基于网络药理学的黄芪抗疲劳作用机制研究
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摘要
目的基于网络药理学方法探讨黄芪抗疲劳可能的作用机制。方法根据课题组前期研究并结合中医药系统药理学数据库和分析平台(TCMSP)指认黄芪中的活性成分,采用Pharm Mapper网络服务器预测其作用靶点;在GeneCards、OMIM数据库中搜索抗疲劳靶点,采用Cytoscape 3.6.0软件构件黄芪活性成分-抗疲劳靶点网络;使用String数据库进行蛋白质-蛋白质相互作用分析,构建蛋白质-蛋白质相互作用网络,通过度值(degree)筛选关键靶点并进行归属;使用DAVID数据库对黄芪抗疲劳作用靶点进行基因本体(GO)富集分析和KEGG通路富集分析,以探究黄芪抗疲劳的作用机制。结果获得黄芪中11种活性成分,包括毛蕊异黄酮葡萄糖苷、毛蕊异黄酮、芒柄花苷、芒柄花素、异黄烷、紫檀烷6种黄酮类成分,黄芪皂苷Ⅰ、Ⅱ、Ⅲ、Ⅳ 4种皂苷类成分及蔗糖。黄芪抗疲劳作用预测靶点有76个,网络分析结果表明,黄芪主要涉及一氧化氮的生物合成、过氧化氢反应、棕色脂肪细胞分化的正调节、活性氧代谢等生物过程,通过调节癌症通路,FoxO、磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(Akt)、低氧诱导因子-1(HIF-1)、血管内皮生长因子(VEGF)、丝裂原活化蛋白激酶(MAPK)、Ca~(2+)信号通路、氧化应激反应等来发挥抗疲劳作用。结论本研究体现了黄芪多成分-多靶点-多途径的作用特点,为进一步开展黄芪抗疲劳作用机制的研究提供了新思路和新方法。
Objective To explore the anti-fatigue mechanism of Astragali Radix based on network pharmacology. Methods The main active ingredients of Astragali Radix were obtained by TCMSP and the results of our previous work. GeneCards and OMIM were used to predict and screen the therapeutic targets of Astragali Radix. The Cytoscape 3.6.0 software was used to construct the active components-targets network of Astragali Radix. The protein interactions network was constructed using the String database and Cytoscape software. The GO and KEGG pathways involved in the targets were analyzed by using DAVID database. Results The results showed that 11 active components including six flavonoids(calycosin-7-O-β-D-glucoside, calycosin, ononin, formononetin, 7,2′-dihydroxy-3,4-dimethoxyisoflavan, 3-hydroxy-9,10-dimethoxypterocarpan), four saponins(astragaloside Ⅰ, Ⅱ, Ⅲ, Ⅳ) and sucrose and 76 targets of Astragali Radix were involved. The network analysis results showed that the process of nitric oxide biosynthesis, hydrogen peroxide reaction, positive regulation on brown adipocyte differentiation, and active oxygen metabolism were mainly involved by adjusting the cancer, FoxO, PI3 K-Akt, HIF-1, VEGF, MAPK and other signaling pathways to exert its antifatigue effect. Conclusion This study reflects the characteristics of multi-components, multi-targets, and multi-pathways of Astragali Radix, which provides new ideas and clues for further research on the mechanism of anti-fatigue effects of Astragali Radix.
Objective To explore the anti-fatigue mechanism of Astragali Radix based on network pharmacology. Methods The main active ingredients of Astragali Radix were obtained by TCMSP and the results of our previous work. GeneCards and OMIM were used to predict and screen the therapeutic targets of Astragali Radix. The Cytoscape 3.6.0 software was used to construct the active components-targets network of Astragali Radix. The protein interactions network was constructed using the String database and Cytoscape software. The GO and KEGG pathways involved in the targets were analyzed by using DAVID database. Results The results showed that 11 active components including six flavonoids(calycosin-7-O-β-D-glucoside, calycosin, ononin, formononetin, 7,2′-dihydroxy-3,4-dimethoxyisoflavan, 3-hydroxy-9,10-dimethoxypterocarpan), four saponins(astragaloside Ⅰ, Ⅱ, Ⅲ, Ⅳ) and sucrose and 76 targets of Astragali Radix were involved. The network analysis results showed that the process of nitric oxide biosynthesis, hydrogen peroxide reaction, positive regulation on brown adipocyte differentiation, and active oxygen metabolism were mainly involved by adjusting the cancer, FoxO, PI3 K-Akt, HIF-1, VEGF, MAPK and other signaling pathways to exert its antifatigue effect. Conclusion This study reflects the characteristics of multi-components, multi-targets, and multi-pathways of Astragali Radix, which provides new ideas and clues for further research on the mechanism of anti-fatigue effects of Astragali Radix.
引文
[1]周宝宽.中医对疲劳的认识[J].中华中医药学刊,2007,25(11):2385-2387.
[2]王景利.运动性疲劳的产生及中医调节机制[J].辽宁体育科技,2005,27(6):42-45.
[3]Son C G.Review of the prevalence of chronic fatigue worldwide[J].Korean Orient Med,2012,33:25-33.
[4]De Meirleir K L,Khaiboullina S F,Frémont M,et al.Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins[J].In Vivo,2013,27(2):177-187.
[5]Norheim K B,Jonsson G,Omdal R.Biological mechanisms of chronic fatigue[J].Rheumatology,2011,50(6):1009-1018.
[6]Cho H J,Kivim?ki M,Bower J E,et al.Association of C-reactive protein and interleukin-6 with new-onset fatigue in the Whitehall II prospective cohort study[J].Psychol Med,2013,43(8):1-11.
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[9]刘傲雪,王晶娟,张贵君,等.基于大鼠体内多成分代谢的黄芪质控成分遴选[J].药物评价研究,2018,41(2):216-222.
[10]张瑞,李科,李爱平,等.基于1H NMR技术黄芪抗疲劳作用的肌肉代谢组学研究[J].药学学报,2018,53(5):782-790.
[11]郭泽,邹娟,张贤,等.黄芪总黄酮小鼠体内抗炎作用研究[J].动物医学进展,2015,36(9):64-66.
[12]刘莎,符州.黄芪的免疫调节作用及其临床应用[J].国际中医中药杂志,2006,28(4):203-206.
[13]卢紫娟,刘海霞,李昆,等.基于网络药理学的脑震宁颗粒治疗脑外伤的机制分析[J].中草药,2018,49(15):3531-3540.
[14]许文倩,秦雪梅,刘月涛.基于网络药理学的黄芪建中汤治疗慢性萎缩性胃炎作用机制研究[J].中草药,2018,49(15):3550-3561.
[15]张王宁,高耀,李科,等.基于网络药理学的黄芪总黄酮治疗肾病综合征的机制研究[J].药学学报,2018,53(9):1429-1441.
[16]高四云,李科,熊一峰,等.恒山仿野生黄芪绝对生长年限鉴别及黄酮和皂苷积累规律研究[J].药学学报,2018,53(1):147-154.
[17]李凤娜,陈晓安.一氧化氮对线粒体生物合成的积极影响[J].生物技术通报,2005(2):57.
[18]冯毅翀,许金叶,赵自明.黄芪总皂苷对运动性疲劳大鼠海马功能和形态的影响[J].中医杂志,2014,55(5):420-423.
[19]Duan F F,Guo Y,Li J W,et al.Antifatigue effect of luteolin-6-C-neohesperidoside on oxidative stress injury induced by forced swimming of rats through modulation of Nrf2/ARE signaling pathways[J].Oxid Med Cell Longev,2017,doi:10.1155/2017/3159358.
[20]Wang X,Qu Y D,Zhang Y F,et al.Antifatigue potential activity of sarcodon imbricatusin acute excise-treated and chronic fatigue syndrome in mice via regulation of Nrf2-mediated oxidative stress[J].Oxid Med Cell Longev,2018,doi:10.1155/2018/9140896.
[21]李爽,艾英伟,阿拉木斯,等.黄芪总苷对运动性疲劳大鼠骨骼肌抗氧化能力、ATP酶活性及乳酸含量的影响[J].吉林体育学院学报,2010,26(3):68-69.
[22]邓书鸿,宋丽,段小菊,等.黄芪提取物HPLC指纹图谱与抗疲劳作用的相关分析[J].中药材,2013,36(2):260-264.
[23]吴铭,周桃英,陈年友.黄芪多糖抗疲劳作用研究[J].湖北农业科学,2014,53(1):175-177.
[24]王亚坤,孙文敬,刘敬泽.D-核糖对大鼠负载游泳后胰岛素、去甲肾上腺素、肾上腺素的影响及其抗疲劳、抗缺氧能力研究[J].食品科学,2008,29(11):591-596.
[25]徐小仙,熊正英.紫草提取物有效成分测定及对骨骼肌自由基代谢和抗疲劳能力影响的实验研究[J].药物分析杂志,2016,36(3):444-450.
[26]陈英松,卢峻,吴七柱,等.艾灸对疲劳模型大鼠血清IL-6和IL-10的影响[J].山东中医杂志,2008,27(6):404-405.
[27]姜振,张林.高压氧对递增负荷训练大鼠腓肠肌P53、Bcl-2蛋白表达的影响[J].中国组织工程研究与临床康复,2009,13(7):1309-1312.
[28]杨燕军,徐海伟,代奇.FoxO调控细胞增殖、分化与凋亡[J].生理科学进展,2008,39(4):362-364.
[29]Hribal M L,Nakae J,Kitamura T,et al.Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factors[J].J Cell Biol,2003,162(4):535-541.
[30]郝少伟.高原低氧环境大强度运动后增压辅助方法对大鼠骨骼肌中HIF-1α及骨骼肌能量代谢的影响[D].西宁:青海师范大学,2014.
[31]崔笑梅,曹建民,周海涛,等.黑果枸杞子对过度训练大鼠骨骼肌MAPK信号通道蛋白表达及抗氧化应激损伤能力的影响[J].中国实验方剂学杂志,2017,23(2):122-128.
[32]任增辉.大强度递增负荷运动对大鼠海马细胞凋亡PI3K/AKT信号通路的影响[D].济南:山东体育学院,2015.
[33]Chen L,Xu B,Liu L,et al.Hydrogen peroxide inhibits m TOR signaling by activation of AMPKalpha leading to apoptosis of neuronal cells[J].Lab Invest,2010,90(5):762-773.
[34]Towler M C,Hardie D G.AMP-activated protein kinase in metabolic control and insulin signaling[J].Circ Res,2007,100(3):328-341.
[35]常盛.PI3K/Akt信号通路与胰岛素抵抗的研究进展[J].中医药导报,2008,14(9):113-115.
[2]王景利.运动性疲劳的产生及中医调节机制[J].辽宁体育科技,2005,27(6):42-45.
[3]Son C G.Review of the prevalence of chronic fatigue worldwide[J].Korean Orient Med,2012,33:25-33.
[4]De Meirleir K L,Khaiboullina S F,Frémont M,et al.Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins[J].In Vivo,2013,27(2):177-187.
[5]Norheim K B,Jonsson G,Omdal R.Biological mechanisms of chronic fatigue[J].Rheumatology,2011,50(6):1009-1018.
[6]Cho H J,Kivim?ki M,Bower J E,et al.Association of C-reactive protein and interleukin-6 with new-onset fatigue in the Whitehall II prospective cohort study[J].Psychol Med,2013,43(8):1-11.
[7]Chu C,Qi L W,Liu E H,et al.Radix Astragali(Astragalus):Latest advancements and trends in chemistry,analysis,pharmacology and pharmacokinetics[J].Cur Org Chem,2010,14(16):1792-1807.
[8]中国药典[S].一部.2015.
[9]刘傲雪,王晶娟,张贵君,等.基于大鼠体内多成分代谢的黄芪质控成分遴选[J].药物评价研究,2018,41(2):216-222.
[10]张瑞,李科,李爱平,等.基于1H NMR技术黄芪抗疲劳作用的肌肉代谢组学研究[J].药学学报,2018,53(5):782-790.
[11]郭泽,邹娟,张贤,等.黄芪总黄酮小鼠体内抗炎作用研究[J].动物医学进展,2015,36(9):64-66.
[12]刘莎,符州.黄芪的免疫调节作用及其临床应用[J].国际中医中药杂志,2006,28(4):203-206.
[13]卢紫娟,刘海霞,李昆,等.基于网络药理学的脑震宁颗粒治疗脑外伤的机制分析[J].中草药,2018,49(15):3531-3540.
[14]许文倩,秦雪梅,刘月涛.基于网络药理学的黄芪建中汤治疗慢性萎缩性胃炎作用机制研究[J].中草药,2018,49(15):3550-3561.
[15]张王宁,高耀,李科,等.基于网络药理学的黄芪总黄酮治疗肾病综合征的机制研究[J].药学学报,2018,53(9):1429-1441.
[16]高四云,李科,熊一峰,等.恒山仿野生黄芪绝对生长年限鉴别及黄酮和皂苷积累规律研究[J].药学学报,2018,53(1):147-154.
[17]李凤娜,陈晓安.一氧化氮对线粒体生物合成的积极影响[J].生物技术通报,2005(2):57.
[18]冯毅翀,许金叶,赵自明.黄芪总皂苷对运动性疲劳大鼠海马功能和形态的影响[J].中医杂志,2014,55(5):420-423.
[19]Duan F F,Guo Y,Li J W,et al.Antifatigue effect of luteolin-6-C-neohesperidoside on oxidative stress injury induced by forced swimming of rats through modulation of Nrf2/ARE signaling pathways[J].Oxid Med Cell Longev,2017,doi:10.1155/2017/3159358.
[20]Wang X,Qu Y D,Zhang Y F,et al.Antifatigue potential activity of sarcodon imbricatusin acute excise-treated and chronic fatigue syndrome in mice via regulation of Nrf2-mediated oxidative stress[J].Oxid Med Cell Longev,2018,doi:10.1155/2018/9140896.
[21]李爽,艾英伟,阿拉木斯,等.黄芪总苷对运动性疲劳大鼠骨骼肌抗氧化能力、ATP酶活性及乳酸含量的影响[J].吉林体育学院学报,2010,26(3):68-69.
[22]邓书鸿,宋丽,段小菊,等.黄芪提取物HPLC指纹图谱与抗疲劳作用的相关分析[J].中药材,2013,36(2):260-264.
[23]吴铭,周桃英,陈年友.黄芪多糖抗疲劳作用研究[J].湖北农业科学,2014,53(1):175-177.
[24]王亚坤,孙文敬,刘敬泽.D-核糖对大鼠负载游泳后胰岛素、去甲肾上腺素、肾上腺素的影响及其抗疲劳、抗缺氧能力研究[J].食品科学,2008,29(11):591-596.
[25]徐小仙,熊正英.紫草提取物有效成分测定及对骨骼肌自由基代谢和抗疲劳能力影响的实验研究[J].药物分析杂志,2016,36(3):444-450.
[26]陈英松,卢峻,吴七柱,等.艾灸对疲劳模型大鼠血清IL-6和IL-10的影响[J].山东中医杂志,2008,27(6):404-405.
[27]姜振,张林.高压氧对递增负荷训练大鼠腓肠肌P53、Bcl-2蛋白表达的影响[J].中国组织工程研究与临床康复,2009,13(7):1309-1312.
[28]杨燕军,徐海伟,代奇.FoxO调控细胞增殖、分化与凋亡[J].生理科学进展,2008,39(4):362-364.
[29]Hribal M L,Nakae J,Kitamura T,et al.Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factors[J].J Cell Biol,2003,162(4):535-541.
[30]郝少伟.高原低氧环境大强度运动后增压辅助方法对大鼠骨骼肌中HIF-1α及骨骼肌能量代谢的影响[D].西宁:青海师范大学,2014.
[31]崔笑梅,曹建民,周海涛,等.黑果枸杞子对过度训练大鼠骨骼肌MAPK信号通道蛋白表达及抗氧化应激损伤能力的影响[J].中国实验方剂学杂志,2017,23(2):122-128.
[32]任增辉.大强度递增负荷运动对大鼠海马细胞凋亡PI3K/AKT信号通路的影响[D].济南:山东体育学院,2015.
[33]Chen L,Xu B,Liu L,et al.Hydrogen peroxide inhibits m TOR signaling by activation of AMPKalpha leading to apoptosis of neuronal cells[J].Lab Invest,2010,90(5):762-773.
[34]Towler M C,Hardie D G.AMP-activated protein kinase in metabolic control and insulin signaling[J].Circ Res,2007,100(3):328-341.
[35]常盛.PI3K/Akt信号通路与胰岛素抵抗的研究进展[J].中医药导报,2008,14(9):113-115.