| Liver fibrosis is the occurrence of liver cell necrosis and inflammatory stimulation, such as liver collagen proliferation and extracellular matrix degradation out of balance, cause abnormal liver deposition of fibrous connective tissue of the pathological process. In recent years, with the pathogenesis of hepatic fibrosis have been making considerable progress, liver fibrosis is considered reversible, therefore the study of liver fibrosis in signal transduction pathways, cytokine gene expression, HSC activation and apoptosis, had been used in the treatment of anti-liver fibrosis. TGF-β1 is multifunctional peptide growth factors with a wide range of potential effects on growth, differentiation, extracellular matrix deposition and immune response. It changes extracellular matrix synthesis of the normal balance between decomposition and synthesis. Increasing the matrix synthesis and corresponding reducing the total proteolytic activity of ECM result in the formation of reticular fibers. Under normal circumstances, TGF-β1 has hardly expressed in liver, which is marked increased in its expression, now TGF-β1 is considered the formation of liver fibrosis are key factors. The term fibrogenesis is encompasses a variety of changes that potentially involve multiple signaling pathways, direct and indirect, including the upregulation of other profibrogenic cytokines. TGF-β1 and Smads both participate in the progression of hepatic fibrosis, TGF-β1 mainly relies on its receptor and a highly conserved family of downstream intracellular signaling protein-mediated Smad protein family. Exert their biological effects. Oxymatrine (OM) is Matrine synthesis by oxidation, purification, extraction. It has been an effective monomer, matrine N-oxides, because oxymatrine has the special structure of oxygen, its molecular polarity was increased and has a unique role and efficacy than Matrine mechanism. In this study, we observed the expression of its receptors TβRI and Smads protein in liver fibrosis, and effects of oxymatrine on Smads protein and its Smads-mediated signal transduction pathway of liver fibrosis in the development process. The main contents are divided into three sections, as follows:1. Effects of OM on CCl4-induced hepatic fibrosis ratsThe test result had displayed that OM had obvious protective effects on CCl4-induced liver fibrosis in rats. Serum level of ALT, AST, HA, LN, CIV, PCIII, the surrogate markers of liver fibrogenesis, increased significantly in hepatic fibrotic rats in model group and were suppressed by treatment with OM. Hyp contents in liver tissue were carried out as an index of liver fibrosis, the increase was effectively reduced by the therapy of OM. Histological results showed that hepatic fibrosis caused by OM was significantly inhibited by OM. OM improved alterations in the liver structure.we further examined serum level of I type collagen and TGF-β1. it was increased markedly in model group and was significantly decreased by treatment with OM. OM had also inhibitory effects on expression of TGF-β1,smad2,Smad3mRNA by using RT-PCR method. But expression of smad7 mRNA was increased.2. Suppressive effect of oxymatrine on TGF-β1 elicited proliferation of hepatic stellate cell proliferation in vitroUsing MTT method based exogenous TGF-β1-stimulating factor to stimulate HSC-T6 model group. Observing effect of OM on the proliferation of HSC-T6 stimulated with TGF-β1. Results show that inhibition rate is proportional to the concentration of OM. It had inhibitory effects on the proliferation of HSC-T6 stimulated with TGF-β1.3. Effects of Oxymatrine on TGF-β/smads signaling pathway in active HSC-T6 cellExtract HSC-T6 total protein. The changes of the expression TβRI,smad2,smad3,smad7 protein in HSC-T6 stimulated with TGF-β1 were detected by western blot. The result showed that the expression of TβRI,smad2,smad3 were remarkably increased in HSC-T6 stimulated with TGF-β1, but the expression of inhibitory Smads protein, smad7, were decreased. Meanwhile, the level of TβRI,smad2,smad3 were obviously decreased after treatment of OM, Which also increased the level of smad7 protein. The results above indicated that OM probably inhibits the proliferation of HSC-T6 stimulated with TGF-β1 via TGF-β/smads signaling pathway.These results show that, OM can be effective in improving liver function, reducing fibrosis in rats with collagen deposition; it is one possible mechanism for the process of fibrosis to inhibit TGF-β/smads signaling pathway. |
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