title: Fluorofenidone attenuates hepatic fibrosis by suppressing the proliferation and activation of hepatic stellate cells.
abstract: Fluorofenidone (AKF-PD) is a novel pyridone agent. The purpose of this study is to investigate the inhibitory effects of AKF-PD on liver fibrosis in rats and the involved molecular mechanism related to hepatic stellate cells (HSCs). Rats treated with dimethylnitrosamine or CCl4 were randomly divided into normal, model, AKF-PD treatment, and pirfenidone (PFD) treatment groups. The isolated primary rat HSCs were treated with AKF-PD and PFD respectively. Cell proliferation and cell cycle distribution were analyzed by bromodeoxyuridine and flow cytometry, respectively. The expression of collagen I and α-smooth muscle actin (α-SMA) were determined by Western blot, immunohistochemical staining, and real-time RT-PCR. The expression of cyclin D1, cyclin E, and p27(kip1) and phosphorylation of MEK, ERK, Akt, and 70-kDa ribosomal S6 kinase (p70S6K) were detected by Western blot. AKF-PD significantly inhibited PDGF-BB-induced HSC proliferation and activation by attenuating the expression of collagen I and α-SMA, causing G0/G1 phase cell cycle arrest, reducing expression of cyclin D1 and cyclin E, and promoting expression of p27(kip1). AKF-PD also downregulated PDGF-BB-induced MEK, ERK, Akt, and p70S6K phosphorylation in HSCs. In rat liver fibrosis, AKF-PD alleviated hepatic fibrosis by decreasing necroinflammatory score and semiquantitative score, and reducing expression of collagen I and α-SMA. AKF-PD attenuated the progression of hepatic fibrosis by suppressing HSCs proliferation and activation via the ERK/MAPK and PI3K/Akt signaling pathways. AKF-PD may be used as a potential novel therapeutic agent against liver fibrosis.
authors: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, China;
authors: Yu
authors: Y
authors: Peng
authors: Huixiang
authors: H
authors: Yang
authors: Nasui
authors: N
authors: Wang
authors: Yan
authors: Y
authors: Ouyang
authors: Yanrong
authors: Y
authors: Yi
authors: Litao
authors: L
authors: Liao
authors: Hong
authors: H
authors: Shen
authors: Gaoyun
authors: G
authors: Hu
authors: Zhaohe
authors: Z
authors: Wang
authors: Lijian
authors: L
authors: Tao
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D011728:Pyridones; D003094:Collagen
keywords: ERK/MAPK; PI3K/Akt; fluorofenidone; hepatic fibrosis; hepatic stellate cells