DOI QR코드

DOI QR Code

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)
  • Received : 2024.03.14
  • Accepted : 2024.05.14
  • Published : 2024.06.30

Abstract

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.

Keywords

Acknowledgement

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

References

  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.  https://doi.org/10.1016/j.fertnstert.2011.09.024
  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.  https://doi.org/10.1152/ajpregu.00331.2011
  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.  https://doi.org/10.1152/ajpregu.00176.2011
  4. Dumesic DA, Lobo RA. Cancer risk and PCOS. Steroids. 2013;78(8):782-5.  https://doi.org/10.1016/j.steroids.2013.04.004
  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.  https://doi.org/10.1210/jc.2013-4109
  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.  https://doi.org/10.1111/j.1365-2249.2008.03683.x
  9. Genc B, Bozan HR, Genc S, Genc K. Stem cell therapy for multiple sclerosis. Adv Exp Med Biol. 2019;1084:145-74.  https://doi.org/10.1007/5584_2018_247
  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.  https://doi.org/10.1007/s11010-020-03946-w
  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.  https://doi.org/10.1142/S0192415X03001636
  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.  https://doi.org/10.15171/apb.2019.010
  18. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria, oxidative stress and cell death. Apoptosis. 2007;12(5):913-22.  https://doi.org/10.1007/s10495-007-0756-2
  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.  https://doi.org/10.1038/nrmicro2070
  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.  https://doi.org/10.2174/187221309787158371
  24. Uchmanowicz I. Oxidative stress, frailty and cardiovascular diseases: current evidence. Adv Exp Med Biol. 2020;1216:65-77.  https://doi.org/10.1007/978-3-030-33330-0_8
  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.  https://doi.org/10.1089/scd.2014.0484
  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.  https://doi.org/10.4103/0975-7406.163438
  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.  https://doi.org/10.1016/j.jcmgh.2021.04.015
  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.  https://doi.org/10.1016/j.yexcr.2015.08.005
  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.