin action after acuteischemic injuriesrdquo Journal of Trauma and Acute Care Surgeryvol 74 no 4 pp 1044ndash1051 2013

[141] Y S Kim Y Ahn M H Hong et al ldquoCurcumin attenu-ates inflammatory responses of TNF-alpha-stimulated humanendothelial cellsrdquo Journal of Cardiovascular Pharmacology vol50 no 1 pp 41ndash49 2007

[142] A Sahebkar ldquoAre curcuminoids effective C-reactive protein-lowering agents in clinical practice Evidence from a meta-analysisrdquo Phytotherapy Research vol 28 no 5 pp 633ndash6422014

[143] F E Parodi D Mao T L Ennis M B Pagano and R WThompson ldquoOral administration of diferuloylmethane (cur-cumin) suppresses proinflammatory cytokines and destructiveconnective tissue remodeling in experimental abdominal aorticaneurysmsrdquo Annals of Vascular Surgery vol 20 no 3 pp 360ndash368 2006

[144] 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

[145] P Manikandan M Sumitra S Aishwarya B M ManoharB Lokanadam and R Puvanakrishnan ldquoCurcumin modulatesfree radical quenching in myocardial ischaemia in ratsrdquo TheInternational Journal of Biochemistry amp Cell Biology vol 36 no10 pp 1967ndash1980 2004

[146] H Farhangkhoee Z A Khan S Chen and S ChakrabartildquoDifferential effects of curcumin on vasoactive factors in the

diabetic rat heartrdquo Nutrition and Metabolism vol 3 article 272006

[147] R Motterlini R Foresti R Bassi and C J Green ldquoCurcuminan antioxidant and anti-inflammatory agent induces hemeoxygenase-1 and protects endothelial cells against oxidativestressrdquo Free Radical Biology and Medicine vol 28 no 8 pp1303ndash1312 2000

[148] J Trujillo L F Granados-Castro C Zazueta A C Anderica-Romero Y I Chirino and J Pedraza-Chaverrı ldquoMitochondriaas a target in the therapeutic properties of curcuminrdquoArchiv derPharmazie vol 347 no 12 pp 873ndash884 2014

[149] X Yang D P Thomas X Zhang et al ldquoCurcumin inhibitsplatelet-derived growth factor-stimulated vascular smoothmuscle cell function and injury-induced neointima formationrdquoArteriosclerosis Thrombosis and Vascular Biology vol 26 no 1pp 85ndash90 2006

[150] H-W Chen and H-C Huang ldquoEffect of curcumin on cell cycleprogression and apoptosis in vascular smooth muscle cellsrdquoBritish Journal of Pharmacology vol 124 no 6 pp 1029ndash10401998

[151] Y Hua J Dolence S Ramanan J Ren and S Nair ldquoBis-demethoxycurcumin inhibits PDGF-induced vascular smoothmuscle cell motility and proliferationrdquoMolecular Nutrition andFood Research vol 57 no 9 pp 1611ndash1618 2013

[152] C Sumbilla D Lewis T Hammerschmidt and G Inesi ldquoTheslippage of the Ca2+ pump and its control by anions andcurcumin in skeletal and cardiac sarcoplasmic reticulumrdquo TheJournal of Biological Chemistry vol 277 no 16 pp 13900ndash139062002

[153] J-M Zingg S T Hasan and M Meydani ldquoMolecular mecha-nisms of hypolipidemic effects of curcuminrdquo BioFactors vol 39no 1 pp 101ndash121 2013

[154] J L Quiles M D Mesa C L Ramırez-Tortosa et al ldquoCurcumalonga extract supplementation reduces oxidative stress andattenuates aortic fatty streak development in rabbitsrdquo Arte-riosclerosis Thrombosis and Vascular Biology vol 22 no 7 pp1225ndash1231 2002

[155] C Nirmala and R Puvanakrishnan ldquoProtective role of cur-cumin against isoproterenol induced myocardial infarction inratsrdquoMolecular andCellular Biochemistry vol 159 no 2 pp 85ndash93 1996

[156] N-P Wang Z-F Wang S Tootle T Philip and Z-Q ZhaoldquoCurcumin promotes cardiac repair and ameliorates cardiacdysfunction following myocardial infarctionrdquo British Journal ofPharmacology vol 167 no 7 pp 1550ndash1562 2012

[157] C-H Yeh T-P Chen Y-C Wu Y-M Lin and P JingLin ldquoInhibition of NF120581B activation with curcumin attenu-ates plasma inflammatory cytokines surge and cardiomyocyticapoptosis following cardiac ischemiareperfusionrdquo Journal ofSurgical Research vol 125 no 1 pp 109ndash116 2005

[158] T Morimoto Y Sunagawa T Kawamura et al ldquoThe dietarycompound curcumin inhibits p300 histone acetyltransferaseactivity and prevents heart failure in ratsrdquo Journal of ClinicalInvestigation vol 118 no 3 pp 868ndash878 2008

[159] N Venkatesan ldquoCurcumin attenuation of acute adriamycinmyocardial toxicity in ratsrdquoBritish Journal of Pharmacology vol124 no 3 pp 425ndash427 1998

[160] T-H Chen Y-C Yang J-C Wang and J-J Wang ldquoCurcumintreatment protects against renal ischemia and reperfusioninjury-induced cardiac dysfunction and myocardial injuryrdquoTransplantation Proceedings vol 45 no 10 pp 3546ndash3549 2013


[161] V Kakkar S K Muppu K Chopra and I P Kaur ldquoCur-cumin loaded solid lipid nanoparticles an efficient formulationapproach for cerebral ischemic reperfusion injury in ratsrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol85 no 3 part A pp 339ndash345 2013

[162] N Ahmad S Umar M Ashafaq et al ldquoA comparative studyof PNIPAM nanoparticles of curcumin demethoxycurcuminand bisdemethoxycurcumin and their effects on oxidative stressmarkers in experimental strokerdquo Protoplasma vol 250 no 6pp 1327ndash1338 2013

[163] J L Funk J B Frye G Davis-Gorman et al ldquoCurcuminoidslimit neutrophil-mediated reperfusion injury in experimentalstroke by targeting the endotheliumrdquo Microcirculation vol 20no 6 pp 544ndash554 2013

[164] K B Soni and R Kuttan ldquoEffect of oral curcumin adminis-tration on serum peroxides and cholesterol levels in humanvolunteersrdquo Indian Journal of Physiology and Pharmacology vol36 no 4 pp 273ndash275 1992

[165] I Alwi T Santoso S Suyono et al ldquoThe effect of curcuminon lipid level in patients with acute coronary syndromerdquo ActaMedica Indonesiana vol 40 no 4 pp 201ndash210 2008

[166] S Chuengsamarn S Rattanamongkolgul B Phonrat RTungtrongchitr and S Jirawatnotai ldquoReduction of atherogenicrisk in patients with type 2 diabetes by curcuminoid extracta randomized controlled trialrdquo Journal of Nutritional Biochem-istry vol 25 no 2 pp 144ndash150 2014

[167] A Sahebkar ldquoA systematic review and meta-analysis of ran-domized controlled trials investigating the effects of curcuminon blood lipid levelsrdquo Clinical Nutrition vol 33 no 3 pp 406ndash414 2014

[168] N Akazawa Y Choi A Miyaki et al ldquoCurcumin ingestionand exercise training improve vascular endothelial function inpostmenopausal womenrdquoNutrition Research vol 32 no 10 pp795ndash799 2012

[169] C J Pan J J Tang Z Y Shao J Wang and N HuangldquoImproved blood compatibility of rapamycin-eluting stent byincorporating curcuminrdquoColloids and Surfaces B Biointerfacesvol 59 no 1 pp 105ndash111 2007

[170] Y-X Liu C-L Xiao Y-X Wang et al ldquoSynthesis structure-activity relationship and in vitro anti-mycobacterial evaluationof 13-n-octylberberine derivativesrdquo European Journal of Medic-inal Chemistry vol 52 pp 151ndash158 2012

[171] HNishino KKitagawaH Fujiki andA Iwashima ldquoBerberinesulfate inhibits tumor-promoting activity of teleocidin in two-stage carcinogenesis onmouse skinrdquoOncology vol 43 no 2 pp131ndash134 1986

[172] J YaoW Kong and J Jiang ldquoLearning from berberine treatingchronic diseases through multiple targetsrdquo Science China LifeSciences 2013

[173] C W Lau X Q Yao Z Y Chen W H Ko and Y HuangldquoCardiovascular actions of berberinerdquo Cardiovascular DrugReviews vol 19 no 3 pp 234ndash244 2001

[174] Q Wang M Zhang B Liang N Shirwany Y Zhu and M-HZou ldquoActivation ofAMP-activated protein kinase is required forberberine-induced reduction of atherosclerosis inmice the roleof uncoupling protein 2rdquo PLoS ONE vol 6 no 9 Article IDe25436 2011

[175] L K Sarna N Wu S-Y Hwang Y L Siow and O KarminldquoBerberine inhibits NADPH oxidase mediated superoxideanion production in macrophagesrdquo Canadian Journal of Physi-ology and Pharmacology vol 88 no 3 pp 369ndash378 2010

[176] CMo LWang J Zhang et al ldquoThe crosstalk betweenNrf2 andAMPK signal pathways is important for the anti-inflammatoryeffect of berberine in LPS-stimulated macrophages andendotoxin-shocked micerdquo Antioxidants and Redox Signalingvol 20 no 4 pp 574ndash588 2014

[177] H W Jeong K C Hsu J-W Lee et al ldquoBerberine suppressesproinflammatory responses through AMPK activation inmacrophagesrdquo American Journal of PhysiologymdashEndocrinologyand Metabolism vol 296 no 4 pp E955ndashE964 2009

[178] X Xie X Chang L Chen et al ldquoBerberine ameliorates experi-mental diabetes-induced renal inflammation and fibronectin byinhibiting the activation of RhoAROCK signalingrdquo Molecularand Cellular Endocrinology vol 381 no 1-2 pp 56ndash65 2013

[179] A-W Feng W Gao G-R Zhou et al ldquoBerberine amelioratesCOX-2 expression in rat small intestinal mucosa partiallythrough PPARgamma pathway during acute endotoxemiardquoInternational Immunopharmacology vol 12 no 1 pp 182ndash1882012

[180] M Xiao L N Men M G Xu G B Wang H T Lv and C LiuldquoBerberine protects endothelial progenitor cell from damage ofTNF-120572 via the PI3KAKTeNOS signaling pathwayrdquo EuropeanJournal of Pharmacology vol 743 pp 11ndash16 2014

[181] Y Wang Y Huang K S L Lam et al ldquoBerberine pre-vents hyperglycemia-induced endothelial injury and enhancesvasodilatation via adenosine monophosphate-activated proteinkinase and endothelial nitric oxide synthaserdquo CardiovascularResearch vol 82 no 3 pp 484ndash492 2009

[182] S Lee H-J Lim H-Y Park K-S Lee J-H Park and Y JangldquoBerberine inhibits rat vascular smooth muscle cell prolifera-tion and migration in vitro and improves neointima formationafter balloon injury in vivo Berberine improves neointimaformation in a rat modelrdquoAtherosclerosis vol 186 no 1 pp 29ndash37 2006

[183] F Zimetti M P Adorni N Ronda R Gatti F Bernini andE Favari ldquoThe natural compound berberine positively affectsmacrophage functions involved in atherogenesisrdquo NutritionMetabolism and Cardiovascular Diseases vol 25 no 2 pp 195ndash201 2015

[184] G Derosa P Maffioli and A F G Cicero ldquoBerberine onmetabolic and cardiovascular risk factors an analysis frompreclinical evidences to clinical trialsrdquo Expert Opinion onBiological Therapy vol 12 no 8 pp 1113ndash1124 2012

[185] W J Kong J Wei P Abidi et al ldquoBerberine is a novelcholesterol-lowering drug working through a unique mecha-nism distinct from statinsrdquo Nature Medicine vol 10 no 12 pp1344ndash1351 2004

[186] H Li B Dong SW ParkH-S LeeWChen and J Liu ldquoHepa-tocyte nuclear factor 1120572 plays a critical role in PCSK9 gene tran-scription and regulation by the natural hypocholesterolemiccompound berberinerdquoThe Journal of Biological Chemistry vol284 no 42 pp 28885ndash28895 2009

[187] Y-J Jia R-X Xu J Sun Y Tang and J-J Li ldquoEnhancedcirculating PCSK9 concentration by berberine through SREBP-2 pathway in high fat diet-fed ratsrdquo Journal of TranslationalMedicine vol 12 article 103 2014

[188] C-W Lau X-Q Yao Z-Y Chen W-H Ko and Y HuangldquoCardiovascular actions of berberinerdquo Cardiovascular DrugReviews vol 19 no 3 pp 234ndash244 2001

[189] L-H Wang X-L Li Q Li et al ldquoBerberine alleviates ischemicarrhythmias via recovering depressed I(to) and I(Ca) currentsin diabetic ratsrdquo Phytomedicine vol 19 no 3-4 pp 206ndash2102012


[190] A Rodriguez-Menchaca T Ferrer-Villada J Lara D Fernan-dez R A Navarro-Polanco and J A Sanchez-Chapula ldquoBlockof hERG channels by berberine mechanisms of voltage- andstate-dependence probed with site-directed mutant channelsrdquoJournal of Cardiovascular Pharmacology vol 47 no 1 pp 21ndash29 2006

[191] F R Neto ldquoElectropharmacological effects of berberine oncanine cardiac Purkinje fibres and ventricular muscle and atrialmuscle of the rabbitrdquo British Journal of Pharmacology vol 108no 2 pp 534ndash537 1993

[192] J-C Liu P Chan Y-J Chen B Tomlinson S-F Hong and J-TCheng ldquoThe antihypertensive effect of the berberine derivative6-protoberberine in spontaneously hypertensive ratsrdquo Pharma-cology vol 59 no 6 pp 283ndash289 1999

[193] M-H Li Y-J Zhang Y-H Yu et al ldquoBerberine improves pres-sure overload-induced cardiac hypertrophy and dysfunctionthrough enhanced autophagyrdquo European Journal of Pharmacol-ogy vol 728 no 1 pp 67ndash76 2014

[194] T Zhang S Yang and J Du ldquoProtective effects of berberineon isoproterenol-induced acute myocardial ischemia in ratsthrough regulating hmgb1-tlr4 axisrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2014 Article ID 8497838 pages 2015

[195] L Liu J Liu Z Huang et al ldquoBerberine improves endothelialfunction by inhibiting endoplasmic reticulum stress in thecarotid arteries of spontaneously hypertensive ratsrdquoBiochemicaland Biophysical Research Communications vol 458 no 4 pp796ndash801 2015

[196] Y-J Zhang S-H Yang M-H Li et al ldquoBerberine attenuatesadverse left ventricular remodeling and cardiac dysfunctionafter acute myocardial infarction in rats role of autophagyrdquoClinical and Experimental Pharmacology and Physiology vol 41no 12 pp 995ndash1002 2014

[197] K Chen G Li F Geng et al ldquoBerberine reduces ischemiareperfusion-induced myocardial apoptosis via activatingAMPK and PI3K-Akt signaling in diabetic ratsrdquo Apoptosis vol19 no 6 pp 946ndash957 2014

[198] X-Q Zhou X-N ZengH Kong andX-L Sun ldquoNeuroprotec-tive effects of berberine on stroke models in vitro and in vivordquoNeuroscience Letters vol 447 no 1 pp 31ndash36 2008

[199] H Dong N Wang L Zhao and F Lu ldquoBerberine in thetreatment of type 2 diabetes mellitus a systemic review andmeta-analysisrdquo Evidence-Based Complementary and AlternativeMedicine vol 2012 Article ID 591654 12 pages 2012

[200] X-H Zeng X-J Zeng and Y-Y Li ldquoEfficacy and safety ofberberine for congestive heart failure secondary to ischemicor idiopathic dilated cardiomyopathyrdquo American Journal ofCardiology vol 92 no 2 pp 173ndash176 2003

[201] W Huang ldquoVentricular tachyarrhythmias treated with berber-inerdquo Zhonghua Xin Xue Guan Bing Za Zhi vol 18 no 3 pp155ndash156 190 1990

[202] C Jiang and Y Kuang ldquoTherapeutic efficacy of berberine in 32arrhythmic patientsrdquoZhong Guo Zhong Xi Yi Jie He Ji Jiu Za Zhivol 5 1998

[203] H Dong Y Zhao L Zhao and F Lu ldquoThe effects of berberineon blood lipids a systemic review andmeta-analysis of random-ized controlled trialsrdquo PlantaMedica vol 79 no 6 pp 437ndash4462013

[204] L Liu Y-L Yu J-S Yang et al ldquoBerberine suppresses intestinaldisaccharidases with beneficial metabolic effects in diabetic

states evidences from in vivo and in vitro studyrdquo Naunyn-Schmiedebergrsquos Archives of Pharmacology vol 381 no 4 pp 371ndash381 2010

[205] F Affuso A Ruvolo F Micillo L Sacca and S Fazio ldquoEffects ofa nutraceutical combination (berberine red yeast rice and poli-cosanols) on lipid levels and endothelial function randomizeddouble-blind placebo-controlled studyrdquo Nutrition Metabolismand Cardiovascular Diseases vol 20 no 9 pp 656ndash661 2010

[206] J Lan Y Zhao F Dong et al ldquoMeta-analysis of the effect andsafety of berberine in the treatment of type 2 diabetes mellitushyperlipemia andhypertensionrdquo Journal of Ethnopharmacologyvol 161 pp 69ndash81 2015

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


AMPK

Resveratrol

Brassica Curcumin

Berberine

SIRT1

ROS Inflammation

Heart Vasculature Brain Kidney

(i) Hypertension(ii) Hypertrophy(iii) Ischemic damage(iv) Drug toxicity(v) Heart failure

(i) EC damage(ii) Platelet activation(iii) VSMC proliferation

(iv) Atherosclerosis

(i) Ischemic damage(ii) BBB disruption(iii) Stroke

(i) Hypertensive and ischemic damage(tubular glomerular and vascular) and migration

PPAR120574PPAR120572NF-120581B TNF-120572

Figure 1 Schematic representation of beneficial effects exerted in the cardiovascular system by resveratrol Brassica oleracea curcumin andberberine The AMPKSIRT-1PPAR120572120574molecular pathway underlying most of the effects of all vegetable compounds is illustrated AMPK51015840-adenosine monophosphate-activated protein kinase SIRT-1 silent mating type information regulation-1 PPAR peroxisome proliferator-activated receptor ROS reactive oxygen species NF-120581B nuclear factor-120581B TNF-120572 tumor necrosis factor-120572 EC endothelial cell VSMCvascular smooth muscle cell BBB blood brain barrier

manufactured products especially red wine [4] It exists inboth cis- and trans-configurations of which trans-resveratrolis the principal biologically active form [5] Interestinglyred wine (therefore resveratrol) was supposed to be one ofthe factors responsible for the ldquoFrench Paradoxrdquo togetherwith several lifestyle and dietary factors The term is usedto describe the low incidence of CVDs in French populationdespite its high intake of saturated fats However the mediandaily dose of resveratrol to be protective is estimated tobe 20mgkgday whereas its concentration in red wine isroughly 198ndash713mgL [6] Therefore the assumption of ahigh quantity of red wine per day would be needed for aman to obtain a protective dose of resveratrol causing serioushealth problems [7 8] However an inverse associationbetween moderate alcohol consumption (30ndash50 grday) andCVDs has been assessed in several epidemiological studiesThe physiological mechanism of the protective effect ofalcohol seems to be at least in part related to its effect inreducing platelet action

21 Molecular Targets and Properties Resveratrol inter-acts with multiple targets in cardio- and cerebrovascular

diseases age-related diseases cancer and so forth [9 10]Themain molecular mechanism mediating resveratrol biologicaleffects is the 51015840-adenosine monophosphate-activated proteinkinase (AMPK)silent mating type information regulation-1(SIRT-1) pathway (Figure 1) [11 12] The precise mechanismthrough which resveratrol activates SIRT-1 is not completelyunderstood [13] Other minor pathways mediate some of theresveratrol effects and they will be briefly mentioned below

The most important properties of resveratrol are con-nected with oxidative stress vascular inflammation andplatelet aggregation In fact resveratrol upregulates theendogenous antioxidant systems such as superoxide dismu-tase (SOD) enzymes in endothelial cells (ECs) and in cardiacmyoblasts and it reduces ROS production [14 15] Moreoverit reduces arachidonic acid and prostaglandin E2 synthesisIt inhibits phospholipase A2 and ciclooxygenase-2 activityit antagonizes the function of the most important moleculesinvolved in inflammation such as nuclear factor-120581B (NF-120581B) tumor necrosis factor-120572 (TNF-120572) interleukin-6 (IL-6)inducible nitric oxide synthase (iNOS) activity and mono-cyte chemotactic protein-1 (MCP-1) [16ndash19] Resveratrol alsoprevents platelet activation by modulating platelet adhesion







































4 Curcumin









5 Berberine























Table1Preclin

icaleffectsof

vegetablec

ompo

unds

Vegetable

Preclin

icaleffects

Reference

Resveratrol

(i)Upregulates

thea

ntioxida

ntsystem

andredu

cesR

OSprod

uctio

n[14

15]

(ii)Inh

ibits

vascular

infla


ation

[16ndash

22]

(iii)Lo

wersB

Pin

anim

alsw

itheither

diabetes

ormetabolicsynd

rome

[33]

(iv)Inh

ibits

very

early

stageso

fatherosclerosis

[4142]

(v)R

educes

lipid

accumulationby

inhibitin

glip

ogenesis

increasin

gapop

tosisand

prom

otinglip

olysis

[55ndash57]


isease

[72]

(vii)


from

celldeaththou

ghapop

tosis

andautoph

agy

[7475]

(viii)P


infarctedmyocardium

[7677]

(ix)P

reventsc

ardiac

hypertroph

yanddysfu

nctio

n[83]

(x)P

romotes

angiog

enesisin

cerebralEC

sand

preventsim

pairm

ento

feNOS-depend

entvasorelaxationof

cerebralarterio

les

[9394]

(xi)Protectsfro

mdo

xorubicin-indu

cedcardiotoxicity

[100ndash102]

(xii)

Antiarrhy

thmiceff

ects

[103]

Brassicaoleracea

(i)Indu

cese

xpressionof

detoxific

ationenzymes

(ARE

targets)

[114]

(ii)L

owerso

x-LD

Lbloo

dlevels

[119]

(iii)Decreases

oxidatives

tressa

ndBP

levelsin

pregnant

femaleS

HRS

P[121]

(iv)P

romotes

optim

alplateletfunctio

nandan

tithrom

botic

effects

[122]

(v)A

ctso

ndifferent

typeso

fcellsinvolved

inatherosclerosis

developm

ent

[123]

(vi)Re

gulates

cholesterold

istrib

ution

[126]

(vii)

Protectsfro

mmyocardialoxida

tived

amagea

ndcelldeathin

ischemia-reperfusio

nratm

odels

[106128]

(viii)N

ephrop

rotectivee

ffects

[129]

Curcum

in

(i)Protectiv

eroleo

nendo

thelium

byindu

cing

HO-1

[147]

(ii)A

ntiproliferativea

ndan

tiapo

ptoticeffectson

VSMCs

atte

nuatingne

ointim

aformation

[149ndash

151]

(iii)Hyp

olipidem

iceffectand

protectio

nfro

maorticfatty

streak

developm

ent

[153154]

(iv)R

educes

collagensynthesis

andfib

rosis

andim

proves

leftventriculare


volumean

dejectio

nfractio

n[156]

(v)R

educes

MIsize

[137]

(vi)Protectsfro

mad

riam

ycin-in

ducedcardiotoxicity

[159]

(vii)

Protectsfro

mcerebralisc

hemicinsult

[138139]

Berberine

(i)Im

proves

thep

roliferativea

bilityo

fEPC

s[180]

(ii)Ind

uces

endo

thelial-d

ependent

vasorelaxatio

nandenhances

endo

thelium-in

depend

entV

SMCdilatatio

n[181]

(iii)InhibitsVS

MCproliferatio

nandmigratio

nandredu

cesn

eointim

aformation

[182]

(iv)L

ipid-lo

wering

prop

ertie

s[185]

(v)P

ositive

inotropican

tiarrhy

thmicand

vasodilatorp

roperties

[188189]

(vi)Antihyp

ertensivee

ffectsinSH

R[19

5](vii)

Preventscardiach

ypertrop

hyandattenu

ates

cardiomyocyteapop

tosis

[193]

(viii)A

ttenu

ates

adverseleft

ventricularr

emod

elingan

dpreservesleft

ventriculars

ystolic

functio

nin

ratm

odelof

MI

[196]

ROSreactiv

eoxygen

speciesBP

blood

pressureeNOSendo

thelialn

itricoxidesin

thaseARE

Antioxidant

Respon

seElem

ents

ox-LDL

oxidized

low-densitylip

oproteinSHRS

Pstr

okepron

espon

taneou

slyhypertensiv

eratsHO-1hem

eoxygenase-1E

Csend

othelialcells

VSMC

vascular

smoo

thmuscularc

ells


EPCs

end

othelialprogenitorc

ells



vegetablec

ompo

unds

Vegetable

Clinicaleffects

Reference

Resveratrol

(i)Decreases

SBPwith

outaffectingDBP

[37]

(ii)E

nhancesA

ch-m


nin

hypertensiv

eand

dyslipidemicpts

[38]

(iii)Im

proves

FMDin

ptsw

itheither

metabolicsynd

romeo

rpreviou

sMI

[3940

](iv

)Decreases

totalcho

lesterolan

dtotaland

ox-LDL

triglyceridesandAp

oBlevelsin

ptsw

ithT2

DMC

ADhyperlip

idem

iaand

otherC

Vris

kfactors

[5354]

(v)Improves

insulin

sensitivity

inbo

thob

esea

ndmetabolicsynd

romep

ts[6667]

(vi)Im

proves

significantly

diastolic

functio

nandmod

estly

systolicfunctio

nin

ptsw

ithprevious

MI

[40]

Brassicaoleracea

(i)Re

ducestotalL

DLcholesteroland

markers

ofoxidatives

tressinsm

okersa

ndhypercho

leste

rolemicpts

[108119]

(ii)Improves

lipid

profi

lesa

ndox-LDLLD

Lcholesterolratio

inT2

DM

pts

[132]

(iii)Lo

wersa

rterialstiff

nessandcentralB

Pin

wom

en[133]

Curcum

in(i)

Decreases

both

totaland

LDLcholesteroland

increasesH


ACSpts

[164

165]

(ii)Increases

FMDin

postm

enop

ausalw

omen

[168]

Berberine

(i)Increasesb

othLV

EFandexercise

capa

city

anddecreasesrates

ofventricularp

rematurec

omplexes

andlong

-term

mortalityin

HFpts

[199]

(ii)R

educes

totalcho



andmod

estly

increasesH


DM

pts

[203205]

(iii)Re

ducesg

lycatedhemog

lobin


ostprand

ialglucoseand

fastingplasmag

lucose

inT2

DM

pts

[204

](iv

)Low

ersS

BPandDBP

inhypertensiv

eT2

DMand

hyperlipidemicpts

[206]

SBP

systo

licbloo

dpressureD

BPdiasto

licbloo

dpressureA

chA

cetylch

olineFM

Dflow


low-densitylip

oproteinH

DLhigh

-densitylip

oprotein

Apoapolipop

roteinT

2DMtype2

diabetes

mellitusC

ADcoron

aryartery

diseaseCV

cardiovascularAC

Sacutec

oron

arysynd

romeLV

EFleft

ventric

ular

ejectio

nfractio

nHFheartfailurepts

patie

nts



6 Conclusions





Acknowledgments


References


































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















































4 Curcumin









5 Berberine























Table1Preclin

icaleffectsof

vegetablec

ompo

unds

Vegetable

Preclin

icaleffects

Reference

Resveratrol

(i)Upregulates

thea

ntioxida

ntsystem

andredu

cesR

OSprod

uctio

n[14

15]

(ii)Inh

ibits

vascular

infla


ation

[16ndash

22]

(iii)Lo

wersB

Pin

anim

alsw

itheither

diabetes

ormetabolicsynd

rome

[33]

(iv)Inh

ibits

very

early

stageso

fatherosclerosis

[4142]

(v)R

educes

lipid

accumulationby

inhibitin

glip

ogenesis

increasin

gapop

tosisand

prom

otinglip

olysis

[55ndash57]


isease

[72]

(vii)


from

celldeaththou

ghapop

tosis

andautoph

agy

[7475]

(viii)P


infarctedmyocardium

[7677]

(ix)P

reventsc

ardiac

hypertroph

yanddysfu

nctio

n[83]

(x)P

romotes

angiog

enesisin

cerebralEC

sand

preventsim

pairm

ento

feNOS-depend

entvasorelaxationof

cerebralarterio

les

[9394]

(xi)Protectsfro

mdo

xorubicin-indu

cedcardiotoxicity

[100ndash102]

(xii)

Antiarrhy

thmiceff

ects

[103]

Brassicaoleracea

(i)Indu

cese

xpressionof

detoxific

ationenzymes

(ARE

targets)

[114]

(ii)L

owerso

x-LD

Lbloo

dlevels

[119]

(iii)Decreases

oxidatives

tressa

ndBP

levelsin

pregnant

femaleS

HRS

P[121]

(iv)P

romotes

optim

alplateletfunctio

nandan

tithrom

botic

effects

[122]

(v)A

ctso

ndifferent

typeso

fcellsinvolved

inatherosclerosis

developm

ent

[123]

(vi)Re

gulates

cholesterold

istrib

ution

[126]

(vii)

Protectsfro

mmyocardialoxida

tived

amagea

ndcelldeathin

ischemia-reperfusio

nratm

odels

[106128]

(viii)N

ephrop

rotectivee

ffects

[129]

Curcum

in

(i)Protectiv

eroleo

nendo

thelium

byindu

cing

HO-1

[147]

(ii)A

ntiproliferativea

ndan

tiapo

ptoticeffectson

VSMCs

atte

nuatingne

ointim

aformation

[149ndash

151]

(iii)Hyp

olipidem

iceffectand

protectio

nfro

maorticfatty

streak

developm

ent

[153154]

(iv)R

educes

collagensynthesis

andfib

rosis

andim

proves

leftventriculare


volumean

dejectio

nfractio

n[156]

(v)R

educes

MIsize

[137]

(vi)Protectsfro

mad

riam

ycin-in

ducedcardiotoxicity

[159]

(vii)

Protectsfro

mcerebralisc

hemicinsult

[138139]

Berberine

(i)Im

proves

thep

roliferativea

bilityo

fEPC

s[180]

(ii)Ind

uces

endo

thelial-d

ependent

vasorelaxatio

nandenhances

endo

thelium-in

depend

entV

SMCdilatatio

n[181]

(iii)InhibitsVS

MCproliferatio

nandmigratio

nandredu

cesn

eointim

aformation

[182]

(iv)L

ipid-lo

wering

prop

ertie

s[185]

(v)P

ositive

inotropican

tiarrhy

thmicand

vasodilatorp

roperties

[188189]

(vi)Antihyp

ertensivee

ffectsinSH

R[19

5](vii)

Preventscardiach

ypertrop

hyandattenu

ates

cardiomyocyteapop

tosis

[193]

(viii)A

ttenu

ates

adverseleft

ventricularr

emod

elingan

dpreservesleft

ventriculars

ystolic

functio

nin

ratm

odelof

MI

[196]

ROSreactiv

eoxygen

speciesBP

blood

pressureeNOSendo

thelialn

itricoxidesin

thaseARE

Antioxidant

Respon

seElem

ents

ox-LDL

oxidized

low-densitylip

oproteinSHRS

Pstr

okepron

espon

taneou

slyhypertensiv

eratsHO-1hem

eoxygenase-1E

Csend

othelialcells

VSMC

vascular

smoo

thmuscularc

ells


EPCs

end

othelialprogenitorc

ells



vegetablec

ompo

unds

Vegetable

Clinicaleffects

Reference

Resveratrol

(i)Decreases

SBPwith

outaffectingDBP

[37]

(ii)E

nhancesA

ch-m


nin

hypertensiv

eand

dyslipidemicpts

[38]

(iii)Im

proves

FMDin

ptsw

itheither

metabolicsynd

romeo

rpreviou

sMI

[3940

](iv

)Decreases

totalcho

lesterolan

dtotaland

ox-LDL

triglyceridesandAp

oBlevelsin

ptsw

ithT2

DMC

ADhyperlip

idem

iaand

otherC

Vris

kfactors

[5354]

(v)Improves

insulin

sensitivity

inbo

thob

esea

ndmetabolicsynd

romep

ts[6667]

(vi)Im

proves

significantly

diastolic

functio

nandmod

estly

systolicfunctio

nin

ptsw

ithprevious

MI

[40]

Brassicaoleracea

(i)Re

ducestotalL

DLcholesteroland

markers

ofoxidatives

tressinsm

okersa

ndhypercho

leste

rolemicpts

[108119]

(ii)Improves

lipid

profi

lesa

ndox-LDLLD

Lcholesterolratio

inT2

DM

pts

[132]

(iii)Lo

wersa

rterialstiff

nessandcentralB

Pin

wom

en[133]

Curcum

in(i)

Decreases

both

totaland

LDLcholesteroland

increasesH


ACSpts

[164

165]

(ii)Increases

FMDin

postm

enop

ausalw

omen

[168]

Berberine

(i)Increasesb

othLV

EFandexercise

capa

city

anddecreasesrates

ofventricularp

rematurec

omplexes

andlong

-term

mortalityin

HFpts

[199]

(ii)R

educes

totalcho



andmod

estly

increasesH


DM

pts

[203205]

(iii)Re

ducesg

lycatedhemog

lobin


ostprand

ialglucoseand

fastingplasmag

lucose

inT2

DM

pts

[204

](iv

)Low

ersS

BPandDBP

inhypertensiv

eT2

DMand

hyperlipidemicpts

[206]

SBP

systo

licbloo

dpressureD

BPdiasto

licbloo

dpressureA

chA

cetylch

olineFM

Dflow


low-densitylip

oproteinH

DLhigh

-densitylip

oprotein

Apoapolipop

roteinT

2DMtype2

diabetes

mellitusC

ADcoron

aryartery

diseaseCV

cardiovascularAC

Sacutec

oron

arysynd

romeLV

EFleft

ventric

ular

ejectio

nfractio

nHFheartfailurepts

patie

nts



6 Conclusions





Acknowledgments


References


































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































Table1Preclin

icaleffectsof

vegetablec

ompo

unds

Vegetable

Preclin

icaleffects

Reference

Resveratrol

(i)Upregulates

thea

ntioxida

ntsystem

andredu

cesR

OSprod

uctio

n[14

15]

(ii)Inh

ibits

vascular

infla


ation

[16ndash

22]

(iii)Lo

wersB

Pin

anim

alsw

itheither

diabetes

ormetabolicsynd

rome

[33]

(iv)Inh

ibits

very

early

stageso

fatherosclerosis

[4142]

(v)R

educes

lipid

accumulationby

inhibitin

glip

ogenesis

increasin

gapop

tosisand

prom

otinglip

olysis

[55ndash57]


isease

[72]

(vii)


from

celldeaththou

ghapop

tosis

andautoph

agy

[7475]

(viii)P


infarctedmyocardium

[7677]

(ix)P

reventsc

ardiac

hypertroph

yanddysfu

nctio

n[83]

(x)P

romotes

angiog

enesisin

cerebralEC

sand

preventsim

pairm

ento

feNOS-depend

entvasorelaxationof

cerebralarterio

les

[9394]

(xi)Protectsfro

mdo

xorubicin-indu

cedcardiotoxicity

[100ndash102]

(xii)

Antiarrhy

thmiceff

ects

[103]

Brassicaoleracea

(i)Indu

cese

xpressionof

detoxific

ationenzymes

(ARE

targets)

[114]

(ii)L

owerso

x-LD

Lbloo

dlevels

[119]

(iii)Decreases

oxidatives

tressa

ndBP

levelsin

pregnant

femaleS

HRS

P[121]

(iv)P

romotes

optim

alplateletfunctio

nandan

tithrom

botic

effects

[122]

(v)A

ctso

ndifferent

typeso

fcellsinvolved

inatherosclerosis

developm

ent

[123]

(vi)Re

gulates

cholesterold

istrib

ution

[126]

(vii)

Protectsfro

mmyocardialoxida

tived

amagea

ndcelldeathin

ischemia-reperfusio

nratm

odels

[106128]

(viii)N

ephrop

rotectivee

ffects

[129]

Curcum

in

(i)Protectiv

eroleo

nendo

thelium

byindu

cing

HO-1

[147]

(ii)A

ntiproliferativea

ndan

tiapo

ptoticeffectson

VSMCs

atte

nuatingne

ointim

aformation

[149ndash

151]

(iii)Hyp

olipidem

iceffectand

protectio

nfro

maorticfatty

streak

developm

ent

[153154]

(iv)R

educes

collagensynthesis

andfib

rosis

andim

proves

leftventriculare


volumean

dejectio

nfractio

n[156]

(v)R

educes

MIsize

[137]

(vi)Protectsfro

mad

riam

ycin-in

ducedcardiotoxicity

[159]

(vii)

Protectsfro

mcerebralisc

hemicinsult

[138139]

Berberine

(i)Im

proves

thep

roliferativea

bilityo

fEPC

s[180]

(ii)Ind

uces

endo

thelial-d

ependent

vasorelaxatio

nandenhances

endo

thelium-in

depend

entV

SMCdilatatio

n[181]

(iii)InhibitsVS

MCproliferatio

nandmigratio

nandredu

cesn

eointim

aformation

[182]

(iv)L

ipid-lo

wering

prop

ertie

s[185]

(v)P

ositive

inotropican

tiarrhy

thmicand

vasodilatorp

roperties

[188189]

(vi)Antihyp

ertensivee

ffectsinSH

R[19

5](vii)

Preventscardiach

ypertrop

hyandattenu

ates

cardiomyocyteapop

tosis

[193]

(viii)A

ttenu

ates

adverseleft

ventricularr

emod

elingan

dpreservesleft

ventriculars

ystolic

functio

nin

ratm

odelof

MI

[196]

ROSreactiv

eoxygen

speciesBP

blood

pressureeNOSendo

thelialn

itricoxidesin

thaseARE

Antioxidant

Respon

seElem

ents

ox-LDL

oxidized

low-densitylip

oproteinSHRS

Pstr

okepron

espon

taneou

slyhypertensiv

eratsHO-1hem

eoxygenase-1E

Csend

othelialcells

VSMC

vascular

smoo

thmuscularc

ells


EPCs

end

othelialprogenitorc

ells



vegetablec

ompo

unds

Vegetable

Clinicaleffects

Reference

Resveratrol

(i)Decreases

SBPwith

outaffectingDBP

[37]

(ii)E

nhancesA

ch-m


nin

hypertensiv

eand

dyslipidemicpts

[38]

(iii)Im

proves

FMDin

ptsw

itheither

metabolicsynd

romeo

rpreviou

sMI

[3940

](iv

)Decreases

totalcho

lesterolan

dtotaland

ox-LDL

triglyceridesandAp

oBlevelsin

ptsw

ithT2

DMC

ADhyperlip

idem

iaand

otherC

Vris

kfactors

[5354]

(v)Improves

insulin

sensitivity

inbo

thob

esea

ndmetabolicsynd

romep

ts[6667]

(vi)Im

proves

significantly

diastolic

functio

nandmod

estly

systolicfunctio

nin

ptsw

ithprevious

MI

[40]

Brassicaoleracea

(i)Re

ducestotalL

DLcholesteroland

markers

ofoxidatives

tressinsm

okersa

ndhypercho

leste

rolemicpts

[108119]

(ii)Improves

lipid

profi

lesa

ndox-LDLLD

Lcholesterolratio

inT2

DM

pts

[132]

(iii)Lo

wersa

rterialstiff

nessandcentralB

Pin

wom

en[133]

Curcum

in(i)

Decreases

both

totaland

LDLcholesteroland

increasesH


ACSpts

[164

165]

(ii)Increases

FMDin

postm

enop

ausalw

omen

[168]

Berberine

(i)Increasesb

othLV

EFandexercise

capa

city

anddecreasesrates

ofventricularp

rematurec

omplexes

andlong

-term

mortalityin

HFpts

[199]

(ii)R

educes

totalcho



andmod

estly

increasesH


DM

pts

[203205]

(iii)Re

ducesg

lycatedhemog

lobin


ostprand

ialglucoseand

fastingplasmag

lucose

inT2

DM

pts

[204

](iv

)Low

ersS

BPandDBP

inhypertensiv

eT2

DMand

hyperlipidemicpts

[206]

SBP

systo

licbloo

dpressureD

BPdiasto

licbloo

dpressureA

chA

cetylch

olineFM

Dflow


low-densitylip

oproteinH

DLhigh

-densitylip

oprotein

Apoapolipop

roteinT

2DMtype2

diabetes

mellitusC

ADcoron

aryartery

diseaseCV

cardiovascularAC

Sacutec

oron

arysynd

romeLV

EFleft

ventric

ular

ejectio

nfractio

nHFheartfailurepts

patie

nts



6 Conclusions





Acknowledgments


References


































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















vegetablec

ompo

unds

Vegetable

Clinicaleffects

Reference

Resveratrol

(i)Decreases

SBPwith

outaffectingDBP

[37]

(ii)E

nhancesA

ch-m


nin

hypertensiv

eand

dyslipidemicpts

[38]

(iii)Im

proves

FMDin

ptsw

itheither

metabolicsynd

romeo

rpreviou

sMI

[3940

](iv

)Decreases

totalcho

lesterolan

dtotaland

ox-LDL

triglyceridesandAp

oBlevelsin

ptsw

ithT2

DMC

ADhyperlip

idem

iaand

otherC

Vris

kfactors

[5354]

(v)Improves

insulin

sensitivity

inbo

thob

esea

ndmetabolicsynd

romep

ts[6667]

(vi)Im

proves

significantly

diastolic

functio

nandmod

estly

systolicfunctio

nin

ptsw

ithprevious

MI

[40]

Brassicaoleracea

(i)Re

ducestotalL

DLcholesteroland

markers

ofoxidatives

tressinsm

okersa

ndhypercho

leste

rolemicpts

[108119]

(ii)Improves

lipid

profi

lesa

ndox-LDLLD

Lcholesterolratio

inT2

DM

pts

[132]

(iii)Lo

wersa

rterialstiff

nessandcentralB

Pin

wom

en[133]

Curcum

in(i)

Decreases

both

totaland

LDLcholesteroland

increasesH


ACSpts

[164

165]

(ii)Increases

FMDin

postm

enop

ausalw

omen

[168]

Berberine

(i)Increasesb

othLV

EFandexercise

capa

city

anddecreasesrates

ofventricularp

rematurec

omplexes

andlong

-term

mortalityin

HFpts

[199]

(ii)R

educes

totalcho



andmod

estly

increasesH


DM

pts

[203205]

(iii)Re

ducesg

lycatedhemog

lobin


ostprand

ialglucoseand

fastingplasmag

lucose

inT2

DM

pts

[204

](iv

)Low

ersS

BPandDBP

inhypertensiv

eT2

DMand

hyperlipidemicpts

[206]

SBP

systo

licbloo

dpressureD

BPdiasto

licbloo

dpressureA

chA

cetylch

olineFM

Dflow


low-densitylip

oproteinH

DLhigh

-densitylip

oprotein

Apoapolipop

roteinT

2DMtype2

diabetes

mellitusC

ADcoron

aryartery

diseaseCV

cardiovascularAC

Sacutec

oron

arysynd

romeLV

EFleft

ventric

ular

ejectio

nfractio

nHFheartfailurepts

patie

nts



6 Conclusions





Acknowledgments


References


































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















6 Conclusions





Acknowledgments


References


































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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