title: A Novel Matrine Derivative WM130 Inhibits Activation of Hepatic Stellate Cells and Attenuates Dimethylnitrosamine-Induced Liver Fibrosis in Rats.
abstract: Activation of hepatic stellate cells (HSCs) is a critical event in process of hepatic fibrogenesis and cirrhosis. Matrine, the active ingredient of Sophora, had been used for clinical treatment of acute/chronic liver disease. However, its potency was low. We prepared a high potency and low toxicity matrine derivate, WM130 (C30N4H40SO5F), which exhibited better pharmacological activities on antihepatic fibrosis. This study demonstrated that WM130 results in a decreased proliferative activity of HSC-T6 cells, with the half inhibitory concentration (IC50) of 68 μM. WM130 can inhibit the migration and induce apoptosis in HSC-T6 cells at both concentrations of 68 μM (IC50) and 34 μM (half IC50). The expression of α-SMA, Collagen I, Collagen III, and TGF-β1 could be downregulated, and the protein phosphorylation levels of EGFR, AKT, ERK, Smad, and Raf (p-EGFR, p-AKT, p-ERK, p-Smad, and p-Raf) were also decreased by WM130. On the DMN-induced rat liver fibrosis model, WM130 can effectively reduce the TGF-β1, AKT, α-SMA, and p-ERK levels, decrease the extracellular matrix (ECM) formation, and inhibit rat liver fibrosis progression. In conclusion, this study demonstrated that WM130 can significantly inhibit the activation of HSC-T6 cells and block the rat liver fibrosis progression by inducing apoptosis, suppressing the deposition of ECM, and inhibiting TGF-β/Smad and Ras/ERK pathways.
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital and National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital and National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Zhangxiao
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital and National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Weidan
authors.initials: W
authors.lastname: Ji
authors.affiliation: Deparment of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital and National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital and National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China ; Department of General Surgery, Wujiang No. 1 People's Hospital, Suzhou 215200, China.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital and National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Xiaoya
authors.initials: X
authors.lastname: Li
authors.affiliation: Deparment of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Chai
authors.affiliation: Deparment of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qiuye
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of General Surgery, Wujiang No. 1 People's Hospital, Suzhou 215200, China.
authors.forename: Quangen
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital and National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Su
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004128:Dimethylnitrosamine / Q000633:toxicity*; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020011:Protective Agents / Q000494:pharmacology*; D011807:Quinolizines / Q000494:pharmacology*; D051381:Rats
chemical_list: D000470:Alkaloids; D020011:Protective Agents; D011807:Quinolizines; C000602836:WM130 compound; D004128:Dimethylnitrosamine