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Eupatilin treatment inhibits transforming growth factor beta-induced endometrial fibrosis in vitro

  • Lee, Chang-Jin (Department of Biomedical Science, School of Life Science, CHA University) ;
  • Hong, Seon-Hwa (CHA Fertility Center Bundang, School of Medicine, CHA University) ;
  • Yoon, Min-Ji (Department of Biomedical Science, School of Life Science, CHA University) ;
  • Lee, Kyung-Ah (Department of Biomedical Science, School of Life Science, CHA University) ;
  • Choi, Dong Hee (CHA Fertility Center Bundang, School of Medicine, CHA University) ;
  • Kwon, Hwang (CHA Fertility Center Bundang, School of Medicine, CHA University) ;
  • Ko, Jung-Jae (Department of Biomedical Science, School of Life Science, CHA University) ;
  • Koo, Hwa Seon (CHA Fertility Center Bundang, School of Medicine, CHA University) ;
  • Kang, Youn-Jung (Department of Biomedical Science, School of Life Science, CHA University)
  • Received : 2019.12.11
  • Accepted : 2019.12.30
  • Published : 2020.06.30

Abstract

Objective: Endometrial fibrosis, the primary pathological feature of intrauterine adhesion, may lead to disruption of endometrial tissue structure, menstrual abnormalities, infertility, and recurrent pregnancy loss. At present, no ideal therapeutic strategy exists for this fibrotic disease. Eupatilin, a major pharmacologically active flavone from Artemisia, has been previously reported to act as a potent inducer of dedifferentiation of fibrotic tissue in the liver and lung. However, the effects of eupatilin on endometrial fibrosis have not yet been investigated. In this study, we present the first report on the impact of eupatilin treatment on transforming growth factor beta (TGF-β)-induced endometrial fibrosis. Methods: The efficacy of eupatilin on TGF-β-induced endometrial fibrosis was assessed by examining changes in morphology and the expression levels of fibrosis markers using immunofluorescence staining and quantitative real-time reverse-transcription polymerase chain reaction. Results: Eupatilin treatment significantly reduced the fibrotic activity of TGF-β-induced endometrial fibrosis in Ishikawa cells, which displayed more circular shapes and formed more colonies. Additionally, the effects of eupatilin on fibrotic markers including alpha-smooth muscle actin, hypoxia-inducible factor 1 alpha, collagen type I alpha 1 chain, and matrix metalloproteinase-2, were evaluated in TGF-β-induced endometrial fibrosis. The expression of these markers was highly upregulated by TGF-β pretreatment and recovered to the levels of control cells in response to eupatilin treatment. Conclusion: Our findings suggest that suppression of TGF-β-induced signaling by eupatilin might be an effective therapeutic strategy for the treatment of endometrial fibrosis.

Keywords

References

  1. Ebrahim N, Mostafa O, El Dosoky RE, Ahmed IA, Saad AS, Mostafa A, et al. Human mesenchymal stem cell-derived extracellular vesicles/estrogen combined therapy safely ameliorates experimentally induced intrauterine adhesions in a female rat model. Stem Cell Res Ther 2018;9:175. https://doi.org/10.1186/s13287-018-0924-z
  2. Ning J, Zhang H, Yang H. MicroRNA-326 inhibits endometrial fibrosis by regulating $TGF-{\beta}$1/Smad3 pathway in intrauterine adhesions. Mol Med Rep 2018;18:2286-92.
  3. Walton KL, Johnson KE, Harrison CA. Targeting $TGF-{\beta}$ mediated SMAD signaling for the prevention of fibrosis. Front Pharmacol 2017;8:461. https://doi.org/10.3389/fphar.2017.00461
  4. Karsdal MA, Manon-Jensen T, Genovese F, Kristensen JH, Nielsen MJ, Sand JM, et al. Novel insights into the function and dynamics of extracellular matrix in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2015;308:G807-30.
  5. Menzies D. Postoperative adhesions: their treatment and relevance in clinical practice. Ann R Coll Surg Engl 1993;75:147-53.
  6. Deans R, Abbott J. Review of intrauterine adhesions. J Minim Invasive Gynecol 2010;17:555-69. https://doi.org/10.1016/j.jmig.2010.04.016
  7. Amin TN, Saridogan E, Jurkovic D. Ultrasound and intrauterine adhesions: a novel structured approach to diagnosis and management. Ultrasound Obstet Gynecol 2015;46:131-9.
  8. Macneal K, Schwartz DA. The genetic and environmental causes of pulmonary fibrosis. Proc Am Thorac Soc 2012;9:120-5. https://doi.org/10.1513/pats.201112-055AW
  9. Pohlers D, Brenmoehl J, Loffler I, Muller CK, Leipner C, Schultze-Mosgau S, et al. TGF-beta and fibrosis in different organs: molecular pathway imprints. Biochim Biophys Acta 2009;1792:746-56. https://doi.org/10.1016/j.bbadis.2009.06.004
  10. Nanthakumar CB, Hatley RJ, Lemma S, Gauldie J, Marshall RP, Macdonald SJ. Dissecting fibrosis: therapeutic insights from the small-molecule toolbox. Nat Rev Drug Discov 2015;14:693-720. https://doi.org/10.1038/nrd4592
  11. Beanes SR, Dang C, Soo C, Ting K. Skin repair and scar formation: the central role of TGF-beta. Expert Rev Mol Med 2003;5:1-22. https://doi.org/10.1017/S1462399403005817
  12. Kramer EL, Clancy JP. $TGF{\beta}$ as a therapeutic target in cystic fibrosis. Expert Opin Ther Targets 2018;22:177-89. https://doi.org/10.1080/14728222.2018.1406922
  13. Tao Q, Wang XN, Mu YP, Feng Q, Peng JH, Liu P, et al. Dynamic change of lipid peroxidation-related protein expression and the intervention effects of Yiguanjian decoction in a rat model of CCl4-induced liver fibrosis. Zhonghua Gan Zang Bing Za Zhi 2012;20:116-21.
  14. Willis BC, Borok Z. TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 2007;293:L525-34.
  15. Biernacka A, Dobaczewski M, Frangogiannis NG. $TGF-{\beta}$ signaling in fibrosis. Growth Factors 2011;29:196-202. https://doi.org/10.3109/08977194.2011.595714
  16. Hinz B. Mechanical aspects of lung fibrosis: a spotlight on the myofibroblast. Proc Am Thorac Soc 2012;9:137-47. https://doi.org/10.1513/pats.201202-017AW
  17. Liu S, Xu SW, Kennedy L, Pala D, Chen Y, Eastwood M, et al. FAK is required for TGFbeta-induced JNK phosphorylation in fibroblasts: implications for acquisition of a matrix-remodeling phenotype. Mol Biol Cell 2007;18:2169-78. https://doi.org/10.1091/mbc.e06-12-1121
  18. Kim HS, Yoon YM, Meang MK, Park YE, Lee JY, Lee TH, et al. Reversion of in vivo fibrogenesis by novel chromone scaffolds. EBio-Medicine 2019;39:484-96.
  19. Nageen B, Sarfraz I, Rasul A, Hussain G, Rukhsar F, Irshad S, et al. Eupatilin: a natural pharmacologically active flavone compound with its wide range applications. J Asian Nat Prod Res 2020;22:1-16. https://doi.org/10.1080/10286020.2018.1492565
  20. Kang YJ, Balter B, Csizmadia E, Haas B, Sharma H, Bronson R, et al. Contribution of classical end-joining to PTEN inactivation in p53-mediated glioblastoma formation and drug-resistant survival. Nat Commun 2017;8:14013. https://doi.org/10.1038/ncomms14013
  21. Santamaria X, Cabanillas S, Cervello I, Arbona C, Raga F, Ferro J, et al. Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman's syndrome and endometrial atrophy: a pilot cohort study. Hum Reprod 2016;31:1087-96. https://doi.org/10.1093/humrep/dew042
  22. Tan J, Li P, Wang Q, Li Y, Li X, Zhao D, et al. Autologous menstrual blood-derived stromal cells transplantation for severe Asherman's syndrome. Hum Reprod 2016;31:2723-9. https://doi.org/10.1093/humrep/dew235
  23. Xiao B, Zhu Y, Huang J, Wang T, Wang F, Sun S. Exosomal transfer of bone marrow mesenchymal stem cell-derived miR-340 attenuates endometrial fibrosis. Biol Open 2019;8:bio039958.
  24. Rivera-Ortega P, Hayton C, Blaikley J, Leonard C, Chaudhuri N. Nintedanib in the management of idiopathic pulmonary fibrosis: clinical trial evidence and real-world experience. Ther Adv Respir Dis 2018;12:1753466618800618.
  25. Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821-9. https://doi.org/10.1183/09031936.00005209

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