Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells.
10.1007/s13238-016-0285-2
- Author:
Yi FENG
1
;
Hai-Yan YING
2
;
Ying QU
2
;
Xiao-Bo CAI
2
;
Ming-Yi XU
2
;
Lun-Gen LU
3
Author Information
1. Department of Gastroenterology, Shanghai General Hospital, Nanjing Medical University, Shanghai, 200080, China. orchidfy@hotmail.com.
2. Department of Gastroenterology, Shanghai General Hospital, Nanjing Medical University, Shanghai, 200080, China.
3. Department of Gastroenterology, Shanghai General Hospital, Nanjing Medical University, Shanghai, 200080, China. Lungenlu1965@163.com.
- Publication Type:Journal Article
- Keywords:
epidermal growth factor receptor;
hepatic fibrosis;
hepatic stellate cell;
matrine derivative;
signal transduction pathway
- MeSH:
Alkaloids;
pharmacology;
Animals;
Cell Line;
Cyclin D1;
metabolism;
Dimethylnitrosamine;
toxicity;
Enzyme Activation;
drug effects;
ErbB Receptors;
metabolism;
G1 Phase Cell Cycle Checkpoints;
drug effects;
Hepatic Stellate Cells;
metabolism;
pathology;
Liver Cirrhosis;
chemically induced;
metabolism;
pathology;
prevention & control;
Phosphorylation;
drug effects;
Proto-Oncogene Proteins c-akt;
metabolism;
Quinolizines;
pharmacology;
Rats
- From:
Protein & Cell
2016;7(9):662-672
- CountryChina
- Language:English
-
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.
