Germacrone improves liver fibrosis by regulating the PI3K/AKT/mTOR signalling pathway. (14th July 2021)

• Record Type: Journal Article
• Authors: Ji, De; Zhao, Qi; Qin, Yuwen; Tong, Huangjin; Wang, Qiaohan; Yu, Mengting; Mao, Chunqin; Lu, Tulin; Qiu, Jinchun; Jiang, Chengxi
• Is Part Of: Cell biology international. Volume 45:Number 9(2021)
• Page Start: 1866
• Page End: 1875
• Publication Date: 2021-07-14
• Subjects: epithelial–mesenchymal transition -- Germacrone -- hepatic stellate cell activation -- liver fibrosis -- proliferation -- PI3K/AKT/mTOR signalling pathway; Cytology -- Periodicals; Cells -- Periodicals; 571.605
• DOI: 10.1002/cbin.11607
• Languages: English
• ISSNs: 1065-6995

Abstract

Abstract: Liver fibrosis is a primary threat to public health, owing to limited therapeutic options. Germacrone (GM) has been shown to exert various curative effects against human diseases, including liver injury. The aim of this study was to investigate the pharmacological effects of GM in the pathophysiology of hepatic fibrosis and determine its potential mechanisms of action. A liver fibrosis rat model was established via carbon tetrachloride (CCl4 ) treatment, and LX‐2 cells were stimulated with TGF‐β1. The effects of GM on liver fibrosis and its relationship with the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway were investigated. In the CCl4 fibrosis‐induced rat model, GM improved histological damage, inhibited the activity of hepatic α‐smooth muscle actin and improved serum alanine aminotransferase and aspartate aminotransferase levels in a dose‐dependent manner. GM potently inhibited hepatic stellate cells (HSCs) growth and epithelial–mesenchymal transition (EMT) progression, as reflected by the altered expression of proliferative (Ki‐67, PCNA and cleaved caspase‐3) and EMT‐related (E‐cadherin and vimentin) proteins. In TGF‐β1‐stimulated LX‐2 cells, GM significantly inhibited the survival and activation of HSCs and induced cell apoptosis. GM also suppressed the migration ability and reversed the EMT process in HSCs. Following GM treatment, the phosphorylation of the PI3K, AKT and mTOR proteins was reduced in the liver of CCl4 ‐treated rats and TGF‐β1‐stimulated LX‐2 cells, indicating that GM may attenuate hepatic fibrosis via the PI3K/AKT/mTOR signalling pathway. These outcomes highlight the anti‐fibrotic effects of GM and suggest that it is a potential therapeutic agent for the treatment of liver fibrosis. Highlight: Liver fibrosis is an important pathological feature in the early stages of liver disease. Germacrone (GM) could potently inhibit hepatic stellate cell (HSC) growth, activation, and migration during the development of liver fibrosis. Mechanistically, GM may regulate HSC proliferation and activation, and epithelial–mesenchymal transition during liver fibrosis by targeting the phosphatidylinositol 3‐kinase/protein kinase B/mammalian target of rapamycin pathway.