基于网络药理学分析厚朴抗抑郁的物质基础及其作用机制
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摘要
目的:采用网络药理学方法探讨厚朴抗抑郁的物质基础及作用机制。方法:通过中国知网,Sci Finder,中药系统药理学数据库和分析平台(TCMSP)等数据库收集厚朴药材的主要化学成分;通过BATMAN-TCM数据库筛选出药物成分潜在作用靶标;基于HPO数据库筛选出抑郁疾病相关靶标;采用String数据库对药物成分潜在靶标与抑郁症靶标进行蛋白质相互作用分析,筛选抗抑郁化学成分及其相关靶点,并通过David数据库对其结果进行功能富集分析。基于以上结果,采用Cytoscape v3. 5. 1软件网络化展现厚朴抗抑郁的"药物靶标-疾病靶标""化学成分-靶标-信号通路"的网络关系图,并通过网络拓扑分析从中筛选出关键靶标并对其进行"成分-靶标蛋白"的分子对接验证,进一步明确关键抗抑郁成分及其靶点。结果:从厚朴收集得到的138种化学成分中筛选得到16个与抑郁症相关的活性成分,涉及74个关键作用靶标;分子对接分析结果表明,与其他成分相比,16种活性成分中的α-衣兰油烯等10种挥发性成分与"药物靶标-疾病靶标"相互作用网络图中的5种关键靶标(degree排名前5)胰岛素受体(INSR),丝裂原活化蛋白激酶1(MAPK1),鸟嘌呤核苷酸结合蛋白α抑制3(GNAI3),磷脂酰肌醇3-激酶受体1(PIK3R1),选择性受体B1(GNB1)均具有较好的结合活性;并且该类成分与目前治疗抑郁症化药的直接靶标毒蕈碱型乙酰胆碱受体M2(CHRM2),5-羟色胺受体(HTR) 2B和HTR2C也均具有较好的亲和活力;通路富集分析结果表明厚朴抗抑郁作用可能通过调节神经营养因子信号通路,MAPK信号通路,钙离子信号通路,神经活性配体-受体相互作用等发挥作用。结论:该研究从网络药理学的角度初步揭示了厚朴抗抑郁的药效物质基础及作用机制,筛选得到16个与抑郁症相关的活性成分,可为抗抑郁药物的开发以及厚朴抗抑郁质量标志物的发现提供参考。
Objective: In this paper,the network pharmacology method was used to explore the material basis and the mechanism of Magnoliae Officinalis Cortex( Houpo) on depressive disorder. Method: Firstly,the main chemical components of Houpo were gathered from CNKI,SciFinder,traditional Chinese medicine systems pharmacology database and analysis platform( TCMSP) and other databases. Next,the potential targets of the chemical ingredients in Houpo were searched and selected by BATMAN-TCM database. The targets of depressive disorder were collected from HPO database. Then all the targets were entered into the search tool( String database) for the retrieval of protein-protein interactions so as to confirm antidepressant chemistries and their related targets. Furthermore, the functional enrichment analysis was carried out through the David database.Based on these above results,the networks of " drug targets-disease targets" and " compounds-targets-pathways" of Houpo on depressive disorder were built by Cytoscape v3. 5. 1 software,respectively. Network topology analysis was used to screen the key targets and the corresponding components. Then molecular docking verification of "component-target proteins" was further conducted. Result: A total of 16 active compounds involving in 74 key targets for depressive disorder were selected and confirmed from 138 chemical components of Houpo. Molecular docking analysis showed that compared with other components,ten volatile components in the 16 active compounds had good binding activities with the top 5 key targets [the top 5 of degree value, including insulin receptor( INS),mitogen-activated protein kinase 1( MAPK1),guanine nucleotide binding protein alpha inhibition 3( GNAI3),phosphatidylinositol 3-kinase receptor 1( PIK3 R1) and selective receptor B1( GNB1) ] and the 3 direct acting targets of popular drugs for depression [muscarinic acetylcholine receptor M2( CHRM2),5-hydroxytryptamine receptor( HTR) 2B and HTR2C ]. The functional enrichment analysis showed the antidepressant mechanism of Houpo mainly involved neurotrophin signaling pathway,MAPK signaling pathway,calcium signaling pathway and neuroactive ligand-receptor interaction,etc. Conclusion: This study reveals the active ingredients and the mechanism of anti-depression of Houpo based on network pharmacology,a total of 16 key active ingredients related to anti-depression are selected. This paper can provide references for development of antidepressants and the discovery of quality markers of Houpo for anti-depression.
Objective: In this paper,the network pharmacology method was used to explore the material basis and the mechanism of Magnoliae Officinalis Cortex( Houpo) on depressive disorder. Method: Firstly,the main chemical components of Houpo were gathered from CNKI,SciFinder,traditional Chinese medicine systems pharmacology database and analysis platform( TCMSP) and other databases. Next,the potential targets of the chemical ingredients in Houpo were searched and selected by BATMAN-TCM database. The targets of depressive disorder were collected from HPO database. Then all the targets were entered into the search tool( String database) for the retrieval of protein-protein interactions so as to confirm antidepressant chemistries and their related targets. Furthermore, the functional enrichment analysis was carried out through the David database.Based on these above results,the networks of " drug targets-disease targets" and " compounds-targets-pathways" of Houpo on depressive disorder were built by Cytoscape v3. 5. 1 software,respectively. Network topology analysis was used to screen the key targets and the corresponding components. Then molecular docking verification of "component-target proteins" was further conducted. Result: A total of 16 active compounds involving in 74 key targets for depressive disorder were selected and confirmed from 138 chemical components of Houpo. Molecular docking analysis showed that compared with other components,ten volatile components in the 16 active compounds had good binding activities with the top 5 key targets [the top 5 of degree value, including insulin receptor( INS),mitogen-activated protein kinase 1( MAPK1),guanine nucleotide binding protein alpha inhibition 3( GNAI3),phosphatidylinositol 3-kinase receptor 1( PIK3 R1) and selective receptor B1( GNB1) ] and the 3 direct acting targets of popular drugs for depression [muscarinic acetylcholine receptor M2( CHRM2),5-hydroxytryptamine receptor( HTR) 2B and HTR2C ]. The functional enrichment analysis showed the antidepressant mechanism of Houpo mainly involved neurotrophin signaling pathway,MAPK signaling pathway,calcium signaling pathway and neuroactive ligand-receptor interaction,etc. Conclusion: This study reveals the active ingredients and the mechanism of anti-depression of Houpo based on network pharmacology,a total of 16 key active ingredients related to anti-depression are selected. This paper can provide references for development of antidepressants and the discovery of quality markers of Houpo for anti-depression.
引文
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[6]姜博,赵永辰.加味半夏厚朴汤治疗脑卒中后轻中度抑郁症临床疗效观察[J].四川中医,2014,32(9):104-106.
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[10]刘学.基于网络药理学方法研究玉屏风散治疗哮喘的作用机理[D].成都:西南交通大学,2017.
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[13] Hsin K Y,Matsuoka Y,Asai Y,et al. systems Dock:a web server for network pharmacology-based prediction and analysis[J]. Nucleic Acids Res,2016,44(W1):W507-W513.
[14] Lopes C T,Franz M,Kazi F,et al. Cytoscape Web:an interactive web-based network browser[J].Bioinformatics,2010,26(18):2347-2348.
[15]张永超,黄世敬. 5-羟色胺受体与抑郁症相关性的研究进展[J].医学综述,2014,20(5):772-775.
[16]王美萍,张文新. CHRM2基因rs1824024多态性与青少年早期抑郁的关系[J].心理学报,2010,42(8):853-861.
[17]王婷婷,吴辉,张蓓蓓,等.抑郁症发病机制与临床抗抑郁药研究进展[J].生命科学仪器,2014(6):28-33.
[18]张清清,王章元,欧阳华,等.度洛西汀治疗抑郁症患者对认知功能及TNF-α、IL-6、IL-10的影响[J].国际精神病学杂志,2017(6):1001-1003.
[19] SUN Y,TAO Y,WANG J,et al. The schizophrenia/bipolar disorder candidate gene GNB1L is regulated in human temporal cortex by a cis-acting element located within the 3'-region[J]. Neurosci Bull,2015,31(1):43-52.
[20] Hsin K Y,Ghosh S,Kitano H. Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology[J]. PLo S One, 2013, 8(12):e83922.
[21] Taliaz D, Stall N. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis[J]. Mol Psychiatry,2010,15(1):80-92.
[22] Brunoni A R,Baeken C,Machado-Vieira R,et al. BDNF blood levels after electroconvulsive therapy in patients with mood disorders:a systematic review and metaanalysis[J]. World J Biol Psychiatry,2014,15(5):411-418.
[23] Cappello S,Attardo A,WU X,et al. The Rho-GTPase cdc42 regulates neural progenitor fate at the apical surface[J]. Nat Neurosci,2006,9(9):1099-1107.
[24] M?ller-Levet C S,Archer S N,Bucca G,et al. Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome[J]. Proc Natl Acad Sci USA,2013,110(12):E1132-E1141.
[25]胡莺燕,洪武,方贻儒.脑源性神经营养因子及其信号通路与抑郁症[J].上海精神医学,2009,21(3):185-187.
[26] Duman C H,Schlesinger L,Kedaman M,et al. A role for MAP kinase singaling in behavioral models of depression an antidepressant treatment[J]. Biol Psychiat,2007,61(5):661-670.
[27] Nowak G,LI Y,Paul I A. Chronic glycine treatment desensitizes the behavioral response to 1-aminocyclopropanecarboxylic acid(ACPC),a partial agonist at the strychnine-insensitive glycine site of the NMDA receptor complex[J]. J Neural Transm(Vienna),2000,107(2):123-131.
[28]钟晓明,毛庆秋,黄真,等.金丝桃提取物对应激动物模型的抗抑郁作用及其机理研究[J].浙江中医药大学学报,2006,30(2):214-216.
[29]张广芬,杨建军. NMDA受体相关抗抑郁药物的研究进展[J].中国药理学通报,2018,34(1):1-4.
[30]连妙芬,贾萍娟,贾震雷,等.帕罗西汀联合尼莫地平治疗卒中后焦虑抑郁躯体化的相关性研究(附80例报告)[J].北京医学,2014,36(10):874-876.
[31]梁静静,吕俊,鲁林荣. T细胞受体(TCR)信号传递的调控及其功能[J].生命科学,2016,28(2):153-161.
[32]顾晓,唐孝达,顾沈阳,等.趋化因子信号对人外周血单个核细胞的免疫活化作用[J].中华泌尿外科杂志,2003,24(7):7959-7961.
[33]段雪涛,晋红宾,易亚乔,等.栝楼薤白半夏汤预处理对大鼠心肌缺血再灌注损伤JAK-STAT细胞信号传导调节的研究[J].中国实验方剂学杂志,2011,17(24):147-150.
[34]傅强,马占强,杨文,等.厚朴酚对慢性温和刺激所致抑郁小鼠的抗抑郁作用研究[J].中药药理与临床,2013,29(2):47-51.
[35]王萍萍,刘保秀,杨桃,等.和厚朴酚对急慢性应激小鼠的抗抑郁作用及机制研究[J].中国药学杂志,2017,52(24):2161-2165.
[36]吴嘉瑞,金燕萍,王凯欢,等.基于网络药理学的“金银花-连翘”药对作用机制分析[J].中国实验方剂学杂志,2017,23(5):179-183.
[37]刘鑫馗,吴嘉瑞,蔺梦娟,等.基于网络药理学的四君子汤作用机制分析[J].中国实验方剂学杂志,2017,23(16):194-202.
[38]夏新中,肖静,夏庭君.顶空固相微萃取-气相色谱/质谱法测定川厚朴挥发性成分[J].长江大学学报:自然科学版,2017,14(20):5-7.
[39]崔建芳,章观德,宋万志.反相离子对高效液相色谱分析厚朴类原植物中季铵生物碱[J].药学学报,1988,23(5):383-387.
[2]张颖,陈宇霞,黄世敬.柴胡及柴胡类复方的抗抑郁研究现状[J].世界中西医结合杂志,2014,9(9):985-988.
[3]龙飞,韩小勤,龙绍疆,等.厚朴叶抗抑郁作用的初步研究[J].成都中医药大学学报,2014,37(1):39-41.
[4]屈晓晟,杨义芳,张静,等.栀子厚朴汤的不同提取方法及其抗抑郁谱效[J].中国医药工业杂志,2014,45(5):424-428.
[5]周鹏,陈林庆,彭晓明,等.半夏厚朴汤加味联合盐酸氟西汀治疗青年抑郁症临床观察[J].中医药研究,2011,9(2):247-248.
[6]姜博,赵永辰.加味半夏厚朴汤治疗脑卒中后轻中度抑郁症临床疗效观察[J].四川中医,2014,32(9):104-106.
[7]陶弘景.名医别录[M].北京:人民卫生出版社,1986:125.
[8] RU J L,LI P,WANG J,et al. TCMSP:a database of systems pharmacology for drug discovery from herbal medicines[J]. J Cheminform,2014,doi:10. 1186/1758-2946-6-13.
[9] LIU Z,GUO F,WANG Y,et al. BATMAN-TCM:a bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine[J]. Sci Rep,2016,doi:10. 1038/srep21146.
[10]刘学.基于网络药理学方法研究玉屏风散治疗哮喘的作用机理[D].成都:西南交通大学,2017.
[11] Robinson P N,Mundlos S. The human phenotype ontology[J]. Clin Genet,2010,77(6):525-534.
[12] Franceschini A,Szklarczyk D,Frankild S,et al. STRING v9. 1:protein-protein interaction networks,with increased coverage and integration[J]. Nucleic Acids Res,2013,41(Database issue):D808-D815.
[13] Hsin K Y,Matsuoka Y,Asai Y,et al. systems Dock:a web server for network pharmacology-based prediction and analysis[J]. Nucleic Acids Res,2016,44(W1):W507-W513.
[14] Lopes C T,Franz M,Kazi F,et al. Cytoscape Web:an interactive web-based network browser[J].Bioinformatics,2010,26(18):2347-2348.
[15]张永超,黄世敬. 5-羟色胺受体与抑郁症相关性的研究进展[J].医学综述,2014,20(5):772-775.
[16]王美萍,张文新. CHRM2基因rs1824024多态性与青少年早期抑郁的关系[J].心理学报,2010,42(8):853-861.
[17]王婷婷,吴辉,张蓓蓓,等.抑郁症发病机制与临床抗抑郁药研究进展[J].生命科学仪器,2014(6):28-33.
[18]张清清,王章元,欧阳华,等.度洛西汀治疗抑郁症患者对认知功能及TNF-α、IL-6、IL-10的影响[J].国际精神病学杂志,2017(6):1001-1003.
[19] SUN Y,TAO Y,WANG J,et al. The schizophrenia/bipolar disorder candidate gene GNB1L is regulated in human temporal cortex by a cis-acting element located within the 3'-region[J]. Neurosci Bull,2015,31(1):43-52.
[20] Hsin K Y,Ghosh S,Kitano H. Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology[J]. PLo S One, 2013, 8(12):e83922.
[21] Taliaz D, Stall N. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis[J]. Mol Psychiatry,2010,15(1):80-92.
[22] Brunoni A R,Baeken C,Machado-Vieira R,et al. BDNF blood levels after electroconvulsive therapy in patients with mood disorders:a systematic review and metaanalysis[J]. World J Biol Psychiatry,2014,15(5):411-418.
[23] Cappello S,Attardo A,WU X,et al. The Rho-GTPase cdc42 regulates neural progenitor fate at the apical surface[J]. Nat Neurosci,2006,9(9):1099-1107.
[24] M?ller-Levet C S,Archer S N,Bucca G,et al. Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome[J]. Proc Natl Acad Sci USA,2013,110(12):E1132-E1141.
[25]胡莺燕,洪武,方贻儒.脑源性神经营养因子及其信号通路与抑郁症[J].上海精神医学,2009,21(3):185-187.
[26] Duman C H,Schlesinger L,Kedaman M,et al. A role for MAP kinase singaling in behavioral models of depression an antidepressant treatment[J]. Biol Psychiat,2007,61(5):661-670.
[27] Nowak G,LI Y,Paul I A. Chronic glycine treatment desensitizes the behavioral response to 1-aminocyclopropanecarboxylic acid(ACPC),a partial agonist at the strychnine-insensitive glycine site of the NMDA receptor complex[J]. J Neural Transm(Vienna),2000,107(2):123-131.
[28]钟晓明,毛庆秋,黄真,等.金丝桃提取物对应激动物模型的抗抑郁作用及其机理研究[J].浙江中医药大学学报,2006,30(2):214-216.
[29]张广芬,杨建军. NMDA受体相关抗抑郁药物的研究进展[J].中国药理学通报,2018,34(1):1-4.
[30]连妙芬,贾萍娟,贾震雷,等.帕罗西汀联合尼莫地平治疗卒中后焦虑抑郁躯体化的相关性研究(附80例报告)[J].北京医学,2014,36(10):874-876.
[31]梁静静,吕俊,鲁林荣. T细胞受体(TCR)信号传递的调控及其功能[J].生命科学,2016,28(2):153-161.
[32]顾晓,唐孝达,顾沈阳,等.趋化因子信号对人外周血单个核细胞的免疫活化作用[J].中华泌尿外科杂志,2003,24(7):7959-7961.
[33]段雪涛,晋红宾,易亚乔,等.栝楼薤白半夏汤预处理对大鼠心肌缺血再灌注损伤JAK-STAT细胞信号传导调节的研究[J].中国实验方剂学杂志,2011,17(24):147-150.
[34]傅强,马占强,杨文,等.厚朴酚对慢性温和刺激所致抑郁小鼠的抗抑郁作用研究[J].中药药理与临床,2013,29(2):47-51.
[35]王萍萍,刘保秀,杨桃,等.和厚朴酚对急慢性应激小鼠的抗抑郁作用及机制研究[J].中国药学杂志,2017,52(24):2161-2165.
[36]吴嘉瑞,金燕萍,王凯欢,等.基于网络药理学的“金银花-连翘”药对作用机制分析[J].中国实验方剂学杂志,2017,23(5):179-183.
[37]刘鑫馗,吴嘉瑞,蔺梦娟,等.基于网络药理学的四君子汤作用机制分析[J].中国实验方剂学杂志,2017,23(16):194-202.
[38]夏新中,肖静,夏庭君.顶空固相微萃取-气相色谱/质谱法测定川厚朴挥发性成分[J].长江大学学报:自然科学版,2017,14(20):5-7.
[39]崔建芳,章观德,宋万志.反相离子对高效液相色谱分析厚朴类原植物中季铵生物碱[J].药学学报,1988,23(5):383-387.