Asiatic acid attenuates CCl4-induced liver fibrosis in rats by regulating the PI3K/AKT/mTOR and Bcl-2/Bax signaling pathways

被引:96
作者
Wei, Liwen [1 ]
Chen, Qingshan [2 ]
Guo, Aijie [1 ]
Fan, Jie [1 ]
Wang, Rong [3 ]
Zhang, Hai [1 ]
机构
[1] Tongli Univ, Shanghai Matern & Infant Hosp 1, Dept Pharm, Sch Med, Shanghai 201204, Peoples R China
[2] Second Milirmy Med Univ, Shanghai Eastern Hepatobiliary Surg Hosp, Dept Pharm, Shanghai 200438, Peoples R China
[3] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Dept Pharm, Sch Med, 280 Mo He Rd, Shanghai 201999, Peoples R China
基金
中国国家自然科学基金;
关键词
Liver fibrosis; Asiatic acid; AKT/mTOR; Bcl-2/Bax; HEPATIC STELLATE CELLS; MOLECULAR-MECHANISMS; STRESS; INFLAMMATION; PROGRESSION;
D O I
10.1016/j.intimp.2018.04.016
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Liver fibrosis is a major pathological feature of chronic liver diseases, and effective therapies are limited at present. Asiatic acid (AA) is a triterpenoid isolated from Centella astatica, which exhibits efficient anti-inflammatory and anti-oxidative activities. In this study, we attempted to evaluate the potential therapeutic effect of AA on CCl4-induced liver fibrosis in rats and to investigate the underlying molecular mechanisms. Liver fibrosis-related indexes including body weight, biochemical parameters, histological changes, the mRNA expression levels of inflammatory cytokines and biomarkers, and changes in the expression of related proteins in liver tissue were assessed. The results showed that AA treatment effectively ameliorated CCl4-induced liver injury and fibrosis. Mechanistically, AA treatment attenuated CCl4-induced oxidative stress, inflammation, and hepatocyte apoptosis and regulated the Bcl-2/Bax signaling pathway in the liver. Additionally, we demonstrated that AA also inhibited hepatic stellate cell activation and extra cellular matrix (ECM) synthesis by regulating the PI3K/AKT/mTOR signaling pathway. In conclusion, these findings suggest that AA prevents the progression of liver fibrosis through multiple mechanisms and indicate that AA might be used for the treatment of liver fibrosis in the future.
引用
收藏
页码:1 / 8
页数:8
相关论文
共 32 条
[1]   Liver fibrosis [J].
Bataller, R ;
Brenner, DA .
JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (02) :209-218
[2]   Extracellular matrix degradation and the role of hepatic stellate cells [J].
Benyon, RC ;
Arthur, MJP .
SEMINARS IN LIVER DISEASE, 2001, 21 (03) :373-384
[3]   Decoding cell death signals in liver inflammation [J].
Brenner, Catherine ;
Galluzzi, Lorenzo ;
Kepp, Oliver ;
Kroemer, Guido .
JOURNAL OF HEPATOLOGY, 2013, 59 (03) :583-594
[4]   Schisandrin B attenuates CCl4-induced liver fibrosis in rats by regulation of Nrf2-ARE and TGF-β/Smad signaling pathways [J].
Chen, Qingshan ;
Zhang, Hai ;
Cao, Yan ;
Li, Ying ;
Sun, Sen ;
Zhang, Junping ;
Zhang, Guoqing .
DRUG DESIGN DEVELOPMENT AND THERAPY, 2017, 11 :2179-2191
[5]   Hepatic inflammation and progressive liver fibrosis in chronic liver disease [J].
Czaja, Albert J. .
WORLD JOURNAL OF GASTROENTEROLOGY, 2014, 20 (10) :2515-2532
[6]   Targeting PI3K signalling in cancer: opportunities, challenges and limitations [J].
Engelman, Jeffrey A. .
NATURE REVIEWS CANCER, 2009, 9 (08) :550-562
[7]   Mesenchymal stem cell therapy for liver fibrosis [J].
Eom, Young Woo ;
Shim, Kwang Yong ;
Baik, Soon Koo .
KOREAN JOURNAL OF INTERNAL MEDICINE, 2015, 30 (05) :580-589
[8]   Mechanisms of hepatic fibrogenesis [J].
Friedman, Scott L. .
GASTROENTEROLOGY, 2008, 134 (06) :1655-1669
[9]   Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism [J].
Galli, A ;
Svegliati-Baroni, G ;
Ceni, E ;
Milani, S ;
Ridolfi, F ;
Salzano, R ;
Tarocchi, M ;
Grappone, C ;
Pellegrini, G ;
Benedetti, A ;
Surrenti, C ;
Casini, A .
HEPATOLOGY, 2005, 41 (05) :1074-1084
[10]   Mechanism underlying mitochondrial protection of asiatic acid against hepatotoxicity in mice [J].
Gao, J ;
Chen, J ;
Tang, XH ;
Pan, LY ;
Fang, F ;
Xu, LZ ;
Zhao, XN ;
Xu, Q .
JOURNAL OF PHARMACY AND PHARMACOLOGY, 2006, 58 (02) :227-233