title: Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells.
abstract: Matrine (MT), the effective component of Sophora flavescens Ait, has been shown to have anti-inflammation, immune-suppressive, anti-tumor, and anti-hepatic fibrosis activities. However, the pharmacological effects of MT still need to be strengthened due to its relatively low efficacy and short half-life. In the present study, we report a more effective thio derivative of MT, MD-1, and its inhibitory effects on the activation of hepatic stellate cells (HSCs) in both cell culture and animal models. Cytological experiments showed that MD-1 can inhibit the proliferation of HSC-T6 cells with a half-maximal inhibitory concentration (IC50) of 62 μmol/L. In addition, MD-1 more strongly inhibits the migration of HSC-T6 cells compared to MT and can more effectively induce G0/G1 arrest and apoptosis. Investigating the biological mechanisms underlying anti-hepatic fibrosis in the presence of MD-1, we found that MD-1 can bind the epidermal growth factor receptor (EGFR) on the surface of HSC-T6 cells, which can further inhibit the phosphorylation of EGFR and its downstream protein kinase B (Akt), resulting in decreased expression of cyclin D1 and eventual inhibition of the activation of HSC-T6 cells. Furthermore, in rats with dimethylnitrosamine (DMN)-induced hepatic fibrosis, MD-1 slowed the development and progression of hepatic fibrosis, protecting hepatic parenchymal cells and improving hepatic functions. Therefore, MD-1 is a potential drug for anti-hepatic fibrosis.
authors.affiliation: Department of Gastroenterology, Shanghai General Hospital, Nanjing Medical University, Shanghai, 200080, China. orchidfy@hotmail.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Gastroenterology, Shanghai General Hospital, Nanjing Medical University, Shanghai, 200080, China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Ying
authors.affiliation: Department of Gastroenterology, Shanghai General Hospital, Nanjing Medical University, Shanghai, 200080, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Gastroenterology, Shanghai General Hospital, Nanjing Medical University, Shanghai, 200080, China.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Cai
authors.affiliation: Department of Gastroenterology, Shanghai General Hospital, Nanjing Medical University, Shanghai, 200080, China.
authors.forename: Ming-Yi
authors.initials: MY
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology, Shanghai General Hospital, Nanjing Medical University, Shanghai, 200080, China. Lungenlu1965@163.com.
authors.forename: Lun-Gen
authors.initials: LG
authors.lastname: Lu
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011807:Quinolizines / Q000494:pharmacology*; D051381:Rats; D000093842:Matrines
chemical_list: D000470:Alkaloids; C530106:Ccnd1 protein, rat; D011807:Quinolizines; D019938:Cyclin D1; C483803:Egfr protein, rat; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D004128:Dimethylnitrosamine; D000093842:Matrines
keywords: epidermal growth factor receptor; hepatic fibrosis; hepatic stellate cell; matrine derivative; signal transduction pathway