Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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The role of ginsenoside Rb1, a potential natural glutathione reductase agonist, in preventing oxidative stress-induced apoptosis of H9C2 cells

  • Fan, Hui-Jie (School of Traditional Chinese Medicine, Southern Medical University) ;
  • Tan, Zhang-Bin (School of Traditional Chinese Medicine, Southern Medical University) ;
  • Wu, Yu-Ting (School of Traditional Chinese Medicine, Southern Medical University) ;
  • Feng, Xiao-Reng (Department of Orthopaedics and Traumatology, Queen Mary Hospital, the University of Hong Kong) ;
  • Bi, Yi-Ming (School of Traditional Chinese Medicine, Southern Medical University) ;
  • Xie, Ling-Peng (School of Traditional Chinese Medicine, Southern Medical University) ;
  • Zhang, Wen-Tong (School of Traditional Chinese Medicine, Southern Medical University) ;
  • Ming, Zhi (School of Traditional Chinese Medicine, Southern Medical University) ;
  • Liu, Bin (Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University) ;
  • Zhou, Ying-Chun (School of Traditional Chinese Medicine, Southern Medical University)
  • Received : 2018.02.24
  • Accepted : 2018.12.10
  • Published : 2020.03.15
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Abstract

Background: Oxidative stress-induced cardiomyocytes apoptosis is a key pathological process in ischemic heart disease. Glutathione reductase (GR) reduces glutathione disulfide to glutathione (GSH) to alleviate oxidative stress. Ginsenoside Rb1 (GRb1) prevents the apoptosis of cardiomyocytes; however, the role of GR in this process is unclear. Therefore, the effects of GRb1 on GR were investigated in this study. Methods: The antiapoptotic effects of GRb1 were evaluated in H9C2 cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, annexin V/propidium iodide staining, and Western blotting. The antioxidative effects were measured by a reactive oxygen species assay, and GSH levels and GR activity were examined in the presence and absence of the GR inhibitor 1,3-bis-(2-chloroethyl)-1-nitrosourea. Molecular docking and molecular dynamics simulations were used to investigate the binding of GRb1 to GR. The direct influence of GRb1 on GR was confirmed by recombinant human GR protein. Results: GRb1 pretreatment caused dose-dependent inhibition of tert-butyl hydroperoxide-induced cell apoptosis, at a level comparable to that of the positive control N-acetyl-L-cysteine. The binding energy between GRb1 and GR was positive (-6.426 kcal/mol), and the binding was stable. GRb1 significantl reduced reactive oxygen species production and increased GSH level and GR activity without altering GR protein expression in H9C2 cells. Moreover, GRb1 enhanced the recombinant human GR protein activity in vitro, with a half-maximal effective concentration of ≈2.317 μM. Conversely, 1,3-bis-(2-chloroethyl)-1-nitrosourea co-treatment significantly abolished the GRb1's apoptotic and antioxidative effects of GRb1 in H9C2 cells. Conclusion: GRb1 is a potential natural GR agonist that protects against oxidative stress-induced apoptosis of H9C2 cells.

Keywords

References

  1. Wu D, Hu Q, Liu X, Pan L, Xiong Q, Zhu YZ. Hydrogen sulfide protects against apoptosis under oxidative stress through SIRT1 pathway in H9c2 cardiomyocytes. Nitric Oxide : Biol Chem 2015;46:204-12. https://doi.org/10.1016/j.niox.2014.11.006
  2. Shafaroodi H, Hashemi M, Sharif ZN, Moezi L, Janahmadi Z, Dehpour AR. The possible role of nitric oxide and oxidative stress in the enhanced apoptosis of cardiac cells in cirrhotic rats. Acta Med Iran 2017;55(1):29-34.
  3. Wang X, Liu X, Zhou Q, Du J, Zhang T, Lu Y, Su S. Ginsenoside Rb1 reduces isoproterenol-induced cardiomyocytes apoptosis in vitro and in vivo. Evidence-based complementary and alternative medicine, vol. 2013. eCAM; 2013.
  4. Song JH, Shin MS, Hwang GS, Oh ST, Hwang JJ, Kang KS. Chebulinic acid attenuates glutamate-induced HT22 cell death by inhibiting oxidative stress, calcium influx and MAPKs phosphorylation. Bioorg Med Chem Lett 2017.
  5. Potts MB, Vaughn AE, McDonough H, Patterson C, Deshmukh M. Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP. J Cell Biol 2005;171(6):925-30. https://doi.org/10.1083/jcb.200504082
  6. Sekhar RV, Patel SG, Guthikonda AP, Reid M, Balasubramanyam A, Taffet GE, Jahoor F. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr 2011;94(3):847-53. https://doi.org/10.3945/ajcn.110.003483
  7. Bolfa P, Vidrighinescu R, Petruta A, Dezmirean D, Stan L, Vlase L, Damian G, Catoi C, Filip A, Clichici S. Photoprotective effects of Romanian propolis on skin of mice exposed to UVB irradiation. Food Chem Toxicol: Int J Pub Br Ind Biol Res Assoc 2013;62:329-42. https://doi.org/10.1016/j.fct.2013.08.078
  8. Kudugunti SK, Vad NM, Ekogbo E, Moridani MY. Efficacy of caffeic acid phenethyl ester (CAPE) in skin B16-F0 melanoma tumor bearing C57BL/6 mice. Invest N Drugs 2011;29(1):52-62. https://doi.org/10.1007/s10637-009-9334-5
  9. Franco R, Bortner C, Schmitz I, Cidlowski JA. Glutathione depletion regulates both extrinsic and intrinsic apoptotic signaling cascades independent from multidrug resistance protein 1. Apoptosis Int J Program Cell Death 2014;19(1):117-34. https://doi.org/10.1007/s10495-013-0900-0
  10. Chen C, Jiang X, Lai Y, Liu Y, Zhang Z. Resveratrol protects against arsenic trioxide-induced oxidative damage through maintenance of glutathione homeostasis and inhibition of apoptotic progression. Environ Mol Mutagen 2015;56(3):333-46. https://doi.org/10.1002/em.21919
  11. Kim SJ, Jung HJ, Hyun DH, Park EH, Kim YM, Lim CJ. Glutathione reductase plays an anti-apoptotic role against oxidative stress in human hepatoma cells. Biochimie 2010;92(8):927-32. https://doi.org/10.1016/j.biochi.2010.03.007
  12. Cereser C, Boget S, Parvaz P, Revol A. Thiram-induced cytotoxicity is accompanied by a rapid and drastic oxidation of reduced glutathione with consecutive lipid peroxidation and cell death. Toxicology 2001;163(2-3):153-62. https://doi.org/10.1016/S0300-483X(01)00401-2
  13. Liu B, Zhang J, Liu W, Liu N, Fu X, Kwan H, Liu S, Liu B, Zhang S, Yu Z, et al. Calycosin inhibits oxidative stress-induced cardiomyocyte apoptosis via activating estrogen receptor-alpha/beta. Bioorg Med Chem Lett 2016;26(1):181-5. https://doi.org/10.1016/j.bmcl.2015.11.005
  14. Li J, Shao ZH, Xie JT, Wang CZ, Ramachandran S, Yin J, Aung H, Li C, Qin G, Vanden Hoek T, et al. The effects of ginsenoside Rb1 on JNK in oxidative injury in cardiomyocytes. Arch Pharm Res 2012;35(7):1259-67. https://doi.org/10.1007/s12272-012-0717-3
  15. Zheng X, Wang S, Zou X, Jing Y, Yang R, Li S, Wang F. Ginsenoside Rb1 improves cardiac function and remodeling in heart failure. Exp Anim 2017;66(3):217-28. https://doi.org/10.1538/expanim.16-0121
  16. Cui YC, Pan CS, Yan L, Li L, Hu BH, Chang X, Liu Y, Fan J, Sun K, Li Q, et al. Ginsenoside Rb1 protects against ischemia/reperfusion-induced myocardial injury via energy metabolism regulation mediated by RhoA signaling pathway. Sci Rep 2017;7:44579. https://doi.org/10.1038/srep44579
  17. Zhu Y, Hu C, Zheng P, Miao L, Yan X, Li H, Wang Z, Gao B, Li Y. Ginsenoside Rb1 alleviates aluminum chloride-induced rat osteoblasts dysfunction. Toxicology 2016;368-369:183-8. https://doi.org/10.1016/j.tox.2016.07.014
  18. Chen W, Wang J, Luo Y, Wang T, Li X, Li A, Li J, Liu K, Liu B. Ginsenoside Rb1 and compound K improve insulin signaling and inhibit ER stress-associated NLRP3 inflammasome activation in adipose tissue. J Ginseng Res 2016;40(4):351-8. https://doi.org/10.1016/j.jgr.2015.11.002
  19. Yu X, Ye L, Zhang H, Zhao J, Wang G, Guo C, Shang W. Ginsenoside Rb1 ameliorates liver fat accumulation by upregulating perilipin expression in adipose tissue of db/db obese mice. J Ginseng Res 2015;39(3):199-205. https://doi.org/10.1016/j.jgr.2014.11.004
  20. Li J, Shao Z, Xie JT, Wang CZ, Ramachandran S, Yin J, Aung H, Li CQ, Qin G, Vanden Hoek T, et al. The effects of ginsenoside Rb1 on JNK in oxidative injury in cardiomyocytes. Arch Pharm Res 2012;35(7):1259-67. https://doi.org/10.1007/s12272-012-0717-3
  21. Sardao VA, Oliveira PJ, Holy J, Oliveira CR, Wallace KB. Vital imaging of H9c2 myoblasts exposed to tert-butylhydroperoxide - characterization of morphological features of cell death. BMC Cell Biol 2007;8:11. https://doi.org/10.1186/1471-2121-8-11
  22. Saha S, Sadhukhan P, Sinha K, Agarwal N, Sil PC. Mangiferin attenuates oxidative stress induced renal cell damage through activation of PI3K induced Akt and Nrf-2 mediated signaling pathways. Biochem Biophy Rep 2016;5:313-27.
  23. Chen J, Guo R, Yan H, Tian L, You Q, Li S, Huang R, Wu K. Naringin inhibits ROSactivated MAPK pathway in high glucose-induced injuries in H9c2 cardiac cells. Basic Clin Pharmacol Toxicol 2014;114(4):293-304. https://doi.org/10.1111/bcpt.12153
  24. Chang G, Liu J, Qin S, Jiang Y, Zhang P, Yu H, Lu K, Zhang N, Cao L, Wang Y, et al. Cardioprotection by exenatide: a novel mechanism via improving mitochondrial function involving the GLP-1 receptor/cAMP/PKA pathway. Int J Mol Med 2018;41(3):1693-703.
  25. Fan CD, Sun JY, Fu XT, Hou YJ, Li Y, Yang MF, Fu XY, Sun BL. Astaxanthin attenuates homocysteine-induced cardiotoxicity in vitro and in vivo by inhibiting mitochondrial dysfunction and oxidative damage. Front Physiol 2017;8:1041.
  26. Shen H, Matsui JI, Lei D, Han L, Ohlemiller KK, Bao J. No dramatic age-related loss of hair cells and spiral ganglion neurons in Bcl-2 over-expression mice or Bax null mice. Mol Neurodegener 2010;5:28. https://doi.org/10.1186/1750-1326-5-28
  27. Chen D, Xia D, Pan Z, Xu D, Zhou Y, Wu Y, Cai N, Tang Q, Wang C, Yan M, et al. Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo. Cell Death Dis 2016;7(10):e2441. https://doi.org/10.1038/cddis.2016.334
  28. Jin WS, Kong ZL, Shen ZF, Jin YZ, Zhang WK, Chen GF. Regulation of hypoxia inducible factor-1alpha expression by the alteration of redox status in HepG2 cells. J Exp Clin Cancer Res: CR 2011;30:61. https://doi.org/10.1186/1756-9966-30-61
  29. Sharov VG, Sabbah HN, Shimoyama H, Goussev AV, Lesch M, Goldstein S. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure. Am J Pathol 1996;148(1):141-9.
  30. 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 Pharmaceut Des 2004;10(8):879-91. https://doi.org/10.2174/1381612043452901
  31. Wang Z, Liao SG, He Y, Li J, Zhong RF, He X, Liu Y, Xiao TT, Lan YY, Long QD, et al. Protective effects of fractions from Pseudostellaria heterophylla against cobalt chloride-induced hypoxic injury in H9c2 cell. J Ethnopharmacol 2013;147(2):540-5. https://doi.org/10.1016/j.jep.2013.03.053
  32. Liu B, Fu XQ, Li T, Su T, Guo H, Zhu PL, Tse AK, Liu SM, YU ZL. Computational and experimental prediction of molecules involved in the anti-melanoma action of berberine. J Ethnopharmacol 2017;208:225-35. https://doi.org/10.1016/j.jep.2017.07.023
  33. Bhattacharyya S, Pal PB, Sil PC. A 35 kD Phyllanthus niruri protein modulates iron mediated oxidative impairment to hepatocytes via the inhibition of ERKs, p38 MAPKs and activation of PI3k/Akt pathway. Food Chem Toxicol: Int J Pub Br Ind Biol Res Assoc 2013;56:119-30. https://doi.org/10.1016/j.fct.2013.02.013
  34. Bhattacharyya S, Ghosh S, Sil PC. Amelioration of aspirin induced oxidative impairment and apoptotic cell death by a novel antioxidant protein molecule isolated from the herb Phyllanthus niruri. PloS One 2014;9(2):e89026. https://doi.org/10.1371/journal.pone.0089026
  35. Chiu PY, Ko KM. Schisandrin B-induced increase in cellular glutathione level and protection against oxidant injury are mediated by the enhancement of glutathione synthesis and regeneration in AML12 and H9c2 cells. BioFactors (Oxford, England) 2006;26(4):221-30. https://doi.org/10.1002/biof.5520260401

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