基于整合药理学的黄芪-三七药对干预ARDS的分子机制研究
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摘要
急性呼吸窘迫综合征(ARDS)是临床常见危重症,病死率极高。名老中医杜怀棠教授经验方益气化瘀解毒方可在一定程度上降低ARDS模型大鼠血清炎症因子水平,提高肺系数及肺通透指数,减轻肺组织炎性损伤,其具体作用机制亟待阐明。本研究以该方益气化瘀核心药对——"黄芪-三七"为研究对象,应用整合药理学平台,对其干预ARDS的分子机制进行探讨分析。"黄芪-三七"药对共预测得到124个活性成分,其中黄芪化合物成分29个,三七化合物成分95个。其干预ARDS作用涉及的前100个核心靶标中治疗ARDS的直接靶标78个,如PTGS2、ARAF、PPP1CC;潜在药物靶标3个,包括ATP1A1、CROT、CPT1A;共同靶标2个:GCK、YWHAE;其干预ARDS的作用涉及MAPK信号通路、PI3K-Akt信号通路、ErbB信号通路、FoxO信号转导通路等相关生物过程和代谢通路。本研究为进一步阐明益气化瘀解毒方治疗ARDS的作用机制提供科学依据,为临床治疗ARDS提供理论依据。
Acute respiratory distress syndrome(ARDS) is a common clinical critical illness with high mortality.Yiqi Huayu Jiedu Decoction of Professor Du Huaitang,can reduce the level of serum inflammatory factors in ARDS model rats to a certain extent,improve the lung coefficient and lung permeability index,reduce the inflammatory damage of the lung tissue,and the specific mechanism of its action needs to be clarified. In this research,Radix Astragali-notoginseng,the core drug pair of Yiqi Huayu Jiedu Decoction were analyzed by the integrative pharmacology platform to study its molecular mechanism for anti-ARDS. 124 active ingredients were predicted,29 for Stragalus Radix,mainly including Astragalus saponins and astragalus polysaccharides,and 95 for Notoginseng Radix,mainly including panax notoginseng saponins,ginsenosides,panax ginseng saponins and amino acids. 78 known disease targets were involved in the first 100 core targets involved in the intervention of ARDS,such as PTGS2,ARAF and PPP1CC. There are 3 potential drug targets,including ATP1A1,CROT and CPT1A,and 2 common targets,including GCK and YWHAE. Its intervention on ARDS involves MAPK signaling pathway,PI3K-Akt signaling pathway,ErbB signaling pathway,FoxO signaling pathway,cell growth and death,non-small cell lung cancer,cell circulation,cell communication,endocrine system,neurotrophic factor signaling pathway and other related biological processes and metabolic pathways. This study provides a scientific basis for further elucidating the mechanism of Yiqi Huayu Jiedu Decoction on ARDS and provides a theoretical basis for the clinical treatment of ARDS.
Acute respiratory distress syndrome(ARDS) is a common clinical critical illness with high mortality.Yiqi Huayu Jiedu Decoction of Professor Du Huaitang,can reduce the level of serum inflammatory factors in ARDS model rats to a certain extent,improve the lung coefficient and lung permeability index,reduce the inflammatory damage of the lung tissue,and the specific mechanism of its action needs to be clarified. In this research,Radix Astragali-notoginseng,the core drug pair of Yiqi Huayu Jiedu Decoction were analyzed by the integrative pharmacology platform to study its molecular mechanism for anti-ARDS. 124 active ingredients were predicted,29 for Stragalus Radix,mainly including Astragalus saponins and astragalus polysaccharides,and 95 for Notoginseng Radix,mainly including panax notoginseng saponins,ginsenosides,panax ginseng saponins and amino acids. 78 known disease targets were involved in the first 100 core targets involved in the intervention of ARDS,such as PTGS2,ARAF and PPP1CC. There are 3 potential drug targets,including ATP1A1,CROT and CPT1A,and 2 common targets,including GCK and YWHAE. Its intervention on ARDS involves MAPK signaling pathway,PI3K-Akt signaling pathway,ErbB signaling pathway,FoxO signaling pathway,cell growth and death,non-small cell lung cancer,cell circulation,cell communication,endocrine system,neurotrophic factor signaling pathway and other related biological processes and metabolic pathways. This study provides a scientific basis for further elucidating the mechanism of Yiqi Huayu Jiedu Decoction on ARDS and provides a theoretical basis for the clinical treatment of ARDS.
引文
[1]Ranieri VM,Rubenfeld GD,Thompson BT,et al.Acute respiratory distress syndrome:the Berlin Definition[J].JAMA,2012,307(23):2526-2533.
[2]Perkins GD,Gates S,Park D,et al.The beta agonist lung injury trial prevention.A randomized controlled trial[J].Am JRespir Crit Care Med,2014,189(6):674-683.
[3]Mcauley DF,Cross LM,Hamid U,et al.Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome(KARE):a randomised,double-blind,placebo-controlled phase 2 trial[J].The Lancet Respiratory Medicine,2017,5(6):484-491.
[4]Mcauley DF,Laffey JG,O′Kane CM,et al.Simvastatin in the acute respiratory distress syndrome[J].N Engl J Med,2014,371(18):1695-1703.
[5]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,2018,11(2):315-320.
[6]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,2017,26(10):1724-1726.
[7]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,2016,66(9):783-788.
[8]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,2017,10(2):141-145.
[9]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,2017,10(3):275-279.
[10]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,2017,42(18):3633-3638.
[11]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,2014,39(3):357-362.
[12]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.
[13]Zhang WJ,Frei B.AstragalosideⅣinhibits NF-kappa B activation and inflammatory gene expression in LPS-treated mice[J].Mediators Inflamm,2015,2015:274314.
[14]Zhu YP,Shen T,Lin YJ,et al.Astragalus polysaccharides suppress ICAM-1 and VCAM-1 expression in TNF-alphatreated human vascular endothelial cells by blocking NF-kappaB activation[J].Acta Pharmacol Sin,2013,34(8):1036-1042.
[15]Yuan Q,Jiang YW,Ma TT,et al.Attenuating effect of Ginsenoside Rb1 on LPS-induced lung injury in rats[J].J Inflamm(Lond),2014,11(1):40.
[16]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,2014,23(15):19-20.
[17]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,2013,33(5):385-389.
[18]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,2003,12(11):899-901.
[19]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,2008,24(11):980-983.
[20]陈宇清,荣令,周新.三七总皂苷对急性肺损伤大鼠血清和支气管肺泡灌洗液肿瘤坏死因子-α、白介素-6和白介素-10水平的影响[J].实用心脑肺血管病杂志,2013,21(2):89-92.
[21]Sathiyamoorthy S,In J,Gayathri S,et al.Generation and gene ontology based analysis of expressed sequence tags(EST)from a Panax ginseng C.A.Meyer roots[J].Molecular Biology Reports,2010,37(7):3465-3472.
[22]巩秀丽.人参皂甙预处理对大鼠急性肺损伤的影响[D].洛阳:河南科技大学,2011.
[23]Takami M,Terry V,Petruzzelli L.Signaling pathways involved in IL-8-dependent activation of adhesion through Mac-1[J].J Immunol,2002,168(9):4559-4566.
[24]Duronio V.The life of a cell:apoptosis regulation by the PI3K/PKB pathway[J].Biochem J,2008,415(3):333-344.
[25]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.
[26]Lemmon MA,Schlessinger J.Cell signaling by receptor tyrosine kinases[J].Cell,2010,141(7):1117-1134.
[27]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.
[28]Zhang X,Tang N,Hadden TJ,et al.Akt,FoxO and regulation of apoptosis[J].Biochim Biophys Acta,2011,1813(11):1978-1986.
[29]Hagenbuchner J,Ausserlechner MJ.Mitochondria and FOX-O3:breath or die[J].Frontiers in Physiology,2013,4:147.
[30]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,2015,30(6):883-892.
[2]Perkins GD,Gates S,Park D,et al.The beta agonist lung injury trial prevention.A randomized controlled trial[J].Am JRespir Crit Care Med,2014,189(6):674-683.
[3]Mcauley DF,Cross LM,Hamid U,et al.Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome(KARE):a randomised,double-blind,placebo-controlled phase 2 trial[J].The Lancet Respiratory Medicine,2017,5(6):484-491.
[4]Mcauley DF,Laffey JG,O′Kane CM,et al.Simvastatin in the acute respiratory distress syndrome[J].N Engl J Med,2014,371(18):1695-1703.
[5]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,2018,11(2):315-320.
[6]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,2017,26(10):1724-1726.
[7]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,2016,66(9):783-788.
[8]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,2017,10(2):141-145.
[9]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,2017,10(3):275-279.
[10]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,2017,42(18):3633-3638.
[11]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,2014,39(3):357-362.
[12]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.
[13]Zhang WJ,Frei B.AstragalosideⅣinhibits NF-kappa B activation and inflammatory gene expression in LPS-treated mice[J].Mediators Inflamm,2015,2015:274314.
[14]Zhu YP,Shen T,Lin YJ,et al.Astragalus polysaccharides suppress ICAM-1 and VCAM-1 expression in TNF-alphatreated human vascular endothelial cells by blocking NF-kappaB activation[J].Acta Pharmacol Sin,2013,34(8):1036-1042.
[15]Yuan Q,Jiang YW,Ma TT,et al.Attenuating effect of Ginsenoside Rb1 on LPS-induced lung injury in rats[J].J Inflamm(Lond),2014,11(1):40.
[16]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,2014,23(15):19-20.
[17]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,2013,33(5):385-389.
[18]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,2003,12(11):899-901.
[19]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,2008,24(11):980-983.
[20]陈宇清,荣令,周新.三七总皂苷对急性肺损伤大鼠血清和支气管肺泡灌洗液肿瘤坏死因子-α、白介素-6和白介素-10水平的影响[J].实用心脑肺血管病杂志,2013,21(2):89-92.
[21]Sathiyamoorthy S,In J,Gayathri S,et al.Generation and gene ontology based analysis of expressed sequence tags(EST)from a Panax ginseng C.A.Meyer roots[J].Molecular Biology Reports,2010,37(7):3465-3472.
[22]巩秀丽.人参皂甙预处理对大鼠急性肺损伤的影响[D].洛阳:河南科技大学,2011.
[23]Takami M,Terry V,Petruzzelli L.Signaling pathways involved in IL-8-dependent activation of adhesion through Mac-1[J].J Immunol,2002,168(9):4559-4566.
[24]Duronio V.The life of a cell:apoptosis regulation by the PI3K/PKB pathway[J].Biochem J,2008,415(3):333-344.
[25]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.
[26]Lemmon MA,Schlessinger J.Cell signaling by receptor tyrosine kinases[J].Cell,2010,141(7):1117-1134.
[27]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.
[28]Zhang X,Tang N,Hadden TJ,et al.Akt,FoxO and regulation of apoptosis[J].Biochim Biophys Acta,2011,1813(11):1978-1986.
[29]Hagenbuchner J,Ausserlechner MJ.Mitochondria and FOX-O3:breath or die[J].Frontiers in Physiology,2013,4:147.
[30]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,2015,30(6):883-892.