基于网络药理学和转录组测序的茱萸醇提取物对肝脏缺血再灌注损伤的保护作用

Chengcheng Guo, Zirong Liu, Hongsheng Liu
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摘要

背景与目的:肝缺血再灌注损伤(Hepatic ischemia-reperfusion injury, HIRI)是导致肝胆外科术后并发症及预后不良的关键因素,但其发病机制尚不清楚。因此,发现HIRI的防治方法和病理机制是非常必要的。方法:动物实验表明,5 g/kg和2.5 g/kg(生药/小鼠体重)剂量的山茱萸醇提取物(DAX)可显著降低HIRI小鼠血清丙胺转氨酶(AST)和天冬氨酸转氨酶(ALT)。这两种转氨酶的水平决定了DAX对HIRI的药效学作用。接下来,我们利用网络药理学和转录组测序的结果获得重要的防治靶基因,并应用分子对接模拟受体与配体结合。最后采用免疫组织化学方法对结果进行验证。结果:当模型组与对照组、给药组与模型组,设置padj < 0.05, | log2FoldChange | >1.0过滤条件时,获得的转录组测序数据集与网络药理学靶点的交集仅为肝素结合表皮生长因子(HBEGF)。然后应用DockThor在线软件,使DAX中所含的马草苷、熊果酸等小分子化合物通过氢键与HBEGF活性位点形成配合物,干扰HIRI。免疫组化检测结果显示,给药组小鼠HBEGF表达较模型组降低(*P < 0.05)。结论:DAX通过下调HBEGF干扰HIRI的发生和发展。我们的实验结果不仅突出了中医药治疗疑难疾患的优势,也为临床探索防治HIRI的新方法提供了参考。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Protective Effect of Dogwood Alcohol Extract on Hepatic Ischemia Reperfusion Injury based on Network Pharmacology and Transcriptomic Sequencing
Background and objective: Hepatic ischemia-reperfusion injury (HIRI) is a key factor leading to complications and poor prognosis after hepatobiliary surgery, but its pathogenesis remains unclear. Hence, it is a very necessary discovery the prevention and treatment methods and pathological mechanism of HIRI. Methods: Our animal experiments indicated that two doses of dogwood alcohol extract (DAX) at 5 g/kg and 2.5 g/kg (crude drug/mouse body mass) could significantly reduce serum alamine aminotransferase (AST) and aspartate aminotransferase (ALT) in HIRI mice. The level of these two transaminases determined the pharmacodynamic effect of DAX on HIRI. Next, we used the results of network pharmacology and transcriptome sequencing to obtain important prevention and cure target genes, and applied molecular docking to simulate receptor and ligand binding. Finally, immunohistochemical method was made use of verifying the results. Results: When the model group vs control group, administration group vs model group, set padj < 0.05, | log2FoldChange | >1.0 filter condition, the intersection between the obtained transcriptome sequencing data set and the network pharmacological target was only heparin-binding epidermal growth factor (HBEGF). Then DockThor online software was applied to make loganin and ursolic acid, small molecular compounds contained in DAX, form complexes with HBEGF active sites through hydrogen bonding to interfere with HIRI. Meanwhile, immunohistochemical test results showed that HBEGF expression decreased in the administration group compared with the model group ( *P < 0.05 ). Conclusions: DAX interferes with the occurrence and development of HIRI by down-regulating HBEGF. Our experimental results not only highlight the advantages of traditional Chinese medicine in treating difficult diseases, but also provide a reference for clinical exploration of new methods to prevent and treat HIRI.
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