基于网络药理学原理的黄芪-金银花药对干预急性呼吸窘迫综合征的分子机制研究
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摘要
[目的]基于网络药理学原理,探讨课题组前期实验有效方益气化瘀解毒方核心药对黄芪-金银花干预急性呼吸窘迫综合征(ARDS)的分子通路及作用机制。[方法]应用整合药理学平台对黄芪、金银花化学成分及ARDS疾病候选靶标进行收集,根据结构相似性原理选取相似性分数≥0. 8的所有药物靶标作为"黄芪-金银花"药对的潜在作用靶标,建立药物候选靶标信息数据库,通过该平台的蛋白质-蛋白质相互作用信息(PPI)数据库,获得"黄芪-金银花"药对作用的潜在靶标与ARDS疾病靶标之间的蛋白质-蛋白质相互作用信息(PPI),通过网络分析,构建"中药-核心成分-关键靶标-主要通路"的可视化网络图,进一步明确中药干预疾病的作用机制。[结果]黄芪-金银花药对共预测得到76个活性成分,其中黄芪化合物成分29个,金银花化合物成分47个。其干预ARDS作用涉及的前100个核心靶标中已知治疗ARDS的直接靶标(known disease target)78个,潜在药物靶标(putative drug target)3个,共同靶标(common target)2个;其干预ARDS的作用涉及ErbB信号通路、FoxO信号转导通路、Ras信号途径、丝裂原活化蛋白激酶(MAPK)信号通路、磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(AKT)信号通路、神经营养因子信号转导通路、细胞生长与死亡等相关生物过程和代谢通路。[结论]黄芪-金银花药对主要活性成分可针对多个靶点、多条通路发挥干预ARDS的作用,其作用与TSC1、NSDHL、GRB2、MYC、MAP2K等关键靶标及ErbB信号通路、FoxO信号转导通路、Ras信号途径、MAPK信号通路和PI3K-AKT信号通路等有关。
[Objective] Based on the principle of network pharmacology, to clarified the molecular pathway and mechanism of Stragalus Radix and Lonicerae Japonicae Flos core drug pair of Yiqi Huayu Jiedu Decoction on acute respiratory distress syndrome(ARDS).[Methods] The chemical constituents of Stragalus Radix and Lonicerae Japonicae Flos and the candidate targets of ARDS were collected by the integrated pharmacological platform. According to the principle of structural similarity, all the drug targets with similarity score(≥0.8) were selected as the potential targets of the "Stragalus Radix and Lonicerae Japonicae Flos " pair, and the candidate target information database was established. PPI(Protein Protein Interaction Information) database was used to obtain the PPI between the potential target of "Stragalus Radix and Lonicerae Japonicae Flos" and the disease target of ARDS. Through network analysis, a visualized network diagram of "traditional Chinese medicine-core component-key target-main pathway" was constructed to further illustrate. The mechanism of Chinese medicine intervening disease is determined. [Results] A total of 76 active constituents were predicted by the Stragalus Radix and Lonicerae Japonicae Flos pair, 29 of which were Astragalus membranaceus and 47 of which were Lonicerae Japonicae Flos. Among the first 100 core targets, 78 known disease targets, 3 putative drug targets and 2 common Targets were involved in the intervention of ARDS, including ErbB signaling pathway, FoxO signaling pathway and Ras signal pathway, MAPK signal pathway, PI3 K-AKT signal pathway, neurotrophic factor signal transduction pathway, cell growth and death and other related biological processes and metabolic pathways. [Conclusion] Main active ingredient of Stragalus Radix and Lonicerae Japonicae Flos drug pair can interfere with ARDS by targeting multiple targets and multiple pathways. Its effect is related to TSC1, NSDHL, GRB2, MYC, MAP2 K,ErbB signaling pathway, FoxO signaling pathway, Ras signaling pathway, MAPK signaling pathway, PI3 K-AKT signaling pathway and so on.
[Objective] Based on the principle of network pharmacology, to clarified the molecular pathway and mechanism of Stragalus Radix and Lonicerae Japonicae Flos core drug pair of Yiqi Huayu Jiedu Decoction on acute respiratory distress syndrome(ARDS).[Methods] The chemical constituents of Stragalus Radix and Lonicerae Japonicae Flos and the candidate targets of ARDS were collected by the integrated pharmacological platform. According to the principle of structural similarity, all the drug targets with similarity score(≥0.8) were selected as the potential targets of the "Stragalus Radix and Lonicerae Japonicae Flos " pair, and the candidate target information database was established. PPI(Protein Protein Interaction Information) database was used to obtain the PPI between the potential target of "Stragalus Radix and Lonicerae Japonicae Flos" and the disease target of ARDS. Through network analysis, a visualized network diagram of "traditional Chinese medicine-core component-key target-main pathway" was constructed to further illustrate. The mechanism of Chinese medicine intervening disease is determined. [Results] A total of 76 active constituents were predicted by the Stragalus Radix and Lonicerae Japonicae Flos pair, 29 of which were Astragalus membranaceus and 47 of which were Lonicerae Japonicae Flos. Among the first 100 core targets, 78 known disease targets, 3 putative drug targets and 2 common Targets were involved in the intervention of ARDS, including ErbB signaling pathway, FoxO signaling pathway and Ras signal pathway, MAPK signal pathway, PI3 K-AKT signal pathway, neurotrophic factor signal transduction pathway, cell growth and death and other related biological processes and metabolic pathways. [Conclusion] Main active ingredient of Stragalus Radix and Lonicerae Japonicae Flos drug pair can interfere with ARDS by targeting multiple targets and multiple pathways. Its effect is related to TSC1, NSDHL, GRB2, MYC, MAP2 K,ErbB signaling pathway, FoxO signaling pathway, Ras signaling pathway, MAPK signaling pathway, PI3 K-AKT signaling pathway and so on.
引文
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[14]赵建军,张建勇,陈玲.黄芪甲苷对急性肺损伤大鼠肺水通道蛋白5表达的影响[J].中国医院药学杂志,2013,32(5):385-389.
[15]宋亚玲,王红梅,倪付勇,等.金银花中酚酸类成分及其抗炎活性研究[J].中草药,2015,45(4):490-495.
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[20]Takami M,Terry V,Petruzzelli L.Signaling pathways involved in IL-8-dependent activation of adhesion through Mac-1[J].JImmunol,2002,168(9):4559-4566.
[21]Duronio V.The life of a cell:apoptosis regulation by the PI3K/PKBpathway[J].Biochem J,2008,415(3):333-344.
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[23]张彦琼,李梢.网络药理学与中医药现代研究的若干进展[J].中国药理学与毒理学杂志,2015,29(6):883-892.
[2]万茂婷,李雁,梁旭,等.中西医结合治疗急性呼吸窘迫综合征临床疗效的Meta分析[J].环球中医药,2018(2):315-320.
[3]方邦江,孙丽华,卜建宏,等.论“急性虚证”理论及其在急救临床的应用(上)[J].中国中医急症,2017,7(10):1724-1726.
[4]李雁,王双,李昕,等.益气化瘀解毒复方联合超低频电磁场处理水对内毒素诱发大鼠急性肺损伤的影响[J].中医杂志,2016,20(9):783-788.
[5]黄瑞音,李雁,李昕,等.益气化瘀解毒方治疗内毒素致ARDS大鼠的炎症作用研究[J].环球中医药,2017,7(2):141-145.
[6]李昕,李雁,刘丽杰,等.益气化瘀解毒方对急性呼吸窘迫综合征大鼠NF-κB/p38MAPK通路的影响[J].环球中医药,2017,7(3):275-279.
[7]许海玉,刘振明,付岩,等.中药整合药理学计算平台的开发与应用[J].中国中药杂志,2017,62(18):3633-3638.
[8]许海玉,杨洪军.整合药理学:中药现代研究新模式[J].中国中药杂志,2014,58(3):357-362.
[9]Zhang Y,Guo Q,Li Q,et al.Main active constituent identification in Guanxinjing capsule,a traditional Chinese medicine,for the treatment of coronary heart disease complicated with depression[J].Acta Pharmacologica Sinica,2018,39(6):975-987.
[10]Yu G,Zhang Y,Ren W,et al.Network pharmacology-based identification of key pharmacological pathways of Yin–Huang–Qing–Fei capsule acting on chronic bronchitis[J].International Journal of COPD,2017(12):85-94.
[11]徐旭,汤立达.黄芪的心血管药理作用研究进展[J].中国新药杂志,2003,11(11):899-901.
[12]刘永琦,李金田,李娟,等.黄芪对肺纤维化大鼠血清细胞因子及肺超微结构的影响[J].中国免疫学杂志,2008,23(11):980-983.
[13]张吉,臧东钰.黄芪甲苷对急性肺损伤大鼠内质网应激介导影响[J].中国民族民间医药,2014,19(15):19-20.
[14]赵建军,张建勇,陈玲.黄芪甲苷对急性肺损伤大鼠肺水通道蛋白5表达的影响[J].中国医院药学杂志,2013,32(5):385-389.
[15]宋亚玲,王红梅,倪付勇,等.金银花中酚酸类成分及其抗炎活性研究[J].中草药,2015,45(4):490-495.
[16]Lemmon MA,Schlessinger J.Cell signaling by receptor tyrosine kinases[J].Cell,2010,141(7):1117-1134.
[17]Oda K,Matsuoka Y,Funahashi A,et al.A comprehensive pathway map of epidermal growth factor receptor signaling[J].Mol Syst Biol,2005(1):2005-2010.
[18]Zhang X,Tang N,Hadden TJ,et al.Akt,FoxO and regulation of apoptosis[J].Biochim Biophys Acta,2011,1813(11):1978-1986.
[19]Hagenbuchner J,Ausserlechner M J.Mitochondria and FOXO3:breath or die[J].Frontiers in Physiology,2013(4):147.
[20]Takami M,Terry V,Petruzzelli L.Signaling pathways involved in IL-8-dependent activation of adhesion through Mac-1[J].JImmunol,2002,168(9):4559-4566.
[21]Duronio V.The life of a cell:apoptosis regulation by the PI3K/PKBpathway[J].Biochem J,2008,415(3):333-344.
[22]Turner MD,Nedjai B,Hurst T,et al.Cytokines and chemokines:At the crossroads of cell signalling and inflammatory disease[J].Biochim Biophys Acta,2014,1843(11):2563-2582.
[23]张彦琼,李梢.网络药理学与中医药现代研究的若干进展[J].中国药理学与毒理学杂志,2015,29(6):883-892.