https://scholars.lib.ntu.edu.tw/handle/123456789/457837
標題: | Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis | 作者: | TUNG-HUNG SU Shiau C.-W Jao P Yang N.-J Tai W.-T CHUN-JEN LIU TAI-CHUNG TSENG HUNG-CHIH YANG CHEN-HUA LIU KAI-WEN HUANG Hu T.-C Huang Y.-J YAO-MING WU Chen L.-J PEI-JER CHEN DING-SHINN CHEN Chen K.-F JIA-HORNG KAO |
公開日期: | 2017 | 出版社: | Nature Publishing Group | 卷: | 7 | 期: | 1 | 來源出版物: | Scientific Reports | 摘要: | This study aimed to investigate the role of src-homology protein tyrosine phosphatase-1 (SHP-1)-signal transducer and activator of transcription 3 (STAT3) pathway in liver fibrogenesis and the anti-fibrotic effect of SHP-1 agonist. The antifibrotic activity of SC-43, a sorafenib derivative with an enhanced SHP-1 activity, was evaluated in two fibrosis mouse models by carbon tetrachloride induction and bile duct ligation. Rat, human, and primary mouse hepatic stellate cells (HSCs) were used for mechanistic investigations. The results showed that SHP-1 protein primarily localized in fibrotic areas of human and mouse livers. SC-43 treatment reduced the activated HSCs and thus effectively prevented and regressed liver fibrosis in both fibrosis mouse models and improved mouse survival. In vitro studies revealed that SC-43 promoted HSC apoptosis, increased the SHP-1 activity and inhibited phospho-STAT3. The enhanced SHP-1 activity in HSCs significantly inhibited HSC proliferation, whereas SHP-1 inhibition rescued SC-43-induced HSC apoptosis. Furthermore, SC-43 interacted with the N-SH2 domain of SHP-1 to enhance the activity of SHP-1 as its antifibrotic mechanism. In conclusion, the SHP-1-STAT3 pathway is crucial in fibrogenesis. SC-43 significantly ameliorates liver fibrosis through SHP-1 upregulation. A SHP-1-targeted antifibrotic therapy may represent a druggable strategy for antifibrotic drug discovery. ? 2017 The Author(s). |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85019215079&doi=10.1038%2fs41598-017-01572-z&partnerID=40&md5=111f486a6ff1f97855e1dd17e9f902af https://scholars.lib.ntu.edu.tw/handle/123456789/457837 |
ISSN: | 2045-2322 | DOI: | 10.1038/s41598-017-01572-z | SDG/關鍵字: | carbanilamide derivative; carbon tetrachloride; diphenyl ether; protein tyrosine phosphatase SHP 1; SC-43 compound; sorafenib; STAT3 protein; animal; apoptosis; bile duct; C57BL mouse; cell line; cell proliferation; chemistry; disease model; drug effect; genetics; hepatic stellate cell; human; ligation; liver cirrhosis; male; metabolism; mutation; pathology; protein domain; rat; Animals; Apoptosis; Bile Ducts; Carbon Tetrachloride; Cell Line; Cell Proliferation; Disease Models, Animal; Hepatic Stellate Cells; Humans; Ligation; Liver Cirrhosis; Male; Mice, Inbred C57BL; Mutation; Phenyl Ethers; Phenylurea Compounds; Protein Domains; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Rats; Sorafenib; STAT3 Transcription Factor |
顯示於: | 醫學系 |
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