基于网络药理学的黄芪抗肺纤维化机制预测与验证研究

来源:用户上传      作者:黎金浓 何娅娜 周辉 邓桂明

　　 〔摘要〕 目的 通过网络药理学分析和实验验证阐释黄芪抗肺纤维化作用机制。方法 从中药系统药理学数据库和分析平台、中药分子机制的生物信息学分析工具中获取黄芪所有化学成分和对应靶点，从DrugBank和DisGeNET数据库获取肺纤维化疾病相关靶点，两者取交集，获得黄芪治疗肺纤维化潜在作用靶点，采用Cytoscape构建成分-靶点图，拓扑分析后通过Degree值筛选黄芪治疗肺纤维化关键活性成分，通过STRING构建靶点蛋白相互作用图，筛选核心靶点，通过基因在线富集分析工具Enrichr分析获得黄芪治疗肺纤维化所涉及的通路;观察黄芪提取物对博来霉素诱导的大鼠肺泡巨噬细胞TGF-β、PTGS2和p-ERK1/2蛋白表达的影响。结果 黄芪含有76个化学成分，作用于563个靶点，肺纤维化疾病相P靶点932个，交集靶点97个，黄芪活性成分-肺纤维化疾病靶点网络图中Degree值排名前4的成分依次为槲皮素（quercetin）、山柰酚（kaempferol）、大豆苷元（daidzein）、刀豆氨酸（canavanine），预测核心靶点分别为PTGS2、MAPK1、MAPK14、EGF、JUN等，涉及糖尿病并发症相关AGE-RAGE、流体切应力与动脉粥样硬化、癌症、IL-17等信号通路;低、中、高剂量黄芪提取物均能够降低博来霉素诱导的NR8383细胞TGF-β1、PTGS2的含量（P<0.05），并下调其p-ERK1/2的表达（P<0.05或P<0.01）。结论 黄芪能够通过多成分、多靶点、多作用途径干预肺纤维化病理过程，其机制与抑制肺泡巨噬细胞TGF-β、PTGS2和p-ERK1/2表达有关，为进一步研究黄芪治疗肺纤维化作用机制奠定基础。
　　 〔关键词〕 肺纤维化;黄芪;网络药理学;效应机制;肺泡巨噬细胞
　　 〔中图分类号〕R259 〔文献标志码〕A 〔文章编号〕doi：10.3969/j.issn.1674-070X.2022.02.018
　　Mechanism prediction and validation research of Huangqi （Astragali Radix） in the
　　treatment of pulmonary fibrosis based on network pharmacology
　　LI Jinnong， HE Yana， ZHOU Hui， DENG Guiming*
　　（The First Affiliated Hospital of Hunan University of Chinese Medicine， Changsha， Hunan 410007， China）
　　〔Abstract〕 Objective To explore the potential mechanism of Huangqi （Astragali Radix） in the treatment of pulmonary fibrosis based on network pharmacology and experimental verification. Methods All chemical components and corresponding targets of Huangqi （Astragali Radix） were obtained from traditional Chinese medicine systems pharmacology database and analysis platform and a bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine， and pulmonary fibrosis disease related targets were obtained from DrugBank and DisGeNET databases. The intersection of the two was taken to obtain the potential targets of Huangqi （Astragali Radix） in the treatment of pulmonary fibrosis. The component-target map was constructed by Cytoscape. After topological analysis， the key active components of Huangqi （Astragali Radix） in the treatment of pulmonary fibrosis were screened by Degree value. The target protein interaction map was constructed by STRING to screen the core targets. The pathways involved in the treatment of pulmonary fibrosis by Huangqi （Astragali Radix） were obtained by Enrichr analysis. The effects of Huangqi （Astragali Radix） extract on the expression of TGF-β， PTGS2 and P-ErK1/2 proteins in bleomycin-induced rat alveolar macrophages was observed. Results Huangqi （Astragali Radix） contained 76 chemical components that acted on 563 targets， 932 targets related to pulmonary fibrosis disease and 97 targets of intersection. The top 4 components in the map of Huangqi （Astragali Radix） components-targets of pulmonary fibrosis disease network were quercetin， kaempferol， daidzein， canavanine. The suppositional targets were PTGS2， MAPK1， MAPK14， EGF， JUN， involving AGE-RAGE in diabetic complications， fluid shear stress and atherosclerosis， cancer， IL-17 signaling pathway and so on. Low， medium and high doses of Huangqi （Astragali Radix） extract could down-regulate the content of TGF-β1 and PTGS2 in bleomycin-induced NR8383 cells （P<0.05）， and down-regulate the expression of P-ERK1/2（P<0.05， P<0.01）. Conclusion Huangqi （Astragali Radix） can act on the whole course of pulmonary fibrosis through multi-component， multi-target and multi-action pathway， the mechanism may be related to down-regulating the expression of TGF-β， PTGS2 and p-ERK1/2 in pulmonary macrophage， which provides a basis for studying on the mechanism of Huangqi （Astragali Radix） in treating pulmonary fibrosis.
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