基于网络药理学预测姜黄素联合小檗碱改善药物性肝损伤的潜在作用机制
Prediction of potential mechanism of curcumin combined with berberine in improving drug-induced liver injury based on network pharmacology
王佳乐 1刘跃 1毛煦1
作者信息
- 1. 牡丹江医学院药学院,黑龙江牡丹江 157011
- 折叠
摘要
目的 将体内实验与网络药理学相结合,初步探讨姜黄素(curcumin,CUR)联合小檗碱(berberine,BBR)改善药物性肝损伤(drug-induced liver injury,DILI)的潜在作用机制.方法 建立对乙酰氨基酚(acetaminophen,APAP)诱导 DILI 动物模型,检测小鼠血清丙氨酸转氨酶(alanine aminotransferase,ALT)与天冬氨酸转氨酶(aspartate aminotransferase,AST)水平.应用网络药理学方法搜集CUR、BBR、DILI相关靶点,通过韦恩映射筛选交集靶点,构建CUR-BBR-DILI蛋白质-蛋白质互作(protein-protein interactions,PPI)网络,进而进行基因本体(gene ontology,GO)功能与京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析.结果 体内实验结果显示CUR联合BBR可显著减少小鼠血清ALT与AST水平,优于单独给药;网络药理学实验结果显示PharmMapper数据库共搜集到CUR相关靶点 291 个、BBR相关靶点 208 个;Genecards数据库共搜集到DILI相关靶点 904 个;Venny 2.1.0 数据库共筛选出 77 个交集靶点;GO与KEGG分析分别得到 52 条基因功能和 20 条信号通路,可能与两药合用改善DILI有关;PPI网络中度值排名前 10 的核心靶点有 9 个富集在PI3K/AKT信号通路,依次为SRC、EGFR、HSP90AA1、IGF1、HRAS、MAPK14、ESR1、CASP3、PTK2.结论 CUR联合BBR可能通过多靶点和多途径的方式协同改善DILI,为阐明两药合用抗DILI的作用机制研究提供理论依据.
Abstract
Objective The potential mechanism of curcumin(CUR)combined with berberine(BBR)in improving drug-induced liver injury(DILI)was preliminarily predicted by a method of in vivo experiment in combination with network pharmacology.Methods The animal model was established by acetaminophen(APAP)-induced DILI and the levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)were detected in serum of mice.The network pharmacological approach was used to collect related targets of CUR,BBR,and DILI;Wayne mapping was carried out to screen intersection targets,followed by establishment of a protein-protein interaction(PPI)network of CUR-BBR-DILI.Functional enrichment analysis of gene ontology(GO)and pathway enrichment analysis of Kyoto Encyclopedia of Genes and Genomes(KEGG)were conducted finally.Results The in vivo experimental results showed that the combination of CUR and BBR can significantly reduce the serum ALT and AST levels in mice,which is better than administration alone;Network pharmacology experiment results exhibited that 291 related targets of CUR and 208 related targets of BBR were collected by PharmMapper database,and 904 related targets of DILI were collected by Genecards database;77 intersection targets were screened by Venny 2.1.0 database;52 gene functions and 20 signal pathways possibly in connection with the improvement of DILI via drug combination were obtained by GO and KEGG analysis,respectively;nine of the top ten core targets according to degree in PPI network were enriched to PI3K/AKT signaling pathway,which were in order as follows:SRC,EGFR,HSP90AA1,IGF1,HRAS,MAPK14,ESR1,CASP3,and PTK2.Conclusion DILI might be synergistically improved by CUR combined BBR through multi-target and multi-pathway manner,providing a theoretical basis for the elucidation of the mechanism of drug combination against DILI.
关键词
姜黄素/小檗碱/药物性肝损伤/网络药理学/对乙酰氨基酚Key words
Curcumin/Berberine/Drug-induced liver injury/Network pharmacology/Acetaminophen引用本文复制引用
基金项目
黑龙江省高等学校基本科研业务费科研项目(2021-KYYWF-0467)
出版年
2024
国家科技期刊平台
NSTL
万方数据