Polyphenols are found ubiquitously in plants and their regular consumption has been associated with a reduced risk of a number of chronic diseases, including cancer, cardiovascular disease (CVD) and neurodegenerative disorders. Rather than exerting direct antioxidant effects, the mechanisms by which polyphenols express these beneficial properties appear to involve their interaction with cellular signaling pathways and related machinery that mediate cell function under both normal and pathological conditions. We illustrate that their interactions with two such pathways, the MAP kinase (ERK, JNK, p38) and PI3？kinase/Akt signaling cascades, allow them to impact upon normal and abnormal cell function, thus influencing the cellular processes involved in the initiation and progression of cancer, CVD and neurodegeneration. For example, their ability to activate ERK in neurons leads to a promotion of neuronal survival and cognitive enhancements, both of which influence the progression of Alzheimer’s disease, whilst ERK activation by polyphenols in vascular endothelial cells influences nitric oxide production, blood pressure and ultimately CVD risk. The main focus of this review is to provide an overview of the role that polyphenols play in the prevention of cancer, cardiovascular disease and neurodegeneration. We present epidemiological data, human intervention study findings, as well as animal and in vitro studies in support of these actions and in each case we consider how their actions at the cellular level may underpin their physiological effects.
References
[1]
Kuriyama, S.; Shimazu, T.; Ohmori, K.; Kikuchi, N.; Nakaya, N.; Nishino, Y.; Tsubono, Y.; Tsuji, I. Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: The Ohsaki study. JAMA？2006, 296, 1255–1265, doi:10.1001/jama.296.10.1255. 16968850
Zern, T.L.; Wood, R.J.; Greene, C.; West, K.L.; Liu, Y.; Aggarwal, D.; Shachter, N.S.; Fernandez, M.L. Grape polyphenols exert a cardioprotective effect in pre- and postmenopausal women by lowering plasma lipids and reducing oxidative stress. J. Nutr.？2005, 135, 1911–1917.
[5]
Jeong, Y.J.; Choi, Y.J.; Kwon, H.M.; Kang, S.W.; Park, H.S.; Lee, M.; Kang, Y.H. Differential inhibition of oxidized LDL-induced apoptosis in human endothelial cells treated with different flavonoids. Br. J. Nutr.？2005, 93, 581–591.
[6]
Fuhrman, B.; Volkova, N.; Coleman, R.; Aviram, M. Grape powder polyphenols attenuate atherosclerosis development in apolipoprotein E deficient (E0) mice and reduce macrophage atherogenicity. J. Nutr.？2005, 135, 722–728.
[7]
Hubbard, G.P.; Wolffram, S.; de Vos, R.; Bovy, A.; Gibbins, J.M.; Lovegrove, J.A. Ingestion of onion soup high in quercetin inhibits platelet aggregation and essential components of the collagen-stimulated platelet activation pathway in man: A pilot study. Br. J. Nutr.？2006, 96, 482–488.
[8]
Ludwig, A.; Lorenz, M.; Grimbo, N.; Steinle, F.; Meiners, S.; Bartsch, C.; Stangl, K.; Baumann, G.; Stangl, V. The tea flavonoid epigallocatechin-3-gallate reduces cytokine-induced VCAM-1 expression and monocyte adhesion to endothelial cells. Biochem. Biophys. Res. Commun.？2004, 316, 659–665.
[9]
Hallund, J.; Bugel, S.; Tholstrup, T.; Ferrari, M.; Talbot, D.; Hall, W.L.; Reimann, M.; Williams, C.M.; Wiinberg, N. Soya isoflavone-enriched cereal bars affect markers of endothelial function in postmenopausal women. Br. J. Nutr.？2006, 95, 1120–1126.
[10]
Hodgson, J.; Croft, K. Dietary flavonoids: Effects on endothelial function and blood pressure. J. Sci. Food Agric.？2006, 86, 2492–2498.
[11]
Joseph, J.A.; Shukitt-Hale, B.; Denisova, N.A.; Bielinski, D.; Martin, A.; McEwen, J.J.; Bickford, P.C. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J. Neurosci.？1999, 19, 8114–8121. 10479711
[12]
Mantena, S.K.; Baliga, M.S.; Katiyar, S.K. Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells. Carcinogenesis？2006, 27, 1682–1691.
[13]
Fabiani, R.; De Bartolomeo, A.; Rosignoli, P.; Servili, M.; Montedoro, G.F.; Morozzi, G. Cancer chemoprevention by hydroxytyrosol isolated from virgin olive oil through G1 cell cycle arrest and apoptosis. Eur. J. Cancer Prev.？2002, 11, 351–358.
[14]
Fini, L.; Hotchkiss, E.; Fogliano, V.; Graziani, G.; Romano, M.; De Vol, E.B.; Qin, H.; Selgrad, M.; Boland, C.R.; Ricciardiello, L. Chemopreventive properties of pinoresinol-rich olive oil involve a selective activation of the ATM-p53 cascade in colon cancer cell lines. Carcinogenesis？2008, 29, 139–146.
[15]
Corona, G.; Deiana, M.; Incani, A.; Vauzour, D.; Dessi, M.A.; Spencer, J.P. Hydroxytyrosol inhibits the proliferation of human colon adenocarcinoma cells through inhibition of ERK1/2 and cyclin D1. Mol. Nutr. Food Res.？2009, 53, 897–903.
[16]
Wang, W.; Heideman, L.; Chung, C.S.; Pelling, J.C.; Koehler, K.J.; Birt, D.F. Cell-cycle arrest at G2/M and growth inhibition by apigenin in human colon carcinoma cell lines. Mol. Carcinog.？2000, 28, 102–110.
[17]
Piao, M.; Mori, D.; Satoh, T.; Sugita, Y.; Tokunaga, O. Inhibition of endothelial cell proliferation, in vitro angiogenesis, and the down-regulation of cell adhesion-related genes by genistein. Combined with a cDNA microarray analysis. Endothelium？2006, 13, 249–266, doi:10.1080/10623320600903940. 16990182
[18]
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell？2000, 100, 57–70.
[19]
D’Archivio, M.; Santangelo, C.; Scazzocchio, B.; Vari, R.; Filesi, C.; Masella, R.; Giovannini, C. Modulatory effects of polyphenols on apoptosis induction: Relevance for cancer prevention. Int. J. Mol. Sci.？2008, 9, 213–228.
[20]
Guo, W.; Kong, E.; Meydani, M. Dietary polyphenols, inflammation, and cancer. Nutr. Cancer？2009, 61, 807–810, doi:10.1080/01635580903285098. 20155620
[21]
Kampa, M.; Nifli, A.P.; Notas, G.; Castanas, E. Polyphenols and cancer cell growth. Rev. Physiol. Biochem. Pharmacol.？2007, 159, 79–113.
[22]
Stoner, G.D.; Mukhtar, H. Polyphenols as cancer chemopreventive agents. J. Cell. Biochem. Suppl.？1995, 22, 169–180.
[23]
Franceschi, S.; Parpinel, M.; La Vecchia, C.; Favero, A.; Talamini, R.; Negri, E. Role of different types of vegetables and fruit in the prevention of cancer of the colon, rectum, and breast. Epidemiology？1998, 9, 338–341. 9583427
[24]
La Vecchia, C.; Chatenoud, L.; Franceschi, S.; Soler, M.; Parazzini, F.; Negri, E. Vegetables and fruit and human cancer: Update of an Italian study. Int. J. Cancer？1999, 82, 151–152.
[25]
Benetou, V.; Orfanos, P.; Lagiou, P.; Trichopoulos, D.; Boffetta, P.; Trichopoulou, A. Vegetables and fruits in relation to cancer risk: Evidence from the Greek EPIC cohort study. Cancer Epidemiol. Biomarkers Prev.？2008, 17, 387–392.
[26]
Feskanich, D.; Ziegler, R.G.; Michaud, D.S.; Giovannucci, E.L.; Speizer, F.E.; Willett, W.C.; Colditz, G.A. Prospective study of fruit and vegetable consumption and risk of lung cancer among men and women. J. Natl. Cancer Inst.？2000, 92, 1812–1823.
[27]
Zhang, S.M.; Hunter, D.J.; Rosner, B.A.; Giovannucci, E.L.; Colditz, G.A.; Speizer, F.E.; Willett, W.C. Intakes of fruits, vegetables, and related nutrients and the risk of non-Hodgkin’s lymphoma among women. Cancer Epidemiol. Biomarkers Prev.？2000, 9, 477–485. 10815692
[28]
Gonzalez, C.A.; Pera, G.; Agudo, A.; Bueno-de-Mesquita, H.B.; Ceroti, M.; Boeing, H.; Schulz, M.; Del Giudice, G.; Plebani, M.; Carneiro, F.; et al. Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Int. J. Cancer？2006, 118, 2559–2566, doi:10.1002/ijc.21678. 16380980
[29]
Favero, A.; Parpinel, M.; Franceschi, S. Diet and risk of breast cancer: Major findings from an Italian case-control study. Biomed. Pharmacother.？1998, 52, 109–115.
[30]
Larsson, S.C.; Andersson, S.O.; Johansson, J.E.; Wolk, A. Fruit and vegetable consumption and risk of bladder cancer: A prospective cohort study. Cancer Epidemiol. Biomarkers Prev.？2008, 17, 2519–2522.
[31]
Larsson, S.C.; Hakansson, N.; Naslund, I.; Bergkvist, L.; Wolk, A. Fruit and vegetable consumption in relation to pancreatic cancer risk: A prospective study. Cancer Epidemiol. Biomarkers Prev.？2006, 15, 301–305.
[32]
Botterweck, A.A.; van den Brandt, P.A.; Goldbohm, R.A. A prospective cohort study on vegetable and fruit consumption and stomach cancer risk in The Netherlands. Am. J. Epidemiol.？1998, 148, 842–853.
[33]
Boffetta, P.; Couto, E.; Wichmann, J.; Ferrari, P.; Trichopoulos, D.; Bueno-de-Mesquita, H.B.; van Duijnhoven, F.J.; Buchner, F.L.; Key, T.; Boeing, H.; et al. Fruit and vegetable intake and overall cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). J. Natl. Cancer Inst.？2010, 102, 529–537, doi:10.1093/jnci/djq072. 20371762
[34]
Martinez, M.E. Primary prevention of colorectal cancer: Lifestyle, nutrition, exercis. Recent Results Cancer Res.？2005, 166, 177–211.
[35]
Li, Q.; Zhao, H.F.; Zhang, Z.F.; Liu, Z.G.; Pei, X.R.; Wang, J.B.; Cai, M.Y.; Li, Y. Long-term administration of green tea catechins prevents age-related spatial learning and memory decline in C57BL/6 J mice by regulating hippocampal cyclic amp-response element binding protein signaling cascade. Neuroscience？2009, 159, 1208–1215.
[36]
Middleton, E., Jr.; Kandaswami, C.; Theoharides, T.C. The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacol. Rev.？2000, 52, 673–751. 11121513
[37]
Duthie, S.J.; Dobson, V.L. Dietary flavonoids protect human colonocyte DNA from oxidative attack in vitro. Eur. J. Nutr.？1999, 38, 28–34, doi:10.1007/s003940050043. 10338685
[38]
Calomme, M.; Pieters, L.; Vlietinck, A.; Vanden Berghe, D. Inhibition of bacterial mutagenesis by Citrus flavonoids. Planta Med.？1996, 62, 222–226.
van Erk, M.J.; Roepman, P.; van der Lende, T.R.; Stierum, R.H.; Aarts, J.M.; van Bladeren, P.J.; van Ommen, B. Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur. J. Nutr.？2005, 44, 143–156, doi:10.1007/s00394-004-0503-1. 15309432
[41]
Khan, W.A.; Wang, Z.Y.; Athar, M.; Bickers, D.R.; Mukhtar, H. Inhibition of the skin tumorigenicity of (±)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene by tannic acid, green tea polyphenols and quercetin in Sencar mice. Cancer Lett.？1988, 42, 7–12.
[42]
Takada, M.; Nakamura, Y.; Koizumi, T.; Toyama, H.; Kamigaki, T.; Suzuki, Y.; Takeyama, Y.; Kuroda, Y. Suppression of human pancreatic carcinoma cell growth and invasion by epigallocatechin-3-gallate. Pancreas？2002, 25, 45–48.
[43]
Inoue, M.; Tajima, K.; Mizutani, M.; Iwata, H.; Iwase, T.; Miura, S.; Hirose, K.; Hamajima, N.; Tominaga, S. Regular consumption of green tea and the risk of breast cancer recurrence: Follow-up study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan. Cancer Lett.？2001, 167, 175–182.
[44]
Takada, M.; Ku, Y.; Habara, K.; Ajiki, T.; Suzuki, Y.; Kuroda, Y. Inhibitory effect of epigallocatechin-3-gallate on growth and invasion in human biliary tract carcinoma cells. World J. Surg.？2002, 26, 683–686.
[45]
Rieger-Christ, K.M.; Hanley, R.; Lodowsky, C.; Bernier, T.; Vemulapalli, P.; Roth, M.; Kim, J.; Yee, A.S.; Le, S.M.; Marie, P.J.; Libertino, J.A.; Summerhayes, I.C. The green tea compound, (？)-epigallocatechin-3-gallate downregulates N-cadherin and suppresses migration of bladder carcinoma cells. J. Cell. Biochem.？2007, 102, 377–388, doi:10.1002/jcb.21299. 17348027
[46]
Leong, H.; Mathur, P.S.; Greene, G.L. Inhibition of mammary tumorigenesis in the C3(1)/SV40 mouse model by green tea. Breast Cancer Res. Treat.？2008, 107, 359–369.
[47]
Larsen, C.A.; Dashwood, R.H. Suppression of Met activation in human colon cancer cells treated with (？)-epigallocatechin-3-gallate: Minor role of hydrogen peroxide. Biochem. Biophys. Res. Commun.？2009, 389, 527–530.
[48]
Khan, N.; Afaq, F.; Saleem, M.; Ahmad, N.; Mukhtar, H. Targeting multiple signaling pathways by green tea polyphenol (？)-epigallocatechin-3-gallate. Cancer Res.？2006, 66, 2500–2505.
[49]
Owen, R.W.; Giacosa, A.; Hull, W.E.; Haubner, R.; Spiegelhalder, B.; Bartsch, H. The antioxidant/anticancer potential of phenolic compounds isolated from olive oil. Eur. J. Cancer？2000, 36, 1235–1247.
[50]
Llor, X.; Pons, E.; Roca, A.; Alvarez, M.; Mane, J.; Fernandez-Banares, F.; Gassull, M.A. The effects of fish oil, olive oil, oleic acid and linoleic acid on colorectal neoplastic processes. Clin. Nutr.？2003, 22, 71–79, doi:10.1054/clnu.2002.0627. 12553953
[51]
Bartoli, R.; Fernandez-Banares, F.; Navarro, E.; Castella, E.; Mane, J.; Alvarez, M.; Pastor, C.; Cabre, E.; Gassull, M.A. Effect of olive oil on early and late events of colon carcinogenesis in rats: Modulation of arachidonic acid metabolism and local prostaglandin E(2) synthesis. Gut？2000, 46, 191–199.
[52]
Solanas, M.; Hurtado, A.; Costa, I.; Moral, R.; Menendez, J.A.; Colomer, R.; Escrich, E. Effects of a high olive oil diet on the clinical behavior and histopathological features of rat DMBA-induced mammary tumors compared with a high corn oil diet. Int. J. Oncol.？2002, 21, 745–753.
[53]
Gill, C.I.; Boyd, A.; McDermott, E.; McCann, M.; Servili, M.; Selvaggini, R.; Taticchi, A.; Esposto, S.; Montedoro, G.; McGlynn, H.; Rowland, I. Potential anti-cancer effects of virgin olive oil phenols on colorectal carcinogenesis models in vitro. Int. J. Cancer？2005, 117, 1–7. 15880398
[54]
Hashim, Y.Z.; Rowland, I.R.; McGlynn, H.; Servili, M.; Selvaggini, R.; Taticchi, A.; Esposto, S.; Montedoro, G.; Kaisalo, L.; Wahala, K.; Gill, C.I. Inhibitory effects of olive oil phenolics on invasion in human colon adenocarcinoma cells in vitro. Int. J. Cancer？2008, 122, 495–500. 17943720
[55]
Corona, G.; Deiana, M.; Incani, A.; Vauzour, D.; Dessi, M.A.; Spencer, J.P. Inhibition of p38/CREB phosphorylation and COX-2 expression by olive oil polyphenols underlies their anti-proliferative effects. Biochem. Biophys. Res. Commun.？2007, 362, 606–611.
[56]
Adams, L.S.; Chen, S. Phytochemicals for breast cancer prevention by targeting aromatase. Front. Biosci.？2009, 14, 3846–3863.
[57]
Khan, S.G.; Katiyar, S.K.; Agarwal, R.; Mukhtar, H. Enhancement of antioxidant and phase II enzymes by oral feeding of green tea polyphenols in drinking water to SKH-1 hairless mice: Possible role in cancer chemoprevention. Cancer Res.？1992, 52, 4050–4052.
[58]
Dhillon, A.S.; Hagan, S.; Rath, O.; Kolch, W. MAP kinase signalling pathways in cancer. Oncogene？2007, 26, 3279–3290.
[59]
Hopfner, M.; Schuppan, D.; Scherubl, H. Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer. World J. Gastroenterol.？2008, 14, 1–14.
[60]
Ramos, S. Cancer chemoprevention and chemotherapy: Dietary polyphenols and signalling pathways. Mol. Nutr. Food Res.？2008, 52, 507–526.
[61]
Fang, J.Y.; Richardson, B.C. The MAPK signalling pathways and colorectal cancer. Lancet Oncol.？2005, 6, 322–327.
[62]
Wang, W.; Wang, X.; Peng, L.; Deng, Q.; Liang, Y.; Qing, H.; Jiang, B. CD24-dependent MAPK pathway activation is required for colorectal cancer cell proliferation. Cancer Sci.？2010, 101, 112–119.
[63]
Corona, G.; Spencer, J.P.; Dessi, M.A. Extra virgin olive oil phenolics: Absorption, metabolism, and biological activities in the GI tract. Toxicol. Ind. Health？2009, 25, 285–293, doi:10.1177/0748233709102951. 19651799
[64]
Sebolt-Leopold, J.S.; Herrera, R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat. Rev. Cancer？2004, 4, 937–947.
[65]
Tsatsanis, C.; Androulidaki, A.; Venihaki, M.; Margioris, A.N. Signalling networks regulating cyclooxygenase-2. Int. J. Biochem. Cell Biol.？2006, 38, 1654–1661.
[66]
Guichard, C.; Pedruzzi, E.; Fay, M.; Marie, J.C.; Braut-Boucher, F.; Daniel, F.; Grodet, A.; Gougerot-Pocidalo, M.A.; Chastre, E.; Kotelevets, L.; Lizard, G.; Vandewalle, A.; Driss, F.; Ogier-Denis, E. Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells. Carcinogenesis？2006, 27, 1812–1827.
[67]
Lee, S.Y.; Munerol, B.; Pollard, S.; Youdim, K.A.; Pannala, A.S.; Kuhnle, G.G.; Debnam, E.S.; Rice-Evans, C.; Spencer, J.P. The reaction of flavanols with nitrous acid protects against N-nitrosamine formation and leads to the formation of nitroso derivatives which inhibit cancer cell growth. Free Radic. Biol. Med.？2006, 40, 323–334.
[68]
Adhami, V.M.; Malik, A.; Zaman, N.; Sarfaraz, S.; Siddiqui, I.A.; Syed, D.N.; Afaq, F.; Pasha, F.S.; Saleem, M.; Mukhtar, H. Combined inhibitory effects of green tea polyphenols and selective cyclooxygenase-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo. Clin. Cancer Res.？2007, 13, 1611–1619. 17332308
[69]
Banerjee, S.; Manna, S.; Mukherjee, S.; Pal, D.; Panda, C.K.; Das, S. Black tea polyphenols restrict benzopyrene-induced mouse lung cancer progression through inhibition of Cox-2 and induction of caspase-3 expression. Asian Pac. J. Cancer Prev.？2006, 7, 661–666.
[70]
Kumar, N.; Shibata, D.; Helm, J.; Coppola, D.; Malafa, M. Green tea polyphenols in the prevention of colon cancer. Front. Biosci.？2007, 12, 2309–2315.
[71]
Chell, S.; Kadi, A.; Williams, A.C.; Paraskeva, C. Mediators of PGE2 synthesis and signalling downstream of COX-2 represent potential targets for the prevention/treatment of colorectal cancer. Biochim. Biophys. Acta？2006, 1766, 104–119.
[72]
van Heist, J.; Niessen, H.; Hoekman, K.; Schalkwij, C. Advanced glycation end products in human cancer tissues: Detection of Nepsilon-(carboxymethyl)lysine and argpryrimidine. Ann. N. Y. Acad. Sci.？2005, 1043, 725–733.
[73]
Bengmark, S. Advanced Glycation and Lipoxidation End Products–Amplifiers of Inflammation: The Role of Food. JPEN J. Parenter. Enteral Nutr.？2007, 31, 430–440.
[74]
Kiho, T.; Usui, S.; Hirano, K.; Aizawa, K.; Inakuma, T. Tomato paste fraction inhibiting the formation of advance glycation end-products. Biosci. Biotechnol. Biochem.？2004, 1, 200–205.
[75]
Lo, C.-Y.; Li, S.; Tan, D.; Pan, M.-H.; Sang, S.; HO, C.-T. Trapping reactions of reactive carbonyl species with tea polyphenols in simulated physiological conditions. Mol. Nutr. Food Res.？2006, 50, 1118–1128.
[76]
Sang, S.; Shao, X.; Bai, N.; Lo, C.-Y.; Yang, C.; HO, C.-T. Tea polyphenol (？)-Epigallocatechin-3-Gallate: A new trapping agent of reactive dicarbonyl species. Chem. Res. Toxicol.？2007, 20, 1862–1870.
[77]
Kuniyasu, H.; Oue, N.; Wakikawa, A.; Shigeishi, N.; Matsutani, N.; Kuraoka, K.; Ito, R.; Yokozaki, H.; Yasui, W. Expression of receptors for advanced glycation end-products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer. J. Pathol.？2001, 196, 163–170.
[78]
Sparvero, L.; Asafu-Adjei, D.; Kang, R.; Tang, D.; Amin, N.; Im, J.; Rutledge, R.; Lin, B.; Amoscato, A.; Zeh, H.; Lotze, M. RAGE (Receptor for Advanced Glycation Endproducts), RAGE Ligands, and their role in Cancer and Inflammation. J. Transl. Med.？2009, 7, 17, doi:10.1186/1479-5876-7-17. 19292913
[79]
Takada, M.; Ku, Y.; Toyama, H.; Suzuki, Y.; Kuroda, Y. Suppressive effects of tea polyphenol and conformational changes with receptor for advanced glycation en products (RAGE) expression in human hepatoma cells. Hepatogastroenterology？2002, 49, 928–931.
[80]
WHO: Cardiovascular diseases (CVDs). Fact sheet No317. Available online: http://www.who.int/mediacentre/factsheets/fs317/en/index.html (accessed on 10 September 2009).
[81]
Ambrose, J.A.; Barua, R.S. The pathophysiology of cigarette smoking and cardiovascular disease: An update. J. Am. Coll. Cardiol.？2004, 43, 1731–1737.
[82]
Jia, C.P.; Chen, M.J.; Huang, S.Z.; Zeng, Y.T. A study of inductive effect of hemin on expression of the beta-globin genes in K562 cells. Yi Chuan？2002, 24, 399–402.
[83]
Tanasescu, M.; Leitzmann, M.F.; Rimm, E.B.; Willett, W.C.; Stampfer, M.J.; Hu, F.B. Exercise type and intensity in relation to coronary heart disease in men. JAMA？2002, 288, 1994–2000.
[84]
Twisk, J.; Gillian-Daniel, D.L.; Tebon, A.; Wang, L.; Barrett, P.H.; Attie, A.D. The role of the LDL receptor in apolipoprotein B secretion. J. Clin. Invest.？2000, 105, 521–532.
[85]
Arts, I.C.; Jacobs, D.R., Jr.; Harnack, L.J.; Gross, M.; Folsom, A.R. Dietary catechins in relation to coronary heart disease death among postmenopausal women. Epidemiology？2001, 12, 668–675.
[86]
Hertog, M.G.; Feskens, E.J.; Hollman, P.C.; Katan, M.B.; Kromhout, D. Dietary antioxidant flavonoids and risk of coronary heart disease: The Zutphen Elderly Study. Lancet？1993, 342, 1007–1011.
[87]
Hertog, M.G.; Feskens, E.J.; Kromhout, D. Antioxidant flavonols and coronary heart disease risk. Lancet？1997, 349, 699.
[88]
Hertog, M.G.; Kromhout, D.; Aravanis, C.; Blackburn, H.; Buzina, R.; Fidanza, F.; Giampaoli, S.; Jansen, A.; Menotti, A.; Nedeljkovic, S.; et al. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch. Intern. Med.？1995, 155, 381–386. 7848021
[89]
Knekt, P.; Jarvinen, R.; Reunanen, A.; Maatela, J. Flavonoid intake and coronary mortality in Finland: A cohort study. BMJ？1996, 312, 478–481.
[90]
Mink, P.J.; Scrafford, C.G.; Barraj, L.M.; Harnack, L.; Hong, C.P.; Nettleton, J.A.; Jacobs, D.R., Jr. Flavonoid intake and cardiovascular disease mortality: A prospective study in postmenopausal women. Am. J. Clin. Nutr.？2007, 85, 895–909.
[91]
Nakachi, K.; Matsuyama, S.; Miyake, S.; Suganuma, M.; Imai, K. Preventive effects of drinking green tea on cancer and cardiovascular disease: Epidemiological evidence for multiple targeting prevention. Biofactors？2000, 13, 49–54.
[92]
Rein, D.; Paglieroni, T.G.; Pearson, D.A.; Wun, T.; Schmitz, H.H.; Gosselin, R.; Keen, C.L. Cocoa and wine polyphenols modulate platelet activation and function. J. Nutr.？2000, 130, 2120S–2126S.
[93]
Renaud, S.; de Lorgeril, M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet？1992, 339, 1523–1526, doi:10.1016/0140-6736(92)91277-F. 1351198
[94]
Yochum, L.; Kushi, L.H.; Meyer, K.; Folsom, A.R. Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women. Am. J. Epidemiol.？1999, 149, 943–949.
[95]
Arts, I.C.; Hollman, P.C. Polyphenols and disease risk in epidemiologic studies. Am. J. Clin. Nutr.？2005, 81, 317S–325S.
[96]
Peters, U.; Poole, C.; Arab, L. Does tea affect cardiovascular disease? A meta-analysis. Am. J. Epidemiol.？2001, 154, 495–503.
[97]
Di Castelnuovo, A.; Rotondo, S.; Iacoviello, L.; Donati, M.B.; De Gaetano, G. Meta-analysis of wine and beer consumption in relation to vascular risk. Circulation？2002, 105, 2836–2844.
[98]
Hooper, L.; Kroon, P.A.; Rimm, E.B.; Cohn, J.S.; Harvey, I.; Le Cornu, K.A.; Ryder, J.J.; Hall, W.L.; Cassidy, A. Flavonoids, flavonoid-rich foods, and cardiovascular risk: A meta-analysis of randomized controlled trials. Am. J. Clin. Nutr.？2008, 88, 38–50. 18614722
[99]
Lin, J.; Rexrode, K.M.; Hu, F.; Albert, C.M.; Chae, C.U.; Rimm, E.B.; Stampfer, M.J.; Manson, J.E. Dietary intakes of flavonols and flavones and coronary heart disease in US women. Am. J. Epidemiol.？2007, 165, 1305–1313.
[100]
Rimm, E.B.; Katan, M.B.; Ascherio, A.; Stampfer, M.J.; Willett, W.C. Relation between intake of flavonoids and risk for coronary heart disease in male health professionals. Ann. Intern. Med.？1996, 125, 384–389.
[101]
Sesso, H.D.; Gaziano, J.M.; Liu, S.; Buring, J.E. Flavonoid intake and the risk of cardiovascular disease in women. Am. J. Clin. Nutr.？2003, 77, 1400–1408.
[102]
Vita, J.A. Polyphenols and cardiovascular disease: Effects on endothelial and platelet function. Am. J. Clin. Nutr.？2005, 81, 292S–297S.
[103]
Rein, D.; Lotito, S.; Holt, R.R.; Keen, C.L.; Schmitz, H.H.; Fraga, C.G. Epicatechin in human plasma: In vivo determination and effect of chocolate consumption on plasma oxidation status. J. Nutr.？2000, 130, 2109–2114. 10917931
[104]
Stein, J.H.; Keevil, J.G.; Wiebe, D.A.; Aeschlimann, S.; Folts, J.D. Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease. Circulation？1999, 100, 1050–1055.
[105]
Wan, Y.; Vinson, J.A.; Etherton, T.D.; Proch, J.; Lazarus, S.A.; Kris-Etherton, P.M. Effects of cocoa powder and dark chocolate on LDL oxidative susceptibility and prostaglandin concentrations in humans. Am. J. Clin. Nutr.？2001, 74, 596–602.
[106]
Desch, S.; Schmidt, J.; Kobler, D.; Sonnabend, M.; Eitel, I.; Sareban, M.; Rahimi, K.; Schuler, G.; Thiele, H. Effect of cocoa products on blood pressure: Systematic review and meta-analysis. Am. J. Hypertens.？2010, 23, 97–103.
[107]
Erlund, I.; Koli, R.; Alfthan, G.; Marniemi, J.; Puukka, P.; Mustonen, P.; Mattila, P.; Jula, A. Favorable effects of berry consumption on platelet function, blood pressure, and HDL cholesterol. Am. J. Clin. Nutr.？2008, 87, 323–331. 18258621
[108]
Grassi, D.; Necozione, S.; Lippi, C.; Croce, G.; Valeri, L.; Pasqualetti, P.; Desideri, G.; Blumberg, J.B.; Ferri, C. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension？2005, 46, 398–405.
[109]
Taubert, D.; Roesen, R.; Lehmann, C.; Jung, N.; Schomig, E. Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide: A randomized controlled trial. JAMA？2007, 298, 49–60.
[110]
Taubert, D.; Roesen, R.; Schomig, E. Effect of cocoa and tea intake on blood pressure: A meta-analysis. Arch. Intern. Med.？2007, 167, 626–634.
[111]
Park, Y.K.; Kim, J.S.; Kang, M.H. Concord grape juice supplementation reduces blood pressure in Korean hypertensive men: Double-blind, placebo controlled intervention trial. Biofactors？2004, 22, 145–147.
[112]
Heiss, C.; Dejam, A.; Kleinbongard, P.; Schewe, T.; Sies, H.; Kelm, M. Vascular effects of cocoa rich in flavan-3-ols. JAMA？2003, 290, 1030–1031.
[113]
Heiss, C.; Finis, D.; Kleinbongard, P.; Hoffmann, A.; Rassaf, T.; Kelm, M.; Sies, H. Sustained increase in flow-mediated dilation after daily intake of high-flavanol cocoa drink over 1 week. J. Cardiovasc. Pharmacol.？2007, 49, 74–80.
[114]
Heiss, C.; Kleinbongard, P.; Dejam, A.; Perre, S.; Schroeter, H.; Sies, H.; Kelm, M. Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers. J. Am. Coll. Cardiol.？2005, 46, 1276–1283.
[115]
Engler, M.B.; Engler, M.M.; Chen, C.Y.; Malloy, M.J.; Browne, A.; Chiu, E.Y.; Kwak, H.K.; Milbury, P.; Paul, S.M.; Blumberg, J.; Mietus-Snyder, M.L. Flavonoid-rich dark chocolate improves endothelial function and increases plasma epicatechin concentrations in healthy adults. J. Am. Coll. Nutr.？2004, 23, 197–204.
[116]
Schroeter, H.; Heiss, C.; Balzer, J.; Kleinbongard, P.; Keen, C.L.; Hollenberg, N.K.; Sies, H.; Kwik-Uribe, C.; Schmitz, H.H.; Kelm, M. Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc. Natl. Acad. Sci. USA？2006, 103, 1024–1029.
[117]
Wang-Polagruto, J.F.; Villablanca, A.C.; Polagruto, J.A.; Lee, L.; Holt, R.R.; Schrader, H.R.; Ensunsa, J.L.; Steinberg, F.M.; Schmitz, H.H.; Keen, C.L. Chronic consumption of flavanol-rich cocoa improves endothelial function and decreases vascular cell adhesion molecule in hypercholesterolemic postmenopausal women. J. Cardiovasc. Pharmacol.？2006, 47 (Suppl. 2), S177–S186; discussion S206-S209, doi:10.1097/00005344-200606001-00013. 16794456
[118]
Grassi, D.; Mulder, T.P.; Draijer, R.; Desideri, G.; Molhuizen, H.O.; Ferri, C. Black tea consumption dose-dependently improves flow-mediated dilation in healthy males. J. Hypertens.？2009, 27, 774–781.
[119]
Widlansky, M.E.; Hamburg, N.M.; Anter, E.; Holbrook, M.; Kahn, D.F.; Elliott, J.G.; Keaney, J.F., Jr.; Vita, J.A. Acute EGCG supplementation reverses endothelial dysfunction in patients with coronary artery disease. J. Am. Coll. Nutr.？2007, 26, 95–102.
[120]
Cuevas, A.M.; Guasch, V.; Castillo, O.; Irribarra, V.; Mizon, C.; San Martin, A.; Strobel, P.; Perez, D.; Germain, A.M.; Leighton, F. A high-fat diet induces and red wine counteracts endothelial dysfunction in human volunteers. Lipids？2000, 35, 143–148.
[121]
Papamichael, C.; Karatzis, E.; Karatzi, K.; Aznaouridis, K.; Papaioannou, T.; Protogerou, A.; Stamatelopoulos, K.; Zampelas, A.; Lekakis, J.; Mavrikakis, M. Red wine’s antioxidants counteract acute endothelial dysfunction caused by cigarette smoking in healthy nonsmokers. Am. Heart J.？2004, 147, E5.
[122]
Pearson, D.A.; Paglieroni, T.G.; Rein, D.; Wun, T.; Schramm, D.D.; Wang, J.F.; Holt, R.R.; Gosselin, R.; Schmitz, H.H.; Keen, C.L. The effects of flavanol-rich cocoa and aspirin on ex vivo platelet function. Thromb. Res.？2002, 106, 191–197, doi:10.1016/S0049-3848(02)00128-7. 12297125
Keevil, J.G.; Osman, H.E.; Reed, J.D.; Folts, J.D. Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation. J. Nutr.？2000, 130, 53–56. 10613766
[125]
Mathur, S.; Devaraj, S.; Grundy, S.M.; Jialal, I. Cocoa products decrease low density lipoprotein oxidative susceptibility but do not affect biomarkers of inflammation in humans. J. Nutr.？2002, 132, 3663–3667.
[126]
Mao, T.K.; van de Water, J.; Keen, C.L.; Schmitz, H.H.; Gershwin, M.E. Modulation of TNF-alpha secretion in peripheral blood mononuclear cells by cocoa flavanols and procyanidins. Dev. Immunol.？2002, 9, 135–141.
[127]
Schramm, D.D.; Karim, M.; Schrader, H.R.; Holt, R.R.; Kirkpatrick, N.J.; Polagruto, J.A.; Ensunsa, J.L.; Schmitz, H.H.; Keen, C.L. Food effects on the absorption and pharmacokinetics of cocoa flavanols. Life Sci.？2003, 73, 857–869.
[128]
Hollenberg, N.K.; Martinez, G.; McCullough, M.; Meinking, T.; Passan, D.; Preston, M.; Rivera, A.; Taplin, D.; Vicaria-Clement, M. Aging, acculturation, salt intake, and hypertension in the Kuna of Panama. Hypertension？1997, 29, 171–176. 9039098
[129]
Stensvold, I.; Tverdal, A.; Solvoll, K.; Foss, O.P. Tea consumption. relationship to cholesterol, blood pressure, and coronary and total mortality. Prev. Med.？1992, 21, 546–553, doi:10.1016/0091-7435(92)90062-M. 1409496
[130]
Yang, Y.C.; Lu, F.H.; Wu, J.S.; Wu, C.H.; Chang, C.J. The protective effect of habitual tea consumption on hypertension. Arch. Intern. Med.？2004, 164, 1534–1540.
[131]
Negishi, H.; Xu, J.W.; Ikeda, K.; Njelekela, M.; Nara, Y.; Yamori, Y. Black and green tea polyphenols attenuate blood pressure increases in stroke-prone spontaneously hypertensive rats. J. Nutr.？2004, 134, 38–42.
[132]
Uchida, S.; Ozaki, M.; Akashi, T.; Yamashita, K.; Niwa, M.; Taniyama, K. Effects of (？)-epigallocatechin-3-O-gallate (green tea tannin) on the life span of stroke-prone spontaneously hypertensive rats. Clin. Exp. Pharmacol. Physiol. Suppl.？1995, 22, S302–S303, doi:10.1111/j.1440-1681.1995.tb02928.x. 9072402
[133]
Duffy, S.J.; Keaney, J.F., Jr.; Holbrook, M.; Gokce, N.; Swerdloff, P.L.; Frei, B.; Vita, J.A. Short- and long-term black tea consumption reverses endothelial dysfunction in patients with coronary artery disease. Circulation？2001, 104, 151–156.
[134]
Hodgson, J.M.; Puddey, I.B.; Burke, V.; Beilin, L.J.; Jordan, N. Effects on blood pressure of drinking green and black tea. J. Hypertens.？1999, 17, 457–463.
Bingham, S.A.; Vorster, H.; Jerling, J.C.; Magee, E.; Mulligan, A.; Runswick, S.A.; Cummings, J.H. Effect of black tea drinking on blood lipids, blood pressure and aspects of bowel habit. Br. J. Nutr.？1997, 78, 41–55.
[137]
Knekt, P.; Isotupa, S.; Rissanen, H.; Heliovaara, M.; Jarvinen, R.; Hakkinen, S.; Aromaa, A.; Reunanen, A. Quercetin intake and the incidence of cerebrovascular disease. Eur. J. Clin. Nutr.？2000, 54, 415–417.
[138]
Andrade, A.C.; Cesena, F.H.; Consolim-Colombo, F.M.; Coimbra, S.R.; Benjo, A.M.; Krieger, E.M.; Luz, P.L. Short-term red wine consumption promotes differential effects on plasma levels of high-density lipoprotein cholesterol, sympathetic activity, and endothelial function in hypercholesterolemic, hypertensive, and healthy subjects. Clinics (Sao Paulo)？2009, 64, 435–442. 19488610
[139]
Spaak, J.; Merlocco, A.C.; Soleas, G.J.; Tomlinson, G.; Morris, B.L.; Picton, P.; Notarius, C.F.; Chan, C.T.; Floras, J.S. Dose-related effects of red wine and alcohol on hemodynamics, sympathetic nerve activity, and arterial diamete. Am. J. Physiol. Heart Circ. Physiol.？2008, 294, H605–H612.
[140]
Hansen, A.S.; Marckmann, P.; Dragsted, L.O.; Finne Nielsen, I.L.; Nielsen, S.E.; Gronbaek, M. Effect of red wine and red grape extract on blood lipids, haemostatic factors, and other risk factors for cardiovascular disease. Eur. J. Clin. Nutr.？2005, 59, 449–455, doi:10.1038/sj.ejcn.1602107. 15674304
[141]
Hodgson, J.M.; Burke, V.; Puddey, I.B. Acute effects of tea on fasting and postprandial vascular function and blood pressure in humans. J. Hypertens.？2005, 23, 47–54.
[142]
Agewall, S.; Wright, S.; Doughty, R.N.; Whalley, G.A.; Duxbury, M.; Sharpe, N. Does a glass of red wine improve endothelial function? Eur. Heart J.？2000, 21, 74–78, doi:10.1053/euhj.1999.1759. 10610747
[143]
Hashimoto, M.; Kim, S.; Eto, M.; Iijima, K.; Ako, J.; Yoshizumi, M.; Akishita, M.; Kondo, K.; Itakura, H.; Hosoda, K.; Toba, K.; Ouchi, Y. Effect of acute intake of red wine on flow-mediated vasodilatation of the brachial artery. Am. J. Cardiol.？2001, 88, 1457–1460.
[144]
Karatzi, K.; Papamichael, C.; Aznaouridis, K.; Karatzis, E.; Lekakis, J.; Matsouka, C.; Boskou, G.; Chiou, A.; Sitara, M.; Feliou, G.; Kontoyiannis, D.; Zampelas, A.; Mavrikakis, M. Constituents of red wine other than alcohol improve endothelial function in patients with coronary artery disease. Coron. Artery Dis.？2004, 15, 485–490.
[145]
Whelan, A.P.; Sutherland, W.H.; McCormick, M.P.; Yeoman, D.J.; de Jong, S.A.; Williams, M.J. Effects of white and red wine on endothelial function in subjects with coronary artery disease. Intern. Med. J.？2004, 34, 224–228.
[146]
Appeldoorn, M.M.; Venema, D.P.; Peters, T.H.; Koenen, M.E.; Arts, I.C.; Vincken, J.P.; Gruppen, H.; Keijer, J.; Hollman, P.C. Some phenolic compounds increase the nitric oxide level in endothelial cells in vitro. J. Agric. Food Chem.？2009, 57, 7693–7699. 19722703
[147]
Schmitt, C.A.; Dirsch, V.M. Modulation of endothelial nitric oxide by plant-derived products. Nitric Oxide？2009, 21, 77–91.
[148]
Fitzpatrick, D.F.; Hirschfield, S.L.; Ricci, T.; Jantzen, P.; Coffey, R.G. Endothelium-dependent vasorelaxation caused by various plant extracts. J. Cardiovasc. Pharmacol.？1995, 26, 90–95.
[149]
Wallerath, T.; Deckert, G.; Ternes, T.; Anderson, H.; Li, H.; Witte, K.; Forstermann, U. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation？2002, 106, 1652–1658, doi:10.1161/01.CIR.0000029925.18593.5C. 12270858
Karim, M.; McCormick, K.; Kappagoda, C.T. Effects of cocoa extracts on endothelium-dependent relaxation. J. Nutr.？2000, 130, 2105S–2108S.
[152]
Chin-Dusting, J.P.; Fisher, L.J.; Lewis, T.V.; Piekarska, A.; Nestel, P.J.; Husband, A. The vascular activity of some isoflavone metabolites: Implications for a cardioprotective role. Br. J. Pharmacol.？2001, 133, 595–605.
[153]
Fitzpatrick, D.F.; Bing, B.; Rohdewald, P. Endothelium-dependent vascular effects of Pycnogenol. J. Cardiovasc. Pharmacol.？1998, 32, 509–515.
[154]
Fitzpatrick, D.F.; Hirschfield, S.L.; Coffey, R.G. Endothelium-dependent vasorelaxing activity of wine and other grape products. Am. J. Physiol.？1993, 265, H774–H778.
[155]
Karamsetty, M.R.; Klinger, J.R.; Hill, N.S. Phytoestrogens restore nitric oxide-mediated relaxation in isolated pulmonary arteries from chronically hypoxic rats. J. Pharmacol. Exp. Ther.？2001, 297, 968–974.
[156]
Woodman, O.L.; Chan, E. Vascular and anti-oxidant actions of flavonols and flavones. Clin. Exp. Pharmacol. Physiol.？2004, 31, 786–790.
[157]
Lorenz, M.; Wessler, S.; Follmann, E.; Michaelis, W.; Dusterhoft, T.; Baumann, G.; Stangl, K.; Stangl, V. A constituent of green tea, epigallocatechin-3-gallate, activates endothelial nitric oxide synthase by a phosphatidylinositol-3-OH-kinase-, cAMP-dependent protein kinase-, and Akt-dependent pathway and leads to endothelial-dependent vasorelaxation. J. Biol. Chem.？2004, 279, 6190–6195. 14645258
[158]
Stoclet, J.C.; Chataigneau, T.; Ndiaye, M.; Oak, M.H.; El Bedoui, J.; Chataigneau, M.; Schini-Kerth, V.B. Vascular protection by dietary polyphenols. Eur. J. Pharmacol.？2004, 500, 299–313.
[159]
Corder, R.; Douthwaite, J.A.; Lees, D.M.; Khan, N.Q.; Viseu Dos Santos, A.C.; Wood, E.G.; Carrier, M.J. Endothelin-1 synthesis reduced by red wine. Nature？2001, 414, 863–864.
[160]
Khan, N.Q.; Lees, D.M.; Douthwaite, J.A.; Carrier, M.J.; Corder, R. Comparison of red wine extract and polyphenol constituents on endothelin-1 synthesis by cultured endothelial cells. Clin. Sci. (Lond.)？2002, 103 (Suppl. 48), 72–75. 12193058
[161]
Steffen, Y.; Gruber, C.; Schewe, T.; Sies, H. Mono-O-methylated flavanols and other flavonoids as inhibitors of endothelial NADPH oxidase. Arch. Biochem. Biophys.？2008, 469, 209–219, doi:10.1016/j.abb.2007.10.012. 17996190
[162]
Steffen, Y.; Schewe, T.; Sies, H. Epicatechin elevates nitric oxide in endothelial cells via inhibition of NADPH oxidase. Biochem. Biophys. Res. Commun.？2007, 359, 828–833.
[163]
Pignatelli, P.; Pulcinelli, F.M.; Celestini, A.; Lenti, L.; Ghiselli, A.; Gazzaniga, P.P.; Violi, F. The flavonoids quercetin and catechin synergistically inhibit platelet function by antagonizing the intracellular production of hydrogen peroxide. Am. J. Clin. Nutr.？2000, 72, 1150–1155.
[164]
Freedman, J.E.; Parker C., III; Li, L.; Perlman, J.A.; Frei, B.; Ivanov, V.; Deak, L.R.; Iafrati, M.D.; Folts, J.D. Select flavonoids and whole juice from purple grapes inhibit platelet function and enhance nitric oxide release. Circulation？2001, 103, 2792–2798. 11401934
[165]
Natella, F.; Nardini, M.; Belelli, F.; Pignatelli, P.; Di Santo, S.; Ghiselli, A.; Violi, F.; Scaccini, C. Effect of coffee drinking on platelets: Inhibition of aggregation and phenols incorporation. Br. J. Nutr.？2008, 100, 1276–1282.
[166]
Steptoe, A.; Gibson, E.L.; Vuononvirta, R.; Hamer, M.; Wardle, J.; Rycroft, J.A.; Martin, J.F.; Erusalimsky, J.D. The effects of chronic tea intake on platelet activation and inflammation: A double-blind placebo controlled trial. Atherosclerosis？2007, 193, 277–282.
[167]
Gresele, P.; Pignatelli, P.; Guglielmini, G.; Carnevale, R.; Mezzasoma, A.M.; Ghiselli, A.; Momi, S.; Violi, F. Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. J. Nutr.？2008, 138, 1602–1608. 18716157
Peppa, M.; Raptis, S. Advanced glycation end products and cardiovascular disease. Curr. Diabetes Rev.？2008, 4, 92–100.
[171]
Schramm, D.; German, J. Potential effects of flavonoids on the etiology of vascular disease. J. Nutr. Biochem.？1998, 9, 560–566.
[172]
Huang, S.-M.; Wu, C.-H.; Yen, G.-C. Effects of flavonoids on the expression of the pro-inflammatory response in human monocytes induced by ligation of the receptor for AGEs. Mol. Nutr. Food Res.？2006, 50, 1129–1139.
[173]
Kim, J.; Lee, E.; Kim, D.; Yu, B.; Chung, H. Kaempferol modulates pro-inflammatory NF-kB activation by suppressing advanced glycation endproducts-induced NADPH oxidase. Age (Dordr.)？2010, 32, 197–208, doi:10.1007/s11357-009-9124-1. 20431987
[174]
Hy, L.X.; Keller, D.M. Prevalence of AD among whites: A summary by levels of severity. Neurology？2000, 55, 198–204.
[175]
Nussbaum, R.L.; Ellis, C.E. Alzheimer’s disease and Parkinson’s disease. N. Engl. J. Med.？2003, 348, 1356–1364.
[176]
de Lau, L.M.; Breteler, M.M. Epidemiology of Parkinson’s disease. Lancet Neurol.？2006, 5, 525–535.
Barzilai, A.; Melamed, E. Molecular mechanisms of selective dopaminergic neuronal death in Parkinson’s disease. Trends Mol. Med.？2003, 9, 126–132.
[179]
Jellinger, K.A. Cell death mechanisms in neurodegeneration. J. Cell. Mol. Med.？2001, 5, 1–17.
[180]
Spires, T.L.; Hannan, A.J. Nature, nurture and neurology: Gene-environment interactions in neurodegenerative disease. FEBS Anniversary Prize Lecture delivered on 27 June 2004 at the 29th FEBS Congress in Warsaw. FEBS J.？2005, 272, 2347–2361, doi:10.1111/j.1742-4658.2005.04677.x. 15885086
[181]
Lindsay, J.; Laurin, D.; Verreault, R.; Hebert, R.; Helliwell, B.; Hill, G.B.; McDowell, I. Risk factors for Alzheimer’s disease: A prospective analysis from the Canadian Study of Health and Aging. Am. J. Epidemiol.？2002, 156, 445–453.
[182]
Orgogozo, J.M.; Dartigues, J.F.; Lafont, S.; Letenneur, L.; Commenges, D.; Salamon, R.; Renaud, S.; Breteler, M.B. Wine consumption and dementia in the elderly: A prospective community study in the Bordeaux area. Rev. Neurol. (Paris)？1997, 153, 185–192. 9296132
[183]
Truelsen, T.; Thudium, D.; Gronbaek, M. Amount and type of alcohol and risk of dementia: The Copenhagen City Heart Study. Neurology？2002, 59, 1313–1319.
[184]
Commenges, D.; Scotet, V.; Renaud, S.; Jacqmin-Gadda, H.; Barberger-Gateau, P.; Dartigues, J.F. Intake of flavonoids and risk of dementia. Eur. J. Epidemiol.？2000, 16, 357–363, doi:10.1023/A:1007614613771. 10959944
[185]
Letenneur, L.; Proust-Lima, C.; Le, G.A.; Dartigues, J.F.; Barberger-Gateau, P. Flavonoid intake and cognitive decline over a 10-year period. Am. J. Epidemiol.？2007, 165, 1364–1371.
[186]
Morris, M.C.; Evans, D.A.; Tangney, C.C.; Bienias, J.L.; Wilson, R.S. Associations of vegetable and fruit consumption with age-related cognitive change. Neurology？2006, 67, 1370–1376.
[187]
Dai, Q.; Borenstein, A.R.; Wu, Y.; Jackson, J.C.; Larson, E.B. Fruit and vegetable juices and Alzheimer’s disease: The Kame Project. Am. J. Med.？2006, 119, 751–759.
[188]
Crozier, A.; Jaganath, I.B.; Clifford, M.N. Dietary phenolics: Chemistry, bioavailability and effects on health. Nat. Prod. Rep.？2009, 26, 1001–1043.
[189]
Manach, C.; Scalbert, A.; Morand, C.; Remesy, C.; Jimenez, L. Polyphenols: Food sources and bioavailability. Am. J. Clin. Nutr.？2004, 79, 727–747.
[190]
Manach, C.; Williamson, G.; Morand, C.; Scalbert, A.; Remesy, C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr.？2005, 81, 230–242. 15640486
[191]
Williamson, G.; Manach, C. Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies. Am. J. Clin. Nutr.？2005, 81, 243–255. 15640487
[192]
Youdim, K.A.; Qaiser, M.Z.; Begley, D.J.; Rice-Evans, C.A.; Abbott, N.J. Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic. Biol. Med.？2004, 36, 592–604, doi:10.1016/j.freeradbiomed.2003.11.023. 14980703
[193]
Passamonti, S.; Vrhovsek, U.; Vanzo, A.; Mattivi, F. Fast access of some grape pigments to the brain. J. Agric. Food Chem.？2005, 53, 7029–7034.
[194]
Kalt, W.; Blumberg, J.B.; McDonald, J.E.; Vinqvist-Tymchuk, M.R.; Fillmore, S.A.; Graf, B.A.; O’Leary, J.M.; Milbury, P.E. Identification of anthocyanins in the liver, eye, and brain of blueberry-fed pigs. J. Agric. Food Chem.？2008, 56, 705–712. 18211026
[195]
Milbury, P.E.; Kalt, W. Xenobiotic metabolism and berry flavonoid transport across the blood-brain barrier. J. Agric. Food Chem.？2010, 58, 3950–3956.
[196]
Youdim, K.A.; Joseph, J.A. A possible emerging role of phytochemicals in improving age-related neurological dysfunctions: A multiplicity of effects. Free Radic. Biol. Med.？2001, 30, 583–594.
[197]
Inanami, O.; Watanabe, Y.; Syuto, B.; Nakano, M.; Tsuji, M.; Kuwabara, M. Oral administration of (-)catechin protects against ischemia-reperfusion-induced neuronal death in the gerbil. Free Radic. Res.？1998, 29, 359–365.
[198]
Luo, Y.; Smith, J.V.; Paramasivam, V.; Burdick, A.; Curry, K.J.; Buford, J.P.; Khan, I.; Netzer, W.J.; Xu, H.; Butko, P. Inhibition of amyloid-beta aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761. Proc. Natl. Acad. Sci. USA？2002, 99, 12197–12202.
[199]
Bastianetto, S.; Zheng, W.H.; Quirion, R. The Ginkgo biloba extract (EGb 761) protects and rescues hippocampal cells against nitric oxide-induced toxicity: Involvement of its flavonoid constituents and protein kinase C. J. Neurochem.？2000, 74, 2268–2277. 10820186
[200]
Tchantchou, F.; Xu, Y.; Wu, Y.; Christen, Y.; Luo, Y. EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer’s disease. FASEB J.？2007, 21, 2400–2408.
[201]
Hsieh, H.-M.; Wua, W.-M.; Hu, M.-L. Soy isoflavones attenuate oxidative stress and improve parameters related to aging and Alzheimer’s disease in C57BL/6J mice treated with D-galactose. Food Chem. Toxicol.？2009, 47, 625–632.
[202]
Shan, Q.; Lu, J.; Zheng, Y.; Li, J.; Zhou, Z.; Hu, B.; Zhang, Z.; Fan, S.; Mao, Z.; Wang, Y.-J.; Ma, D. Purple Sweet Potato Color Ameliorates Cognition Deficits and Attenuates Oxidative Damage and Inflammation in AgingMouse Brain Induced by D-Galactose. J. Biomed. Biotechnol.？2009, 2009, 564737.
[203]
Munch, G.; Thome, J.; Foley, P.; Schinzel, R.; Riederer, P. Advanced glycation endproducts in ageing and Alzheimer’s disease. Brain Res. Brain Res. Rev.？1997, 23, 134–143.
[204]
Ramasamy, R.; Vannucci, S.; Yan, S.; Herold, K.; Yan, S.; Schmidt, A. Advanced glycation end products and RAGE: A common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology？2005, 15, 16–28, doi:10.1093/glycob/cwi053. 15764591
[205]
Datla, K.P.; Christidou, M.; Widmer, W.W.; Rooprai, H.K.; Dexter, D.T. Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinson’s disease. Neuroreport？2001, 12, 3871–3875.
[206]
Vauzour, D.; Corona, G.; Spencer, J.P. Caffeic acid, tyrosol and p-coumaric acid are potent inhibitors of 5-S-cysteinyl-dopamine induced neurotoxicity. Arch. Biochem. Biophys.？2010, 501, 106–111, doi:10.1016/j.abb.2010.03.016. 20361927
Spencer, J.P. Food for thought: The role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performance. Proc. Nutr. Soc.？2008, 67, 238–252.
[209]
Spencer, J.P. Flavonoids: Modulators of brain function? Br. J. Nutr.？2008, 99 (E-Suppl. 1), ES60–ES77. 18503736
[210]
Rendeiro, C.; Spencer, J.P.; Vauzour, D.; Butler, L.T.; Ellis, J.A.; Williams, C.M. The impact of flavonoids on spatial memory in rodents: From behaviour to underlying hippocampal mechanisms. Genes Nutr.？2009, 4, 251–270.
[211]
Vauzour, D.; Vafeiadou, K.; Rodriguez-Mateos, A.; Rendeiro, C.; Spencer, J.P. The neuroprotective potential of flavonoids: A multiplicity of effects. Genes Nutr.？2008, 3, 115–126.
[212]
Krikorian, R.; Nash, T.A.; Shidler, M.D.; Shukitt-Hale, B.; Joseph, J.A. Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment. Br. J. Nutr.？2010, 103, 730–734.
[213]
Macready, A.L.; Kennedy, O.B.; Ellis, J.A.; Williams, C.M.; Spencer, J.P.; Butler, L.T. Flavonoids and cognitive function: A review of human randomized controlled trial studies and recommendations for future studies. Genes Nutr.？2009, 4, 227–242.
[214]
How, P.S.; Cox, R.; Ellis, J.A.; Spencer, J.P.E. The impact of plant-derived flavonoids on mood, memory and motor skills in UK adults. Proc. Nutr. Soc.？2007, 66, 87A.
[215]
Krikorian, R.; Shidler, M.D.; Nash, T.A.; Kalt, W.; Vinqvist-Tymchuk, M.R.; Shukitt-Hale, B.; Joseph, J.A. Blueberry supplementation improves memory in older adults. J. Agric. Food Chem.？2010, 58, 3996–4000.
[216]
Joseph, J.A.; Shukitt-Hale, B.; Denisova, N.A.; Prior, R.L.; Cao, G.; Martin, A.; Taglialatela, G.; Bickford, P.C. Long-term dietary strawberry, spinach, or vitamin E supplementation retards the onset of age-related neuronal signal-transduction and cognitive behavioral deficits. J. Neurosci.？1998, 18, 8047–8055. 9742171
[217]
Joseph, J.A.; Shukitt-Hale, B.; Denisova, N.A.; Bielinski, D.; Martin, A.; McEwen, J.J.; Bickford, P.C. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J. Neurosci.？1999, 19, 8114–8121. 10479711
[218]
Casadesus, G.; Shukitt-Hale, B.; Stellwagen, H.M.; Zhu, X.; Lee, H.G.; Smith, M.A.; Joseph, J.A. Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats. Nutr. Neurosci.？2004, 7, 309–316.
[219]
Williams, C.M.; El Mohsen, M.A.; Vauzour, D.; Rendeiro, C.; Butler, L.T.; Ellis, J.A.; Whiteman, M.; Spencer, J.P. Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radic. Biol. Med.？2008, 45, 295–305.
[220]
Ramirez, M.R.; Izquierdo, I.; do Carmo Bassols Raseira, M.; Zuanazzi, J.A.; Barros, D.; Henriques, A.T. Effect of lyophilised Vaccinium berries on memory, anxiety and locomotion in adult rats. Pharmacol. Res.？2005, 52, 457–462.
[221]
Barros, D.; Amaral, O.B.; Izquierdo, I.; Geracitano, L.; do Carmo Bassols Raseira, M.; Henriques, A.T.; Ramirez, M.R. Behavioral and genoprotective effects of Vaccinium berries intake in mice. Pharmacol. Biochem. Behav.？2006, 84, 229–234.
[222]
Goyarzu, P.; Malin, D.H.; Lau, F.C.; Taglialatela, G.; Moon, W.D.; Jennings, R.; Moy, E.; Moy, D.; Lippold, S.; Shukitt-Hale, B.; Joseph, J.A. Blueberry supplemented diet: Effects on object recognition memory and nuclear factor-kappa B levels in aged rats. Nutr. Neurosci.？2004, 7, 75–83.
[223]
Shukitt-Hale, B.; Carey, A.; Simon, L.; Mark, D.A.; Joseph, J.A. Effects of Concord grape juice on cognitive and motor deficits in aging. Nutrition？2006, 22, 295–302.
[224]
Chan, Y.C.; Hosoda, K.; Tsai, C.J.; Yamamoto, S.; Wang, M.F. Favorable effects of tea on reducing the cognitive deficits and brain morphological changes in senescence-accelerated mice. J. Nutr. Sci. Vitaminol.？2006, 52, 266–273.
[225]
Hartman, R.E.; Shah, A.; Fagan, A.M.; Schwetye, K.E.; Parsadanian, M.; Schulman, R.N.; Finn, M.B.; Holtzman, D.M. Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer’s disease. Neurobiol. Dis.？2006, 24, 506–515.
[226]
Bhat, N.R.; Zhang, P.; Lee, J.C.; Hogan, E.L. Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J. Neurosci.？1998, 18, 1633–1641.
[227]
Clostre, F. Gingko Biloba extract (EGb 761). State of knowledge in the dawn of the year 2000. Ann. Pharm. Fr.？1999, 57, 1S8–1S88. 10481350
[228]
Cohen-Salmon, C.; Venault, P.; Martin, B.; Raffalli-Sebille, M.J.; Barkats, M.; Clostre, F.; Pardon, M.C.; Christen, Y.; Chapouthier, G. Effects of Ginkgo biloba extract (EGb 761) on learning and possible actions on aging. J. Physiol. Paris？1997, 91, 291–300, doi:10.1016/S0928-4257(97)82409-6. 9457661
Itil, T.M.; Eralp, E.; Ahmed, I.; Kunitz, A.; Itil, K.Z. The pharmacological effects of Gingko Biloba, a plant extract, on the brain of dementia patients in comparinson with tacrine. Psychopharmacology？1998, 34, 391–396.
[231]
Shif, O.; Gillette, K.; Damkaoutis, C.M.; Carrano, C.; Robbins, S.J.; Hoffman, J.R. Effects of Ginkgo biloba administered after spatial learning on water maze and radial arm maze performance in young adult rats. Pharmacol. Biochem. Behav.？2006, 84, 17–25, doi:10.1016/j.pbb.2006.04.003. 16740301
[232]
Spencer, J.P. The interactions of flavonoids within neuronal signalling pathways. Genes Nutr.？2007, 2, 257–273.
[233]
Vauzour, D.; Vafeiadou, K.; Rice-Evans, C.; Williams, R.J.; Spencer, J.P. Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons. J. Neurochem.？2007, 103, 1355–1367.
[234]
Williams, R.J.; Spencer, J.P.; Rice-Evans, C. Flavonoids: Antioxidants or signalling molecules? Free Radic. Biol. Med.？2004, 36, 838–849, doi:10.1016/j.freeradbiomed.2004.01.001. 15019969
[235]
Winter, J.C. The effects of an extract of Ginkgo biloba, EGb 761, on cognitive behavior and longevity in the rat. Physiol. Behav.？1998, 63, 425–433, doi:10.1016/S0031-9384(97)00464-2. 9469738
[236]
Pu, F.; Mishima, K.; Irie, K.; Motohashi, K.; Tanaka, Y.; Orito, K.; Egawa, T.; Kitamura, Y.; Egashira, N.; Iwasaki, K.; Fujiwara, M. Neuroprotective effects of quercetin and rutin on spatial memory impairment in an 8-arm radial maze task and neuronal death induced by repeated cerebral ischemia in rats. J. Pharmacol. Sci.？2007, 104, 329–334.
[237]
Maher, P.; Akaishi, T.; Abe, K. Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc. Natl. Acad. Sci. USA？2006, 103, 16568–16573.
[238]
Stoll, S.; Scheuer, K.; Pohl, O.; Muller, W.E. Ginkgo biloba extract (EGb 761) independently improves changes in passive avoidance learning and brain membrane fluidity in the aging mouse. Pharmacopsychiatry？1996, 29, 144–149. 8858713
[239]
Topic, B.; Hasenohrl, R.U.; Hacker, R.; Huston, J.P. Enhanced conditioned inhibitory avoidance by a combined extract of Zingiber officinale and Ginkgo biloba. Phytother. Res.？2002, 16, 312–315, doi:10.1002/ptr.870. 12112284
[240]
Vafeiadou, K.; Vauzour, D.; Lee, H.Y.; Rodriguez-Mateos, A.; Williams, R.J.; Spencer, J.P. The citrus flavanone naringenin inhibits inflammatory signalling in glial cells and protects against neuroinflammatory injury. Arch. Biochem. Biophys.？2009, 484, 100–109.
[241]
Wang, X.; Chen, S.; Ma, G.; Ye, M.; Lu, G. Genistein protects dopaminergic neurons by inhibiting microglial activation. Neuroreport？2005, 16, 267–270.
[242]
Bhat, N.R.; Feinstein, D.L.; Shen, Q.; Bhat, A.N. p38 MAPK-mediated transcriptional activation of inducible nitric-oxide synthase in glial cells. Roles of nuclear factors, nuclear factor kappa B, cAMP response element-binding protein, CCAAT/enhancer-binding protein-beta, and activating transcription factor-2. J. Biol. Chem.？2002, 277, 29584–29592. 12048217
[243]
Lee, S.-J.; Lee, K.-W. Protective Effect of (？)-Epigallocatechin Gallate against Advanced Glycation Endproducts-Induced Injury in Neuronal Cells. Biol. Pharm. Bull.？2007, 30, 1369–1373.
[244]
Vlahos, C.J.; Matter, W.F.; Hui, K.Y.; Brown, R.F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem.？1994, 269, 5241–5248.
[245]
Spencer, J.P.; Rice-Evans, C.; Williams, R.J. Modulation of pro-survival Akt/protein kinase B and ERK1/2 signaling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability. J. Biol. Chem.？2003, 278, 34783–34793. 12826665
