g(m1)-ganglioside and Liver-Cirrhosis

Fuzheng Huayu (FZHY) is a Chinese compound herbal preparation which consists of six Chinese herbs. This study examines the preventative effects of FZHY on liver fibrosis induced by carbon tetrachloride (CCl(4)) and explores its possible mechanisms of action.. Liver fibrosis was induced in male C57BL/6N mice by injecting a 10% CCl(4) solution intraperitoneal twice a week for six weeks. After 6 weeks of treatment, serum ALT and AST assay, liver tissue histological examination and immunostaining were carried out to examine the liver function and fibrosis degree. The expression levels of alpha-smooth muscle actin (SMA) were measured by quantitative real-time PCR and western blot. Hepatic natural killer (NK) cells were isolated from liver and evaluated by FACS.. Upon pathological examination, the FZHY-treated mice showed significantly reduced liver damage. The expression of α-SMA increased markedly upon treatment with CCl(4) and the increase was reversed by FZHY treatment. FZHY treatment also enhanced the activation of hepatic NK cells and the production of interferon-gamma (IFN-γ). The protective effects of FZHY were reversed in the mice that were depleted of NK cells by anti-ASGM-1 Ab treatment.. FZHY can efficiently inhibit CCl(4)-induced liver fibrosis. Furthermore, the depletion of NK cells attenuates the protective effects of FZHY. We conclude that FZHY could be an effective drug for liver fibrosis, and its mechanism of action involves the activation of hepatic NK cells.

Topics: Actins; Alanine Transaminase; Animals; Aspartate Aminotransferases; Autoantibodies; Carbon Tetrachloride; Disease Models, Animal; Drugs, Chinese Herbal; G(M1) Ganglioside; Interferon-gamma; Killer Cells, Natural; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL

Sphingosine kinase (SphK) is involved in numerous biological processes, including cell growth, proliferation, and differentiation. However, whether SphK participates in the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) to myofibroblasts has been unknown. In a carbon tetrachloride-treated mouse model, SphK1 was expressed in BMSCs in damaged liver. Furthermore, mRNA expression of both SphK1 and transforming growth factor β1 (TGF-β1) was significantly increased after liver injury, with a positive correlation between them. The SphK inhibitor SKI significantly blocked BMSC differentiation to myofibroblasts during liver injury (the proportion of BMSC-derived myofibroblasts decreased markedly, compared with no SKI treatment) and attenuated the extent of liver fibrosis. Using primary mouse BMSCs, we demonstrated that TGF-β1 induced BMSC differentiation to myofibroblasts, accompanied by the up-regulation of SphK1 and modulation of sphingosine 1-phosphate (S1P) receptor (S1PR) expression. Notably, pharmacological or siRNA-mediated inhibition of SphK1 abrogated the prodifferentiating effect of TGF-β1. Moreover, using either S1PR subtype-specific antagonists or specific siRNAs, we found that the prodifferentiating effect of TGF-β1 was mediated by S1PR(1) and S1PR(3). These data suggest that SphK1 activation by TGF-β1 leads to differentiation of BMSCs to myofibroblasts mediated by S1PR(1) and S1PR(3) up-regulation, thus providing new information on the mechanisms by which TGF-β1 gives rise to fibrosis and opening new perspectives for pharmacological treatment of liver fibrosis.

Topics: Animals; Bone Marrow; Carbon Tetrachloride; Cell Differentiation; Cell Proliferation; Cells, Cultured; Enzyme Inhibitors; G(M1) Ganglioside; Gene Knockdown Techniques; Liver Cirrhosis; Mesenchymal Stem Cells; Mice; Mice, Inbred ICR; Myofibroblasts; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; RNA, Small Interfering; Transforming Growth Factor beta1; Up-Regulation