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Molecular mechanisms of the cardiovascular protective effects of polyphenols

  • Ramaroson Andriantsitohaina (a1), Cyril Auger (a2), Thierry Chataigneau (a2), Nelly Étienne-Selloum (a2), Huige Li (a3), M. Carmen Martínez (a1), Valérie B. Schini-Kerth (a2) and Ismail Laher (a4)...

Epidemiological studies have reported a greater reduction in cardiovascular risk and metabolic disorders associated with diets rich in polyphenols. The antioxidant effects of polyphenols are attributed to the regulation of redox enzymes by reducing reactive oxygen species production from mitochondria, NADPH oxidases and uncoupled endothelial NO synthase in addition to also up-regulating multiple antioxidant enzymes. Although data supporting the effects of polyphenols in reducing oxidative stress are promising, several studies have suggested additional mechanisms in the health benefits of polyphenols. Polyphenols from red wine increase endothelial NO production leading to endothelium-dependent relaxation in conditions such as hypertension, stroke or the metabolic syndrome. Numerous molecules contained in fruits and vegetables can activate sirtuins to increase lifespan and silence metabolic and physiological disturbances associated with endothelial NO dysfunction. Although intracellular pathways involved in the endothelial effects of polyphenols are partially described, the molecular targets of these polyphenols are not completely elucidated. We review the novel aspects of polyphenols on several targets that could trigger the health benefits of polyphenols in conditions such as metabolic and cardiovascular disturbances.

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*Corresponding author: I. Laher, email
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1 CC Chuang & MK McIntosh (2011) Potential mechanisms by which polyphenol-rich grapes prevent obesity-mediated inflammation and metabolic diseases. Annu Rev Nutr 31, 155176.

3 J Kuhnau (1976) The flavonoids. A class of semi-essential food components: their role in human nutrition. World Rev Nutr Diet 24, 117191.

4 MG Hertog , PC Hollman , MB Katan , et al. (1993) Intake of potentially anticarcinogenic flavonoids and their determinants in adults in The Netherlands. Nutr Cancer 20, 2129.

5 J Lin , KM Rexrode , F Hu , et al. (2007) Dietary intakes of flavonols and flavones and coronary heart disease in US women. Am J Epidemiol 165, 13051313.

6 X Wu , GR Beecher , JM Holden , et al. (2006) Concentrations of anthocyanins in common foods in the United States and estimation of normal consumption. J Agric Food Chem 54, 40694075.

8 T Walle , F Hsieh , MH DeLegge , et al. (2004) High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos 32, 13771382.

9 I Fleming (2010) Molecular mechanisms underlying the activation of eNOS. Pflugers Arch 459, 793806.

11 KK Griendling , D Sorescu & M Ushio-Fukai (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 86, 494501.

13 KK Griendling & GA FitzGerald (2003) Oxidative stress and cardiovascular injury: Part II: animal and human studies. Circulation 108, 20342040.

14 A Virdis , L Ghiadoni & S Taddei (2010) Human endothelial dysfunction: EDCFs. Pflugers Arch 459, 10151023.

15 F Sofi , F Cesari , R Abbate , et al. (2008) Adherence to Mediterranean diet and health status: meta-analysis. BMJ 337, a1344.

16 S Renaud & M de Lorgeril (1992) Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339, 15231526.

17 A Basu , M Rhone & TJ Lyons (2010) Berries: emerging impact on cardiovascular health. Nutr Rev 68, 168177.

19 VB Schini-Kerth , C Auger , JH Kim , et al. (2010) Nutritional improvement of the endothelial control of vascular tone by polyphenols: role of NO and EDHF. Pflugers Arch 459, 853862.

20 E Andriambeloson , AL Kleschyov , B Muller , et al. (1997) Nitric oxide production and endothelium-dependent vasorelaxation induced by wine polyphenols in rat aorta. Br J Pharmacol 120, 10531058.

22 GG Duthie , MW Pedersen , PT Gardner , et al. (1998) The effect of whisky and wine consumption on total phenol content and antioxidant capacity of plasma from healthy volunteers. Eur J Clin Nutr 52, 733736.

24 SV Madeira , C Auger , E Anselm , et al. (2009) eNOS activation induced by a polyphenol-rich grape skin extract in porcine coronary arteries. J Vasc Res 46, 406416.

25 E Anselm , M Chataigneau , M Ndiaye , et al. (2007) Grape juice causes endothelium-dependent relaxation via a redox-sensitive Src- and Akt-dependent activation of eNOS. Cardiovasc Res 73, 404413.

26 M Chalopin , A Tesse , MC Martinez , et al. (2010) Estrogen receptor alpha as a key target of red wine polyphenols action on the endothelium. PLoS One 5, e8554.

27 N Peng , JT Clark , J Prasain , et al. (2005) Antihypertensive and cognitive effects of grape polyphenols in estrogen-depleted, female, spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 289, R771R775.

28 A Machha & MR Mustafa (2005) Chronic treatment with flavonoids prevents endothelial dysfunction in spontaneously hypertensive rat aorta. J Cardiovasc Pharmacol 46, 3640.

29 R Jimenez , R Lopez-Sepulveda , M Kadmiri , et al. (2007) Polyphenols restore endothelial function in DOCA-salt hypertension: role of endothelin-1 and NADPH oxidase. Free Radic Biol Med 43, 462473.

30 RS de Moura , DZ Miranda , AC Pinto , et al. (2004) Mechanism of the endothelium-dependent vasodilation and the antihypertensive effect of Brazilian red wine. J Cardiovasc Pharmacol 44, 302309.

31 M Sarr , M Chataigneau , S Martins , et al. (2006) Red wine polyphenols prevent angiotensin II-induced hypertension and endothelial dysfunction in rats: role of NADPH oxidase. Cardiovasc Res 71, 794802.

32 DG Harrison , H Cai , U Landmesser , et al. (2003) Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease. J Renin Angiotensin Aldosterone Syst 4, 5161.

33 R Miyazaki , T Ichiki , T Hashimoto , et al. (2008) SIRT1, a longevity gene, downregulates angiotensin II type 1 receptor expression in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 28, 12631269.

34 Y Steffen , C Gruber , T Schewe , et al. (2008) Mono-O-methylated flavanols and other flavonoids as inhibitors of endothelial NADPH oxidase. Arch Biochem Biophys 469, 209219.

35 MO Kane , N Etienne-Selloum , SV Madeira , et al. (2010) Endothelium-derived contracting factors mediate the Ang II-induced endothelial dysfunction in the rat aorta: preventive effect of red wine polyphenols. Pflugers Arch 459, 671679.

36 S Agewall , S Wright , RN Doughty , et al. (2000) Does a glass of red wine improve endothelial function? Eur Heart J 21, 7478.

37 MB Engler , MM Engler , CY Chen , et al. (2004) Flavonoid-rich dark chocolate improves endothelial function and increases plasma epicatechin concentrations in healthy adults. J Am Coll Nutr 23, 197204.

38 SJ Duffy , JA Vita , M Holbrook , et al. (2001) Effect of acute and chronic tea consumption on platelet aggregation in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 21, 10841089.

39 ME Widlansky , NM Hamburg , E Anter , et al. (2007) Acute EGCG supplementation reverses endothelial dysfunction in patients with coronary artery disease. J Am Coll Nutr 26, 95102.

40 J Lekakis , LS Rallidis , I Andreadou , et al. (2005) Polyphenolic compounds from red grapes acutely improve endothelial function in patients with coronary heart disease. Eur J Cardiovasc Prev Rehabil 12, 596600.

41 D Taubert , R Roesen , C Lehmann , et al. (2007) Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide: a randomized controlled trial. JAMA 298, 4960.

42 YK Park , JS Kim & MH Kang (2004) Concord grape juice supplementation reduces blood pressure in Korean hypertensive men: double-blind, placebo controlled intervention trial. Biofactors 22, 145147.

43 M Aviram & L Dornfeld (2001) Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure. Atherosclerosis 158, 195198.

44 JA Baur & DA Sinclair (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5, 493506.

45 S Bradamante , L Barenghi & A Villa (2004) Cardiovascular protective effects of resveratrol. Cardiovasc Drug Rev 22, 169188.

46 H Li & U Forstermann (2009) Resveratrol: a multifunctional compound improving endothelial function. Editorial to: “Resveratrol supplementation gender independently improves endothelial reactivity and suppresses superoxide production in healthy rats” by S. Soylemez et al. Cardiovasc Drugs Ther 23, 425429.

47 H Li , N Xia & U Forstermann (2012) Cardiovascular effects and molecular targets of resveratrol. Nitric Oxide 26, 102110.

48 Z Cao & Y Li (2004) Potent induction of cellular antioxidants and phase 2 enzymes by resveratrol in cardiomyocytes: protection against oxidative and electrophilic injury. Eur J Pharmacol 489, 3948.

49 Y Li , Z Cao & H Zhu (2006) Upregulation of endogenous antioxidants and phase 2 enzymes by the red wine polyphenol, resveratrol in cultured aortic smooth muscle cells leads to cytoprotection against oxidative and electrophilic stress. Pharmacol Res 53, 615.

50 Z Ungvari , Z Orosz , A Rivera , et al. (2007) Resveratrol increases vascular oxidative stress resistance. Am J Physiol Heart Circ Physiol 292, H2417H2424.

51 M Tanno , A Kuno , T Yano , et al. (2010) Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure. J Biol Chem 285, 83758382.

52 N Xia , A Daiber , A Habermeier , et al. (2010) Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice. J Pharmacol Exp Ther 335, 149154.

54 G Hasko & P Pacher (2010) Endothelial Nrf2 activation: a new target for resveratrol? Am J Physiol Heart Circ Physiol 299, H10H12.

55 Z Ungvari , Z Bagi , A Feher , et al. (2010) Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 299, H18H24.

56 M Thirunavukkarasu , SV Penumathsa , S Koneru , et al. (2007) Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of nitric oxide, thioredoxin, and heme oxygenase. Free Radic Biol Med 43, 720729.

57 RP Brandes & J Kreuzer (2005) Vascular NADPH oxidases: molecular mechanisms of activation. Cardiovasc Res 65, 1627.

58 KK Griendling (2004) Novel NAD(P)H oxidases in the cardiovascular system. Heart 90, 491493.

59 H Zhang , J Zhang , Z Ungvari , et al. (2009) Resveratrol improves endothelial function: role of TNF{alpha} and vascular oxidative stress. Arterioscler Thromb Vasc Biol 29, 11641171.

60 H Xu , C Goettsch , N Xia , et al. (2008) Differential roles of PKCalpha and PKCepsilon in controlling the gene expression of Nox4 in human endothelial cells. Free Radic Biol Med 44, 16561667.

61 U Forstermann & T Munzel (2006) Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 113, 17081714.

62 H Li & U Forstermann (2009) Prevention of atherosclerosis by interference with the vascular nitric oxide system. Curr Pharm Des 15, 31333145.

63 NJ Alp , MA McAteer , J Khoo , et al. (2004) Increased endothelial tetrahydrobiopterin synthesis by targeted transgenic GTP-cyclohydrolase I overexpression reduces endothelial dysfunction and atherosclerosis in ApoE-knockout mice. Arterioscler Thromb Vasc Biol 24, 445450.

64 P Wohlfart , H Xu , A Endlich , et al. (2008) Antiatherosclerotic effects of small-molecular-weight compounds enhancing endothelial nitric-oxide synthase (eNOS) expression and preventing eNOS uncoupling. J Pharmacol Exp Ther 325, 370379.

65 MN Cruz , L Luksha , H Logman , et al. (2006) Acute responses to phytoestrogens in small arteries from men with coronary heart disease. Am J Physiol Heart Circ Physiol 290, H1969H1975.

67 MM Appeldoorn , DP Venema , TH Peters , et al. (2009) Some phenolic compounds increase the nitric oxide level in endothelial cells in vitro. J Agric Food Chem 57, 76937699.

68 CM Klinge , NS Wickramasinghe , MM Ivanova , et al. (2008) Resveratrol stimulates nitric oxide production by increasing estrogen receptor alpha-Src-caveolin-1 interaction and phosphorylation in human umbilical vein endothelial cells. FASEB J 22, 21852197.

69 KJ Pearson , JA Baur , KN Lewis , et al. (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8, 157168.

70 F Murad (2006) Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development. N Engl J Med 355, 20032011.

71 L Gojkovic-Bukarica , A Novakovic , V Kanjuh , et al. (2008) A role of ion channels in the endothelium-independent relaxation of rat mesenteric artery induced by resveratrol. J Pharmacol Sci 108, 124130.

72 J Ruef , M Moser , W Kubler , et al. (2001) Induction of endothelin-1 expression by oxidative stress in vascular smooth muscle cells. Cardiovasc Pathol 10, 311315.

73 I Lekli , G Szabo , B Juhasz , et al. (2008) Protective mechanisms of resveratrol against ischemia–reperfusion-induced damage in hearts obtained from Zucker obese rats: the role of GLUT-4 and endothelin. Am J Physiol Heart Circ Physiol 294, H859H866.

77 C Rius , M Abu-Taha , C Hermenegildo , et al. (2010) Trans- but not cis-resveratrol impairs angiotensin-II-mediated vascular inflammation through inhibition of NF-kappaB activation and peroxisome proliferator-activated receptor-gamma upregulation. J Immunol 185, 37183727.

78 J Olholm , SK Paulsen , KB Cullberg , et al. (2010) Anti-inflammatory effect of resveratrol on adipokine expression and secretion in human adipose tissue explants. Int J Obes (Lond) 34, 15461553.

79 L Kang , W Heng , A Yuan , et al. (2010) Resveratrol modulates adipokine expression and improves insulin sensitivity in adipocytes: relative to inhibition of inflammatory responses. Biochimie 92, 789796.

80 A Kumar & SS Sharma (2010) NF-kappaB inhibitory action of resveratrol: a probable mechanism of neuroprotection in experimental diabetic neuropathy. Biochem Biophys Res Commun 394, 360365.

82 A Di Santo , A Mezzetti , E Napoleone , et al. (2003) Resveratrol and quercetin down-regulate tissue factor expression by human stimulated vascular cells. J Thromb Haemost 1, 10891095.

84 LM Szewczuk , L Forti , LA Stivala , et al. (2004) Resveratrol is a peroxidase-mediated inactivator of COX-1 but not COX-2: a mechanistic approach to the design of COX-1 selective agents. J Biol Chem 279, 2272722737.

85 KR Patel , E Scott , VA Brown , et al. (2011) Clinical trials of resveratrol. Ann N Y Acad Sci 1215, 161169.

86 F Perez-Vizcaino , J Duarte , R Jimenez , et al. (2009) Antihypertensive effects of the flavonoid quercetin. Pharmacol Rep 61, 6775.

87 Y Hanasaki , S Ogawa & S Fukui (1994) The correlation between active oxygens scavenging and antioxidative effects of flavonoids. Free Radic Biol Med 16, 845850.

88 LC Wilms , JC Kleinjans , EJ Moonen , et al. (2008) Discriminative protection against hydroxyl and superoxide anion radicals by quercetin in human leucocytes in vitro. Toxicol In vitro 22, 301307.

89 K Sakao , M Fujii & DX Hou (2009) Clarification of the role of quercetin hydroxyl groups in superoxide generation and cell apoptosis by chemical modification. Biosci Biotechnol Biochem 73, 20482053.

90 F Perez-Vizcaino , J Duarte & R Andriantsitohaina (2006) Endothelial function and cardiovascular disease: effects of quercetin and wine polyphenols. Free Radic Res 40, 10541065.

91 NK Khoo , CR White , L Pozzo-Miller , et al. (2010) Dietary flavonoid quercetin stimulates vasorelaxation in aortic vessels. Free Radic Biol Med 49, 339347.

92 CR Kuhlmann , CA Schaefer , C Kosok , et al. (2005) Quercetin-induced induction of the NO/cGMP pathway depends on Ca2+-activated K+ channel-induced hyperpolarization-mediated Ca2+-entry into cultured human endothelial cells. Planta Med 71, 520524.

93 S Suri , XH Liu , S Rayment , et al. (2010) Quercetin and its major metabolites selectively modulate cyclic GMP-dependent relaxations and associated tolerance in pig isolated coronary artery. Br J Pharmacol 159, 566575.

96 M Romero , R Jimenez , M Sanchez , et al. (2009) Quercetin inhibits vascular superoxide production induced by endothelin-1: role of NADPH oxidase, uncoupled eNOS and PKC. Atherosclerosis 202, 5867.

97 I Mackraj , T Govender & S Ramesar (2008) The antihypertensive effects of quercetin in a salt-sensitive model of hypertension. J Cardiovasc Pharmacol 51, 239245.

98 L Actis-Goretta , JI Ottaviani & CG Fraga (2006) Inhibition of angiotensin converting enzyme activity by flavanol-rich foods. J Agric Food Chem 54, 229234.

99 EM Neto-Neves , MF Montenegro , CA Dias-Junior , et al. (2010) Chronic treatment with quercetin does not inhibit angiotensin-converting enzyme in vivo or in vitro. Basic Clin Pharmacol Toxicol 107, 825829.

100 C Boesch-Saadatmandi , A Loboda , AE Wagner , et al. (2011) Effect of quercetin and its metabolites isorhamnetin and quercetin-3-glucuronide on inflammatory gene expression: role of miR-155. J Nutr Biochem 22, 293299.

101 WM Loke , JM Proudfoot , JM Hodgson , et al. (2010) Specific dietary polyphenols attenuate atherosclerosis in apolipoprotein E-knockout mice by alleviating inflammation and endothelial dysfunction. Arterioscler Thromb Vasc Biol 30, 749757.

102 S Wein , N Behm , RK Petersen , et al. (2010) Quercetin enhances adiponectin secretion by a PPAR-gamma independent mechanism. Eur J Pharm Sci 41, 1622.

103 MK Hwang , NR Song , NJ Kang , et al. (2009) Activation of phosphatidylinositol 3-kinase is required for tumor necrosis factor-alpha-induced upregulation of matrix metalloproteinase-9: its direct inhibition by quercetin. Int J Biochem Cell Biol 41, 15921600.

104 RY Huang , YL Yu , WC Cheng , et al. (2010) Immunosuppressive effect of quercetin on dendritic cell activation and function. J Immunol 184, 68156821.

106 SC Bae , WJ Jung , EJ Lee , et al. (2009) Effects of antioxidant supplements intervention on the level of plasma inflammatory molecules and disease severity of rheumatoid arthritis patients. J Am Coll Nutr 28, 5662.

107 L Navarro-Nunez , J Rivera , JA Guerrero , et al. (2009) Differential effects of quercetin, apigenin and genistein on signalling pathways of protease-activated receptors PAR(1) and PAR(4) in platelets. Br J Pharmacol 158, 15481556.

108 L Navarro-Nunez , ML Lozano , C Martinez , et al. (2010) Effect of quercetin on platelet spreading on collagen and fibrinogen and on multiple platelet kinases. Fitoterapia 81, 7580.

109 B Wright , LA Moraes , CF Kemp , et al. (2010) A structural basis for the inhibition of collagen-stimulated platelet function by quercetin and structurally related flavonoids. Br J Pharmacol 159, 13121325.

110 C Manach , C Morand , V Crespy , et al. (1998) Quercetin is recovered in human plasma as conjugated derivatives which retain antioxidant properties. FEBS Lett 426, 331336.

112 PC Hollman , M vd Gaag , MJ Mengelers , et al. (1996) Absorption and disposition kinetics of the dietary antioxidant quercetin in man. Free Radic Biol Med 21, 703707.

113 P Galindo , I Rodriguez-Gomez , S Gonzalez-Manzano , et al. (2012) Glucuronidated quercetin lowers blood pressure in spontaneously hypertensive rats via deconjugation. PLoS One 7, e32673.

114 C Felgines , S Talavera , O Texier , et al. (2005) Blackberry anthocyanins are mainly recovered from urine as methylated and glucuronidated conjugates in humans. J Agric Food Chem 53, 77217727.

116 K Azuma , A Ohyama , K Ippoushi , et al. (2008) Structures and antioxidant activity of anthocyanins in many accessions of eggplant and its related species. J Agric Food Chem 56, 1015410159.

117 MM Rahman , T Ichiyanagi , T Komiyama , et al. (2006) Superoxide radical- and peroxynitrite-scavenging activity of anthocyanins; structure–activity relationship and their synergism. Free Radic Res 40, 9931002.

118 CY Chen , L Yi , X Jin , et al. (2010) Delphinidin attenuates stress injury induced by oxidized low-density lipoprotein in human umbilical vein endothelial cells. Chem Biol Interact 183, 105112.

119 R Domitrovic & H Jakovac (2010) Antifibrotic activity of anthocyanidin delphinidin in carbon tetrachloride-induced hepatotoxicity in mice. Toxicology 272, 110.

120 J Cvorovic , F Tramer , M Granzotto , et al. (2010) Oxidative stress-based cytotoxicity of delphinidin and cyanidin in colon cancer cells. Arch Biochem Biophys 501, 151157.

121 S Martin , E Andriambeloson , K Takeda , et al. (2002) Red wine polyphenols increase calcium in bovine aortic endothelial cells: a basis to elucidate signalling pathways leading to nitric oxide production. Br J Pharmacol 135, 15791587.

122 C Baron-Menguy , A Bocquet , AL Guihot , et al. (2007) Effects of red wine polyphenols on postischemic neovascularization model in rats: low doses are proangiogenic, high doses anti-angiogenic. FASEB J 21, 35113521.

123 TM Scarabelli , S Mariotto , S Abdel-Azeim , et al. (2009) Targeting STAT1 by myricetin and delphinidin provides efficient protection of the heart from ischemia–reperfusion-induced injury. FEBS Lett 583, 531541.

124 MC Lazze , R Pizzala , P Perucca , et al. (2006) Anthocyanidins decrease endothelin-1 production and increase endothelial nitric oxide synthase in human endothelial cells. Mol Nutr Food Res 50, 4451.

125 NQ Khan , DM Lees , JA Douthwaite , et al. (2002) Comparison of red wine extract and polyphenol constituents on endothelin-1 synthesis by cultured endothelial cells. Clin Sci (Lond) 103, Suppl. 48, 72S75S.

126 L Actis-Goretta , JI Ottaviani , CL Keen , et al. (2003) Inhibition of angiotensin converting enzyme (ACE) activity by flavan-3-ols and procyanidins. FEBS Lett 555, 597600.

127 D Ojeda , E Jimenez-Ferrer , A Zamilpa , et al. (2010) Inhibition of angiotensin convertin enzyme (ACE) activity by the anthocyanins delphinidin- and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa. J Ethnopharmacol 127, 710.

128 JY Kwon , KW Lee , JE Kim , et al. (2009) Delphinidin suppresses ultraviolet B-induced cyclooxygenases-2 expression through inhibition of MAPKK4 and PI-3 kinase. Carcinogenesis 30, 19321940.

129 MK Hwang , NJ Kang , YS Heo , et al. (2009) Fyn kinase is a direct molecular target of delphinidin for the inhibition of cyclooxygenase-2 expression induced by tumor necrosis factor-alpha. Biochem Pharmacol 77, 12131222.

130 N Teller , W Thiele , U Boettler , et al. (2009) Delphinidin inhibits a broad spectrum of receptor tyrosine kinases of the ErbB and VEGFR family. Mol Nutr Food Res 53, 10751083.

131 A Dreiseitel , G Korte , P Schreier , et al. (2009) sPhospholipase A(2) is inhibited by anthocyanidins. J Neural Transm 116, 10711077.

132 A Dreiseitel , P Schreier , A Oehme , et al. (2008) Inhibition of proteasome activity by anthocyanins and anthocyanidins. Biochem Biophys Res Commun 372, 5761.

133 M Garcia-Alonso , G Rimbach , JC Rivas-Gonzalo , et al. (2004) Antioxidant and cellular activities of anthocyanins and their corresponding vitisins A – studies in platelets, monocytes, and human endothelial cells. J Agric Food Chem 52, 33783384.

134 JE Freedman , Cr Parker , L Li , et al. (2001) Select flavonoids and whole juice from purple grapes inhibit platelet function and enhance nitric oxide release. Circulation 103, 27922798.

136 M Avila , DM Ojcius & O Yilmaz (2009) The oral microbiota: living with a permanent guest. DNA Cell Biol 28, 405411.

137 JT Hwang , DY Kwon & SH Yoon (2009) AMP-activated protein kinase: a potential target for the diseases prevention by natural occurring polyphenols. N Biotechnol 26, 1722.

138 B Dasgupta & J Milbrandt (2007) Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A. 104, 72177222.

139 M Zang , S Xu , KA Maitland-Toolan , et al. (2006) Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55, 21802191.

140 JH Um , SJ Park , H Kang , et al. (2010) AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59, 554563.

141 SV Penumathsa , M Thirunavukkarasu , L Zhan , et al. (2008) Resveratrol enhances GLUT-4 translocation to the caveolar lipid raft fractions through AMPK/Akt/eNOS signalling pathway in diabetic myocardium. J Cell Mol Med 12, 23502361.

142 J Lu , DM Wu , YL Zheng , et al. (2010) Quercetin activates AMP-activated protein kinase by reducing PP2C expression protecting old mouse brain against high cholesterol-induced neurotoxicity. J Pathol 222, 199212.

143 J Ahn , H Lee , S Kim , et al. (2008) The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem Biophys Res Commun 373, 545549.

144 M Takikawa , S Inoue , F Horio , et al. (2010) Dietary anthocyanin-rich bilberry extract ameliorates hyperglycemia and insulin sensitivity via activation of AMP-activated protein kinase in diabetic mice. J Nutr 140, 527533.

145 JC Milne , PD Lambert , S Schenk , et al. (2007) Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712716.

146 S Michan & D Sinclair (2007) Sirtuins in mammals: insights into their biological function. Biochem J 404, 113.

147 JC Milne & JM Denu (2008) The Sirtuin family: therapeutic targets to treat diseases of aging. Curr Opin Chem Biol 12, 1117.

148 L Guarente (2006) Sirtuins as potential targets for metabolic syndrome. Nature 444, 868874.

149 M Lagouge , C Argmann , Z Gerhart-Hines , et al. (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127, 11091122.

150 M Pacholec , JE Bleasdale , B Chrunyk , et al. (2010) SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 285, 83408351.

151 F Liang , S Kume & D Koya (2009) SIRT1 and insulin resistance. Nat Rev Endocrinol 5, 367373.

152 F Picard , M Kurtev , N Chung , et al. (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429, 771776.

153 L Bordone , MC Motta , F Picard , et al. (2006) Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 4, e31.

154 I Mattagajasingh , CS Kim , A Naqvi , et al. (2007) SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 104, 1485514860.

155 A Csiszar , N Labinskyy , JT Pinto , et al. (2009) Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol 297, H13H20.

156 Z Chen , IC Peng , X Cui , et al. (2010) Shear stress, SIRT1, and vascular homeostasis. Proc Natl Acad Sci U S A 107, 1026810273.

157 JM Davis , EA Murphy , MD Carmichael , et al. (2009) Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance. Am J Physiol Regul Integr Comp Physiol 296, R1071R1077.

158 BD Gehm , JM McAndrews , PY Chien , et al. (1997) Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci U S A 94, 1413814143.

159 GG Kuiper , B Carlsson , K Grandien , et al. (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138, 863870.

160 L Le Corre , N Chalabi , L Delort , et al. (2006) Differential expression of genes induced by resveratrol in human breast cancer cell lines. Nutr Cancer 56, 193203.

161 JY Deng , PS Hsieh , JP Huang , et al. (2008) Activation of estrogen receptor is crucial for resveratrol-stimulating muscular glucose uptake via both insulin-dependent and -independent pathways. Diabetes 57, 18141823.

162 A Schlachterman , F Valle , KM Wall , et al. (2008) Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model. Transl Oncol 1, 1927.

163 P Miodini , L Fioravanti , G Di Fronzo , et al. (1999) The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function. Br J Cancer 80, 11501155.

164 GG Kuiper , JG Lemmen , B Carlsson , et al. (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139, 42524263.

165 M Maggiolini , A Vivacqua , G Fasanella , et al. (2004) The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells. J Biol Chem 279, 2700827016.

166 JN Lin , VC Lin , KM Rau , et al. (2010) Resveratrol modulates tumor cell proliferation and protein translation via SIRT1-dependent AMPK activation. J Agric Food Chem 58, 15841592.

167 JA Baur , KJ Pearson , NL Price , et al. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337342.

168 X Hou , S Xu , KA Maitland-Toolan , et al. (2008) SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem 283, 2001520026.

169 F Lan , JM Cacicedo , N Ruderman & Y Ido (2008) SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 283, 2762827635.

171 Z Liu , Y Song , X Zhang , et al. (2005) Effects of trans-resveratrol on hypertension-induced cardiac hypertrophy using the partially nephrectomized rat model. Clin Exp Pharmacol Physiol 32, 10491054.

172 A Biala , E Tauriainen , A Siltanen , et al. (2010) Resveratrol induces mitochondrial biogenesis and ameliorates Ang II-induced cardiac remodeling in transgenic rats harboring human renin and angiotensinogen genes. Blood Press 19, 196205.

174 J Behbahani , SJ Thandapilly , XL Louis , et al. (2010) Resveratrol and small artery compliance and remodeling in the spontaneously hypertensive rat. Am J Hypertens 23, 12731278.

175 M Romero , R Jimenez , B Hurtado , et al. (2010) Lack of beneficial metabolic effects of quercetin in adult spontaneously hypertensive rats. Eur J Pharmacol 627, 242250.

176 M Galisteo , MF Garcia-Saura , R Jimenez , et al. (2004) Effects of chronic quercetin treatment on antioxidant defence system and oxidative status of deoxycorticosterone acetate-salt-hypertensive rats. Mol Cell Biochem 259, 9199.

177 M Diebolt , B Bucher & R Andriantsitohaina (2001) Wine polyphenols decrease blood pressure, improve NO vasodilatation, and induce gene expression. Hypertension 38, 159165.

178 I Bernatova , O Pechanova , P Babal , et al. (2002) Wine polyphenols improve cardiovascular remodeling and vascular function in NO-deficient hypertension. Am J Physiol Heart Circ Physiol 282, H942H948.

179 O Pechanova , I Bernatova , P Babal , et al. (2004) Red wine polyphenols prevent cardiovascular alterations in L-NAME-induced hypertension. J Hypertens 22, 15511559.

180 A Simonyi , Q Wang , RL Miller , et al. (2005) Polyphenols in cerebral ischemia: novel targets for neuroprotection. Mol Neurobiol 31, 135147.

181 S Yousuf , F Atif , M Ahmad , et al. (2009) Resveratrol exerts its neuroprotective effect by modulating mitochondrial dysfunctions and associated cell death during cerebral ischemia. Brain Res 1250, 242253.

182 C Li , Z Yan , J Yang , et al. (2010) Neuroprotective effects of resveratrol on ischemic injury mediated by modulating the release of neurotransmitter and neuromodulator in rats. Neurochem Int 56, 495500.

183 MC Saleh , BJ Connell & TM Saleh (2010) Resveratrol preconditioning induces cellular stress proteins and is mediated via NMDA and estrogen receptors. Neuroscience 166, 445454.

184 D Della-Morte , KR Dave , RA DeFazio , et al. (2009) Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience 159, 9931002.

185 W Dong , N Li , D Gao , et al. (2008) Resveratrol attenuates ischemic brain damage in the delayed phase after stroke and induces messenger RNA and protein express for angiogenic factors. J Vasc Surg 48, 709714.

186 F Rivera , G Costa , A Abin , et al. (2008) Reduction of ischemic brain damage and increase of glutathione by a liposomal preparation of quercetin in permanent focal ischemia in rats. Neurotox Res 13, 105114.

187 IK Hwang , CH Lee , KY Yoo , et al. (2009) Neuroprotective effects of onion extract and quercetin against ischemic neuronal damage in the gerbil hippocampus. J Med Food 12, 990995.

188 MI Sweeney , W Kalt , SL MacKinnon , et al. (2002) Feeding rats diets enriched in lowbush blueberries for six weeks decreases ischemia-induced brain damage. Nutr Neurosci 5, 427431.

189 MF Ritz , Y Curin , A Mendelowitsch , et al. (2008) Acute treatment with red wine polyphenols protects from ischemia-induced excitotoxicity, energy failure and oxidative stress in rats. Brain Res 1239, 226234.

191 MP Robich , LM Chu , M Chaudray , et al. (2010) Anti-angiogenic effect of high-dose resveratrol in a swine model of metabolic syndrome. Surgery 148, 453462.

192 L Rivera , R Moron , A Zarzuelo , et al. (2009) Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem Pharmacol 77, 10531063.

193 P Fischer-Posovszky , V Kukulus , D Tews , et al. (2010) Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner. Am J Clin Nutr 92, 515.

194 L Rivera , R Moron , M Sanchez , et al. (2008) Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats. Obesity (Silver Spring) 16, 20812087.

195 T Sutra , C Oiry , J Azay-Milhau , et al. (2008) Preventive effects of nutritional doses of polyphenolic molecules on cardiac fibrosis associated with metabolic syndrome: involvement of osteopontin and oxidative stress. J Agric Food Chem 56, 1168311687.

196 A Agouni , AH Lagrue-Lak-Hal , HA Mostefai , et al. (2009) Red wine polyphenols prevent metabolic and cardiovascular alterations associated with obesity in Zucker fatty rats (Fa/Fa). PLoS One 4, e5557.

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British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
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