基于网络药理学探析远志散治疗痴呆的分子生物机制研究（英文）
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摘要
目的采用网络药理学技术预测远志散治疗老年痴呆的主要活性成分、潜在靶点及分子作用机制。方法通过数据库及文献构建远志散的化学成分库,进行反向分子对接预测潜在靶点,构建成分-靶标网络;通过与AD的靶标网络进行映射、分析,获得"有效成分-AD靶标"网络;通过网络分析筛选出关键靶点;通过与已知文献报道的靶点进行对比,分析预测靶点的合理性。结果远志散各味中药共有180种化学成分作用于AD靶标,其作用靶标包括三个关键靶标(环氧酶-2、毒蕈碱型乙酰胆碱受体M1、毒蕈碱型乙酰胆碱受体M2)及一个重要靶标(乙酰胆碱酯酶)。可能通过调节乙酰胆碱受体活性及与β-淀粉样蛋白结合从而治疗阿兹海默症,其生物过程可能集中于乙酰胆碱受体信号通路、突触传递的负调节等。结论远志散治疗老年痴呆符合中药多成分-多靶点-多途径的特点,网络分析所获得的重要靶点在文献研究中占有很大比例,具有一定的合理性。
Objective To predict the main active ingredients, potential targets and molecular mechanisms of Yuan Zhi powder in treatment of dementia by using network pharmacology. Methods A database of chemical constituents of Yuan Zhi powder was constructed by using databases and literatures. Potential targets were predicted by reverse molecular docking, and then a component-target network was constructed. The target network of Alzheimer's disease(AD) was mapped and analyzed to obtain the "active ingredient-AD target" network. The key targets were screened through network analysis. Finally, the rationality of the prediction was analyzed by comparing with the target reported in the literatures. Results There were 180 chemical constituents acting on the AD target, and the targets included three key targets(cyclooxygenase-2, muscarinic acetylcholine receptor M1, and muscarinic acetylcholine receptor M2) and an important target(acetylcholine esterase). Alzheimer's disease may be treated by regulating the activity of acetylcholine receptors and the binding to β-amyloid protein, and its biological process may be concentrated in the acetylcholine receptor signal pathway, negative regulation of synaptic transmission and so on. Conclusion The fact that Yuan Zhi powder can treat AD is consistent with the characteristics of multi-components-multitargets-multiple pathways of traditional Chinese medicine. The important targets obtained from network analysis have a large proportion in literature research, so network analysis have some rationality.
Objective To predict the main active ingredients, potential targets and molecular mechanisms of Yuan Zhi powder in treatment of dementia by using network pharmacology. Methods A database of chemical constituents of Yuan Zhi powder was constructed by using databases and literatures. Potential targets were predicted by reverse molecular docking, and then a component-target network was constructed. The target network of Alzheimer's disease(AD) was mapped and analyzed to obtain the "active ingredient-AD target" network. The key targets were screened through network analysis. Finally, the rationality of the prediction was analyzed by comparing with the target reported in the literatures. Results There were 180 chemical constituents acting on the AD target, and the targets included three key targets(cyclooxygenase-2, muscarinic acetylcholine receptor M1, and muscarinic acetylcholine receptor M2) and an important target(acetylcholine esterase). Alzheimer's disease may be treated by regulating the activity of acetylcholine receptors and the binding to β-amyloid protein, and its biological process may be concentrated in the acetylcholine receptor signal pathway, negative regulation of synaptic transmission and so on. Conclusion The fact that Yuan Zhi powder can treat AD is consistent with the characteristics of multi-components-multitargets-multiple pathways of traditional Chinese medicine. The important targets obtained from network analysis have a large proportion in literature research, so network analysis have some rationality.
引文
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[19]SUN F.Protective effects of made cassoside on dementia mice induced by chronic aluminum toxicity.Chong Qing:Chong Qing Medical University,2006.
[20]WANG D.Discovery of novel muscarinic M1 receptor agonists and evaluation of its effects on Alzheimer disease animal model.Shanghai:Huadong East China Normal University,2012.
[21]LEVEY A I.Immunological localization of m1-m5muscarinic acetylcholine receptors in peripheral tissues and brain.Life Sciences,1993,52(5-6):441.
[22]SONG Q.Effect and mechanism of T-006 on learning and memory in functional impairment model animals.Guang Zhou:Sun Yat-sen University,2016.
[23]CAI B,WANG Y J,WANG Y,et al.Effect of Soybean Isoflavone on Acetylcholine Metabolism in Rats with Alzheimer's Disease.Journal of Anhui University of Chinese Medicine,2013,32(1):57.
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[25]WANG H F.Effect of alpha7 cholinergic receptor agonist DMXB on cognitive impairment in patients with Aβinjury and its molecular mechanism.Nan Jing:Nan Jing Medical University,2009.
[26]HU J.Neuroprotection and mechanism ofα7 Nicotinic Acetylcholine receptor.Nan Jing:Nan Jing Medical University,2012.
[27]PAN W S.Effects of dihydrotestosterone on spatial learning and memory and hippocampal synaptic plasticity in AD-induced SAMP8 male mice at MCI stage.Shi Jia Zhuang:Hebei Medical University,2015.
[2]PU M M,XU B,TAN T N.An overview of brain science and brain-like research.Chinese Academy of Sciences,2016,31(7):725-736
[3]CHANK Y,WANG W,WU J J,et al.Epidemiology of Alzheimer's disease and other forms of dementia in China,1990-2010:a systematic review and analysis.Lancet,2013,381(9882):2016.
[4]HE J.Study on etiology,pathogenesis and treatment of Alzheimer's disease in traditional Chinese medicine.Shizhen Guoyi Sinopharm,2012,23(11):2933-2934.
[5]XU S H.Status quo of research on Alzheimer's disease.Chinese Journal of Rural Medicine and Pharmacy,2012,19(2):87.
[6]ZHAO J(Song dynasty).Saint General Collection of Beneficial Herbal Formulas.Beijing:People's Medical Publishing House,2013,2183.
[7]AMATURRASOOL H,AHMED M.Designing Second Generation Anti-Alzheimer Compounds as Inhibitors of Human Acetylcholinesterase:Computational Screening of Synthetic Molecules and Dietary Phytochemicals.Plos One,2015,10(9):e0136509.
[8]MAO J,HUANG S,LIU S,et al.A herbal medicine for Alzheimer's disease and its active constituents promote neural progenitor proliferation.Aging Cell,2015,14(5):784.
[9]GAO B B,XU S P,LIU X M,et al.Comparison of Nootropic Effects of Kaixins an Prescription and Kaixinsan without Poria cocos(Schw.)Wolf to Alzheimer's Mice Model.Chinese Journal of Comparative Medicine,2010,20(7):57.
[10]FAN X,SHAO L,FANG H,et al.Cross-Platform comparison of microarray-based multiple-class prediction.Plos One,2011,6(1):e16067.
[11]LI S,ZHANG B,JIANG D,et al.Herb network construction and co-module analysis for uncovering the combination rule of traditional Chinese herbal formulae.BMC Bioinformatics,2010,11(11):1.
[12]ZHAO J,JIANG P,ZHANG W D.Molecular networks for the study of TCM Pharmacology.Briefings in Bioinformatics,2010,11(4):417.
[13]XUE R,FANG Z,ZHANG M,et al.TCMID:Traditional Chinese Medicine integrative database for herb molecular mechanism analysis.Nucleic Acids Res,2013,4:1089.
[14]CHEN C Y.TCM Database@Taiwan:the world's largest traditional Chinese medicine database for drug screening in silico.Plos One,2011,6(1):e15939.
[15]COUSINS K R.Computer review of Chem Draw Ultra12.0.Journal of the American Chemical Society,2011,133(21):8388.
[16]LIU X,OUYANG S,YU B,et al.Pharm Mapper server:a web server for potential drug target identification using pharmacophore mapping approach.Nucleic Acids Research,2010,38(Web Server issue):W609.
[17]ZHUGE H,ZHANG J.Topological centrality and its e-Science applications.J Assoc Inf Sci Tech,2010,61(9):1824.
[18]CHEN X G.New ideas and new targets for pharmacological research.Chinese Peking Union Medical University Press,2012.
[19]SUN F.Protective effects of made cassoside on dementia mice induced by chronic aluminum toxicity.Chong Qing:Chong Qing Medical University,2006.
[20]WANG D.Discovery of novel muscarinic M1 receptor agonists and evaluation of its effects on Alzheimer disease animal model.Shanghai:Huadong East China Normal University,2012.
[21]LEVEY A I.Immunological localization of m1-m5muscarinic acetylcholine receptors in peripheral tissues and brain.Life Sciences,1993,52(5-6):441.
[22]SONG Q.Effect and mechanism of T-006 on learning and memory in functional impairment model animals.Guang Zhou:Sun Yat-sen University,2016.
[23]CAI B,WANG Y J,WANG Y,et al.Effect of Soybean Isoflavone on Acetylcholine Metabolism in Rats with Alzheimer's Disease.Journal of Anhui University of Chinese Medicine,2013,32(1):57.
[24]BELLUCCI A,LUCCARINI I,SCALI C,et al.Cholinergic dysfunction,neuronal damage and axonal loss in Tg CRND8mice.Neurobiology of Disease,2006,23(2):260.
[25]WANG H F.Effect of alpha7 cholinergic receptor agonist DMXB on cognitive impairment in patients with Aβinjury and its molecular mechanism.Nan Jing:Nan Jing Medical University,2009.
[26]HU J.Neuroprotection and mechanism ofα7 Nicotinic Acetylcholine receptor.Nan Jing:Nan Jing Medical University,2012.
[27]PAN W S.Effects of dihydrotestosterone on spatial learning and memory and hippocampal synaptic plasticity in AD-induced SAMP8 male mice at MCI stage.Shi Jia Zhuang:Hebei Medical University,2015.