人参皂苷Rg1治疗斯氏狸殖吸虫所致肝纤维化的机制研究

Infection of Pagumogonimus skrjabini can lead to liver fibrosis, blocking or reversing the infection caused liver fibrosis is the key to prevent further occurrence of cirrhosis. Reported in the literature, NADPH oxidase (NOX) generate reactive oxygen species (ROS) which mediated the ERK signal pathway and activated proliferation of hepatic stellate cells(HSC), the result can induce the formation of liver fibrosis. Hepatic stellate cell activation-associated protein (STAP) of decompose can hydrogen peroxide of ROS, inhibiting hepatic fibrosis. At the same time,the study found that ginsenosides Rg1, the ginseng and Panax main active ingredient, has antioxidant and anti-fibrotic role. But to infection of Pagumogonimus skrjabini leading to liver fibrosis, Ginsenoside Rg1 can improve liver fibrosis and related molecular mechanism is not clear. this study will esablish is to develop animal models of Pagumogonimus skrjabini infection leading to liver fibrosis by Ginsenoside Rg1 treatment, The effect will be evaluated to resistance the hepatic fibrosis role by Rg1, the dose-effect relationship and time-effect relationship will be analyzed. ROS, NOX, STAP, ERK signal pathway and collagen factor changes will be discovering in the liver tissue . The aim will explore the Ginsenoside Rg1 is whether to inhibit expression of NOX and promote STAP generation,which the result can reduce ROS and effect ERK signal pathway or proliferation of hepatic stellate cell. This is the ultimate goal that the Rg1 is whether to reduce collagen synthesis and improve Pagumogonimus skrjabini infection-induced liver fibrosis. This study will be to promote the development and utilization of of Yunnan Panax and its extract.

斯氏狸殖吸虫感染可导致肝纤维化的发生，阻断或逆转该虫感染所引起的肝纤维化是预防进一步发生肝硬化的关键。文献报道，NOX可通过产生ROS介导ERK信号通路激活肝星状细胞（HSC）的增殖，诱导肝纤维化；STAP可分解ROS中的过氧化氢，抑制肝纤维化。研究发现，人参皂苷Rg1（简称Rg1）是人参和三七中主要的活性成分，具有抗氧化和抗纤维化等作用。但在斯氏狸殖吸虫感染导致肝纤维化中，Rg1是否可以改善肝纤维化及相关的分子机制不清楚。本研究拟建立斯氏狸殖吸虫感染导致肝纤维化动物模型，评价Rg1抗肝纤维化作用及其剂量和时间效应关系；研究肝脏组织中ROS、NOX、STAP、ERK信号通路和胶原生成的相关因子的改变，探讨Rg1是否通过抑制NOX的表达和促进STAP的生成，减少ROS，从而影响ERK信号通路和HSC的增殖，降低胶原合成，改善该虫感染所致肝纤维化。本研究将促进对云南三七及提取物的开发和利用。

斯氏狸殖吸虫感染可导致肝纤维化的发生，阻断或逆转该虫感染所引起的肝纤维化是预防进一步发生肝硬化的关键。文献报道，NOX可通过产生ROS介导ERK信号通路激活肝星状细胞（HSC）的增殖，诱导肝纤维化；STAP可分解ROS中的过氧化氢，抑制肝纤维化。研究发现，人参皂苷Rg1（简称Rg1）是人参和三七中主要的活性成分，具有抗氧化和抗纤维化等作用。但在斯氏狸殖吸虫感染导致肝纤维化中，Rg1是否可以改善肝纤维化及相关的分子机制不清楚。.本研究通过采集疫源地溪蟹，解剖获得斯氏狸殖吸虫囊蚴，注释至大鼠体内，从而复制斯氏狸殖吸虫感染致大鼠肝纤维化的动物模型，设置相应对照和Rg1治疗的剂量梯度。通过一系列的分子生物学实验方法，研究血清炎症学指标（IL-1、IL-6、TNF-α）、肝脏TGF-β1/Smads信号通路关键因子(TGF-β1、Smad2/3、Smad7)、ERK信号通路关键因子（ERK1/2、α-SMA）和纤维化主要指标（MMP2、MMP9、COL I、COL III）的mRNA表达、蛋白质表达及部分磷酸化水平，探讨人参皂苷Rg1在斯氏狸殖吸虫感染致肝纤维化的大鼠模型中抗肝纤维化的分子机制。 .该研究发现：①斯氏狸殖吸虫感染通过炎症反应激活了TGF-β1/Smads及ERK信号通路，促使MMP2和MMP9表达上调、COL-I和COL-III增加，最终导致肝纤维化。②Rg1可能通过减轻炎症反应，调控TGF-β1/Smads及ERK信号通路，引起MMP2、MMP9、TIMP的mRNA水平和蛋白质水平表达变化，导致COL I、COL III的蛋白质含量下降，最终起到缓解斯氏狸殖吸虫感染所致的肝纤维化。该研究进一步探索了斯氏狸殖吸虫感染致大鼠肝纤维化的分子机制，明确了Rg1可作为治疗该病的候选药物，有利于促进云南三七的主要活性成份Rg1的开发利用。