Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Fisetin Protects C2C12 Mouse Myoblasts from Oxidative Stress-Induced Cytotoxicity through Regulation of the Nrf2/HO-1 Signaling

  • Cheol Park (Division of Basic Sciences, College of Liberal Studies, Dong-eui University) ;
  • Hee-Jae Cha (Department of Parasitology and Genetics, Kosin University College of Medicine) ;
  • Da Hye Kim (Anti-Aging Research Center and Core-Facility Center for Tissue Regeneration, Dong-eui University) ;
  • Chan-Young Kwon (Department of Oriental Neuropsychiatry, Dong-eui University College of Korean Medicine) ;
  • Shin-Hyung Park (Department of Pathology, Dong-eui University College of Korean Medicine) ;
  • Su Hyun Hong (Anti-Aging Research Center and Core-Facility Center for Tissue Regeneration, Dong-eui University) ;
  • EunJin Bang (Anti-Aging Research Center and Core-Facility Center for Tissue Regeneration, Dong-eui University) ;
  • Jaehun Cheong (Department of Molecular Biology, Pusan National University) ;
  • Gi-Young Kim (Department of Marine Life Science, Jeju National University) ;
  • Yung Hyun Choi (Anti-Aging Research Center and Core-Facility Center for Tissue Regeneration, Dong-eui University)
  • Received : 2022.12.26
  • Accepted : 2023.01.13
  • Published : 2023.05.28
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Abstract

Fisetin is a bioactive flavonol molecule and has been shown to have antioxidant potential, but its efficacy has not been fully validated. The aim of the present study was to investigate the protective efficacy of fisetin on C2C12 murine myoblastjdusts under hydrogen peroxide (H2O2)-induced oxidative damage. The results revealed that fisetin significantly weakened H2O2-induced cell viability inhibition and DNA damage while blocking reactive oxygen species (ROS) generation. Fisetin also significantly alleviated cell cycle arrest by H2O2 treatment through by reversing the upregulation of p21WAF1/CIP1 expression and the downregulation of cyclin A and B levels. In addition, fisetin significantly blocked apoptosis induced by H2O2 through increasing the Bcl-2/Bax ratio and attenuating mitochondrial damage, which was accompanied by inactivation of caspase-3 and suppression of poly(ADP-ribose) polymerase cleavage. Furthermore, fisetin-induced nuclear translocation and phosphorylation of Nrf2 were related to the increased expression and activation of heme oxygenase-1 (HO-1) in H2O2-stimulated C2C12 myoblasts. However, the protective efficacy of fisetin on H2O2-mediated cytotoxicity, including cell cycle arrest, apoptosis and mitochondrial dysfunction, were greatly offset when HO-1 activity was artificially inhibited. Therefore, our results indicate that fisetin as an Nrf2 activator effectively abrogated oxidative stress-mediated damage in C2C12 myoblasts.

Keywords

Acknowledgement

This research was funded by the National Research Foundation of Korea Grant (2021R1A2C2009549) and Korea Environment Industry & Technology Institute (KEITI) through Project to Make Multi-ministerial National Biological Research Resources More Advanced funded by Korea Ministry of Environment (MOE) (No. 2021003420002).

References

  1. Szarka A, Lorincz T, Hajdinak P. 2022, Friend or foe: the relativity of (anti) oxidative agents and pathways. Int. J. Mol. Sci. 23: 5188.
  2. Redza-Dutordoir M, Averill-Bates DA. 2021. Interactions between reactive oxygen species and autophagy: special issue: death mechanisms in cellular homeostasis. Biochim. Biophys. Acta. Mol. Cell. Res. 1868: 119041.
  3. Zhang B, Pan C, Feng C, Yan C, Yu Y, Chen Z, et al. 2022. Role of mitochondrial reactive oxygen species in homeostasis regulation. Redox Rep. 27: 45-52. https://doi.org/10.1080/13510002.2022.2046423
  4. Checa J, Aran JM. 2020. Reactive oxygen species: drivers of physiological and pathological processes. J. Inflamm. Res. 13: 1057-1073. https://doi.org/10.2147/JIR.S275595
  5. Liu K, Luo M, Wei S. 2019. The bioprotective effects of polyphenols on metabolic syndrome against oxidative stress: evidences and perspectives. Oxid. Med. Cell. Longev. 2019: 6713194.
  6. Rana A, Samtiya M, Dhewa T, Mishra V, Aluko RE. 2022. Health benefits of polyphenols: a concise review. J. Food Biochem. 13: e14264.
  7. Mehta P, Pawar A, Mahadik K, Bothiraja C. 2018. Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. Biomed. Pharmacother. 106: 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079
  8. Grynkiewicz G, Demchuk OM. 2019. New perspectives for fisetin. Front. Chem. 7: 697.
  9. Prem PN, Sivakumar B, Boovarahan SR, Kurian GA. 2022. Recent advances in potential of fisetin in the management of myocardial ischemia-reperfusion injury-A systematic review. Phytomedicine 101: 154123.
  10. Farooqi AA, Naureen H, Zahid R, Youssef L, Attar R, Xu B. 2021. Chemopreventive role of fisetin: regulation of cell signaling pathways in different cancers. Pharmacol. Res. 172: 105784.
  11. Hanneken A, Lin FF, Johnson J, Maher P. 2006. Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death. Invest. Ophthalmol. Vis. Sci. 47: 3164-3177. https://doi.org/10.1167/iovs.04-1369
  12. Park C, Noh JS, Jung Y, Leem SH, Hyun JW, Chang YC, et al. 2022. Fisetin attenuated oxidative stress-induced cellular damage in ARPE-19 human retinal pigment epithelial cells through Nrf2-mediated activation of heme oxygenase-1. Front. Pharmacol. 13: 927898.
  13. Pei F, Pei H, Su C, Du L, Wang J, Xie F, et al. 2021. Fisetin alleviates neointimal hyperplasia via PPARγ/PON2 antioxidative pathway in SHR rat artery injury model. Oxid. Med. Cell. Longev. 2021: 6625517.
  14. Rodius S, de Klein N, Jeanty C, Sanchez-Iranzo H, Crespo I, Ibberson M, et al. 2020. Fisetin protects against cardiac cell death through reduction of ROS production and caspases activity. Sci. Rep. 10: 2896.
  15. Dong B, Liu C, Xue R, Wang Y, Sun Y, Liang Z, et al. 2018. Fisetin inhibits cardiac hypertrophy by suppressing oxidative stress. J. Nutr. Biochem. 62: 221-229. https://doi.org/10.1016/j.jnutbio.2018.08.010
  16. Park C, Lee H, Hong S, Molagoda IMN, Jeong JW, Jin CY, et al. 2021. Inhibition of lipopolysaccharide-induced inflammatory and oxidative responses by trans-cinnamaldehyde in C2C12 myoblasts. Int. J. Med. Sci. 18: 2480-2492. https://doi.org/10.7150/ijms.59169
  17. Jeong MJ, Lim DS, Kim SO, Park C, Leem SH, Lee H, et al. 2022. Protection of oxidative stress-induced DNA damage and apoptosis by rosmarinic acid in murine myoblast C2C12 cells. Biotechnol. Bioprocess Eng. 27: 171-182. https://doi.org/10.1007/s12257-021-0248-1
  18. Lee H, Kim DH, Kim JH, Park SK, Jeong JW, Kim MY, et al. 2021. Urban aerosol particulate matter promotes necrosis and autophagy via reactive oxygen species-mediated cellular disorders that are accompanied by cell cycle arrest in retinal pigment epithelial cells. Antioxidants (Basel) 10: 149.
  19. Mukherjee S, Park JP, Yun JW. 2022. Carboxylesterase3 (Ces3) interacts with bone morphogenetic protein 11 and promotes differentiation of osteoblasts via Smad1/5/9 pathway. Biotechnol. Bioprocess Eng. 27: 1-16. https://doi.org/10.1007/s12257-021-0133-y
  20. Choi YH. 2022. Tacrolimus induces apoptosis in leukemia Jurkat cells through inactivation of the reactive oxygen species-dependent phosphoinositide-3-kinase/Akt signaling pathway. Biotechnol. Bioprocess Eng. 27: 183-192. https://doi.org/10.1007/s12257-021-0199-6
  21. Abrigo J, Simon F, Cabrera D, Vilos C, Cabello-Verrugio C. 2019. Mitochondrial dysfunction in skeletal muscle pathologies. Curr. Protein Pept. Sci. 20: 536-546. https://doi.org/10.2174/1389203720666190402100902
  22. Sambasivan R, Tajbakhsh S. 2015. Adult skeletal muscle stem cells. Results Probl. Cell Differ. 56: 191-213. https://doi.org/10.1007/978-3-662-44608-9_9
  23. Santa-Gonzalez GA, Gomez-Molina A, Arcos-Burgos M, Meyer JN, Camargo M. 2016. Distinctive adaptive response to repeated exposure to hydrogen peroxide associated with upregulation of DNA repair genes and cell cycle arrest. Redox Biol. 9: 124-133. https://doi.org/10.1016/j.redox.2016.07.004
  24. Yu Y, Cui Y, Niedernhofer LJ, Wang Y. 2016. Occurrence, biological consequences, and human health relevance of oxidative stress-induced DNA damage. Chem. Res. Toxicol. 29: 2008-2039. https://doi.org/10.1021/acs.chemrestox.6b00265
  25. Li H, Guan K, Liu D, Liu M. 2022. Identification of mitochondria-related hub genes in sarcopenia and functional regulation of MFG-E8 on ROS-mediated mitochondrial dysfunction and cell cycle arrest. Food Funct. 13: 624-638. https://doi.org/10.1039/D1FO02610K
  26. Habibi P, Ostad SN, Heydari A, Aliebrahimi S, Montazeri V, Foroushani AR, et al. 2022. Effect of heat stress on DNA damage: a systematic literature review. Int. J. Biometeorol. 66: 2147-2158. https://doi.org/10.1007/s00484-022-02351-w
  27. Kang KA, Piao MJ, Kim KC, Cha JW, Zheng J, Yao CW, et al. 2014. Fisetin attenuates hydrogen peroxide-induced cell damage by scavenging reactive oxygen species and activating protective functions of cellular glutathione system. In Vitro Cell. Dev. Biol. Anim. 50: 66-74. https://doi.org/10.1007/s11626-013-9681-6
  28. Jenkins T, Gouge J. 2021. Nrf2 in cancer, detoxifying enzymes and cell death programs. Antioxidants (Basel) 10: 1030.
  29. Shaw P, Chattopadhyay A. 2020. Nrf2-ARE signaling in cellular protection: mechanism of action and the regulatory mechanisms. J. Cell. Physiol. 235: 3119-3130. https://doi.org/10.1002/jcp.29219
  30. Yu C, Xiao JH. 2021. The Keap1-Nrf2 system: a mediator between oxidative stress and aging. Oxid. Med. Cell. Longev. 2021: 6635460.
  31. Yu ZY, Ma D, He ZC, Liu P, Huang J, Fang Q, et al. 2018. Heme oxygenase-1 protects bone marrow mesenchymal stem cells from iron overload through decreasing reactive oxygen species and promoting IL-10 generation. Exp. Cell Res. 362: 28-42. https://doi.org/10.1016/j.yexcr.2017.10.029
  32. Cordaro M, D'Amico R, Fusco R, Peritore AF, Genovese T, Interdonato L, et al. 2022. Discovering the effects of fisetin on NF-κB/NLRP-3/NRF-2 molecular pathways in a mouse model of vascular dementia induced by repeated bilateral carotid occlusion. Biomedicines 10: 1448.
  33. Yen JH, Wu PS, Chen SF, Wu MJ. 2017. Fisetin protects PC12 cells from tunicamycin-mediated cell death via reactive oxygen species scavenging and modulation of Nrf2-driven gene expression, SIRT1 and MAPK signaling in PC12 cells. Int. J. Mol. Sci. 18: 852.
  34. Mubarok W, Elvitigala KCML, Nakahata M, Kojima M, Sakai S. 2022. Modulation of cell-cycle progression by hydrogen peroxide-mediated cross-linking and degradation of cell-adhesive hydrogels. Cells 11: 881.
  35. Ding Y, Zhang Z, Yue Z, Ding L, Zhou Y, Huang Z, et al. 2019. Rosmarinic acid ameliorates H2O2-induced oxidative stress in L02 cells through MAPK and Nrf2 pathways. Rejuvenation Res. 22: 289-288.
  36. Dai Y, Jin F, Wu W, Kumar SK. 2019. Cell cycle regulation and hematologic malignancies. Blood Sci. 1: 34-43. https://doi.org/10.1097/BS9.0000000000000009
  37. Taylor WR, Stark GR. 2001. Regulation of the G2/M transition by p53. Oncogene 20: 1803-1815. https://doi.org/10.1038/sj.onc.1204252
  38. Drysch M, Schmidt SV, Becerikli M, Reinkemeier F, Dittfeld S, Wagner JM, et al. 2021. Myostatin deficiency protects C2C12 cells from oxidative stress by inhibiting intrinsic activation of apoptosis. Cells 10: 1680.
  39. Choi YH. 2021. Trans-cinnamaldehyde protects C2C12 myoblasts from DNA damage, mitochondrial dysfunction and apoptosis caused by oxidative stress through inhibiting ROS production. Genes Genomics 43: 303-312. https://doi.org/10.1007/s13258-020-00987-9
  40. Yu LM, Zhang WH, Han XX, Li YY, Lu Y, Pan J, et al. 2019. Hypoxia-induced ROS contribute to myoblast pyroptosis during obstructive sleep apnea via the NF-κB/HIF-1α signaling pathway. Oxid. Med. Cell. Longev. 2019: 4596368.
  41. Tiwari S, Dewry RK, Srivastava R, Nath S, Mohanty TK. 2022. Targeted antioxidant delivery modulates mitochondrial functions, ameliorates oxidative stress and preserve sperm quality during cryopreservation. Theriogenology 179: 22-31. https://doi.org/10.1016/j.theriogenology.2021.11.013
  42. Bock FJ, Tait SWG. 2020. Mitochondria as multifaceted regulators of cell death. Nat. Rev. Mol. Cell. Biol. 21: 85-100. https://doi.org/10.1038/s41580-019-0173-8
  43. Kiraz Y, Adan A, Kartal Yandim M, Baran Y. 2016. Major apoptotic mechanisms and genes involved in apoptosis. Tumour Biol. 37: 8471-86. https://doi.org/10.1007/s13277-016-5035-9
  44. Sarwar MS, Xia YX, Liang ZM, Tsang SW, Zhang HJ. 2020. Mechanistic pathways and molecular targets of plant-derived anticancer ent-Kaurane diterpenes. Biomolecules 10: 144.