Food Science and Biotechnology

, Volume 22, Issue 2, pp 485–491 | Cite as

Polymeric procyanidin fraction from defatted grape seeds protects HepG2 cells against oxidative stress by inducing phase II enzymes via Nrf2 activation

  • Younghwa Kim
  • Youngmin Choi
  • Hyeonmi Ham
  • Heon-Sang Jeong
  • Junsoo Lee
Research Article

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that regulates antioxidant response element (ARE)-driven phase II detoxification enzymes. In this study, induction of phase II enzymes via Nrf2/ARE activation in the cytoprotective effect of crude polyphenol extract (CPE), oligomeric procyanidin fraction (OPF), and polymeric procyanidin fraction (PPF) from defatted grape seeds in HepG2 cells was evaluated. Among these treatments, the treatment with PPF significantly increased Nrf2 protein expression in the nuclear fraction. Treating the samples increased heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) protein expression in a dose-dependent manner, and PPF significantly increased the levels of phase II enzymes. Cellular generation of reactive oxygen species (ROS) were effectively reduced by PPF. These results suggest that pretreatment with PPF shows a cytoprotective effect by inhibiting ROS production and inducing HO-1 and NQO1 expression via Nrf2 activation in HepG2 cells.

Keywords

procyanidin heme oxygenase-1 NAD(P)H: quinone oxidoreductase 1 nuclear factor-erythroid 2-related factor antioxidant response element 

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References

  1. 1.
    Loguercio C, Federico A. Oxidative stress in viral and alcoholic hepatitis. Free Radical Bio. Med. 34: 1–10 (2003)CrossRefGoogle Scholar
  2. 2.
    Ravindra PS, Shashwat S, Suman K. Free radicals and oxidative stress in neurodegenerative diseases: Relevance of dietary antioxidants. J. Indian Acad. Clin. Med. 5: 218–225 (2004)Google Scholar
  3. 3.
    Shah AM, Channon KM. Free radicals and redox signalling in cardiovascular disease. Heart 90: 486–487 (2004)CrossRefGoogle Scholar
  4. 4.
    Valko M, Morris H, Mazur M, Rapta P, Bilton RF. Oxygen free radical generating mechanisms in the colon: Do the semiquinones of vitamin K play a role in the aetiology of colon cancer? Biochim. Biophys. Acta 1527: 161–166 (2001)CrossRefGoogle Scholar
  5. 5.
    Chen XL, Kunsch C. Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: A new therapeutic approach for the treatment of inflammatory diseases. Curr. Pharm. Design 10: 879–891 (2004)CrossRefGoogle Scholar
  6. 6.
    Moskaug JO, Carlsen H, Myhrstad MC, Blomhoff R. Polyphenols and glutathione synthesis regulation. Am. J. Clin. Nutr. 81(S): 277–283 (2005)Google Scholar
  7. 7.
    Eberhardt MV, Jeffery EH. When dietary antioxidants perturb the thiol redox. J. Sci. Food Agr. 86: 1996–1998 (2006)CrossRefGoogle Scholar
  8. 8.
    Zhao CR, Gao ZH, Qu XJ. Nrf2-ARE signaling pathway and natural products for cancer chemoprevention. Cancer Epidermiol. 34: 523–533 (2010)CrossRefGoogle Scholar
  9. 9.
    Zhang Y, Gordon GB. A strategy for cancer prevention: Stimulation of the Nrf2-ARE signaling pathway. Mol. Cancer Ther. 3: 885–893 (2004)Google Scholar
  10. 10.
    Jaiswal AK. Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radical Bio. Med. 36: 1199–1207 (2004)CrossRefGoogle Scholar
  11. 11.
    Keum YS, Jeong WS, Kong AN. Chemoprevention by isothiocyanates and their underlying molecular signaling mechanisms. Mutat. Res. 555: 191–202 (2004)CrossRefGoogle Scholar
  12. 12.
    Owuor ED, Kong AN. Antioxidants and oxidants regulated signal transduction pathways. Biochem. Pharmacol. 64: 765–770 (2002)CrossRefGoogle Scholar
  13. 13.
    Numazawa S, Ishikawa M, Yoshida A, Tanaka S, Yoshida T. A typical protein kinase C mediates activation of NF-E 2-related factor 2 in response to oxidative stress. Am. J. Physiol.-Cell Ph. 285: 334–342 (2003)Google Scholar
  14. 14.
    Nakaso K, Yano H, Fukuhara Y, Takeshima T, Wada-Isoe K, Nakashima K. PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett. 546: 181–184 (2003)CrossRefGoogle Scholar
  15. 15.
    Del Bas MJ, Fernandez-Larrea J, Blay M, Ardevol A, Salvado M, Arola L, Blade C. Grape seed procyanidins improve atherosclerotic risk index and induce liver CYP7A1 and SHP expression in healthy rats. FASEB J. 19: 479–481 (2005)Google Scholar
  16. 16.
    Montagut G, Onnockx S, Vaqué M, Bladé C, Blay M, Fernández-Larrea J, Pujadas G, Salvadó MJ, Arola L, Pirson I, Ardévol A, Pinent M. Oligomers of grape-seed procyanidin extract activate the insulin receptor and key targets of the insulin signaling pathway differently from insulin. J. Nutr. Biochem. 21: 476–481 (2010)CrossRefGoogle Scholar
  17. 17.
    Kim Y, Choi Y, Ham H, Jeong HS, Lee J. Antioxidant and cytoprotective effects of oligomeric and polymeric procyanidin fractions from defatted grape seed in PC12 cells. J. Med. Food 15: 490–494 (2012)CrossRefGoogle Scholar
  18. 18.
    Pierini R, Kroon PA, Guyot S, Ivory K, Johnson IT, Belshaw NJ. Procyanidin effects on oesophageal adenocarcinoma cells strongly depend on flavan-3-ol degree of polymerization. Mol. Nutr. Food Res. 52: 1399–1407 (2008)CrossRefGoogle Scholar
  19. 19.
    Wang H, Joseph JA. Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radical Bio. Med. 27: 612–616 (1999)CrossRefGoogle Scholar
  20. 20.
    Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Bioph. Res. Co. 236: 313–322 (1997)CrossRefGoogle Scholar
  21. 21.
    Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Gene. Dev. 13: 76–86 (1999)CrossRefGoogle Scholar
  22. 22.
    Hwang YP, Choi JH, Choi JM, Chung YC, Jeong HG. Protective mechanisms of anthocyanins from purple sweet potato against tertbutyl hydroperoxide-induced hepatotoxicity. Food Chem. Toxicol. 49: 2081–2089 (2011)CrossRefGoogle Scholar
  23. 23.
    Na HK, Kim EH, Jung JH, Lee HH, Hyun JW, Surh YJ. (-)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells. Arch. Biochem. Biophys. 476: 171–177 (2008)CrossRefGoogle Scholar
  24. 24.
    Tanigawa S, Fujii M, Hou DX. Action of Nrf2 and Keap1 in AREmediated NQO1 expression by quercetin. Free Radical Bio. Med. 42: 1690–1703 (2007)CrossRefGoogle Scholar
  25. 25.
    Lee JS, Surh YJ. Nrf2 as a novel molecular target for chomoprevention. Cancer Lett. 224: 171–184 (2005)CrossRefGoogle Scholar
  26. 26.
    Hayes JD, Ellis EM, Neal GE, Harrison DJ, Manson MM. Cellular response to cancer chemopreventive agents: Contribution of the antioxidant responsive element to the adaptive response to oxidative and chemical stress. Biochem. Soc. Symp. 64: 141–168 (1999)Google Scholar
  27. 27.
    Keum YS, Han YH, Liew C, Kim JH, Xu C, Yuan X, Shakarjian MP, Chong S, Kong AN. Induction of heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) by a phenolic antioxidant, butylated hydroxyanisole (BHA), and its metabolite, tert-butylhydroquinone (TBHQ) in primary-cultured human and rat hepatocytes. Pharmacol. Res. 23: 2586–2594 (2006)CrossRefGoogle Scholar
  28. 28.
    MacLeod AK, Kelly VP, Higgins LG, Kelleher MO, Price SA, Bigley AL, Betton GR, Hayes JD. Expression and localization of rat aldo-keto reductases and induction of the 1B13 and 1D2 isoforms by phenolic antioxidants. Drug Metab. Dispos. 38: 341–346 (2010)CrossRefGoogle Scholar
  29. 29.
    Subramaniam SR, Ellis EM. Esculetin-induced protection of human hepatoma HepG2 cells against hydrogen peroxide is associated with the Nrf2-dependent induction of the NAD(P)H:quinone oxidoreductase 1 gene. Toxicol. Appl. Pharm. 250: 130–136 (2011)CrossRefGoogle Scholar
  30. 30.
    Nioi P, Hayes JD. Contribution of NAD(P)H:quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors. Mutat. Res. 555: 149–171 (2004)CrossRefGoogle Scholar
  31. 31.
    Wu CC, Hsu MC, Hsieh CW, Lin JB, Lai PH, Wung BS. Upregulation of heme oxygenase-1 by epigallocatechin-3-gallate via the phosphatidylinositol 3-kinase/Akt and ERK pathways. Life Sci. 78: 2889–2897 (2007)CrossRefGoogle Scholar
  32. 32.
    Granado-Serrano AB, Angeles Martín M, Goya L, Bravo L, Ramos S. Time-course regulation of survival pathways by epicatechin on HepG2 cells. J. Nutr. Biochem. 20: 115–124 (2009)CrossRefGoogle Scholar
  33. 33.
    Heo HJ, Lee CY. Protective effects of quercetin and vitamin C against oxidative stress-induced neurodegeneration. J. Agr. Food Chem. 52: 7514–7517 (2004)CrossRefGoogle Scholar
  34. 34.
    Ramiro-Puig E, Castell M. Cocoa: Antioxidant and immunomodulator. Brit. J. Nutr. 101: 931–940 (2009)CrossRefGoogle Scholar
  35. 35.
    Takahashi T, Marita K, Akagi R, Sassa S. Heme oxygenase-1: A novel therapeutic target in oxidative tissue injuries. Curr. Med. Chem. 11: 1545–1561 (2004)CrossRefGoogle Scholar
  36. 36.
    Hwang YP, Choi JH, Han EH, Kim HK, Kang SK, Chung YC, Jeong HG. Protective mechanisms of Aralia continentalis extract against tert-butyl hydroperoxide-induced hepatotoxicity: In vivo and in vitro studies. Food Chem. Toxicol. 46: 3512–3521 (2008)CrossRefGoogle Scholar
  37. 37.
    Zhang Y, Guan L, Wang X, Wen T, Xing J, Zhao J. Protection of chlorophyllin against oxidative damage by inducing HO-1 and NQO1 expression mediated by PI3K/Akt and Nrf2. Free Radical Bio. Med. 42: 362–371 (2008)CrossRefGoogle Scholar

Copyright information

© The Korean Society of Food Science and Technology and Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Younghwa Kim
    • 1
  • Youngmin Choi
    • 1
  • Hyeonmi Ham
    • 1
  • Heon-Sang Jeong
    • 1
  • Junsoo Lee
    • 1
  1. 1.Department of Food Science and TechnologyChungbuk National UniversityCheongju, ChungbukKorea

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