| 单味中药治疗心肌梗死的药效物质及作用机制：基于网络药理学和多靶标分子对接方法 |
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| 引用本文： | 赵石,刘珂娣,段佳林,陶星茹,李伟红,白杨,卫培峰,奚苗苗,杨红莲. 单味中药治疗心肌梗死的药效物质及作用机制：基于网络药理学和多靶标分子对接方法[J]. 南方医科大学学报, 2022, 42(1): 13-25. DOI: 10.12122/j.issn.1673-4254.2022.01.02 |
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| 作者姓名： | 赵石 刘珂娣 段佳林 陶星茹 李伟红 白杨 卫培峰 奚苗苗 杨红莲 |
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| 作者单位： | 陕西中医药大学药学院，陕西 咸阳 712046；西北工业大学医学研究院，陕西 西安 710072；陕西中医药大学第二附属医院国家药物临床试验机构，陕西 咸阳 712021；西安天工生物医药研究所，陕西 西安 710032；陕西中医药大学附属医院临床医学研究中心，陕西 咸阳 712099 |
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| 摘 要： | 目的 应用网络药理学及分子对接技术，发现治疗心肌梗死（MI）效果较优的中药，并进一步探讨其药效物质及作用机制。方法 通过TCMSP数据库，根据指定的标准，筛选含有治疗MI的活性成分较多的中药。利用Genecards、OMIM、PharmGkb、PharmMapper数据库获取中药与MI的相关靶标，采用Venny2.1.0软件建立药物靶标与疾病靶标的共同靶标网络。通过R语言对共同靶标进行 GO及 KEGG信号通路富集分析；通过 STRING数据库对共同靶标进行蛋白蛋白相互作用网络构建；通过Cytoscape3.7.2软件中的cytoHubba工具对PPI网络涉及的靶标进行分析并确定关键靶标；通过R语言对关键靶标进行GO及KEGG信号通路富集分析。应用SYBYL-X2.1.1软件对潜在药效物质及关键靶标进行分子对接，以Total Score≥6为参考，筛选药效物质并验证其与关键靶标的对接结合性。复制人脐静脉内皮细胞氧糖剥夺模型，通过蛋白质免疫印迹检测对潜在药效物质与治疗MI的关键靶标进行验证。结果 本研究筛选出丹参、降香含有治疗MI的活性成分较多，涉及PTGS2、KDR等治疗MI的关键靶标16个，主要涉及炎症反应、血管新生、能量代谢与氧化应激等生物过程，HIF-1、VEGF、TNF等信号通路，丹参中的香紫苏醇与PTGS2、降香中的芒柄花黄素与KDR对接Total Score最高。Western blot结果显示，低、中、高计量的紫苏醇与芒柄花黄素分别能够抑制PTGS2与促进KDR的表达，且呈剂量-效应依赖关系，其中中、高剂量组差异具有统计学意义（P<0.05）。结论 中药丹参、降香治疗MI的疗效较优，其作用机制可能与丹参、降香中的潜在药效物质香紫苏醇及芒柄花黄素调控PTGS2与KDR的表达，调节炎症反应、血管新生、氧化应激与能量代谢，进而发挥心肌保护作用有关。
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| 关 键 词： | 网络药理学；分子对接；心肌梗死；药效物质；中药 |
Identification of traditional Chinese drugs containing active ingredients for treating myocardial infarction and analysis of their therapeutic mechanisms by network pharmacology and molecular docking |
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| ZHAO Shi,LIU Kedi,DUAN Jialin,TAO Xingru,LI Weihong,BAI Yang,WEI Peifeng,XI Miaomiao,YANG Honglian. Identification of traditional Chinese drugs containing active ingredients for treating myocardial infarction and analysis of their therapeutic mechanisms by network pharmacology and molecular docking[J]. Journal of Southern Medical University, 2022, 42(1): 13-25. DOI: 10.12122/j.issn.1673-4254.2022.01.02 |
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| Authors: | ZHAO Shi LIU Kedi DUAN Jialin TAO Xingru LI Weihong BAI Yang WEI Peifeng XI Miaomiao YANG Honglian |
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| Affiliation: | School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046, China; Institute of Medicine, Northwestern Polytechnical University, Xi'an 710072, China; National Institute of Drug Clinical Trials, Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712021, China; Xi'an TANK Medicinal Biology Institute, Xi'an 710032, China; Clinical Medical Research Center, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712099, China |
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| Abstract: | Objective To identify traditional Chinese drugs that contain active ingredients for treatment of myocardial infarction (MI) and explore their therapeutic mechanisms using network pharmacology and molecular docking technology. Methods The TCMSP database was used for screening the traditional Chinese drugs containing active ingredients for treating MI, and the related targets of MI and the candidate drugs were obtained from Genecards, OMIM, PharmGkb and PharmMapper databases. The common target network of the drug targets and disease targets was established usingVenny2.1.0 software. GO and KEGG signal pathway enrichment analysis of the common targets was performed, and the protein-protein interaction (PPI) network was constructed for the targets. The targets in the PPI network were analyzed to identify the key targets, for which GO and KEGG pathway enrichment analyses were performed. Molecular docking was performed for the candidate ingredients and the key targets, and a total score ≥6 was used as the criteria for screening the therapeutic ingredients and their docking binding with key targets was verified. A human umbilical vein endothelial cell(HUVEC) model of oxygen-glucose deprivation (OGD) was used to validate the candidate ingredients and the key therapeutic targets for MI by Western blotting. Results Our analysis identified Salvia miltiorrhiza and Dalbergiae odoriferae as the candidate drugs rich in active ingredients for treatment of MI. These ingredients involved 16 key therapeutic targets for MI, which participated in such biological processes as inflammatory response, angiogenesis, energy metabolism and oxidative stress and the pathways including HIF-1, VEGF, and TNF pathways. Sclareol and PTGS2 in Salvia miltiorrhiza and formononetin and KDR in Dalbergiae odoriferae all had high docking total scores. Western blotting showed that at medium and high doses, sclareol significantly inhibited PTGS2 expression and formononetin promoted KDR expressions in the cell models in a dose-dependent manner (P<0.05). Conclusion Both Salvia miltiorrhiza and Dalbergiae odoriferae have good therapeutic effects on MI. Sclareol in Salvia miltiorrhiza and formononetin in Dalbergiae odoriferae regulate the expressions of KDR and PTGS2, respectively, to modulate the inflammatory response, angiogenesis, oxidative stress and energy metabolism and thus produce myocardial protective effects. |
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| Keywords: | network pharmacology molecular docking myocardial infarction pharmacodynamic substances traditional Chinese drugs, |
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