基于网络药理学、分子对接和实验验证探讨莪术-鳖甲药对抗肝纤维化的作用机制  

Mechanism of Curcumae Rhizoma-Trionycis Carapax drug pair in thetreatment of liver fibrosis based on network pharmacology,molecular docking and experiment validation

作　　者：周玉娇 廖珊珊 高攀 杨钰敏 李秋杏 秦旭华[1] 金沈锐[2] ZHOU Yu-jiao;LIAO Shan-shan;GAO Pan;YANG Yu-min;LI Qiu-xing;QIN Xu-hua;JIN Shen-rui(College of Pharmacy,Chengdu University of Traditional Chinese Medicine;College of Basic Medicine,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China)

机构地区：[1]成都中医药大学药学院 [2]成都中医药大学基础医学院,成都611137

出　　处：《天然产物研究与开发》2024年第5期856-867,共12页Natural Product Research and Development

基　　金：国家中医药管理局项目(003112011013);四川省科技厅项目(319022032)。

摘　　要：采用网络药理学、分子对接技术和实验验证探讨莪术-鳖甲药对(Curcumae Rhizoma-Trionycis Carapax,CRTC)抗肝纤维化的作用机制。首先搜集鳖甲和莪术的化学成分和靶点信息;然后将两味药的作用靶点合并去重。使用疾病数据库以获取肝纤维化的相关基因。提取CRTC和肝纤维化的交集靶点,进一步对“药物-潜在活性成分-潜在靶点”网络进行可视化展示。将交集靶点导入STRING数据库以构建蛋白-蛋白相互作用网络(PPI);然后进行GO功能和KEGG通路富集分析并可视化,再用Autodock Vina软件实现分子对接模型的构建。最后通过体内实验对网络药理学预测的靶点及通路进行实验验证。共筛选得到CRTC与肝纤维化的交集靶点共65个。PPI网络中筛选得到度值排名前四的靶点分别为白细胞介素-6(interleukin-6,IL-6)、丝氨酸/苏氨酸蛋白激酶1(Akt serine/threonine kinase 1,AKT1)、信号传导及转录激活因子3(signal transducer and activator of transcription 3,STAT3)、过氧化物酶体增殖物激活受体γ(peroxisome proliferative activated receptor gamma,PPARG)。GO功能富集分析显示涉及的生物过程有1025条,细胞组分有41条,分子功能有84条;KEGG通路富集分析得到149条通路,其中关键通路有EGFR酪氨酸激酶抑制剂耐药性。分子对接结果显示IL-6、STAT3等核心靶点与其对应成分均有良好的结合活性。体内动物实验结果证实CRTC能改善肝纤维化的病理学形态,且显著抑制了IL-6、EGFR、STAT3的表达。综上所述,CRTC通过多靶点、多通路发挥其抗肝纤维化作用,其机制与网络药理和分子对接技术预测的IL-6/EGFR/STAT信号轴相关。The mechanism of Curcumae Rhizoma-Trionycis Carapax drug pair(CRTC)in treating liver fibrosis was explored by using network pharmacology,molecular docking technology and experiment validation.Firstly,we collected the chemical components and targets information of Curcumae Rhizoma(CR)and Trionycis Carapax(TC);then merged the targets of the two drugs and removed duplicates.We used diverse disease databases to obtain genes information related to liver fibrosis.And we extracted the intersection targets of CRTC and liver fibrosis,further visualized the network of“drugs-potential active ingredients-potential targets”.We imported intersection targets into the STRING database to construct a protein-protein interaction(PPI)network;performed GO function and KEGG pathway enrichment analysis and visualization,and then used AutodockVina software to construct molecular docking models.Finally,the targets and pathways predicted by network pharmacology were experimentally validated through in vivo experiments.Totally,65 intersection targets between CRTC and liver fibrosis were identified.In PPI network,the top 4 with the highest node connection values are interleukin-6(IL-6),Akt serine/threonine kinase 1(AKT1),signal transducer and activator of transcription 3(STAT3)and peroxisome proliferative activated receptor gamma(PPARG),respectively.GO functional enrichment analysis involved 1025 biological processes,41 cell components,and 84 molecular functions.KEGG pathway enrichment analysis identified 149 pathways,including key pathways such as EGFR tyrosine kinase inhibitor resistance.Molecular docking results showed that IL-6,STAT3 and other core targets had good binding activity with their corresponding components.The in vivo animal experimental results confirmed that CRTC can improve the pathological morphology of liver fibrosis and significantly inhibit the expression of IL-6,EGFR,and STAT3.In conclusion,CRTC acts against liver fibrosis through multiple targets and multiple pathways,its mechanism is related to the IL-6/EGFR/STA

关 键 词：莪术-鳖甲药对 肝纤维化 网络药理学 分子对接 实验验证 

分 类 号：R285[医药卫生—中药学]