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. 2016 Feb 29;25(1):319–327. doi: 10.1007/s10068-016-0045-3

6-shogaol attenuates H2O2-induced oxidative stress via upregulation of Nrf2-mediated γ-glutamylcysteine synthetase and heme oxygenase expression in HepG2 cells

Jin-Kyoung Kim 1, Hae-Dong Jang 1,✉
PMCID: PMC6049361  PMID: 30263273

Abstract

The signaling pathway by which 6-shogaol protects HepG2 cells against H2O2-induced oxidative stress was investigated. Cellular anti-oxidant activities, the GSH level, and anti-oxidant response element (ARE) promoter activity were analyzed. Activated protein kinases and nuclear transcription factor-erythroid 2-related factor 2 (Nrf2) accumulation in the nucleus, and phase II detoxification and anti-oxidant enzymes were analyzed using western blotting. 6-Shogaol enhanced cellular anti-oxidant activities, the GSH level, and ARE promoter activities. Nrf2 accumulation in the nucleus, c-jun N-terminal kinase (JNK) activation, and γ-glutamylcysteine synthetase (GCS) and heme oxygenase-1 (HO-1) expressions were increased by 6-shogaol. Blockage of the JNK signaling pathway removed the elicitation effect of 6-shogaol on JNK activation, Nrf2 accumulation in nucleus, and GCS and HO-1 expression, but partially suppressed cellular anti-oxidant activities and ARE promoter activities. 6-shogaol exerts an indirect cellular anti-oxidant activity based on up-regulation of GCS and HO-1 via a JNK-mediated Nrf2 signaling pathway.

Keywords: 6-shogaol, oxidative stress, c-jun N-terminal kinase-mediated, γ-glutamylcysteine synthetase, heme oxygenase-1

References

  • 1.Clarkson P M, Thompson HS. Antioxidants: What role do they play in physical activity and health. Am. J. Clin. Nutr. 2000;72:637S–646S. doi: 10.1093/ajcn/72.2.637S. [DOI] [PubMed] [Google Scholar]
  • 2.Dinkova-Kostova AT, Talalay P. Direct and indirect antioxidant properties of inducers of cytoprotective proteins. Mol. Nutr. Food Res. 2008;52:S128–S138. doi: 10.1002/mnfr.200700195. [DOI] [PubMed] [Google Scholar]
  • 3.Dinkova-Kostova AT, Cheah J, Samouilov A, Zweiser JL, Bozak RE, Hicks RJ, Talalay P. Phenolic Michael reaction acceptors: Combined direct and indirect antioxidant defense against electrophiles and oxidants. Med. Chem. 2007;3:261–268. doi: 10.2174/157340607780620680. [DOI] [PubMed] [Google Scholar]
  • 4.Dinkova-Kostova AT, Wang XJ. Induction of the Keap1/Nrf2/ARE pathway by oxidizable diphenol. Chem.-Biol. Interact. 2011;192:101–106. doi: 10.1016/j.cbi.2010.09.010. [DOI] [PubMed] [Google Scholar]
  • 5.Bryan HK, Olayanju A, Goldrin CE, Park BK. The Nrf2 cell defense pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem. Pharmacol. 2013;85:705–717. doi: 10.1016/j.bcp.2012.11.016. [DOI] [PubMed] [Google Scholar]
  • 6.Li Y, Paonessa JD, Zhang Y. Mechanism of chemical activation of Nrf2. PLos On. 2012;7:1–7. doi: 10.1371/journal.pone.0035122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Park JH, Lee JK, Kim HS, Chung ST, Eom JH, Kim KA, Chung SJ, Paik SY, Oh HY. Immunomodulatory effect of caffeic acid phenethyl ester in Balb/c mice. Int. Immunopharmacol. 2004;4:429–436. doi: 10.1016/j.intimp.2004.01.013. [DOI] [PubMed] [Google Scholar]
  • 8.Baird L, Dinkova-Kostova AT. The cytoprotective role of the Keap1-Nrf2 pathway. Arch. Toxicol. 2011;85:241–272. doi: 10.1007/s00204-011-0674-5. [DOI] [PubMed] [Google Scholar]
  • 9.Itoh K, Tong KI, Yamamoto M. Molecular mechanism activation of Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radical Bio. Med. 2004;36:1208–1213. doi: 10.1016/j.freeradbiomed.2004.02.075. [DOI] [PubMed] [Google Scholar]
  • 10.Govindarajan VS. Ginger–Chemistry, technology, and quality evaluation: Part 1. Crit. Rev. Sci. Nutr. 2001;17:1–96. doi: 10.1080/10408398209527343. [DOI] [PubMed] [Google Scholar]
  • 11.Bhattarai S, Tran VH, Duke CC. The stability of gingerol and shogaol in aqueous solutions. J. Pharm. Sci. 2001;90:1658–1664. doi: 10.1002/jps.1116. [DOI] [PubMed] [Google Scholar]
  • 12.Lu DL, Li XZ, Dai F, Kang Y, Li Y, Ma MM, Ren XR, Du GW, Jin XL, Zhou B. Influence of side chain structure changes on antioxidant potency of the [6]-gingerol related compounds. Food Chem. 2014;165:191–197. doi: 10.1016/j.foodchem.2014.05.077. [DOI] [PubMed] [Google Scholar]
  • 13.Shao X, Lv L, Parks T, Wu H, Ho CT, Sang S. Quantitative analysis of ginger components in commercial products using liquid chromatography with electrochemical array detection. J. Agr. Food Chem. 2010;58:12608–12614. doi: 10.1021/jf1029256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Li F, Nitteranon V, Tang X, Liang J, Zhang G, Parkin KL, Hu Q. In vitro antioxidant and anti-inflammatory activities of 1-dehydro-[6]-gingerdione, 6-shogaol, 6-dehydroshogaol and hexahydrocurcumin. Food Chem. 2012;135:332–337. doi: 10.1016/j.foodchem.2012.04.145. [DOI] [PubMed] [Google Scholar]
  • 15.Peng F, Tao O, Wu X, Dou H, Spencer S, Mang C, Xu L, Sun L, Zhao Y, Li H, Zeng S, Liu G, Hao X. Cytotoxic, cytoprotective and antioxidant effects of isolated phenloic compounds from fresh ginger. Fitoterapi. 2012;83:568–585. doi: 10.1016/j.fitote.2011.12.028. [DOI] [PubMed] [Google Scholar]
  • 16.Pan MH, Hsieh MC, Hsu PC, Ho SY, Lai CS, Wu H, Sang SM, Ho CT. 6-Shogaol suppresses lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages. Mol. Nutr. Food Res. 2008;52:1467–1477. doi: 10.1002/mnfr.200700515. [DOI] [PubMed] [Google Scholar]
  • 17.Shim SH, Kim SH, Choi DS, Kwon YB, Kwon JK. Anti-inflammatory effects of [6]-shogaol: Potential roles of HDAC inhibition and HSP70 induction. Food Chem. Toxicol. 2011;49:2734–2740. doi: 10.1016/j.fct.2011.08.012. [DOI] [PubMed] [Google Scholar]
  • 18.Chen HD, Soroka DN, Hu Y, Chen X, Sang SM. Characterization of thiolconjugated metabolites of ginger components shogaols in mouse and human urine and modulation of the glutathione levels in cancer cells by [6]-shogaol. Mol. Nutr. Food Res. 2013;57:447–458. doi: 10.1002/mnfr.201200679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Chen CY, Liu TZ, Liu YW, Tseng WC, Liu RH, Lu FJ, Kuo SH, Chen CH. 6-Shogaol (alkanone form Ginger) induces apoptotoc cell death of human hepatoma p53 mutant Mahlavu subline via an oxidative stress-mediate caspasedependent mechanism. J. Agr. Food Chem. 2007;55:948–954. doi: 10.1021/jf0624594. [DOI] [PubMed] [Google Scholar]
  • 20.Shukla Y, Singh M. Cancer preventive properties of ginger: A brief review. Food Chem. Toxicol. 2007;45:683–690. doi: 10.1016/j.fct.2006.11.002. [DOI] [PubMed] [Google Scholar]
  • 21.Dugasani S, Pichika MR, Nadarajah VD, Balijepalli MK, Tandra S, Korlakunta JN. Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. J. Ethnopharmacol. 2010;127:515–520. doi: 10.1016/j.jep.2009.10.004. [DOI] [PubMed] [Google Scholar]
  • 22.Gan FF, Ling H, Ang X, Reddy SA, Lee SSH, Yang H, Tan SH, Hayes JD, Chui WK, Chew EH. Anovel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-κB and Nrf2-Keap1 signaling pathways. Toxicol. Appl. Pharmacol. 2013;272:852–862. doi: 10.1016/j.taap.2013.07.011. [DOI] [PubMed] [Google Scholar]
  • 23.Bak MJ, Ok S, Jun M, Jeong WS. 6-Shogaol-rich extract from ginger upregulates the antioxidant defense systems in cells and mice. Molecule. 2012;17:8037–8055. doi: 10.3390/molecules17078037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Lautraite S, Bigot-Lasserre D, Bars R, Carmichael N. Optimization of cell-based assays for medium through screening of oxidative stress. Toxicol. In Vitro. 2003;17:207–220. doi: 10.1016/S0887-2333(03)00005-5. [DOI] [PubMed] [Google Scholar]
  • 25.Grindel BJ, Rohe B, Safford SE, Bennett JJ, Farach-Carson MC. Tumor necrosis factor-α treatment of HepG2 cells mobilizes a cytoplasmic pool of Erp57/1,25D3-MARRS to the nucleus. J. Cell Biochem. 2011;112:2606–2615. doi: 10.1002/jcb.23187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Dickerson DA, Forman JA. Cellular glutathione and thiols metabolism. Biochem. Pharmacol. 2002;64:1019–1026. doi: 10.1016/S0006-2952(02)01172-3. [DOI] [PubMed] [Google Scholar]
  • 27.Kay HY, Yang JW, Kim TH, Lee DY, Kang BM, Ryu JH, Jeon R, Kim SG. Ajeone, a stable garlic by-product, has an antioxidant effects through Nrf2-mediated glutamate-cysteine ligase induction in HepG2 cells and primary hepatocytes. J. Nutr. 2010;140:2011–2019. doi: 10.3945/jn.110.121277. [DOI] [PubMed] [Google Scholar]
  • 28.Granado-Serrano A, Martin MA, Bravo L, Goya L, Ramos S. Quercetin modulates Nrf2 and glutathione-related defenses in HepG2 cells: Involvement of p38. Chem.-Biol. Interact. 2012;195:154–164. doi: 10.1016/j.cbi.2011.12.005. [DOI] [PubMed] [Google Scholar]
  • 29.Yang JH, Shin BY, Han JY, Kim MG, Wi JE, Kim YW, Cho IJ, Kim SC, Shin SM, Ki SH. Isorhamnetin protects against oxidative stress by activating Nrf2 and inducing the expression of its target genes. Toxicol. Appl. Pharmacol. 2014;274:293–301. doi: 10.1016/j.taap.2013.10.026. [DOI] [PubMed] [Google Scholar]
  • 30.Scharf G, Prustomersky S, Knasmuller S, Schulte-Hermann R, Huber WW. Enhancement of glutathione and γ-glutamylcysteine synthetase, the rate limiting enzyme of glutathione synthesis, by chemoprotective plant-derived food and beverage components in the human hepatoma cell line HepG2. Nutr. Cance. 2003;45:74–83. doi: 10.1207/S15327914NC4501_9. [DOI] [PubMed] [Google Scholar]

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