中国中药杂志

2021, v.46(20) 5351-5361

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基于网络药理学探讨大承气汤治疗脓毒症的作用机制及关键靶点通路验证
Mechanism and experimental verification of Dachengqi Decoction in treatment of sepsis based on network pharmacology

付智慧;赵灵灵;周霖;李新存;张晓川;
FU Zhi-hui;ZHAO Ling-ling;ZHOU Lin;LI Xin-cun;ZHANG Xiao-chuan;Department of Traditional Chinese Medicine, the First Affiliated Hospital of Zhengzhou University;Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University;Henan Precision Medicine Clinical Mass Spectrometry Engineering Research Center;

摘要(Abstract):

采用网络药理学预测大承气汤治疗脓毒症的活性成分及作用机制。借助TCMSP、UniPot、DrugBank数据库检索大承气汤的化学成分及作用靶点,通过OMIM、GeneCards数据库获取脓毒症的相关靶点,利用OmicShare云平台选取大承气汤与脓毒症一致的靶点,利用STRING数据库及Cytoscape 3.7.2软件构建"中药材-活性成分-靶点-疾病""活性成分-重要靶点-关键通路"以及蛋白相互作用(protein-protein interaction, PPI)网络并分析,采用DAVID数据库进行基因本体(gene ontology, GO)功能富集分析和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes, KEGG)信号通路富集分析(P<0.05),最后采用动物实验验证部分关键靶点及信号通路。经数据库分析,获得大承气汤40个活性成分和157个作用靶点,脓毒症2 407个作用靶点,药物-疾病共同靶点91个,关键靶点涉及磷脂酰肌醇3催化亚基γ亚型蛋白(PIK3CG)、前列腺素G/H合成酶2(PTGS2)、前列腺素G/H合成酶1(PTGS1)、环磷酸腺苷(cAMP)依赖性蛋白激酶催化亚基(PRKACA)、凝血酶受体(F2R)、二肽基肽酶4(DPP4)等,GO功能富集分析共得到条目533条,主要涉及药物的反应、凋亡过程的负调控、一氧化氮生物合成过程的正调控、脂多糖介导信号通路等,KEGG通路分析共得到信号通路125条,主要涉及磷脂酰肌醇-3激酶/蛋白激酶B(PI3K/Akt)信号通路、癌症通路、乙型肝炎信号通路等;动物实验证实大承气汤可下调炎症细胞相关因子白细胞介素1β(IL-1β)、白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α)(P<0.01),降低肺组织湿/干重比、髓过氧化物酶(myeloperoxidase, MPO)水平(P<0.01)以及PI3K、Akt的磷酸化水平(P<0.01),表明大承气汤可作用于炎症相关靶点,通过抑制PI3K/Akt信号通路改善脓毒症,验证了网络药理学的部分预测结果。大承气汤通过多成分、多靶点、多通路治疗脓毒症,为后续深入研究大承气汤治疗脓毒症的作用机制奠定了一定的基础。
This study aims to predict the material basis and mechanism of Dachengqi Decoction in the treatment of sepsis based on network pharmacology. The chemical constituents and targets of Dachengqi Decoction were retrieved from TCMSP, UniPot and DrugBank and the targets for the treatment of sepsis from OMIM and GeneCards. The potential targets of Dachengqi Decoction for the treatment of sepsis were screened by OmicShare. STRING database and Cytoscape 3.7.2 were used to construct the Chinese medicinal-active component-target-disease, active component-key target-key pathway, and protein-protein interaction(PPT) networks. The gene ontology(GO) term enrichment analysis and Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis were performed by DAVID(P<0.05). Finally, the animal experiment was conducted to verify some targets and pathways. A total of 40 active components and 157 targets of the Dachengqi Decoction, 2 407 targets for the treatment of sepsis, and 91 common targets of the prescription and the disease were also obtained. The key targets were prostaglandin G/H synthase 2(PTGS2), prostaglandin G/H synthase 1(PTGS1), protein kinase cAMP-dependent catalytic-α(PRKACA), coagulation factor 2 receptor(F2 R), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic gamma subunit(PIK3 CG), dipeptidyl peptidase 4(DPP4), etc. A total of 533 terms and 125 pathways were obtained for the 91 targets. The main terms were the response to drug, negative regulation of apoptotic process, positive regulation of nitric oxide biosynthetic process and lipopolysaccharide-mediated signaling pathway, and the pathways included pathways in cancer, hepatitis B, and phosphatidylinositol 3-kinase and protein kinase B(PI3 K/Akt) signaling pathway. The animal experiment confirmed that Dachengqi Decoction can down-regulate inflammatory cytokines interleukin-1β(IL-1β), IL-6 and tumor necrosis factor α(TNF-α)(P<0.01). It could also reduce the wet/dry weight ratio of lung tissue, the level of myeloperoxidase(MPO) and the phosphorylation of PI3 K and Akt(P<0.01). These results indicated that Dchengqi Decoction could act on inflammation-related targets and improve sepsis by inhibiting PI3 K/Akt signaling pathway. The animal experiment supported the predictions of network pharmacology. Dachengqi Decoction intervenes sepsis via multiple components, multiple targets, and multiple pathways. The result lays a foundation for further research on the mechanism of Dachengqi Decoction in the treatment of sepsis.

关键词(KeyWords): 网络药理学;大承气汤;脓毒症;作用机制
network pharmacology;Dachengqi Decoction;sepsis;mechanism

Abstract:

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基金项目(Foundation): 河南省科技发展计划项目(212102310346,202102310191);; 河南省高等学校重点科研项目(21A360026,19A320070)

作者(Author): 付智慧;赵灵灵;周霖;李新存;张晓川;
FU Zhi-hui;ZHAO Ling-ling;ZHOU Lin;LI Xin-cun;ZHANG Xiao-chuan;Department of Traditional Chinese Medicine, the First Affiliated Hospital of Zhengzhou University;Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University;Henan Precision Medicine Clinical Mass Spectrometry Engineering Research Center;

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