黄药子致肝脏损伤的网络毒理学分析及验证

Network Toxicological Analysis and Verification of Liver Injury Induced by Dioscorea Bulbifera L.

关键词:  网络毒理学  黄药子  肝脏毒性  PI3K/Akt信号通路

Key words:  network toxicology  Dioscorea bulbifera L.  hepatotoxicity  PI3K/Akt signaling pathway

摘要:

目的 采用网络毒理学方法对黄药子导致肝脏损伤的毒理作用及机制进行预测，并通过动物试验对预测结果进行验证。方法 通过TCMSP结合TOXNET筛选黄药子致肝损伤的毒性成分，利用Pharm Mapper数据库预测黄药子毒性成分作用靶点，应用Gene Cards和CTD筛选肝脏损伤靶点，采用Cytoscape软件构建黄药子“毒性成分-靶点”及“毒性成分-肝脏损伤靶点”网络，利用STRING数据库构建蛋白互作网络，分析黄药子致肝脏损伤的关键靶点。通过DAVID平台对黄药子致肝损伤靶点进行通路富集分析。通过动物试验对黄药子致肝脏损伤的机制进行验证。结果 通过TCMSP获得黄药子63个成分，TOXNET网站筛选出黄药子致肝脏损伤的8个毒性成分，黄药子致肝损伤的关键靶点为Akt1、INS、VEGFA；其机制涉及PI3K/Akt、HIF-1、Ras以及Rap1等信号通路。动物试验结果表明，黄药子水煎液可使血清ALT、AST和ALP水平升高，肝脏组织中MDA含量升高及SOD和GSH活性降低，黄药子可降低肝脏p-Akt与p-PI3K蛋白表达。结论 黄药子导致肝损伤是通过多成分、多靶点作用于多种信号通路的结果，与其下调肝脏组织中PI3K/Akt信号通路有关。

Abstract:

OBJECTIVE To predict the toxicological effects and mechanisms of Dioscorea bulbifera L. causing liver damage by the network toxicology method, and verify the prediction results through animal experiments. METHODS TCMSP combined with TOXNET was used to screen the toxic components of Dioscorea bulbifera L. that caused liver damage, and the Pharm Mapper database was used to predict the target of the toxic components of Dioscorea bulbifera L.. Gene Cards and CTD were used to screen liver damage targets, and Cytoscape software was used to construct a network of "toxic components-targets" and "toxic components-liver damage targets" of Dioscorea bulbifera L.. The STRING database was used to construct a protein interaction network and analyze the key targets of Dioscorea bulbifera L. induced liver damage. Pathway enrichment analysis was performed on the targets of Dioscorea bulbifera L. induced liver damage through the DAVID platform. The mechanism of Dioscorea bulbifera L. induced liver damage was verified through animal experiments. RESULTS The 63 components of Dioscorea bulbifera L. were obtained through TCMSP. The TOXNET website screened out 8 toxic components of Dioscorea bulbifera L. that caused liver damage. The key targets of Dioscorea bulbifera L. caused liver damage were Akt1, INS, VEGFA. Its mechanism included many signal pathways, such as PI3K/Akt, HIF-1, Ras, Rap1, etc. The results of animal experiments showed that decoction of Dioscorea bulbifera L. could increase serum ALT, AST and ALP levels, increase the content of MDA in liver tissue and decrease SOD and GSH activities. Dioscorea bulbifera L. could reduce p-Akt and p-PI3K protein expression in liver. CONCLUSION The liver damage caused by Dioscorea bulbifera L. is the result of multiple signal pathways through multiple components and multiple targets. It is related to the reduction of the PI3K/Akt signal pathway in liver tissue.