藏药沙棘总黄酮防治慢性支气管炎的网络药理学研究
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摘要
目的:探讨藏药沙棘总黄酮(TFH)防治慢性支气管炎的潜在作用机制,为其进一步开发利用提供参考。方法:利用中药系统药理学分析平台数据库筛选TFH有效成分,通过PharmMapper网络服务系统、BATMAN-TCM网络药理学研究平台、DrugBank数据库、OMIM数据库预测并匹配TFH有效成分作用于慢性支气管炎的潜在靶点(即靶基因),借助生物分子功能注释系统3.0进行GO富集和KEGG通路注释分析,采用Cytoscape 3.5.1软件构建TFH防治慢性支气管炎的"成分-靶点-通路"网络,并进行网络拓扑学分析。结果:共筛选出槲皮素、表儿茶素、槲皮素-3-甲基醚等13个TFH有效成分,涉及PIK3CG、PRKCA、ALOX5基因等30个潜在作用靶点。上述靶点多分布于细胞膜和细胞质中,且主要通过蛋白质氨基酸磷酸化反应、信号转导等生物过程以及蛋白结合、转移酶活性调节等分子功能来发挥对慢性支气管炎的防治作用。上述靶点共涉及64条通路,靶点富集数量排名前10位的通路分别为Fc epsilon RI信号通路、血管内皮生长因子信号通路、丝裂原激活的蛋白激酶信号通路、T细胞受体信号通路、胶质瘤、ErbB信号通路、Toll样受体信号通路、自然杀伤细胞介导的细胞毒性、非小细胞肺癌、黏着斑。TFH防治慢性支气管炎的"成分-靶点-通路"网络共有107个节点、449条边,平均节点度值为8.299,网络中心度为0.411。其中,Fc epsilon RI信号通路、血管内皮生长因子信号通路和丝裂原激活的蛋白激酶信号通路是该网络的核心通路(节点度值≥9,中介中心性>0.001),MAPK1、PIK3CG、AKT1等基因是该网络的核心靶点(节点度值≥40,中介中心性>0.1)。结论:TFH有效成分槲皮素、表儿茶素、槲皮素-3-甲基醚等可能通过Fc epsilon RI信号通路、丝裂原激活的蛋白激酶信号通路、血管内皮生长因子信号通路等作用于MAPK1、PIK3CG、AKT1等靶点,进而发挥对慢性支气管炎的防治作用。
OBJECTIVE:To investigate the potential prevention and treatment mechanism of total flavonoids of Tibetan medicine Hippophae rhamnoidesh(TFH)on chronic bronchitis,and to provide reference for further development and utilization.METHODS:TCM system pharmacology analysis platform database(TCMSP) was used to screen effective components of TFH.PharmMapper network service system,BATMAN-TCM network pharmacology research platform,DrugBank database and OMIM database were all used to predict and match effective components of TFH on the potential target(target gene)of chronic bronchitis.GO enrichment and KEGG pathway annotation analysis were conducted by biomolecular function annotation system 3.0. Cytoscape3.5.1 software was used to establish TFH"component-target-pathway"network for the prevention and treatment of chronic bronchitis. The network topology was also analyzed. RESULTS: The network analysis indicated that there were 13 active components in TFH,such as quercetin,ent-epicatechin and quercetin-3-methylethter,which could interact with 30 potential targets,such as PIK3 CG,PRKCA,ALOX5,etc. Above targets were mainly distributed in cell membrane and cytoplasm. TFH played prevention and treatment effect through biological processes as protein amino acid phosphorylation reaction, signal transduction,and molecular functions such as protein binding,transferase activity regulation. Above targets involved 64 pathways in total. Top 10 pathways in the list of target enrichment number were Fc epsilon RI signaling pathway,VEGF signaling pathway,MAPK signaling pathway,T cell receptor signaling pathway, glioma, ErbB signaling pathway,Toll-like receptor signaling pathway,natural killer cell mediated pathway,non-small cell lung cancer and focal adhesion. There were 107 nodes,449 edges,8.299 flatness and 0.411 network centricity in the"component-target-pathway"network for the prevention and treatment of chronic bronchitis. Fc epsilon RI signaling pathway,VEGF signaling pathway and MAPK signaling pathway were the core pathways of this network(node degree≥9, intermediary centrality>0.001). MAPK1,PIK3 CG and AKT1 were the core targets of the network(node degree≥40, intermediary centrality>0.1). CONCLUSIONS:The effective components of TFH as quercetin,ent-epicatechin,quercetin-3-methylethter act on the targets of MAPK1,PIK3 CG and AKT1 through Fc epsilon RI signaling pathway,VEGF signaling pathway and MAPK signaling pathway,and then play a role in the prevention and treatment of chronic bronchitis.
OBJECTIVE:To investigate the potential prevention and treatment mechanism of total flavonoids of Tibetan medicine Hippophae rhamnoidesh(TFH)on chronic bronchitis,and to provide reference for further development and utilization.METHODS:TCM system pharmacology analysis platform database(TCMSP) was used to screen effective components of TFH.PharmMapper network service system,BATMAN-TCM network pharmacology research platform,DrugBank database and OMIM database were all used to predict and match effective components of TFH on the potential target(target gene)of chronic bronchitis.GO enrichment and KEGG pathway annotation analysis were conducted by biomolecular function annotation system 3.0. Cytoscape3.5.1 software was used to establish TFH"component-target-pathway"network for the prevention and treatment of chronic bronchitis. The network topology was also analyzed. RESULTS: The network analysis indicated that there were 13 active components in TFH,such as quercetin,ent-epicatechin and quercetin-3-methylethter,which could interact with 30 potential targets,such as PIK3 CG,PRKCA,ALOX5,etc. Above targets were mainly distributed in cell membrane and cytoplasm. TFH played prevention and treatment effect through biological processes as protein amino acid phosphorylation reaction, signal transduction,and molecular functions such as protein binding,transferase activity regulation. Above targets involved 64 pathways in total. Top 10 pathways in the list of target enrichment number were Fc epsilon RI signaling pathway,VEGF signaling pathway,MAPK signaling pathway,T cell receptor signaling pathway, glioma, ErbB signaling pathway,Toll-like receptor signaling pathway,natural killer cell mediated pathway,non-small cell lung cancer and focal adhesion. There were 107 nodes,449 edges,8.299 flatness and 0.411 network centricity in the"component-target-pathway"network for the prevention and treatment of chronic bronchitis. Fc epsilon RI signaling pathway,VEGF signaling pathway and MAPK signaling pathway were the core pathways of this network(node degree≥9, intermediary centrality>0.001). MAPK1,PIK3 CG and AKT1 were the core targets of the network(node degree≥40, intermediary centrality>0.1). CONCLUSIONS:The effective components of TFH as quercetin,ent-epicatechin,quercetin-3-methylethter act on the targets of MAPK1,PIK3 CG and AKT1 through Fc epsilon RI signaling pathway,VEGF signaling pathway and MAPK signaling pathway,and then play a role in the prevention and treatment of chronic bronchitis.
引文
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[24]魏志成,童东,杨娟,等.基于网络药理学的沙棘总黄酮治疗心肌缺血的作用机制研究[J].中国中药杂志,2017,42(7):1238-1244.
[25]VALENTA R.The future of antigen-specific immunotherapy of allergy[J].Nat Rev Immunol,2002,2(6):446-453.
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[27]孟晓明.枇杷叶三萜酸对慢性支气管炎防治作用的部分机制研究[D].合肥:安徽医科大学,2008.
[28]牛欢,丁毅鹏.VEGF在COPD发病机制中的研究进展[J].海南医学,2015,26(8):1183-1186.
[29]HOSHINO M,TAKAHASHI M,TAKAI Y,et al.Inhaled corticosteroids decrease vascularity of the bronchia mucosa in patients with asthma[J].Clin Exp Amergy,2001,31(5):722-730.
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[31]ALLERHEILIGEN SR.Next-generation model-based drug discovery and development:quantitative and systems pharmacology[J].Clin Pharmacol Ther,2010,88(1):135-137.
[2]白若杂纳.月王药诊:2012年版[M].毛继祖,马世林,译.上海:上海科学技术出版社:2012:67.
[3]藏医药理学编写小组.藏医药理学[M].北京:民族出版社,2004:189.
[4]蒂玛尔·丹增彭措.晶珠本草[M].毛继祖,罗尚达,王振华,等,译.上海:上海科学技术出版社,1986:65.
[5]多步杰.藏医内科学[M].北京:民族出版社,2004:188-189.
[6]尹永芹,黄峰,黄永昌.东风桔对大鼠慢性支气管炎的治疗作用及其机制研究[J].中草药,2014,45(19):2809-2813.
[7]许晖.慢性支气管与年龄、吸烟的关系[J].中国医药导报,2008,5(31):157-158.
[8]董长林.吸烟与慢性支气管的相关性研究[J].江苏预防医学,2000,11(2):19.
[9]MORELLE W,SUTTON-SMITH M,MORRIS HR,et al.FAB-MS characterization of sialyl Lewis x determinants on polylactosamine chains of human airway mucins secreted by patients suffering from cystic fibrosis or chronic bronchitis[J].Glycoconj J,2001,18(9):699-708.
[10]李旻辉,刘勇,廉永善,等.沙棘[M].北京:中国医药科技出版社,2016:98.
[11]HOPKINS AL.Network pharmacology:the next paradigm in drug discovery[J].Nat Chem Biol,2008,4(11):682-690.
[12]ZHANG Y,MAO X,GUO Q,et al.Network pharmacology-based approaches capture essence of Chinese herbal medicines[J].Chin Herbal Med,2016,8(2):107-116.
[13]NAIR MP,MAHAJAN S,REYNOLDS JL,et al.The flavonoid quercetin inhibits proinflammatory cytokine(tumor necrosis factor alpha)gene expression in normal peripheral blood mononuclear cells via modulation of the NF-kappa beta system.[J].Clin Vaccine Immunol,2006,13(3):319-328.
[14]阮洪生,牟晋珠.表儿茶素对脂多糖诱导RAW264.7细胞分泌炎症因子的影响[J].中国实验方剂学杂志,2017,23(4):159-163.
[15]PARK SH,GONG JH,CHOI YJ,et al.Kaempferol inhibits endoplasmic reticulum stress-associated mucus hypersecretion in airway epithelial cells and ovalbumin-sensitized mice[J].PloS One,2015,10(11):e0143526.
[16]滕丹,栾新尧.异鼠李素的药效学研究进展[J].中医药临床杂志,2016,28(4):593-596.
[17]KIM SH,PEI QM,JIANG P,et al.Role of licochalcone Ain VEGF-induced proliferation of human airway smooth muscle cells:implications for asthma[J].Growth Factors,2017,35(1):39-47.
[18]邹亚,郭盛,景晓平,等.清肺口服液通过ERK1/2通路调控RSV所致呼吸道炎症损伤的机制[J].中国实验方剂学杂志,2018,24(2):86-91.
[19]K?CHELE M,HENNIGE AM,MACHANN J,et al.Variation in the phosphoinositide 3-kinase gamma gene affects plasma HDL-cholesterol without modification of metabolic or inflammatory markers[J].PLoS One,2015,10(12):e0144494.
[20]莫碧文,王昌明,张珍祥,等.磷脂酰肌醇3激酶促进支气管哮喘大鼠气道平滑肌细胞增殖[J].基础医学与临床,2006,26(5):489-493.
[21]陈景德.化痰方对慢性支气管炎大鼠EGFR合成黏蛋白MUC5AC影响的研究[D].武汉:湖北中医学院,2005.
[22]LEE HM,TAKEYAMA K,DABBAGH K,et a1.Agarose plug instillation causes goblet cell metaplasia by activating EGF receptors in rat airways[J].Am J Physiol Lung Cell Mol Physio1,2000,278(1):185-192.
[23]唐策,文检,杨娟,等.藏药翼首草抗类风湿性关节炎活性成分靶点的网络药理学研究[J].中国药房,2017,28(19):2666-2670.
[24]魏志成,童东,杨娟,等.基于网络药理学的沙棘总黄酮治疗心肌缺血的作用机制研究[J].中国中药杂志,2017,42(7):1238-1244.
[25]VALENTA R.The future of antigen-specific immunotherapy of allergy[J].Nat Rev Immunol,2002,2(6):446-453.
[26]WU K,BI Y,SUN K,et al.IL-10-producing type 1 regulatory T cells and allergy[J].Cell Mol Immunol,2007,4(4):269-275.
[27]孟晓明.枇杷叶三萜酸对慢性支气管炎防治作用的部分机制研究[D].合肥:安徽医科大学,2008.
[28]牛欢,丁毅鹏.VEGF在COPD发病机制中的研究进展[J].海南医学,2015,26(8):1183-1186.
[29]HOSHINO M,TAKAHASHI M,TAKAI Y,et al.Inhaled corticosteroids decrease vascularity of the bronchia mucosa in patients with asthma[J].Clin Exp Amergy,2001,31(5):722-730.
[30]LEIL TA,ERMAKOV S.Editorial:the emerging discipline of quantitative systems pharmacology[J].Front Phpline of quantitative systems pharmacology[J].Front Pharmacol,2015.DOI:10.3389/fphar.2015.00129.
[31]ALLERHEILIGEN SR.Next-generation model-based drug discovery and development:quantitative and systems pharmacology[J].Clin Pharmacol Ther,2010,88(1):135-137.