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 sh...
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| Format: | Article |
| Language: | English |
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Oxford University Press
2016-06-01
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| Series: | Protein & Cell |
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| Online Access: | http://link.springer.com/article/10.1007/s13238-016-0285-2 |
| _version_ | 1797728838811123712 |
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| author | Yi Feng Hai-yan Ying Ying Qu Xiao-bo Cai Ming-yi Xu Lun-gen Lu |
| author_facet | Yi Feng Hai-yan Ying Ying Qu Xiao-bo Cai Ming-yi Xu Lun-gen Lu |
| author_sort | Yi Feng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T11:19:53Z |
| format | Article |
| id | doaj.art-902ebde3164d4d11b7fe142a827a5c3d |
| institution | Directory Open Access Journal |
| issn | 1674-800X 1674-8018 |
| language | English |
| last_indexed | 2024-03-12T11:19:53Z |
| publishDate | 2016-06-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | Protein & Cell |
| spelling | doaj.art-902ebde3164d4d11b7fe142a827a5c3d2023-09-02T01:17:45ZengOxford University PressProtein & Cell1674-800X1674-80182016-06-017966267210.1007/s13238-016-0285-2Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cellsYi Feng0Hai-yan Ying1Ying Qu2Xiao-bo Cai3Ming-yi Xu4Lun-gen Lu5Department of Gastroenterology, Shanghai General Hospital, Nanjing Medical UniversityDepartment of Gastroenterology, Shanghai General Hospital, Nanjing Medical UniversityDepartment of Gastroenterology, Shanghai General Hospital, Nanjing Medical UniversityDepartment of Gastroenterology, Shanghai General Hospital, Nanjing Medical UniversityDepartment of Gastroenterology, Shanghai General Hospital, Nanjing Medical UniversityDepartment of Gastroenterology, Shanghai General Hospital, Nanjing Medical UniversityAbstract 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.http://link.springer.com/article/10.1007/s13238-016-0285-2matrine derivativehepatic stellate cellhepatic fibrosisepidermal growth factor receptorsignal transduction pathway |
| spellingShingle | Yi Feng Hai-yan Ying Ying Qu Xiao-bo Cai Ming-yi Xu Lun-gen Lu Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells Protein & Cell matrine derivative hepatic stellate cell hepatic fibrosis epidermal growth factor receptor signal transduction pathway |
| title | Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells |
| title_full | Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells |
| title_fullStr | Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells |
| title_full_unstemmed | Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells |
| title_short | Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells |
| title_sort | novel matrine derivative md 1 attenuates hepatic fibrosis by inhibiting egfr activation of hepatic stellate cells |
| topic | matrine derivative hepatic stellate cell hepatic fibrosis epidermal growth factor receptor signal transduction pathway |
| url | http://link.springer.com/article/10.1007/s13238-016-0285-2 |
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