Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Proteomic analyses reveal that ginsenoside Rg3(S) partially reverses cellular senescence in human dermal fibroblasts by inducing peroxiredoxin

  • Jang, Ik-Soon (Biological Disaster Analysis Group, Korea Basic Science Institute) ;
  • Jo, Eunbi (Biological Disaster Analysis Group, Korea Basic Science Institute) ;
  • Park, Soo Jung (Department of Sasang Constitutional Medicine, College of Korean Medicine, Woosuk University) ;
  • Baek, Su Jeong (Biological Disaster Analysis Group, Korea Basic Science Institute) ;
  • Hwang, In-Hu (Neuroscience Research Institute, Korea University College of Medicine) ;
  • Kang, Hyun Mi (Bio & Health Research Institute, ACT (Advanced Cosmeceutical Technology)) ;
  • Lee, Je-Ho (Biological Disaster Analysis Group, Korea Basic Science Institute) ;
  • Kwon, Joseph (Biological Disaster Analysis Group, Korea Basic Science Institute) ;
  • Son, Junik (Chung-Ang University College of Medicine) ;
  • Kwon, Ho Jeong (Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University) ;
  • Choi, Jong-Soon (Biological Disaster Analysis Group, Korea Basic Science Institute)
  • Received : 2018.01.08
  • Accepted : 2018.07.30
  • Published : 2020.01.15
Download PDF
⟨ Previous Next ⟩

Abstract

Background: The cellular senescence of primary cultured cells is an irreversible process characterized by growth arrest. Restoration of senescence by ginsenosides has not been explored so far. Rg3(S) treatment markedly decreased senescence-associated β-galactosidase activity and intracellular reactive oxygen species levels in senescent human dermal fibroblasts (HDFs). However, the underlying mechanism of this effect of Rg3(S) on the senescent HDFs remains unknown. Methods: We performed a label-free quantitative proteomics to identify the altered proteins in Rg3(S)-treated senescent HDFs. Upregulated proteins induced by Rg3(S) were validated by real-time polymerase chain reaction and immunoblot analyses. Results: Finally, 157 human proteins were identified, and variable peroxiredoxin (PRDX) isotypes were highly implicated by network analyses. Among them, the mitochondrial PRDX3 was transcriptionally and translationally increased in response to Rg3(S) treatment in senescent HDFs in a time-dependent manner. Conclusion: Our proteomic approach provides insights into the partial reversing effect of Rg3 on senescent HDFs through induction of antioxidant enzymes, particularly PRDX3.

Keywords

References

  1. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013;153:1194-217. https://doi.org/10.1016/j.cell.2013.05.039
  2. Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes Dev 2014;28:99-114. https://doi.org/10.1101/gad.235184.113
  3. Watanabe K, Shibuya S, Koyama H, Ozawa Y, Toda T, Yokote K, Shimizu T. Sod1 loss induces intrinsic superoxide accumulation leading to p53-mediated growth arrest and apoptosis. Int J Mol Sci 2013;14:10998-1010. https://doi.org/10.3390/ijms140610998
  4. Neumann CA, Krause DS, Carman CV, Das S, Dubey DP, Abraham JL, Bronson RT, Fujiwara Y, Orkin SH, Van Etten RA. Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defense and tumour suppression. Nature 2003;424:561-5. https://doi.org/10.1038/nature01819
  5. Han YH, Kim HS, Kim JM, Kim SK, Yu DY, Moon EY. Inhibitory role of peroxiredoxin II (Prdx II) on cellular senescence. FEBS Lett 2005;579:4897-902. https://doi.org/10.1016/j.febslet.2005.07.049
  6. Pandey KB, Rizvi SI. Resveratrol up-regulates the erythrocyte plasma membrane redox system and mitigates oxidation-induced alterations in erythrocytes during aging in humans. Rejuvenation Res 2013;16:232-40. https://doi.org/10.1089/rej.2013.1419
  7. Yokozawa T, Satoh A, Cho EJ. Ginsenoside-Rd attenuates oxidative damage related to aging in senescence-accelerated mice. J Pharm Pharmacol 2004;56:107-13. https://doi.org/10.1211/0022357022449
  8. Zhao HF, Li Q, Li Y. Long-term ginsenoside administration prevents memory loss in aged female C57BL/6J mice by modulating the redox status and upregulating the plasticity-related proteins in hippocampus. Neuroscience 2011;183:189-202. https://doi.org/10.1016/j.neuroscience.2011.03.048
  9. Oh SJ, Oh Y, Rhu IW, Kim K, Lim CJ. Protective properties of ginsenoside Rb3 against UV-B radiation-induced oxidative stress in HaCaT keratinocytes. Biosci Biotechnol Biochem 2015;80:95-103. https://doi.org/10.1080/09168451.2015.1075862
  10. Chen Y, Zhao Z, Chen H, Brand E, Yi T, Qin M, Liang Z. Determination of ginsenosides in Asian and American ginsengs by liquid chromatographyquadrupole/time-of-flight MS: assessing variations based on morphological characteristics. J Ginseng Res 2017;41:10-22. https://doi.org/10.1016/j.jgr.2015.12.004
  11. Wang CZ, Aung HH, Zhang B, Sun S, Li XL, He H, Xie JT, He TC, Du W, Yuan CS. Chemopreventive effects of heat-processed Panax quinquefolius root on human breast cancer cells. Anticancer Res 2008;28:2545-51.
  12. Jeong D, Irfan M, Kim SD, Kim S, Oh JH, Park CK, Kim HK, Rhee MH. Ginsenoside Rg3-enriched Red Ginseng Extract Inhibits Platelet Activation and in vivo thrombus formation. J Ginseng Res 2017;41:548-55. https://doi.org/10.1016/j.jgr.2016.11.003
  13. Zhang H, Li Z, Zhou Z, Yang H, Zhong Z, Lou C. Antidepressant-like effects of ginsenosides: a comparison of ginsenoside Rb3 and its four deglycosylated derivatives, Rg3, Rh2, compound K, and 20-protopanaxadiol in mice models of despair. Pharmacol Biochem Behav 2016;140:17-26. https://doi.org/10.1016/j.pbb.2015.10.018
  14. Hou J, Kim S, Sung C, Choi C. Ginsenoside Rg3 prevents oxidative stressinduced astrocytic senescence and ameliorates senescence paracrine effects on glioblastoma. Molecules 2017;22:E1516.
  15. Peng Y, Zhang R, Kong L, Shen Y, Xu D, Zheng F, Liu J, Wu Q, Jia B, Zhang J. Ginsenoside Rg3 inhibits the senescence of prostate stromal cells through down-regulation of interleukin 8 expression. Oncotarget 2017;8:64779-92. https://doi.org/10.18632/oncotarget.17616
  16. Zhang F, Li M, Wu X, Hu Y, Cao Y, Wang X, Xiang S, Li H, Jiang L, Tan Z, et al. 20(S)-ginsenoside Rg3 promotes senescence and apoptosis in gallbladder cancer cells via the p53 pathway. Drug Des Devel Ther 2015;9:3969-87.
  17. Lim CJ, Choi WY, Jung HJ. Stereoselective skin anti-photoaging propertied of ginsenoside Rg3 in UV-B-irradiated keratinocytes. Biol Pharm Bull 2014;37:1583-90. https://doi.org/10.1248/bpb.b14-00167
  18. Sohn EJ, Kim JM, Kang SH, Kwon J, An HJ, Sung JS, Cho KA, Jang IS, Choi JS. Restoring effects of natural anti-oxidant quercetin on cellular senescent human dermal fibroblasts. Am J Chin Med 2018;46:853-73. https://doi.org/10.1142/s0192415x18500453
  19. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, et al. A biomarker that identified senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995;92:9363-7. https://doi.org/10.1073/pnas.92.20.9363
  20. Eruslanov E, Kusmartsev S. Identification of ROS using oxidized DCFDA and flow-cytometry. Meth Mol Biol 2010;594:57-72. https://doi.org/10.1007/978-1-60761-411-1_4
  21. Yu H, Wakim B, Li M, Halligan B, Tint GS, Patel SB. Quantifying rat proteins in neonatal mouse brain by 'tube-gel' protein digestion label-free shotgun proteomics. Proteome Sci 2007;5:17. https://doi.org/10.1186/1477-5956-5-17
  22. Kwon J, Park SH, Park C, Kwon SO, Choi JS. Analysis of membrane proteome by data-dependent LC-MS/MS combined with data-independent LC-MSE technique. J Anal Sci Tech 2010;1:78-85. https://doi.org/10.5355/JAST.2010.78
  23. Galbiati F, Volonte D, Liu J, Capozza F, Frank PG, Zhu I, Pestell RG, Lisanti MP. Caveolin-1 expression negatively regulates cell cycle progression by inducing $G_{0}/G_{1}$ arrest via a $p53/p21^{WAF1/Cip1}$-dependent mechanism. Mol Biol Cell 2001;12:2229-44. https://doi.org/10.1091/mbc.12.8.2229
  24. Li SG, Yan MZ, Zhang D, Ye M, Deng JJ. Effects of ginsenoside Rg1 on the senescence of vascular smooth muscle cells. Genet Mol Res 2016;15:15038409.
  25. Chen C, Mu XY, Zhou Y, Shun K, Geng S, Liu J, Wang JW, Chen J, Li TY, Wang YP. Ginsenoside Rg1 enhances the resistance of hematopoietic stem/progenitor cells to radiation-induced aging in mice. Acta Pharmacol Sin 2014;35:143-50. https://doi.org/10.1038/aps.2013.136
  26. Wei X, Su F, Su X, Hu T, Hu S. Stereospecific antioxidant effects of ginsenoside Rg3 on oxidative stress induced by cyclophosphamide in mice. Fitoterapia 2012;83:636-42. https://doi.org/10.1016/j.fitote.2012.01.006
  27. Park MW, Ha J, Chung SH. 20(S)-ginsenoside Rg3 enhances glucosestimulated insulin secretion and activates AMPK. Biol Pharm Bull 2008;31:748-51. https://doi.org/10.1248/bpb.31.748
  28. Liu JP, Lu D, Nicholson RC, Zao WJ, Li PY, Wang F. Toxicity of a novel antitumor agent 20(S)-ginsenoside Rg3 via CHOP-mediated DR5 upregulation in human hepatocellular carcinoma cells. Mol Cancer Ther 2012;12:274-85. https://doi.org/10.1158/1535-7163.MCT-12-0054
  29. Xia T, Wang YN, Zhou CX, Wu LM, Liu Y, Zeng QH, Zhang XL, Yao JH, Wang M, Fang JP. Ginsenoside Rh2 and Rg3 inhibit cell proliferation and induce apoptosis by increasing mitochondrial reactive oxygen species in human leukemia Jurkat cells. Mol Med Rep 2017;15:3591-8. https://doi.org/10.3892/mmr.2017.6459
  30. Bak MJ, Jeong WS, Kim KB. Detoxifying effect of fermented black ginseng on $H_{2}O_{2}$-induced oxidative stress in HepG2 cells. Int J Mol Med 2014;34:1516-22. https://doi.org/10.3892/ijmm.2014.1972
  31. Xing W, Yang L, Peng Y, Wang Q, Gao M, Yang M, Xiao X. Ginsenoside Rg3 attenuates sepsis-induced injury and mitochondrial dysfunction in liver via AMPL-mediated autophagy flux. Biosci Rep 2017;39:20170934.
  32. Moon YJ, Kwon J, Yun SH, Lim HL, Kim MS, Kang SG, Lee JH, Choi JS, Kim SI, Chung YH. Proteome analyses of hydrogen-producing hyperthermophilic archaeon Thermococcus onnurineus NA1 in different one-carbon substrate culture conditions. Mol Cell Proteomics 2012;11:M111. 015420.
  33. Mao Q, Zhang PH, Yang J, Xu JD, Kong M, Shen H, Zhu H, Bai M, Zhou L, Li GF, et al. iTRAQ-based proteomic analysis of ginsenoside F2 on human gastric carcinoma cells SGC7901. Evidence Based Comp Altern Med 2016:2635483.
  34. Jung KJ, Kim DH, Lee EK, Song CW, Yu BP, Chung HY. Oxidative stress induces inactivation of protein phosphatase 2A, promoting proinflammatory $NF-{\kappa}B$ inaged rat kidney. Free Rad Biol Med 2013;61:206-17. https://doi.org/10.1016/j.freeradbiomed.2013.04.005
  35. Wu WB, Menon R, Xu YY, Zhao JR, Wang YL, Liu Y, Zhang HJ. Downregulation of peroxiredoxin-3 by hydrophobic bile acid induces mitochondrial dysfunction and cellular senescence in human trophoblasts. Sci Rep 2016;6:38946. https://doi.org/10.1038/srep38946
  36. Jin DY, Chae HZ, Rhee SG, Jeang KT. Regulatory role for a novel human thioreoxin peroxidase in NF-B activation. J Biol Chem 1997;272:30952-61. https://doi.org/10.1074/jbc.272.49.30952
  37. Rhee SG, Kang SW, Jeong W, Chang TS, Wang KS, Woo HA. Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. Curr Opin Cell Biol 2005;17:183-9. https://doi.org/10.1016/j.ceb.2005.02.004
  38. Koussounadis A, Langdon SP, Um IH, Harrison DH, Smith VA. Relationship between differentially expressed mRNA and mRNA-protein correlations in a xenograft model system. Sci Rep 2015;5:10775. https://doi.org/10.1038/srep10775
  39. Ivanina AV, Sokolova IM, Sukhotin AA. Oxidative stress and expression of chaperones in aging mollusks. Comp Biochem Physiol B Biochem Mol Biol 2008;150:53-61. https://doi.org/10.1016/j.cbpb.2008.01.005
  40. Rea IM, McNerlan S, Pckley AG. Serum heat shock protein and anti-heat shock protein antibody levels in aging. Exp Gerontol 2001;36:341-52. https://doi.org/10.1016/S0531-5565(00)00215-1
  41. Lee YH, Lee JC, Moon HJ, Jung Je, Sharma M, Park BH, Yi HK, Jhee EC. Differential effect of oxidative stress on the apoptosis of early and late passage human diploid fibroblasts: implication of heat shock protein 60. Cell Biochem Funct 2008;26:502-8. https://doi.org/10.1002/cbf.1473
  42. Chen L, Na R, Ran Q. Enhanced defense against mitochondrial hydrogen peroxide attenuates age-associated cognition decline. Neurobiol Aging 2014;35:2552-61. https://doi.org/10.1016/j.neurobiolaging.2014.05.007
  43. Olahova M, Veal EA. A peroxiredoxin, PRDX-2, is required for insulin secretion and insulin/IIS-dependent regulation of stress resistance and longevity. Aging Cell 2015;14:558-68. https://doi.org/10.1111/acel.12321
  44. Kayashima Y, Yamakawa-Kobayashi K. Involvement of Prx3, a Drosophila ortholog of the thiol-dependent peroxidase PRDX3, in age-dependent oxidative stress resistance. Biomed Res 2012;33:319-22. https://doi.org/10.2220/biomedres.33.319

Cited by

  1. Activation of Ca 2+ ‐AMPK‐mediated autophagy by ginsenoside Rg3 attenuates cellular senescence in human dermal fibroblasts vol.11, pp.8, 2021, https://doi.org/10.1002/ctm2.521