Differential Modulation of Apoptotic Processes by Proanthocyanidins as a Dietary Strategy for Delaying Chronic Pathologies

REFERENCES

• Agarwal , C. , Sharma , Y. , Zhao , J. and Agarwal , R. 2000 . A polyphenolic fraction from grape seeds causes irreversible growth inhibition of breast carcinoma MDA-MB468 cells by inhibiting mitogen-activated protein kinases activation and inducing G1 arrest and differentiation . Clin. Cancer Res , 6 : 2921 – 2930 .
   PubMed Web of Science ®Google Scholar
• Agarwal , C. , Singh , R. P. and Agarwal , R. 2002 . Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome C release . Carcinogenesis. , 23 : 1869 – 1876 .
   PubMed Web of Science ®Google Scholar
• Anuradha , C. D. , Kanno , S. and Hirano , S. 2001 . Oxidative damage to mitochondria is a preliminary step to caspase-3 activation in fluoride-induced apoptosis in HL-60 cells . Free Radic. Biol. Med. , 31 : 367 – 373 .
   PubMed Web of Science ®Google Scholar
• Aparicio-Fernández , X. , García-Gasca , T. , Yousef , G. G. , Lila , M. A. , González de Mejia , E. and Loarca-Pina , G. 2006 . Chemopreventive activity of polyphenolics from black Jamapa bean (Phaseolus vulgaris L.) on HeLa and HaCaT cells . J. Agric. Food Chem , 54 : 2116 – 2122 .
   PubMed Web of Science ®Google Scholar
• Aparicio-Fernández , X. , Reynoso-Camacho , R. , Castaño-Tostado , E. , García-Gasca , T. , González de Mejía , E. , Guzmán-Maldonado , S. H. , Elizondo , G. , Yousef , G. G. , Lila , M. A. and Loarca-Pina , G. 2008 . Antiradical capacity and induction of apoptosis on HeLa cells by a Phaseolus vulgaris extract . Plant Foods Hum. Nutr. , 63 : 35 – 40 .
   PubMed Web of Science ®Google Scholar
• Arbel-Goren , R. , Levy , Y. , Ronen , D. and Zick , Y. 2005 . Cyclin-dependent kinase inhibitors and JNK act as molecular switches, regulating the choice between growth arrest and apoptosis induced by galectin-8 . J. Biol. Chem. , 280 : 19105 – 14 .
   PubMed Web of Science ®Google Scholar
• Aron , P. and Kennedy , J. 2008 . Flavan-3-ols: Nature, occurrence and biological activity . Mol. Nutr. Food Res. , 52 : 79 – 104 .
   PubMed Web of Science ®Google Scholar
• Aruoma , O. I. , Bahorun , T. and Jen , L. S. 2003 . Neuroprotection by bioactive components in medicinal and food plant extracts . Mutat. Res. Rev. , 544 : 203 – 215 .
   PubMed Web of Science ®Google Scholar
• Aruoma , O. I. , Sun , B. , Fujii , H. , Neergheen , V. S. , Bahorun , T. , Kang , K. S. and Sung , M. K. 2006 . Low molecular proanthocyanidin dietary biofactor Oligonol: Its modulation of oxidative stress, bioefficacy, neuroprotection, food application and chemoprevention potentials . Biofactors. , 27 : 245 – 265 .
   PubMed Web of Science ®Google Scholar
• Baba , S. , Osakabe , N. and Natsume , M. 2002 . Absorption and urinary excretion of procyanidin B22 [epicatechin- (4beta-8)-epicatechin] in rats . Free Radic. Biol. Med. , 33 : 142 – 148 .
   PubMed Web of Science ®Google Scholar
• Bagchi , M. , Kuszynski , C. A. , Balmoori , J. , Joshi , S. S. , Stohs , S. J. and Bagchi , D. 2001 . Protective effects of antioxidants against smokeless tobacco – induced oxidative stress and modulation of Bcl-2 and p53 genes in human oral keratinocytes . Free Radic. Res. , 35 : 181 – 194 .
   PubMed Web of Science ®Google Scholar
• Bai , J. and Cederbaum , A. I. 2006 . Cycloheximide protects HepG2 cells from serum withdrawal-induced apoptosis by decreasing p53 and phosphorylated p53 levels . J. Pharmacol. Exp. Ther. , 319 : 1435 – 1443 .
   PubMed Web of Science ®Google Scholar
• Baines , C. P. and Molkentin , J. D. 2005 . Stress signaling pathways that modulate cardiac myocyte apoptosis . J. Mol. Cell Cardiol. , 38 : 47 – 62 .
   PubMed Web of Science ®Google Scholar
• Besson , A. , Dowdy , S. F. and Roberts , J. M. 2008 . CDK inhbitors: Cell cycle regulators and beyond . Dev. Cell. , 14 : 159 – 169 .
   PubMed Web of Science ®Google Scholar
• Bladé , C. , Arola , L. and Salvadó , M. J. 2010 . Hypolipidemic effects of proanthocyanidins and their underlying biochemical and molecular mechanisms . Mol. Nutr. Food Res. , 54 : 37 – 59 .
   PubMed Web of Science ®Google Scholar
• Bloom , J. and Cross , F. R. 2007 . Multiple levels of cyclin specificity in cell-cycle control . Nat. Rev. Mol. Cell Biol. , 8 : 149 – 160 .
   PubMed Web of Science ®Google Scholar
• Bouaziz , A. , Romera-Castillo , C. , Linares-Palomino , P. J. , Altarejos , J. , Bartegi , A. , Rosado , J. A. and Salido , G. M. 2007 . Cinnamtannin B-1 from bay wood exhibits antiapoptotic effects in human platelets . Apoptosis. , 12 : 489 – 498 .
   PubMed Web of Science ®Google Scholar
• Buonocore , G. , Perrone , S. and Bracci , R. 2001 . Free radicals and brain damage in the newborn . Biol. Neonate. , 79 : 180 – 186 .
   PubMedGoogle Scholar
• Chen , C. , Yi , L. , Jin , X. , Mi , M. T. , Zhang , T. , Ling , W. H. and Yu , B. 2010 . Delphinidin attenuates stress injury induced by oxidized low-density lipoprotein in human umbilical vein endothelial cells . Chem. Biol. Interact. , 183 : 105 – 112 .
   PubMed Web of Science ®Google Scholar
• Cho , E. S. , Lee , K. W. and Lee , H. J. 2008 . Cocoa procyanidins protect PC12 cells from hydrogen-peroxide-induced apoptosis by inhibiting activation of p38 MAPK and JNK . Mutat. Res. , 640 : 123 – 130 .
   PubMed Web of Science ®Google Scholar
• Chou , S. , Kaur , M. , Thompson , J. , Agarwal , R. and Agarwal , C. 2010 . Influence of gallate esterification on the activity of procyanidin B2 in androgen-dependent human prostate carcinoma LNCaP cells . Pharmaceut. Res. , 27 : 619 – 627 .
   PubMed Web of Science ®Google Scholar
• Crozier , A. , Jaganath , I. B. and Clifford , M. N. 2009 . Dietary phenolics: Chemistry, bioavailability and effects on health . Nat. Prod. Rep. , 26 : 1001 – 1043 .
   PubMed Web of Science ®Google Scholar
• De Bruyne , T. , Pieters , L. , Deelstra , H. and Vlietinck , A. 1999 . Condensed vegetable tannins: Biodiversity in structure and biological activities . Biochem. Syst. Ecol. , 27 : 445 – 459 .
   Web of Science ®Google Scholar
• de la Iglesia , R. , Milagro , F. I. , Campión , J. , Boqué , N. and Martínez , J. A. 2010 . Healthy properties of proanthocyanidins . Biofactors. , 36 : 159 – 168 .
   PubMed Web of Science ®Google Scholar
• Déziel , B. A. , Kunal , P. and Neto , C. 2010 . Proanthocyanidins from the American cranberry (Vaccinium macrocarpon) inhibit matrix metalloproteinase-2 and matrix metalloproteinase-9 activity in human prostate cancer cells via alterations in multiple cellular signalling pathways . J. Cell. Biochem. , 111 : 742 – 754 .
   PubMed Web of Science ®Google Scholar
• Du , Y. , Guo , H. and Lou , H. 2007 . Grape seed polyphenols protect cardiac cells from apoptosis via induction of endogenous antioxidant enzymes . J. Agric. Food Chem. , 55 : 1695 – 1701 .
   PubMed Web of Science ®Google Scholar
• Du , Y. and Lou , H. 2008 . Catechin and proanthocyanidin B4 from grape seeds prevent doxorubicin-induced toxicity in cardiomyocytes . Eur. J. Pharmacol. , 591 : 96 – 101 .
   PubMed Web of Science ®Google Scholar
• Duan , Y. , Zhang , H. , Xu , F. , Xieb , B. , Yangc , X. , Wanga , Y. and Yana , Y. 2010 . Inhibition effect of procyanidins from lotus seedpod on mouse B16 melanoma in vivo and in vitro . Food Chem , 122 : 84 – 91 .
   Web of Science ®Google Scholar
• Engelbrecht , A. M. , Mattheyse , M. , Ellis , B. , Loos , B. , Thomas , M. , Smith , R. , Peters , S. , Smith , C. and Myburgh , K. 2007 . Proanthocyanidin from grape seeds inactivates the PI3-kinase/PKB pathway and induces apoptosis in a colon cancer cell line . Cancer Letters. , 258 : 144 – 153 .
   PubMed Web of Science ®Google Scholar
• Fang , J. , Nakamura , H. and Iyer , A. K. 2007 . Tumor-targeted induction of oxystress for cancer therapy . J. Drug Target. , 15 : 475 – 486 .
   PubMed Web of Science ®Google Scholar
• Feng , Y. , Liu , Y. M. and Michael , M. 2007 . Grape seed extract given three hours after injury suppresses lipid peroxidation and reduces hypoxic-ischemic brain injury in neonatal rats . Pediatr. Res. , 61 : 295 – 300 .
   PubMed Web of Science ®Google Scholar
• Ferreira , D. , Guyot , S. , Marnet , N. , Delgadillo , I. , Renard , C. M. and Coimbra , M. A. 2002 . Composition of phenolic compounds in a Portuguese pear (Pyrus communis l. var. S. Bartolomeu) and changes after sun-drying . J. Agric. Food Chem. , 50 : 4537 – 4544 .
   PubMed Web of Science ®Google Scholar
• Finkel , E. 2001 . The mitochondrion: Is it central to apoptosis? . Science , 29 : 624 – 626 .
   Google Scholar
• Gao , N. , Budhraja , A. , Cheng , S. , Yao , H. , Zhang , Z. and Shi , X. 2009 . Induction of apoptosis in human leukemia cells by grape seed extract occurs via activation of c-Jun NH2-terminal kinase . Clin. Cancer Res. , 15 : 140 – 149 .
   PubMed Web of Science ®Google Scholar
• Ghosh , D. and Scheepens , A. 2009 . Vascular action of polyphenols . Mol. Nutr. Food Res. , 53 : 322 – 331 .
   PubMed Web of Science ®Google Scholar
• Gossé , F. , Roussi , S. , Guyot , S. , Schoenfelder , A. , Mann , A. , Bergerat , J. P. , Seiler , N. and Raul , F. 2006 . Potentiation of apple procyanidin-triggered apoptosis by the polyamine oxidase inactivator MDL 72527 in human colon cancer-derived metastatic cells . Int. J. Oncolo. , 29 : 423 – 428 .
   PubMed Web of Science ®Google Scholar
• Gossé , F. , Roussi , S. , Lobstein , A. , Fischer , B. , Seiler , N. and Raul , F. 2005 . Chemopreventive properties of apple procyanidins on human colon cancer-derived metastatic SW620 cells and in a rat model of colon carcinogenesis . Carcinogenesis , 26 : 1291 – 1295 .
   PubMed Web of Science ®Google Scholar
• Gulgun , M. , Erdem , O. , Oztas , E. , Kesik , V. , Balamtekin , N. , Vurucu , S. , Kul , M. , Kismet , E. and Koseoglu , V. 2009 . Proanthocyanidin prevents methotrexate-induced intestinal damage and oxidative stress . Exp. Toxicol. Pathol. , 62 ( 2 ) : 109 – 115 .
   PubMed Web of Science ®Google Scholar
• Guyot , S. , Marnet , N. , Laraba , D. , Sanoner , P. and Drilleau , J.-F. 1998 . Reversed-phase HPLC following thiolysis for quantitative estimation and characterization of the four main classes of phenolic compounds in different tissue zones of a French cider apple variety (Malus domestica var. Kermerrien) . J. Agric. Food Chem. , 46 : 1698 – 1705 .
   Web of Science ®Google Scholar
• Haddad , J. J. 2004 . Mitogen-activated protein kinases and the evolution of Alzheimer's: A revolutionary neurogenetic axis for therapeutic intervention . Prog. Neurobiol. , 73 : 359 – 377 .
   PubMed Web of Science ®Google Scholar
• Hong , H. and Yi-Min , Q. 2006 . Grape seed proanthocyanidin extract induced mitochondria-associated apoptosis in human acute myeloid leukaemia 14.3D10 cells . Chinese Med. J. , 119 : 417 – 421 .
   PubMed Web of Science ®Google Scholar
• Horenstein , M. S. , Vander Heide , R. S. and L’Ecuyer , T. J. 2000 . Molecular basis of anthracycline-induced cardiotoxicity and its prevention . Mol. Genet. Metab. , 71 : 436 – 444 .
   PubMed Web of Science ®Google Scholar
• Hudson , T. S. , Hartle , D. K. , Hursting , S. D , Nunez , N. P. , Wang , T. T. , Young , H. A. , Arany , P. and Green , J. E. 2007 . Inhibition of prostate cancer growth by muscadine grape skin extract and resveratrol through distinct mechanisms . Cancer Res. , 67 : 8396 – 8405 .
   PubMed Web of Science ®Google Scholar
• Ito , Y. , Kosuge , Y. , Sakikubo , T. , Horie , K. , Ishikawa , N. , Obokata , N. , Yokoyama , E. , Yamashina , K. , Yamamoto , M. , Saito , H. , Arakawa , M. and Ishige , K. 2003 . Protective effect of S-allyl-cysteine, a garlic compound, on amyloid [beta]-protein-induced cell death in nerve growth factor-differentiated PC12 cells . Neurosci. Res. , 46 : 119 – 125 .
   PubMed Web of Science ®Google Scholar
• Johnson , G. L. and Lapadat , R. 2002 . Mitogen-activated protein kinase pathways mediated by ERK, JNK, p38 protein kinases . Science , 298 : 1911 – 1912 .
   PubMed Web of Science ®Google Scholar
• Joseph , J. A. , Shukitt-Hale , B. , Denisova , N. A. , Bielinski , D. , Martin , A. , McEwen , J. J. and Bickford , P. C. 1999 . Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioural deficits with blueberry, spinach or strawberry dietary supplementation . J. Neurosci. , 19 : 8114 – 8121 .
   PubMed Web of Science ®Google Scholar
• Joshi , S. S. , Kuszynski , C. A. and Bagchi , D. 2001 . The cellular and molecular basis of health benefits of grape seed proanthocyanidin extract . Curr. Pharm. Biotechnol. , 2 : 187 – 200 .
   PubMedGoogle Scholar
• Kaur , M. , Mandair , R. , Agarwal , R. and Agarwal , C. 2008 . Grape seed extract induces cell cycle arrest and apoptosis in human colon carcinoma cells . Nutr. Cancer. , 60 ( Suppl 1 ) : 2 – 11 .
   PubMedGoogle Scholar
• Kaur , M. , Singh , R. P. , Gu , M. , Agarwal , R. and Agarwal , C. 2006 . Grape seed extract inhibits in vitro and in vivo growth of human colorectal carcinoma cells . Clin. Cancer Res. , 12 : 6194 – 6202 .
   PubMed Web of Science ®Google Scholar
• Kenny , T. P. , Keen , C. L. , Schmitz , H. H. and Gershwin , M. E. 2007 . Immune effects of cocoa procyanidin oligomers on peripheral blood mononuclear cells . Exp. Biol. Med. , 232 : 293 – 300 .
   PubMed Web of Science ®Google Scholar
• Khan , N. , Afaq , F. and Mukhtar , H. 2007 . Apoptosis by dietary factors: The suicide solution for delaying cancer growth . Carcinogenesis , 2 : 233 – 239 .
   Google Scholar
• Kim , H. , Hall , P. , Smith , M. , Kirk , M. , Prasain , J. K. , Barnes , S. and Grubbs , C. 2004 . Chemoprevention by grape seed extract and genistein in carcinogen-induced mammary cancer in rats is diet dependent . J. Nutr. , 134 : S3445 – 34452 .
   PubMed Web of Science ®Google Scholar
• Kluck , R. M. , Bossy-Wetzel , E. , Green , D. R. and Newmeyer , D. D. 1997 . The release of cytochrome C from mitochondria: A primary site for Bcl-2 regulation of apoptosis . Science. , 275 : 1132 – 1136 .
   PubMed Web of Science ®Google Scholar
• Kozikowski , A. P. , Tückmantel , Böttcher , W. , Romanczyk , G. and Jr , L. J. 2003 . Studies in polyphenol chemistry and bioactivity. 4. Synthesis of trimeric, tetrameric, pentameric, and higher oligomeric epicatechin-derived procyanidins having all-4ß, 8-interflavan connectivity and their inhibition of cancer cell growth through cell cycle arrest . J. Org. Chem. , 68 : 1641 – 1658 .
   PubMed Web of Science ®Google Scholar
• Li , C. , Wang , Y. , Yu , Y. , Zhang , M. , Sugano , S. , Wang , Z. and Chang , Z. 2008 . Both ERK and JNK pathways are required for PMA-induced MD-2 gene expression during HL-60 cells differentiation . Biol. Cell. , 100 : 365 – 375 .
   PubMed Web of Science ®Google Scholar
• Li , M. H. , Jang , J. H. , Sun , B. and Surh , Y. J. 2004a . Protective effects of oligomers of grape seed polyphenols against beta-amyloid-induced oxidative cell death . Ann. NY Acad. Sci. , 1030 : 317 – 329 .
   PubMed Web of Science ®Google Scholar
• Li , P. , Nijhawan , D. and Wang , X. 2004b . Mitochondrial activation of apoptosis . Cell , 116 : S57 – S61 .
   PubMedGoogle Scholar
• Li , W. , Sanki , A. , Karim , R. Z. , Thompson , J. F. , Soon Lee , C. , Zhuang , L. , McCarthy , S. W. and Scolyer , R. A. 2006 . The role of cell cycle regulatory proteins in the pathogenesis of melanoma . Pathology , 38 : 287 – 301 .
   PubMed Web of Science ®Google Scholar
• Lizarraga , D. , Lozano , C. , Briedé , J. J. , van Delft , J. H. , Touriño , S. , Centelles , J. J. , Torres , J. L. and Cascante , M. 2007 . The importance of polymerization and galloylation for the antiproliferative properties of procyanidin-rich natural extracts . FEBS J , 274 : 4802 – 4811 .
   PubMed Web of Science ®Google Scholar
• Luo , J. , Manning , B. D. and Cantley , L. C. 2003 . Targeting the PI3-K–Akt pathway in human cancer: Rationale and promise . Cancer Cell. , 4 : 257 – 262 .
   PubMed Web of Science ®Google Scholar
• Ma , H. , Liu , B. , Feng , D. , Xie , H. , Li , R. , Yuchi , Y. , Wang , H. and Wang , J. 2010 . Pinus massoniana bark extract selectively induces apoptosis in human hepatoma cells, possibly through caspase-dependent pathways . Int. J. Mol. Med. , 25 : 751 – 759 .
   PubMed Web of Science ®Google Scholar
• Maldonado-Celis , M. E. , Bousserouel , S. , Gossé , F. , Lobstein , A. and Raul , F. 2009a . Apple procyanidins activate apoptotic signaling pathway in human colon adenocarcinoma cells by a lipid-raft independent mechanism . Biochem. Biophys. Res. Comm. , 388 : 372 – 376 .
   PubMed Web of Science ®Google Scholar
• Maldonado-Celis , M. E. , Bousserouel , S. , Gossé , F. , Minker , C. , Lobstein , A. and Raul , F. 2009b . Differential induction of apoptosis by apple procyanidins in TRAIL-sensitive human colon tumor cells and derived TRAIL-resistant metastatic cells . J. Cancer Mol. , 5 : 21 – 30 .
   Google Scholar
• Mandel , S. and Youdim , M. 2004 . Catechin polyphenols: Neurodegeneration and neuroprotection in neurodegenerative diseases . Free Rad. Biol. Med. , 37 : 304 – 317 .
   PubMed Web of Science ®Google Scholar
• Mantena , S. , Baliga , M. S. and Katiyar , S. K. 2006 . Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells . Carcinogenesis , 27 : 1682 – 1691 .
   PubMed Web of Science ®Google Scholar
• Martin , K. R. 2006 . Targeting apoptosis with dietary bioactive agents . Exp. Biol. Med. , 231 : 117 – 129 .
   PubMed Web of Science ®Google Scholar
• Mattson , M. P. and Kroemer , G. 2003 . Mitochondria in cell death: Novel targets for neuroprotection and cardioprotection . Trends Mol. Med. , 9 : 196 – 205 .
   PubMed Web of Science ®Google Scholar
• Meeran , S. M. and Katiyar , S. K. 2007 . Grape seed proanthocyanidins promote apoptosis in human epidermoid carcinoma A431 cells through alterations in Cdki-Cdk-cyclin cascade, and caspase-3 activation via loss of mitochondrial membrane potential . Exp. Dermatol. , 16 : 405 – 415 .
   PubMed Web of Science ®Google Scholar
• Miura , T. , Chiba , M. , Kasai , K. , Nozaka , H. , Nakamura , T. , Shoji , T. , Kanda , T. , Ohtake , Y. and Sato , T. 2008 . Apple procyanidins induce tumor cell apoptosis through mitochondrial pathway activation of caspase-3 . Carcinogenesis , 29 : 585 – 593 .
   PubMed Web of Science ®Google Scholar
• Morioka , T. , Suzui , M. , Nabandith , V. , Inamine , M. , Aniya , Y. , Nakayama , T. , Ichiba , T. and Yoshimi , N. 2005 . Modifying effects of Terminalia catappa on azoxymethane-induced colon carcinogenesis in male F344 rats . Eur. J. Cancer Prev. , 14 : 101 – 105 .
   PubMed Web of Science ®Google Scholar
• Morishima , N. K. , Takenouchi , H. , Shibata , T. , Shibata , T. and Yasuhiko , Y. 2002 . An endoplasmic reticulum stress-specific caspase cascade in apoptosis . J. Biol. Chem. , 277 : 34287 – 34294 .
   PubMed Web of Science ®Google Scholar
• Mota , K. , Dias , G. , Pinto , M. , Luiz-Ferreira , A. , Souza-Brito , A. R. , Hiruma-Lima , C. A. , Barbosa-Filho , J. M. and Batista , L. M. 2009 . Flavonoids with gastroprotective activity . Molecules. , 14 : 979 – 1012 .
   PubMed Web of Science ®Google Scholar
• Murakami , A. 2009 . Chemoprevention with phytochemicals targeting inducible nitric oxide synthase . Forum Nutr , 61 : 193 – 203 .
   PubMed Web of Science ®Google Scholar
• Nomoto , H. , Iigo , M. , Hamada , H. , Kojima , S. and Tsuda , H. 2004 . Chemoprevention of colorectal cancer by grape seed proanthocyanidin is accompanied by a decrease in proliferation and increase in apoptosis . Nutr. Cancer. , 49 ( 1 ) : 81 – 88 .
   PubMed Web of Science ®Google Scholar
• O’Brien , M. and Kirby , R. 2008 . Apoptosis: A review of pro-apoptotic and anti-apoptotic pathway and dysregulation and disease . J. Vet. Emerg. Crit. Care. , 1 : 572 – 585 .
   Google Scholar
• Ono , K. , Hasegawa , K. , Naike , H. and Yamada , M. 2004 . Curcumin has potent anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro . J. Neurosci. Res. , 75 : 742 – 750 .
   PubMed Web of Science ®Google Scholar
• Pataki , T. , Bak , I. , Kovacs , P. , Bagchi , D. , Das , D. K. and Tosaki , A. 2002 . Grape seed proanthocyanidins improved cardiac recovery during reperfusion after ischemia in isolated rat hearts . Am. J. Clin. Nutr. , 75 : 894 – 899 .
   PubMed Web of Science ®Google Scholar
• Perl , M. , Chung , C. S. and Ayala , A. 2005 . Apoptosis. Crit. Care Med , 33 ( 12, Suppl ) : S526 – S529 .
   Google Scholar
• Pierini , R. , Kroon , P. A. , Guyot , S. , Ivory , K. , Johnson , I. T. and Belshaw , N. J. 2008 . Procyanidin effects on oesophageal adenocarcinoma cells strongly depend on flavan-3-ol degree of polymerization . Mol. Nutr. Food Res. , 52 : 1399 – 1407 .
   PubMed Web of Science ®Google Scholar
• Pinent , M. , Bladé , C. , Salvadó , M. J. , Blay , M. , Pujadas , G. , Fernández-Larrea , J. , Arola , L. and Ardévol , A. 2006 . Procyanidin effects on adipocyte-related pathologies . Crit. Rev. Food Sci. Nutr. , 46 : 543 – 550 .
   PubMed Web of Science ®Google Scholar
• Prasain , J. K. , Peng , N. , Dai , Y. , Moore , R. , Arabshahi , A. , Wilson , L. , Barnes , S. , Michael Wyss , J. , Kim , H. and Watts , R. L. 2009 . Liquid chromatography tandem mass spectrometry identification of proanthocyanidins in rat plasma after oral administration of grape seed extract . Phytomedicine. , 16 : 233 – 243 .
   PubMed Web of Science ®Google Scholar
• Puiggròs , F. , Llópiz , N. , Ardévol , A. , Bladé , C. , Arola , L. and Salvadó , M. J. 2005 . Grape seed procyanidins prevent oxidative injury by modulating the expression of antioxidant enzyme systems . J. Agric. Food Chem. , 53 : 6080 – 6086 .
   PubMed Web of Science ®Google Scholar
• Rao , R. V. , Ellerby , H. M. and Bredesen , D. E. 2004 . Coupling endoplasmic reticulum stress to the cell death program . Cell Death Differ , 11 : 372 – 380 .
   PubMed Web of Science ®Google Scholar
• Ray , S. D. , Parikh , H. and Bagchi , D. 2005 . Proanthocyanidin exposure to B6C3F1 mice significantly attenuates dimethylnitrosamine-induced liver tumor induction and mortality by differentially modulating programmed and unprogrammed cell deaths . Mutat. Res. , 579 : 81 – 106 .
   PubMed Web of Science ®Google Scholar
• Rohdewald , P. 2002 . A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology . Int. J. Clin. Pharmacol. Ther. , 40 : 158 – 168 .
   PubMed Web of Science ®Google Scholar
• Roig , R. , Cascón , E. , Arola , L. , Bladé , C. and Salvadó , M. J. 2002 . Procyanidins protect Fao cells against hydrogen peroxide-induced oxidative stress . Biochim. Biophys. Acta. , 1572 : 25 – 30 .
   PubMed Web of Science ®Google Scholar
• Roy , A. M. , Baliga , M. S. , Elmets , C. A. and Katiyar , S. K. 2005 . Grape seed proanthocyanidins induce apoptosis through p53, Bax, and Caspase 3 pathways . Neoplasia , 7 : 24 – 36 .
   PubMed Web of Science ®Google Scholar
• Saporito , M. S. , Thomas , B. A. and Scott , R. W. 2000 . MPTP activates c-Jun NH2-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo . J. Neurochem. , 75 : 1200 – 1208 .
   PubMed Web of Science ®Google Scholar
• Sardao , V. A. , Oliveira , P. J. , Holy , J. , Oliveira , C. R. and Wallace , K. B. 2008 . Morphological alterations induced by doxorubicin on H9c2myoblasts: Nuclear, mitochondrial, and cytoskeletal targets . Cell Biol. Toxicol. , 25 : 227 – 243 .
   PubMed Web of Science ®Google Scholar
• Scalbert , A. , Johnson , I. T. and Saltmarsh , M. 2005 . Polyphenols: Antioxidants and beyond . Am. J. Clin. Nutr. , 81 : 215S – 217S .
   PubMed Web of Science ®Google Scholar
• Sen , C. K. and Packer , L. 1996 . Antioxidant and redox regulation of gene transcription . FASEB J , 10 : 709 – 720 .
   PubMed Web of Science ®Google Scholar
• Serrano , J. , Puupponen-Pimi , A. R. , Dauer , A. , Aura , A. M. and Saura-Calixto , F. 2009 . Tannins: Current knowledge of food sources, intake, bioavailability and biological effects . Mol. Nutr. Food Res. , 53 : S310 – S329 .
   PubMed Web of Science ®Google Scholar
• Shang , X. J. , Yao , G. , Sun , G. Y. , Sun , Y. , Teng , W. H. and Huang , Y. F. 2009 . Procyanidin induces apoptosis and necrosis of prostate cancer cell line PC-3 in a mitochondrion-dependent manner . J. Androl. , 30 : 122 – 126 .
   PubMed Web of Science ®Google Scholar
• Shankar , S. , Ganapathy , S. and Srivastava , R. K. 2007 . Green tea polyphenols: Biology and therapeutic implications in cancer . Front Biosci , 12 : 4884 – 4899 .
   Google Scholar
• Shao , Z. H. , Becker , L. B. , Van den Hoek , T. L. , Schumacker , P. T. , Li , C. Q. , Zhao , D. , Wojcik , K. , Anderson , T. , Qin , Y. , Dey , L. and Yuan , C. S. 2003a . Grape seed proanthocyanidin extract attenuates oxidant injury in cardiomyocytes . Pharmacol. Res. , 47 : 463 – 469 .
   PubMed Web of Science ®Google Scholar
• Shao , Z. H. , Hsu , C. W. , Chang , W. T. , Waypa , G. B. , Li , J. , Li , D. , Li , C. Q. , Anderson , T. , Qin , Y. , Schumacker , P. T. , Becker , L. B. and Hoek , T. L. 2006 . Cytotoxicity induced by grape seed proanthocyanidins: Role of nitric oxide . Cell Biol. Toxicol. , 22 : 149 – 158 .
   PubMed Web of Science ®Google Scholar
• Shao , Z. H. , Vanden Hoek , T. L. , Xie , J. , Wojcik , K. , Chan , K. C. , Li , C. Q. , Hamann , K. , Qin , Y. , Schumacker , P. T. , Becker , L. B. and Yuan , C. S. 2003b . Grape seed proanthocyanidins induce pro-oxidant toxicity in cardiomyocytes . Cardiovasc. Toxicol. , 3 : 331 – 339 .
   PubMedGoogle Scholar
• Sharma , S. and Katiyar , S. K. 2010 . Dietary grape seed proanthocyanidins inhibit UVB-induced cyclooxygenase-2 expression and other inflammatory mediators in UVB-exposed skin and skin tumors of SKH-1 hairless mice . Pharm. Res. , 27 : 1092 – 1102 .
   PubMed Web of Science ®Google Scholar
• Sherr , C. J. 2004 . Principles of tumor suppression . Cell , 116 : 235 – 246 .
   PubMed Web of Science ®Google Scholar
• Singh , R. P. , Tyagi , A. K. , Dhanalakshmi , S. , Agarwal , R. and Agarwal , C. 2004 . Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein- 3 . Int. J. Cancer. , 108 : 733 – 740 .
   PubMed Web of Science ®Google Scholar
• Singletary , K. W. and Meline , B. 2001 . Effect of grape seed proanthocyanidins on colon aberrant crypts and breast tumors in a rat dual-organ tumor model . Nutr. Cancer. , 139 : 252 – 258 .
   Google Scholar
• Skibola , C. F. and Smith , M. T. 2000 . Potential health impacts of excessive flavonoid intake . Free Radic. Biol. Med. , 29 : 375 – 83 .
   PubMed Web of Science ®Google Scholar
• So , F. V. , Guthrie , N. , Chambers , A. F. , Moussa , M. and Carroll , K. K. 1996 . Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices . Nutr Cancer , 26 : 167 – 181 .
   PubMed Web of Science ®Google Scholar
• Steinberg , F. M. , Bearden , M. M. and Keen , C. L. 2003 . Cocoa and chocolate flavonoids: Implications for cardiovascular health . J. Am Diet. Assoc. , 103 : 215 – 223 .
   PubMed Web of Science ®Google Scholar
• Stephens , L. , Williams , R. and Hawkins , P. 2005 . Phosphoinositide 3- kinases as drug targets in cancer . Curr. Opin. Pharmacol. , 5 : 357 – 365 .
   PubMed Web of Science ®Google Scholar
• Surh , Y. J. 2003 . Cancer chemoprevention with dietary phytochemicals . Nat. Rev. Cancer. , 3 : 768 – 780 .
   PubMed Web of Science ®Google Scholar
• Sutherland , B. A. , Rahman , R. M. A. and Appleton , I. 2006 . Mechanisms of action of green tea catechins, with a focus on ischemia-induced neurodegeneration . J. Nutr. Biochem , 17 : 291 – 306 .
   PubMed Web of Science ®Google Scholar
• Tamago , E. , Robino , G. , Obbili , A. , Bardini , P. , Aragno , M. , Parola , M. and Danni , O. 2003 . H2O2 and 4-hydroxinonenal mediate amyloidd [beta]-induced neuronal apoptosis by activating JNKs and p38MAPK . Exp. Neurol. , 180 : 144 – 155 .
   PubMed Web of Science ®Google Scholar
• Tanaka , N. , Sekiya , N. , Hattori , M. , Goto , H. , Shibahara , N. , Shimada , Y. and Terasawa , K. 2003 . Measurement of plasma procyanidin B2 and procyanidin B3 levels after oral administration in rat . Phytomedicine. , 10 : 122 – 126 .
   PubMed Web of Science ®Google Scholar
• Terra , X. , Montagut , G. , Bustos , M. , Llopiz , N. , Ardèvol , A. , Bladé , C. , Fernández-Larrea , J. , Pujadas , G. , Salvadó , J. , Arola , L. and Blay , M. 2009 . Grape seed procyanidins prevent low-grade inflammation by modulating cytokine expression in rats fed a high-fat diet . J. Nutr. Biochem. , 20 : 210 – 218 .
   PubMed Web of Science ®Google Scholar
• Terra , X. , Valls , J. , Vitrac , X. , Mérrillon , J. M. , Arola , L. , Ardèvol , A. , Bladé , C. , Fernández-Larrea , J. , Pujadas , G. , Salvadó , J. and Blay , M. 2007 . Grape seed procyanidins act as antiinflammatory agents in endotoxin-stimulated RAW 264.7 macrophages by inhibiting NFκB signaling pathway . J. Agric. Food Chem. , 55 : 4357 – 4365 .
   PubMed Web of Science ®Google Scholar
• Tournier , C. , Hess , P. , Yang , D. D. , Xu , J. , Turner , T. K. , Nimnual , A. , Bar-Sagi , D. , Jones , S. N. , Flavell , R. A. and Davis , R. J. 2000 . Requirement of JNK for stress-induced activation of the cytochrome C-mediated death pathway . Science , 288 : 870 – 874 .
   PubMed Web of Science ®Google Scholar
• Tron , V. A. , Rosenthal , D. and Sauder , D. N. 1988 . Epidermal interleukin-1 is increased in cutaneous T-cell lymphoma . J. Invest. Dermatol. , 90 : 378 – 81 .
   PubMed Web of Science ®Google Scholar
• Tsang , C. , Auger , C. , Mullen , W. , Bornet , A. , Rouanet , J. M. , Crozier , A. and Teissedre , P. L. 2005 . The absorption, metabolism and excretion of flavan-3-ols and procyanidins following the ingestion of a grape seed extract by rats . Br. J. Nutr. , 94 : 170 – 181 .
   PubMed Web of Science ®Google Scholar
• Tyagi , A. , Agarwal , R. and Agarwal , C. 2003 . Grape seed extract inhibits EGF-induced and constitutively active mitogenic signaling but activates JNK in human prostate carcinoma DU145 cells: Possible role in antiproliferation and apoptosis . Oncogene. , 22 : 1302 – 1316 .
   PubMed Web of Science ®Google Scholar
• Urpi-Sarda , M. , Monagas , M. , Khana , N. , Lamuela-Raventos , R. M. , Santos-Buelga , C. , Sacanella , E. , Castell , M. , Permanyer , J. and Andres-Lacueva , C. 2009 . Epicatechin, procyanidins, and phenolic microbial metabolites after cocoa intake in humans and rats . Anal. Bioanal. Chem. , 394 : 1545 – 1556 .
   PubMed Web of Science ®Google Scholar
• Velmurugan , B. , Singh , R. P. , Agarwal , R. and Agarwal , C. 2010a . Dietary-feeding of grape seed extract prevents azoxymethane-induced colonic aberrant crypt foci formation in Fischer 344 rats . Mol. Carcinog. , 49 : 641 – 652 .
   PubMed Web of Science ®Google Scholar
• Velmurugan , B. , Singh , R. P. , Kaul , N. , Agarwal , R. and Agarwal , C. 2010b . Dietary feeding of grape seed extract prevents intestinal tumorigenesis in APCmin/+ Mice1. . Neoplasia. , 12 : 95 – 102 .
   PubMed Web of Science ®Google Scholar
• Wada , T. and Penninger , J. M. 2004 . Mitogen-activated protein kinases in apoptosis regulation . Oncogene , 23 : 2838 – 2849 .
   PubMed Web of Science ®Google Scholar
• Watanabe , T. , Nakagawa , K. , Ohata , S. , Kitagawa , D. , Nishitai , G. , Seo , J. , Tanemura , S. , Shimizu , N. , Kishimoto , H. , Wada , T. , Aoki , J. , Arai , H. , Iwatsubo , T. , Mochita , M. , Watanabe , T. , Satake , M. , Ito , Y. , Matsuyama , T. , Mak , T. W. , Penninger , J. M. , Nishina , H. and Katada , T. 2002 . SEK/MKK4-mediated SAPK/JNK signaling participates in embryonic hepatoblast proliferation via a pathway different from NF-κB-induced anti-apoptosis . Dev. Biol. , 250 : 332 – 347 .
   PubMed Web of Science ®Google Scholar
• Wouters , K. A. , Kremer , L. C. , Miller , T. L. , Herman , E. H. and Lipshultz , S. E. 2005 . Protecting against anthracycline-induced myocardial damage: A review of the most promising strategies . Br. J. Haematol. , 131 : 561 – 578 .
   PubMed Web of Science ®Google Scholar
• Xu , Z. , Kukekov , N. V. and Greene , L. A. 2003 . POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis . EMBO J , 22 : 252 – 261 .
   PubMed Web of Science ®Google Scholar
• Ye , X. , Krohn , R. L. , Liu , W. , Joshi , S. S. , Kuszynski , C. A. , McGinn , T. R. , Bagchi , M. , Preuss , H. G. , Stohs , S. J. and Bagchi , D. 1999 . The cytotoxic effects of a novel IH636 grape seed proanthocyanidin extract on cultured human cancer cells . Mol. Cell Biochem. , 196 : 99 – 108 .
   PubMed Web of Science ®Google Scholar
• Zaveri , N. T. 2006 . Green tea and its polyphenolic catechins: Medicinal uses in cancer and non-cancer applications . Life Sci , 78 : 2073 – 2080 .
   PubMed Web of Science ®Google Scholar
• Zbarsky , V. , Datla , K. P. , Parkar , S. , Rai , D. K. , Aruoma , O. I. and Dexter , D. T. 2005 . Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson's disease . Free Rad. Res. , 39 : 1119 – 1125 .
   PubMed Web of Science ®Google Scholar
• Zhu , X. , Lee , H. G. , Raina , A. K. , Perry , G. and Smith , M. A. 2002 . The role of mitogen-activated protein kinase pathways in Alzheimer's disease . Neurosignals , 11 : 270 – 281 .
   PubMed Web of Science ®Google Scholar
• Zong , W. , Li , C. , Hatzivassiliou , G. , Lindsten , T. , Yu , Q. C. , Yuan , J. and Thompson , C. B. 2003 . Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis . J. Cell Biol. , 16 : 59 – 69 .
   Google Scholar