基于网络药理学和分子对接方法探讨健脾利湿养肝方治疗慢加急性肝衰竭的作用机制  

The molecular mechanism of spleen-strengthening and moisture-nourishing liver prescription in treatment of acute-on-chronic liver failure based on network pharmacology and experimental verification

作　　者：黄琦 李静 马文峰[1,2] 韩志毅[1,2] 孙嘉玲 张卫[1,2] 孙新锋[1,2] 陈剑平[1,4] 周小舟[1,2,3] Huang Qi;LI Jing;MA Wen-feng;HAN Zhi-yi;SUN Jia-ling;ZHANG Wei;SUN Xin-feng;CHEN Jian-ping;ZHOU Xiao-zhou(School of the Fourth Clinical Medicine,Guangzhou University of Chinese Medicine,Guangzhou 510006,China;National Key Specialty of Clinical Liver Disease(Traditional Chinese Medicine)of Shenzhen Traditional Chinese Medicine Hospital,Shenzhen Guangdong 518033,China;School of Chinese Medicine,Macao University of Science and Technology,Macao 999078,China;Key Laboratory of Traditional Chinese Medicine Formulation Research,Shenzhen Traditional Chinese Medicine Hospital,Shenzhen Guangdong 518033)

机构地区：[1]广州中医药大学第四临床医学院,广东广州510006 [2]深圳市中医院国家临床肝病(中医)重点专科,广东深圳518033 [3]澳门科技大学中医药学院,中国澳门999078 [4]深圳市中医院中药制剂研究重点实验室,广东深圳518033

出　　处：《中国药理学通报》2024年第3期557-564,共8页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No82205209);深圳市科研计划项目(NoJCYJ20210324120405015,JCYJ20180302173542393)。

摘　　要：目的运用网络药理学和分子对接探究养肝方治疗慢加急性肝衰竭(acute-on-chronic liver failure,ACLF)的作用机制。方法依托TCMSP及GeneCards等多种数据库,获得健脾利湿养肝方治疗ACLF疾病的相关靶点。应用String及Cytoscape构建作用靶点的PPI网络,筛选出核心作用靶点并采用DAVID进行GO功能注释和KEGG通路富集分析。对健脾利湿养肝方重复出现的活性成分以生物利用度OB值≥30%,类药性DL≥0.18为筛选条件,分选出中药复方健脾利湿养肝方的主要活性成分,并对该主要活性成分与核心作用靶点亲和力进行分子对接及动物体内实验验证。结果共获得健脾利湿养肝方治疗ACLF的活性成分536个,交集靶点基因244个,并筛选出核心靶点基因7个。分子对接显示核心靶基因AKT1、SRC、VEGFA、STAT3、EGFR、MAPK3、HRAS与健脾利湿养肝方中的主要活性成分槲皮素亲和力较好,具有很强的结合活性。另外,体内实验验证健脾利湿养肝方能够降低HRAS、EGFR、STAT3、SRC、VEGFA的表达,以延缓ACLF疾病进展。结论健脾利湿养肝方可能作用于HRAS、EGFR、STAT3、SRC、VEGFA等核心靶点,以达到治疗ACLF的作用。Aim To explore the mechanism of spleen-strengthening and moisture-nourishing liver prescription(JPLSYGF)in the treatment of acute-on-chronic liver failure using network pharmacology and the molecular docking.Methods Relying on TCMSP and GeneCards and other databases,the relevant targets of JPLSYGF in the treatment of acute-on-chronic liver failure were obtained.String and Cytoscape were used to construct PPI networks of targets,core targets were screened out,and DAVID was used for GO function annotation and KEGG pathway enrichment analysis.The main active ingredients of the traditional Chinese medicine compound formula for JPLSYGF were selected with a bioavailability OB value of≥30%and a drug-like DL≥0.18 as the screening conditions,and the molecular docking and in vivo tests were carried out on the affinity of the main active ingredient with the core target.Results A total of 536 active ingredients were obtained for the treatment of acute-on-chronic liver failure,and 244 intersecting target genes and 7 core target genes were screened.Molecular docking showed that the core target genes AKT1,SRC,VEGFA,STAT3,EGFR,MAPK3,HRAS had good affinity with quercetin,the main active component in the JPLSYGF,and had strong binding activity.In addition,in vivo tests verified that the JPLSYGF could reduce the expression of HRAS,EGFR,STAT3,SRC,and VEGFA,to delay the progression of acute-on-chronic liver failure.Conclusions JPLSYGF may act on core targets such as HRAS,EGFR,STAT3,SRC,VEGFA and so on,to achieve the effect of treating acute-on-chronic liver failure.

关 键 词：健脾利湿养肝方 慢加急性肝衰竭 网络药理学 分子对接 信号通路 槲皮素 

分 类 号：R-332[医药卫生] R242R289.5R319R575.3