肝豆灵抑制Notch信号通路干预铜负荷致肝纤维化大鼠肝脏上皮-间质转化
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安徽省高校自然科学研究重点项目(KJ2016A409);安徽中医药大学自然科学研究重点项目(2017zrzd003);安徽中医药大学大学生创新创业基金项目(2017119)


Gandouling Exerts Interventional Effect on Liver Epithelial-Mesenchymal Transition in Rats with Copper Overload-Induced Liver Fibrosis by Inhibiting the Notch Signaling Pathway
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    目的 探讨肝豆灵抑制Notch信号通路干预铜负荷大鼠肝纤维化上皮-间质转化(epithelial-mesenchymal transition,EMT)的作用机制。方法 将雄性SD大鼠40只随机分为正常组,模型组,肝豆灵小、中、大剂量组,除正常组给予正常饲料外,其他各组喂饲硫酸铜饮食复制铜负荷大鼠肝纤维化模型。检测血清丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天冬氨酸氨基转移酶(aspartate aminotransferase, AST)、碱性磷酸酶(alkaline phosphatase,ALP)、透明质酸(hyaluronic acid,HA)水平及肝组织羟脯氨酸(hydroxyproline,Hyp)含量;分别采用苏木精-伊红染色和Masson染色观察肝组织病理损伤及胶原沉积状况;采用RT-PCR检测肝组织转化生长因子-β1(transforming growth factor beta 1, TGF-β1)、Jagged1、Notch1、Notch3、Snail mRNA,采用Western blot检测Hes1、E-cadherin蛋白表达水平,采用免疫组织化学法检测α-SMA表达水平。结果 与正常组比较,模型组血清ALT、AST、ALP、HA水平及肝组织Hyp、胶原纤维含量均显著升高(P<0.05),肝组织TGF-β1、Jagged1、Notch1、Notch3、Snail mRNA表达水平以及肝组织Hes1、α-SMA蛋白表达水平显著升高(P<0.05),E-cadherin蛋白表达水平显著降低(P<0.05);与模型组比较,肝豆灵中、大剂量组E-cadherin蛋白表达水平显著升高(P<0.05),其余上述指标均显著降低(P<0.05)。结论 肝豆灵通过抑制Notch信号通路,干预EMT环节,减少肌成纤维细胞转化生成及活化增殖,降低胶原纤维沉积而抗肝纤维化。

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    Objective To investigate the mechanism of action of Gandouling in the intervention of liver epithelial-mesenchymal transition (EMT) in rats with copper overload-induced liver fibrosis by inhibiting the Notch signaling pathway. Methods A total of 40 male Sprague-Dawley rats were randomly divided into normal group, model group, and low-, middle-, and high-dose Gandouling groups. The rats in the normal group were given normal diet, and those in the other groups were given copper sulfate diet to establish a rat model of copper overload-induced liver fibrosis. Serum levels of alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), alkaline phosphatase (ALP), and hyaluronic acid (HA) and the content of hydroxyproline (Hyp) in liver tissue were measured. Hematoxylin and eosin staining and Masson staining were used to observe liver pathological injury and collagen deposition. RT-PCR was used to measure the mRNA expression of transforming growth factor-β1 (TGF-β1), Jagged1, Notch1, Notch3, and Snail in liver tissue, Western blot was used to measure the protein expression of Hes1 and E-cadherin, and immunohistochemistry was used to measure the expression of alpha-smooth muscle actin (ɑ-SMA). Results Compared with the normal group, the model group had significant increases in serum levels of ALT, AST, ALP, and HA, the content of Hyp and collagen fibers in liver tissue, the mRNA expression of TGF-β1, Jagged1, Notch1, Notch3, and Snail in liver tissue, and the protein expression of Hes1 and ɑ-SMA in liver tissue (P<0.05) and a significant reduction in the protein expression of E-cadherin (P<0.05). Compared with the model group, the middle- and high-dose Gandouling groups had a significant increase in the protein expression of E-cadherin (P<0.05) and significant reductions in all the other indices (P<0.05). Conclusion Gandouling exerts an interventional effect on EMT by inhibiting the Notch signaling pathway and can alleviate liver fibrosis by reducing the transformation, activation, and proliferation of myofibroblasts and the accumulation of collagen fibers.

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吴 鹏,王亚东,方 颖,李茂涛,蒋怀周,鲍远程.肝豆灵抑制Notch信号通路干预铜负荷致肝纤维化大鼠肝脏上皮-间质转化[J].安徽中医药大学学报,2018,37(6):79-84

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  • 在线发布日期: 2018-12-04