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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Genistein alleviates pulmonary fibrosis by inactivating lung fibroblasts

  • Seung-hyun Kwon (Veterans Medical Research Institute, Veterans Health Service Medical Center) ;
  • Hyunju Chung (Core Research Laboratory, Medical Science Research Institute, Kyung Hee University Hospital at Gangdong) ;
  • Jung-Woo Seo (Core Research Laboratory, Medical Science Research Institute, Kyung Hee University Hospital at Gangdong) ;
  • Hak Su Kim (Veterans Medical Research Institute, Veterans Health Service Medical Center)
  • Received : 2023.06.15
  • Accepted : 2023.09.24
  • Published : 2024.03.31
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Abstract

Pulmonary fibrosis is a serious lung disease that occurs predominantly in men. Genistein is an important natural soybean-derived phytoestrogen that affects various biological functions, such as cell migration and fibrosis. However, the antifibrotic effects of genistein on pulmonary fibrosis are largely unknown. The antifibrotic effects of genistein were evaluated using in vitro and in vivo models of lung fibrosis. Proteomic data were analyzed using nano-LC-ESI-MS/MS. Genistein significantly reduced transforming growth factor (TGF)-β1-induced expression of collagen type I and α-smooth muscle actin (SMA) in MRC-5 cells and primary fibroblasts from patients with idiopathic pulmonary fibrosis (IPF). Genistein also reduced TGF-β1-induced expression of p-Smad2/3 and p-p38 MAPK in fibroblast models. Comprehensive protein analysis confirmed that genistein exerted an anti-fibrotic effect by regulating various molecular mechanisms, such as unfolded protein response, epithelial mesenchymal transition (EMT), mammalian target of rapamycin complex 1 (mTORC1) signaling, cell death, and several metabolic pathways. Genistein was also found to decrease hydroxyproline levels in the lungs of BLM-treated mice. Genistein exerted an anti-fibrotic effect by preventing fibroblast activation, suggesting that genistein could be developed as a pharmacological agent for the prevention and treatment of pulmonary fibrosis.

Keywords

Acknowledgement

We would like to thank Editage (www.editage.co.kr) for English language editing. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2020R1F1A1049629), a VHS Medical Center Research Grant from the Republic of Korea (VHSMC 21001) and a 2019 research grant from the Medical Science Research Institute of Kyung Hee University Hospital at Gangdong.

References

  1. Lederer DJ and Martinez FJ (2018) Idiopathic pulmonary fibrosis. N Engl J Med 378, 1811-1823
  2. Richeldi L, Collard HR and Jones MG (2017) Idiopathic pulmonary fibrosis. Lancet 389, 1941-1952
  3. Raghu G, Chen SY, Hou Q, Yeh WS and Collard HR (2016) Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old. Eur Respir J 48, 179-186
  4. Sathish V, Martin YN and Prakash YS (2015) Sex steroid signaling: implications for lung diseases. Pharmacol Ther 150, 94-108
  5. Smith LC, Moreno S, Robertson L et al (2018) Transforming growth factor beta1 targets estrogen receptor signaling in bronchial epithelial cells. Respir Res 19, 160
  6. Avouac J, Pezet S, Gonzalez V et al (2020) Estrogens Counteract the profibrotic effects of TGF-beta and their inhibition exacerbates experimental dermal fibrosis. J Invest Dermatol 140, 593-601 e597
  7. Pedram A, Razandi M, Narayanan R and Levin ER (2016) Estrogen receptor beta signals to inhibition of cardiac fibrosis. Mol Cell Endocrinol 434, 57-68
  8. Mankhey RW, Wells CC, Bhatti F and Maric C (2007) 17beta-Estradiol supplementation reduces tubulointerstitial fibrosis by increasing MMP activity in the diabetic kidney. Am J Physiol Regul Integr Comp Physiol 292, R769-777
  9. Voltz JW, Card JW, Carey MA et al (2008) Male sex hormones exacerbate lung function impairment after bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 39, 45-52
  10. Morani A, Barros RP, Imamov O et al (2006) Lung dysfunction causes systemic hypoxia in estrogen receptor beta knockout (ERbeta-/-) mice. Proc Natl Acad Sci U S A 103, 7165-7169
  11. Tissier R, Waintraub X, Couvreur N et al (2007) Pharmacological postconditioning with the phytoestrogen genistein. J Mol Cell Cardiol 42, 79-87
  12. Lee GS, Choi KC, Kim HJ and Jeung EB (2004) Effect of genistein as a selective estrogen receptor beta agonist on the expression of Calbindin-D9k in the uterus of immature rats. Toxicol Sci 82, 451-457
  13. Hillman GG, Singh-Gupta V, Lonardo F et al (2013) Radioprotection of lung tissue by soy isoflavones. J Thorac Oncol 8, 1356-1364
  14. Day RM, Barshishat-Kupper M, Mog SR et al (2008) Genistein protects against biomarkers of delayed lung sequelae in mice surviving high-dose total body irradiation. J Radiat Res 49, 361-372
  15. Ning Y, Chen J, Shi Y et al (2020) Genistein ameliorates renal fibrosis through regulation snail via m6A RNA Demethylase ALKBH5. Front Pharmacol 11, 579265
  16. Salas AL, Montezuma TD, Farina GG, Reyes-Esparza J and Rodriguez-Fragoso L (2008) Genistein modifies liver fibrosis and improves liver function by inducing uPA expression and proteolytic activity in CCl4-treated rats. Pharmacology 81, 41-49
  17. Yang R, Jia Q, Liu XF and Ma SF (2018) Effect of genistein on myocardial fibrosis in diabetic rats and its mechanism. Mol Med Rep 17, 2929-2936
  18. Sharifi-Rad J, Quispe C, Imran M et al (2021) Genistein: an integrative overview of its mode of action, pharmacological properties, and health benefits. Oxid Med Cell Longev 2021, 3268136
  19. Ganai AA and Farooqi H (2015) Bioactivity of genistein: a review of in vitro and in vivo studies. Biomed Pharmacother 76, 30-38
  20. Todd NW, Luzina IG and Atamas SP (2012) Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenesis Tissue Repair 5, 11
  21. Yanai H, Shteinberg A, Porat Z et al (2015) Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients. Aging (Albany NY) 7, 664-672
  22. Kolosova I, Nethery D and Kern JA (2011) Role of Smad2/3 and p38 MAP kinase in TGF-beta1-induced epithelial-mesenchymal transition of pulmonary epithelial cells. J Cell Physiol 226, 1248-1254
  23. Finnson KW, Almadani Y and Philip A (2020) Non-canonical (non-SMAD2/3) TGF-beta signaling in fibrosis: mechanisms and targets. Semin Cell Dev Biol 101, 115-122
  24. Ravanti L, Heino J, Lopez-Otin C and Kahari VM (1999) Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein kinase. J Biol Chem 274, 2446-2455
  25. Huang X, Chen S, Xu L et al (2005) Genistein inhibits p38 map kinase activation, matrix metalloproteinase type 2, and cell invasion in human prostate epithelial cells. Cancer Res 65, 3470-3478
  26. Varone F, Mastrobattista A, Franchi P et al (2018) Pulmonary fibrolysis in a patient with idiopathic pulmonary fibrosis: improvement of clinical and radiological pattern after treatment with pirfenidone. Clin Respir J 12, 347-351
  27. Sakai N and Tager AM (2013) Fibrosis of two: epithelial cell-fibroblast interactions in pulmonary fibrosis. Biochim Biophys Acta 1832, 911-921
  28. Stewart AG, Thomas B and Koff J (2018) TGF-beta: master regulator of inflammation and fibrosis. Respirology 23, 1096-1097
  29. Chitra P, Saiprasad G, Manikandan R and Sudhandiran G (2015) Berberine inhibits Smad and non-Smad signaling cascades and enhances autophagy against pulmonary fibrosis. J Mol Med (Berl) 93, 1015-1031
  30. Camara J and Jarai G (2010) Epithelial-mesenchymal transition in primary human bronchial epithelial cells is Smad-dependent and enhanced by fibronectin and TNF-alpha. Fibrogenesis Tissue Repair 3, 2
  31. Itoigawa Y, Harada N, Harada S et al (2015) TWEAK enhances TGF-beta-induced epithelial-mesenchymal transition in human bronchial epithelial cells. Respir Res 16, 48
  32. Kim HS, Yoo HJ, Lee KM et al (2021) Stearic acid attenuates profibrotic signalling in idiopathic pulmonary fibrosis. Respirology 26, 255-263
  33. Kim HS, Moon SJ, Lee SE, Hwang GW, Yoo HJ and Song JW (2021) The arachidonic acid metabolite 11,12-epoxyeicosatrienoic acid alleviates pulmonary fibrosis. Exp Mol Med 53, 864-874
  34. Zhao YD, Yin L, Archer S et al (2017) Metabolic heterogeneity of idiopathic pulmonary fibrosis: a metabolomic study. BMJ Open Respir Res 4, e000183
  35. Ung CY, Onoufriadis A, Parsons M, McGrath JA and Shaw TJ (2021) Metabolic perturbations in fibrosis disease. Int J Biochem Cell Biol 139, 106073
  36. Kendall RT and Feghali-Bostwick CA (2014) Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol 5, 123
  37. Kim S, Nam Y, Kim MJ et al (2023) Proteomic analysis for the effects of non-saponin fraction with rich polysaccharide from Korean Red Ginseng on Alzheimer's disease in a mouse model. J Ginseng Res 47, 302-310
  38. Tyanova S and Cox J (2018) Perseus: a bioinformatics platform for integrative analysis of proteomics data in cancer research. Methods Mol Biol 1711, 133-148