TCMATHF：a bioinformatics platform to predict pharmacological action of drug and dynamic molecular changes against from myocardial infarction to heart failure.pdf

中国药理学与毒理学杂志2023年9月第37卷增刊1Chin J Pharmacol Toxicol，Vol 37，Suppl 1,Sep 2023sioninjury;cardiacmicrovascularendothelialcells;network pharmacology;molecular dockingFoundationitem:NationalNaturalScienceFoundation of China(82030124);National Natural Science Foundation of China(82174015);Science and Technology Innovation Project of ChinaAcademyofTraditionalChineseMedicine(CI2021A04609)First author:Cao Ce,E-mail:Corresponding author:LIU Jianxun,E-mail:W2-4-2基于药理实验及网络药理学探讨冠心苏合胶囊治疗急性心肌梗死的作用机制钱 铭1，2，熊 媛2，程 龙3，杨 慧1，3（1.南京大学医学院附属鼓楼医院药学部，江苏南京 210008；2.中国药科大学附属南京鼓楼医院，江苏 南京 210008；3.南京中医药大学附属南京鼓楼医院，江苏 南京 210008）摘要：目的 使用药理学实验结合网络药理学揭示冠心苏合胶囊（GXSH）治疗急性心肌梗死（AMI）的药效作用及靶点机制。方法 构建异丙肾上腺素诱导的AMI小鼠模型，灌胃给予GXSH（0.5，1和2 mgkg-1），观察各组小鼠心脏组织病理学变化，检测肌酸激酶（CK）、肌酸激酶同工酶（CK-MB）、乳酸脱氢酶（LDH）、肌钙蛋白（cTnT）、谷草转氨酶（AST）、谷丙转氨酶（ALT）的水平。通过TCMSP和ETCM数据库检索GXSH的化学成分，SwissTargetPrediction 和 GeneCards 数据库获取活性成分潜在靶点和AMI的靶点，构建“XSH活性成分-AMI靶点”网络，并于DAVID数据库进行GO和KEGG富集分析。结果 HE染色显示GXSH明显减轻AMI小鼠心肌组织损伤，降低CK、CK-MB、LDH、cTnT、AST 和 ALT 水平（P0.05）。网络药理学收集整理得到95个GXSH治疗AMI的潜在靶点，富集于流体剪切应力与动脉粥样硬化、AGE-RAGE 信号通路、氧化应激等信号通路。结论GXSH具有显著的防治AMI作用，其机制可能与调控流体剪切应力与动脉粥样硬化、AGE-RAGE信号通路、氧化应激等信号通路有关。关键词：冠心苏合胶囊；急性心肌梗死；网络药理学；作用机制基 金 项 目：国 家 自 然 科 学 基 金 青 年 项 目（82204720）；中 央 高 校 基 本 科 研 业 务 费（3332022085）作者简介：钱 铭，E-mail：通讯作者：杨 慧，E-mail：W2-4-3TCMATHF:a bioinformatics platform to predictpharmacologicalactionofdruganddynamicmolecularchangesagainstfrommyocardial infarction to heart failureXIYujie1，2，TANGXuan1，GUOFeifei1，YANG Hongjun1，2，3(1.Institute of Chinese Materia Medica,ChinaAcademy of Chinese Medical Sciences,Beijing100700,China;2.Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases,Experimental Research Center,China Academy of Chinese Medical Sciences,Beijing 100700,China;3.China Academy of Chinese Medical Sciences,Beijing 100700,China)Abstract:OBJECTIVETo investigate thecharacteristics and regulations of medication indifferent stages of disease by constructing adynamic disease network and a cellular featurenetwork spanning from myocardial infarction toheart failure.METHODSBased on transcriptome and single-cell sequencing data from amouse model of left anterior descending coronary artery ligation,a dynamic early-middle-latenetwork and cellular feature network were constructed by integrating differential gene expression trends and biological functions.The robustness of the perturbation effect of traditional Chinese medicine(TCM)on the disease networkwas calculated based on multi-target TCM,andwe acquired the foundational data by analyzingthe results of effectiveness.The predictive platform was scrutinized and assessed with regardsto the functional attributes of FDA approved-drugs and compound prescriptions,in order todetermine the primary stages of intervention andthe drug patterns actions in the progression of 26中国药理学与毒理学杂志2023年9月第37卷增刊1Chin J Pharmacol Toxicol，Vol 37，Suppl 1，Sep 2023heart failure.RESULTS In this study,we developedapredictionandanalysisplatformforassessing the efficacy of drugs using a network-based approach.The accuracy of the systemwas validated by FDA approved-drugs.It wasfound that blood-activating drugs,heat-clearingdrugs,andphlegm-expellingdrugsexhibitedfavorable intervention effects during the early tomiddle stages of the disease by investigating theeffects of single herbs and TCM prescriptions ondisease progression.Similarly,phlegm-expellingdrugs,spirit-nourishingdrugs,anddiureticshowed better intervention effects during the middle to late stages.These findings were consistent with the clinical use of drugs.Analysis of theclustering heatmap results of TCM prescriptionsrevealed that the formulas aimed at qi stagnationand blood stasis had a strong effect in earlystage,while the formulas for qi and yin deficiencyand cardiorenal yang deficiency had a strongeffect in the middle to late stages.Furthermore,analysis of the single-cell feature network demonstrated that TCM had advantages in modulatingthe changes in fibroblasts,myofibroblasts,endothelial cells,and granulocytes during the pathological process.Additionally,most prescriptionsexhibited strong perturbation effects on the feature network of NK-T cells,granulocytes,macrophages,andmyofibroblasts.CONCLUSIONThis platform quantitatively evaluates the primaryaction stages and characteristics of TCM and formulas involved in the dynamic process of myocardial infarction to heart failure based on theeffective prediction of the efficacy of TCM andFDA approved-drugs.It provides reference forthe precise clinical application of TCM and formulas with multiple targets and multiple pathways.Key words:myocardial infarction;heart failure;dynamic network;single cell;drug perturbationFoundation item:National Science and Technology Major Project(2019YFC1708904);theFundamental Research Funds for the CentralPublic Welfare Research Institutes(ZZ13-YQ-048);and the Fundamental Research Funds forthe Central Public Welfare Research Institutes(ZXKT21008)Correspondingauthor:GUOFeifei,E-mail:;YANGHongjun,E-mail:.W2-4-4基于网络药理学及分子对接探讨灯盏生脉胶囊治疗冠心病的作用机制杨 慧1，2，程 龙2，熊 媛3，钱 铭1（1.南京大学医学院附属鼓楼医院药学部，江苏 南京 210008；2.南京中医药大学附属南京鼓楼医院，江苏 南京 210008；3.中国药科大学附属南京鼓楼医院，江苏 南京 210008）摘要：目的 使用网络药理学结合分子对接技术探讨灯盏生脉胶囊治疗冠心病的潜在作用靶点及机制。方法 结合TCMSP和ETCM数据库检索灯盏生脉胶囊的化学成分，SwissTargetPrediction数据库获取活性成分的潜在靶点。检索 GeneCards和DisGeNET数据库获取冠心病靶点，构建“灯盏生脉胶囊活性成分-冠心病靶点”网络。对关键活性成分和核心靶点进行分子对接，验证结合特性。于 DAVID 数据库进行 GO 和 KEGG 富集分析。结果 共获得灯盏生脉胶囊的 54个活性化合物作用于 136个冠心病靶点。分子对接显示关键活性成分（山奈酚、槲皮素、木犀草素、芹菜素、野黄 芩 素）与 核 心 靶 点（AKT1、SRC、PPARG、EGFR 和 ESR1）具有良好的结合特性。KEGG 富集分析显示灯盏生脉胶囊主要通过调控内分泌抵抗、糖尿病并发症中的AGE-RAGE信号通路、流体剪切应力与动脉粥样硬化、脂质与动脉粥样硬化、松弛素信号通路等途径治疗冠心病。结论 灯盏生脉胶囊通过“多成分、多靶点、多途径”发挥治疗冠心病的作用。关键词：灯盏生脉胶囊；冠心病；网络药理学；分子对接；作用机制基金项目：中央高校基本科研业务费（3332022085）；国家自然科学基金青年项目（82204720）作者简介：杨 慧，E-mail：通讯作者：钱 铭，E-mail：W2-5 肿瘤W2-5-1基于TMT蛋白质组学和网络药理学探讨常春藤皂苷元抑制宫颈癌SiHa细胞线粒体自噬的作用机制 27