TGF-β Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1α-Induced Epithelial Mesenchymal Transition
| العنوان: | TGF-β Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1α-Induced Epithelial Mesenchymal Transition |
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| المؤلفون: | Chun Hwa Kim, Min-Jin Kim, Dae-Kee Kim, Jeong-Seok Nam, Jung-Shin Kim, Yhun Yhong Sheen, So-Yeon Park, Sang-A Park |
| المصدر: | Cellular Physiology and Biochemistry, Vol 38, Iss 2, Pp 571-588 (2016) CELLULAR PHYSIOLOGY AND BIOCHEMISTRY(38): 2 |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | 0301 basic medicine, TGF-β, Liver Cirrhosis, Male, Pathology, medicine.medical_specialty, Epithelial-Mesenchymal Transition, Physiology, Receptor, Transforming Growth Factor-beta Type I, Biology, Protein Serine-Threonine Kinases, lcsh:Physiology, Cell Line, lcsh:Biochemistry, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, TGF beta signaling pathway, medicine, Hepatic Stellate Cells, Animals, Humans, lcsh:QD415-436, Epithelial–mesenchymal transition, HIF1α, Receptor, Protein Kinase Inhibitors, Hepatic stellate cell, Aniline Compounds, EW-7197, lcsh:QP1-981, Kinase, Cholestatic liver injury, Triazoles, medicine.disease, Hypoxia-Inducible Factor 1, alpha Subunit, Oxidative Stress, 030104 developmental biology, Liver, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Epithelial mesenchymal transition, TGF-beta, HIF1 alpha, Receptors, Transforming Growth Factor beta, Transforming growth factor |
| الوصف: | Background/Aims: Hypoxia is an environmental factor that aggravates liver fibrosis. HIF1 alpha activates hepatic stellate cells (HSCs) and increases transforming growth factor-beta (TGF-beta) signaling and the epithelial mesenchymal transition (EMT), accelerating the progression of fibrosis. We evaluated the anti-fibrotic therapeutic potential of a small-molecule inhibitor of TGF-beta type I receptor kinase, EW-7197, on HIF1 alpha-derived TGF-beta signaling in cholestatic liver fibrosis. Methods: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1 alpha-derived TGF-beta signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in liver tissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofluorescence (IF), chromatin immunoprecipitation (ChIP) assays, real-time PCR, and western blotting. Results: In our BDL rat model, orally administered EW-7197 inhibited fibrosis and attenuated HIF1 alpha-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1 alpha-derived HS[activation and expression of EMT markers in LX-2 cells in vitro. Conclusion: This study suggests that FW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1 alpha-induced TGF-beta signaling. (C) 2016 The Author(s) Published by S. Karger AG, Basel |
| تدمد: | 1421-9778 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cf7a60c53bba0c7a663ad291a193216bTest https://pubmed.ncbi.nlm.nih.gov/26845171Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....cf7a60c53bba0c7a663ad291a193216b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14219778 |
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