首页|人参干预动脉粥样硬化中细胞焦亡的作用机制探讨

人参干预动脉粥样硬化中细胞焦亡的作用机制探讨

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目的 研究人参调控动脉粥样硬化(atherosclerosis,AS)中细胞焦亡(pyroptosis)以发挥治疗作用的关键成分、作用靶点与信号通路,探究人参作用AS中细胞焦亡的具体机制.方法 通过TCMSP、HERB与Swiss Target Prediction数据库筛选人参的活性成分及其对应的标准化靶点;利用OMIM、GeneCards、TTD数据库中AS相关靶点和分析GEO数据库中AS组织和正常组织RNA测序数据的差异表达基因获取AS的标准化靶点,通过GeneCards筛选细胞焦亡相关靶点;通过微生信平台获取交集基因,对其构建蛋白质-蛋白质相互作用网络,分析筛选核心靶点;利用 R 语言"clusterProfiler"包对靶点进行 GO 与 KEGG 富集分析;使用Cytoscape 3.9.1 软件构建"活性成分-靶点-通路-疾病网络图"并分析人参的关键成分;利用AutoDock Vina对核心靶点与关键成分进行分子对接;随后选取核心靶点与关键成分的对接结果使用Gromacs软件进行 50 ns分子动力学模拟验证,运用分子力学/泊松-玻尔兹曼表面积法对最后 10 ns蛋白质与配体的自由结合能进行分析.结果 获得人参的 22 个活性成分及 588 个标准化靶点,共获得 36 个人参-细胞焦亡相关AS靶点,其中核心靶点为肿瘤坏死因子(tumor necrosis factor,TNF)、丝氨酸/苏氨酸激酶(serine/threonine kinase,AKT)1、白细胞介素(interleukin,IL)-1β、过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptor gamma,PPARG).GO与KEGG富集结果显示人参-细胞焦亡相关AS靶点主要与脂多糖的反应、DNA 结合转录因子、核受体活性以及TNF信号通路和核因子(nuclear factor,NF)-κB信号通路有关.筛选获得人参作用于AS中细胞焦亡靶点的关键成分为山柰酚(kaempferol)、吉九里香碱(girinimbin)、脱氧三尖杉酯碱(deoxyharringtonine)与戈米辛 B(gomisin B).分子对接结果初步表明核心靶点与关键成分有良好的结合能力.分子动力学模拟结果显示TNF与关键成分形成的复合物的波动较小,在Nacl溶液环境下十分稳定;结合自由能分析结果表明关键复合物中核心靶点与关键成分的结合自由能较低,具有较好的结合能力.结论 人参可能通过TNF、AKT1、IL-1β、PPARG等核心靶点调控TNF信号通路与NF-κB等信号通路,抑制 AS中的细胞焦亡.
Study on Mechanism of Ginseng Regulating Pyroptosis in Atherosclerosis
Objective To explore the key compounds,targets and signaling pathways associated with ginseng in the regulation of pyroptosis in atherosclerosis(AS)and explain the mechanism of ginseng in regulating pyroptosis in AS.Method The TCMSP database,HERB database and Swiss Target Prediction database were deployed to detect active compounds and their standardized targets in ginseng.Targets related to AS were obtained from OMIM,GeneCards and TTD database,and integration with differentially expressed genes(DEGs)analyzed from RNA sequencing data of AS tissues and normal tissues from the Gene Expression Omnibus(GEO)database.Pyroptosis-related targets were identified using GeneCards,and bioinformatics platforms were utilized to determine intersecting genes.Protein-protein interaction networks were constructed to analyze key targets.Gene Ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)enrichment analysis of the targets was conducted using the"clusterProfiler"package in R language.Cytoscape 3.9.1 software was employed to construct the Network diagram of"active compound-target-pathway-disease"illustrating the relationships among active compounds,targets,pathways,and disease.AutoDock Vina was deployed to validate the molecular docking between the core target and key compounds.Gromacs was employed to perform 50 ns molecular dynamics simulation of the results of molecular docking between TNF and key compounds,the free binding energies of the last 10 ns between proteins and ligands were analyzed through the molecular dynamics/Poisson Boltzmann surface area method(MM/PBSA).Results 22 active compounds,588 targets of ginseng and 36 ginseng-pyroptosis associated atherosclerosis targets were obtained from the analysis.4 key targets were predicted:tumor necrosis factor(TNF),serine/threonine kinase(AKT)1,interleukin(IL)-1β and peroxisome proliferator-activated receptor gamma(PPARG).The results of GO and KEGG enrichment indicated that ginseng-pyroptosis associated atherosclerosis targets were mainly associated with response to lipopolysaccharide,DNA-binding transcription factor binding,nuclear receptor activity,TNF signaling pathway and nuclear factor(NF)-κB signaling pathway.After analyzing the network diagram of"active compound-target-pathway-disease",the key compounds of ginseng were analyzed as Kaempferol,Girinimbin,Deoxyharringtonine,and Gomisin B.Molecular docking using AutoDock Vina affirmed superior binding capabilities between key targets and compounds.Molecular dynamics simulations demonstrated low fluctuations and high stabilities in the solution environment of NaCl for key complexes.Analysis of free binding energies over the last 10 ns indicated a superior binding capacity of key targets and key compounds.Conclusion This study revealed that ginseng may inhibit pyroptosis in AS by regulating the TNF signaling pathway,NF-κB and other signaling pathways through core targets such as TNF,AKT1,IL-1β,and PPARG.

PyroptosisGinsengAtherosclerosisNetwork pharmacologyTranscriptomicsMolecular dockingMolecular dynamics simulation

赵培彰、杨桢、何湛湛、陶旭光、陈香云、丁薇、褚策、袁雨露、许咏琪、张雨欣、赵红霞、汪文来

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四川大学华西临床医学院,成都 610041

北京中医药大学,北京 100029

中国中医科学院中医基础理论研究所,北京 100700

细胞焦亡 人参 动脉粥样硬化 网络药理学 转录组学 分子对接 分子动力学模拟

中国中医科学院科技创新工程重大攻关项目中央级公益性科研院所基本科研业务费专项中央级公益性科研院所基本科研业务费专项中央级公益性科研院所基本科研业务费专项中央级公益性科研院所基本科研业务费专项中央级公益性科研院所基本科研业务费专项中央级公益性科研院所基本科研业务费专项北京市中医药科技发展基金项目

CI2021A00606YZX202237YZX202241YZX202246YZ2020042YZX-202325YZX-202329JJ2018-99

2024

中国中医基础医学杂志
中国中医研究院基础理论研究所

中国中医基础医学杂志

CSTPCD
影响因子：0.779
ISSN：1006-3250
年,卷(期)：2024.30(7)
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