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Protective Effects of Changbudodam-tang on Cell Death Signals on the Bone Marrow-Derived Human Mesenchymal Stem Cells via Regulation of MKK7/JNK/c-Jun Signaling Pathway

  • Hee-Jae Yoon (Department of Obstetrics and Gynecology, College of Korean Medicine, Daejeon University) ;
  • Si-Yoon Cho (Department of Obstetrics and Gynecology, College of Korean Medicine, Daejeon University) ;
  • Hyeong-Geug Kim (Department of Leukopak Research and Developement, QPS Bio-Kinetic) ;
  • Ji-Yeon Lee (Department of Obstetrics and Gynecology, College of Korean Medicine, Daejeon University)
  • 투고 : 2024.03.14
  • 심사 : 2024.05.14
  • 발행 : 2024.06.30

초록

Objectives: Polycystic ovary syndrome (PCOS) is one of the most common disorders and it shows up to 20% prevalence in reproductive-aged women populations, but no cures are available to date. We aimed to investigate the protective effects of Changbudodam-tang (CBD) on cell death signaling pathways, inflammation, and oxidative stress observed in Bone-Marrow derived human mesenchymal stem cell (BM-hMSC) by means of PCOS therapeutics in the future. Methods: BM-hMSCs were applied with cell deaths and injuries. Apoptosis and pyroptosis signals were quenched with their related signaling pathways using quantitative PCR, Western blot, and fluorescence image analysis. Results: Our data clearly displayed hydrogen peroxide- and nigericin-treated cell death signaling pathways via regulations of mitochondrial integrity and interleukin (IL)-1β at the cellular levels (p < 0.01 or 0.001). We further observed that pre-treatment with CBD showed protective effects against oxidative stress by enhancement of antioxidant components at the cellular level, with respect to both protein and mRNA expression levels (p < 0.05, 0.01 or 0.001). The mechanisms of CBD were examined by Western blot analysis, and it showed anti-cell death, anti-inflammatory, and antioxidant effects via normalizations of the Jun N-terminal kinase/mitogen-activated protein kinase kinase 7/c-Jun signaling pathways. Conclusion: This study confirmed the pharmacological properties of CBD by regulation of cellular oxidation and the inflammation-provoked cell death condition of BM-hMSCs, which is mediated by the MKK7/JNK/c-Jun signaling pathway.

키워드

과제정보

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. RS-2023-00209469).

참고문헌

  1. Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97(1):28-38.e25. 
  2. Clapp C, de la Escalera GM. Peripheral regulation of prolactin by oxytocin: focus on "systemic oxytocin induces a prolactin secretory rhythm via the pelvic nerve in ovariectomized rats". Am J Physiol Regul Integr Comp Physiol. 2011;301(3):R674-5. 
  3. Helena CV, Cristancho-Gordo R, Gonzalez-Iglesias AE, Tabak J, Bertram R, Freeman ME. Systemic oxytocin induces a prolactin secretory rhythm via the pelvic nerve in ovariectomized rats. Am J Physiol Regul Integr Comp Physiol. 2011;301(3):R676-81. 
  4. Dumesic DA, Lobo RA. Cancer risk and PCOS. Steroids. 2013;78(8):782-5. 
  5. Gonzalez F, Sia CL, Bearson DM, Blair HE. Hyperandrogenism induces a proinflammatory TNFα response to glucose ingestion in a receptor-dependent fashion. J Clin Endocrinol Metab. 2014;99(5):E848-54. 
  6. Zhang J, Bao Y, Zhou X, Zheng L. Polycystic ovary syndrome and mitochondrial dysfunction. Reprod Biol Endocrinol. 2019;17(1):67. 
  7. Mohammadi M. Oxidative stress and polycystic ovary syndrome: a brief review. Int J Prev Med. 2019;10:86. 
  8. Choi JJ, Yoo SA, Park SJ, Kang YJ, Kim WU, Oh IH, et al. Mesenchymal stem cells overexpressing interleukin-10 attenuate collagen-induced arthritis in mice. Clin Exp Immunol. 2008;153(2):269-76. 
  9. Genc B, Bozan HR, Genc S, Genc K. Stem cell therapy for multiple sclerosis. Adv Exp Med Biol. 2019;1084:145-74. 
  10. Chen S, Tang K, Hu P, Tan S, Yang S, Yang C, et al. Atractylenolide III alleviates the apoptosis through inhibition of autophagy by the mTOR-dependent pathway in alveolar macrophages of human silicosis. Mol Cell Biochem. 2021;476(2):809-18. 
  11. Lin MJ, Chen HW, Liu PH, Cheng WJ, Kuo SL, Kao MC. The prescription patterns of traditional Chinese medicine for women with polycystic ovary syndrome in Taiwan: a nationwide population-based study. Medicine (Baltimore). 2019;98(24):e15890. 
  12. Hu W, Xie N, Zhu H, Jiang Y, Ding S, Ye S, et al. The effective compounds and mechanisms of Cang-Fu-Dao-Tan Formula in treating polycystic ovary syndrome based on UPLC/Q-TOF-MS/MS, network pharmacology and molecular experiments. J Pharm Biomed Anal. 2024;239:115867. 
  13. Lee JC, Pak SC, Lee SH, Lim SC, Bai YH, Jin CS, et al. The effect of herbal medicine on nerve growth factor in estradiol valerate-induced polycystic ovaries in rats. Am J Chin Med. 2003;31(6):885-95. 
  14. Li MF, Zhou XM, Li XL. The effect of berberine on polycystic ovary syndrome patients with insulin resistance (PCOS-IR): a meta-analysis and systematic review. Evid Based Complement Alternat Med. 2018;2018:2532935. 
  15. Chugh RM, Park HS, El Andaloussi A, Elsharoud A, Esfandyari S, Ulin M, et al. Mesenchymal stem cell therapy ameliorates metabolic dysfunction and restores fertility in a PCOS mouse model through interleukin-10. Stem Cell Res Ther. 2021;12(1):388. 
  16. Kauffman AS, Thackray VG, Ryan GE, Tolson KP, Glidewell-Kenney CA, Semaan SJ, et al. A novel letrozole model recapitulates both the reproductive and metabolic phenotypes of polycystic ovary syndrome in female mice. Biol Reprod. 2015;93(3):69. 
  17. Nouri F, Nematollahi-Mahani SN, Sharifi AM. Preconditioning of mesenchymal stem cells with non-toxic concentration of hydrogen peroxide against oxidative stress induced cell death: the role of hypoxia-inducible factor-1. Adv Pharm Bull. 2019;9(1):76-83. 
  18. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria, oxidative stress and cell death. Apoptosis. 2007;12(5):913-22. 
  19. Lee C, Nam JS, Lee CG, Park M, Yoo CM, Rhee HW, et al. Analysing the mechanism of mitochondrial oxidation-induced cell death using a multifunctional iridium(III) photosensitiser. Nat Commun. 2021;12(1):26. 
  20. Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009;7(2):99-109. 
  21. Yu P, Zhang X, Liu N, Tang L, Peng C, Chen X. Pyroptosis: mechanisms and diseases. Signal Transduct Target Ther. 2021;6(1):128. 
  22. Li Y, Jiang Q. Uncoupled pyroptosis and IL-1β secretion downstream of inflammasome signaling. Front Immunol. 2023;14:1128358. 
  23. Khansari N, Shakiba Y, Mahmoudi M. Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat Inflamm Allergy Drug Discov. 2009;3(1):73-80. 
  24. Uchmanowicz I. Oxidative stress, frailty and cardiovascular diseases: current evidence. Adv Exp Med Biol. 2020;1216:65-77. 
  25. Atashi F, Modarressi A, Pepper MS. The role of reactive oxygen species in mesenchymal stem cell adipogenic and osteogenic differentiation: a review. Stem Cells Dev. 2015;24(10):1150-63. 
  26. Navaratnarajah T, Bellmann M, Seibt A, Anand R, Degistirici O, Meisel R, et al. Mesenchymal stem cells improve redox homeostasis and mitochondrial respiration in fibroblast cell lines with pathogenic MT-ND3 and MT-ND6 variants. Stem Cell Res Ther. 2022;13(1):256. 
  27. Irato P, Santovito G. Enzymatic and non-enzymatic molecules with antioxidant function. Antioxidants (Basel). 2021;10(4):579. 
  28. Jeeva JS, Sunitha J, Ananthalakshmi R, Rajkumari S, Ramesh M, Krishnan R. Enzymatic antioxidants and its role in oral diseases. J Pharm Bioallied Sci. 2015;7 Suppl 2:S331-3. 
  29. Fang Z, Kim HG, Huang M, Chowdhury K, Li MO, Liangpunsakul S, et al. Sestrin proteins protect against lipotoxicity-induced oxidative stress in the liver via suppression of c-Jun N-terminal kinases. Cell Mol Gastroenterol Hepatol. 2021;12(3):921-42. 
  30. Semba T, Sammons R, Wang X, Xie X, Dalby KN, Ueno NT. JNK signaling in stem cell self-renewal and differentiation. Int J Mol Sci. 2020;21(7):2613. 
  31. Gu H, Huang Z, Yin X, Zhang J, Gong L, Chen J, et al. Role of c-Jun N-terminal kinase in the osteogenic and adipogenic differentiation of human adipose-derived mesenchymal stem cells. Exp Cell Res. 2015;339(1):112-21. 
  32. Serna R, Ramrakhiani A, Hernandez JC, Chen CL, Nakagawa C, Machida T, et al. c-JUN inhibits mTORC2 and glucose uptake to promote self-renewal and obesity. iScience. 2022;25(6):104325.