系统药理学方法研究猴头菇活性成分治疗阿尔茨海默病的作用机制（英文）
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摘要
目的应用系统药理学方法研究猴头菇对阿尔茨海默病(AD)的潜在治疗作用。方法从TCMDatabase@Taiwan、Pubmed、Pubchem等数据库中筛选猴头菇的活性成分。利用SEA(相似性集成方法)数据库预测作用靶点,利用DisGeNET数据库筛选治疗AD的潜在作用靶点。建立了化合物-目标-AD网络。生物信息学分析采用GO分析和通路富集分析。结果用网络药理学方法筛选出21种猴头菇活性成分,显示其活性化合物的预测靶点451个,其中165个靶点与AD相关。猴头菇的活性化合物的药效作用靶点高度富集到与AD相关的信号通路和生物学过程,如胆碱能突触传递、炎症相关通路、神经营养因子信号通路等。结论我们的研究结果表明,猴头菇活性化合物以协同的方式与多个靶点多种途径相互作用,其对AD的治疗作用主要与抗炎、抗凋亡、增强突触传递等途径相关。
Objective To confirm evidence regarding the potential therapeutic effect of Hericium erinaceus(H.erinaceus,Hou Tou Gu,猴头菇) on Alzheimer's disease(AD) using a system pharmacological approach in silico.Methods The active compounds of H.erinaceus were screened from the TCMDatabase@Taiwan,PubMed,and Pubchem.The predicted targets of H.erinaceus were selected by using the Similarity Ensemble Approach Database and the DisGeNET database was used to screen the targets related to AD.The compound-target-AD network was built.GO analysis and Pathway enrichment analysis were used for bioinformatics analysis.Results A total of 21 kinds of H.erinaceus active compounds were screened by network pharmacology,showing 451 predicted targets of active compounds.Among them,165 targets were associated with AD,and the compounds in H.erinaceus were highly connected to AD-related signaling pathways and biological processes,such as cholinergic synaptic transmission,inflammation-related pathways and neurotrophin signaling pathway.Conclusions Our results indicate that compounds in H.erinaceus interact with multiple targets in a synergetic way and the anti-inflammatory,anti-apoptosis and synaptic transmission enhancing effects of H.erinaceus might contribute to its major therapeutic effects on Alzheimer's disease.
Objective To confirm evidence regarding the potential therapeutic effect of Hericium erinaceus(H.erinaceus,Hou Tou Gu,猴头菇) on Alzheimer's disease(AD) using a system pharmacological approach in silico.Methods The active compounds of H.erinaceus were screened from the TCMDatabase@Taiwan,PubMed,and Pubchem.The predicted targets of H.erinaceus were selected by using the Similarity Ensemble Approach Database and the DisGeNET database was used to screen the targets related to AD.The compound-target-AD network was built.GO analysis and Pathway enrichment analysis were used for bioinformatics analysis.Results A total of 21 kinds of H.erinaceus active compounds were screened by network pharmacology,showing 451 predicted targets of active compounds.Among them,165 targets were associated with AD,and the compounds in H.erinaceus were highly connected to AD-related signaling pathways and biological processes,such as cholinergic synaptic transmission,inflammation-related pathways and neurotrophin signaling pathway.Conclusions Our results indicate that compounds in H.erinaceus interact with multiple targets in a synergetic way and the anti-inflammatory,anti-apoptosis and synaptic transmission enhancing effects of H.erinaceus might contribute to its major therapeutic effects on Alzheimer's disease.
引文
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[36]FERREIRA-VIEIRA TH,GUIMARAES IM,SILVA FR,et al.Alzheimer's disease:targeting the cholinergic system.Current Neuropharmacology,2016,14(1):101-115.
[37]KAMKWALALA AR,NEWHOUSE PA.Beyond Acetylcholinesterase inhibitors:novel cholinergic treatments for Alzheimer's disease.Current Alzheimer Research,2017,14(4):377-392.
[38]HUANG C,ZHENG C,LI Y,et al.Systems pharmacology in drug discovery and therapeutic insight for herbal medicines.Briefings in Bioinformatics,2014,15(5):710-733.
[2]BHARDWAJ D,MITRA C,NARASIMHULU CA,et al.Alzheimer's disease-current status and future directions.Journal of Medicinal Food,2017,20(12):1141-1151.
[3]WALKER D,LUE LF.Anti-inflammatory and immune therapy for Alzheimer's disease:current status and future directions.Current Neuropharmacology,2007,5(4):232-243.
[4]KITANO H.A robustness-based approach to systemsoriented drug design.Nature Reviews Drug Discovery,2007,6(3):202-210.
[5]QIANG WJ,CHEN Y,HE FY,et al.Molecular biological mechanisms of Yuan Zhi Powder in the treatment of Alzheimer's disease:an analysis based on network pharmacology.Digital Chinese Medicine,2018,1(01):90-101.
[6]SONG Z,YIN F,XIANG B,et al.Systems pharmacological approach to investigate the mechanism of Acori Tatarinowii Rhizoma for Alzheimer's disease.Evidencebased Complementary and Alternative Medicine,2018,2018:5194016.
[7]KAWAGISHI H,ANDO M,SAKAMOTO H,et al.Hericenones C,D and E,stimulators of nerve growth factor(NGF)-synthesis,from the mushroom Hericium erinaceum.Tetrahedron Letters,1991,32(35):4561-4564.
[8]KAWAGISHI H,ANDO M,SHINBA K,et al.Chromans,hericenones F,G and H from the mushroom Hericium erinaceum.Phytochemistry,1992,32(1):175-178.
[9]KAWAGISHI H,SHIMADA A,SHIRAI R,et al.Erinacines A,B and C,strong stimulators of nerve growth factor(NGF)-synthesis,from the mycelia of Hericium erinaceum.Tetrahedron Letters,1994,35(10):1569-1572.
[10]KAWAGISHI H,SHIMADA A,HOSOKAWA S,et al.Erinacines E,F,and G,stimulators of nerve growth factor(NGF)-synthesis,from the mycelia of Hericium erinaceum.Tetrahedron Letters,1996,37(41):7399-7402.
[11]LEE E W,SHIZUKI K,HOSOKAWA S,et al.Two novel diterpenoids,erinacines H and I from the mycelia of Hericium erinaceum.Bioscience,Biotechnology,and Biochemistry,2000,64(11):2402-2405.
[12]FANG J,LIU C,WANG Q,et al.In silico polypharmacology of natural products.Briefings in Bioinformatics,2017,19(6):1153-1171.
[13]KEISER MJ,ROTH BL,ARMBRUSTER BN,et al.Relating protein pharmacology by ligand chemistry.Nature Biotechnology,2007,25(2):197-206.
[14]WU CH,APWEILER R,BAIROCH A,et al.The Universal Protein Resource(UniProt):an expanding universe of protein information.Nucleic Acids Research,2006,34(Database issue):D187-191.
[15]ALTMAN RB.PharmGKB:a logical home for knowledge relating genotype to drug response phenotype.Nature Genetic,2007,39(4):426.
[16]ZHU F,HAN B,KUMAR P,et al.Update of TTD:Therapeutic Target Database.Nucleic Acids Research,2010,38(Database issue):D787-791.
[17]DAVIS AP,GRONDIN CJ,JOHNSON RJ,et al.The Comparative Toxicogenomics Database:update 2019.Nucleic Acids Research,2019,47(D1):D948-948D954.
[18]PI?ERO J,BRAVOà,QUERALT-ROSINACH N,et al.DisGeNET:a comprehensive platform integrating information on human disease-associated genes and variants.Nucleic Acids Research,2017,45(D1):D833-833D839.
[19]SHANNON P,MARKIEL A,OZIER O,et al.Cytoscape:a software environment for integrated models of biomolecular interaction networks.Genome Research,2003,13(11):2498-2504.
[20]ASHBURNER M,BALL CA,BLAKE JA,et al.Gene ontology:tool for the unification of biology.Nature Genetics,2000,25(1):25-29.
[21]LIU JH,LI L,SHANG XD,et al.Anti-Helicobacter pylori activity of bioactive components isolated from Hericium erinaceus.Journal of Ethnopharmacology,2016,183:54-58.
[22]DILING C,TIANQIAO Y,JIAN Y,et al.Docking studies and biological evaluation of a potentialβ-secretase inhibitor of 3-Hydroxyhericenone F from Hericium erinaceus.Frontiers in Pharmacology,2017,8:219.
[23]KOBAYASHI S,TAMANOI H,HASEGAWA Y,et al.Divergent synthesis of bioactive resorcinols isolated from the fruiting bodies of Hericium erinaceum:total syntheses of hericenones A,B,and I,hericenols B-D,and erinacerins A and B.Journal of Organic Chemistry,2014,79(11):5227-5238.
[24]TZENG TT,CHEN CC,LEE LY,et al.Erinacine A-enriched Hericium erinaceus mycelium ameliorates Alzheimer's disease-related pathologies in APPswe/PS1dE9 transgenic mice.Journal of Biomedical Science,2016,23(1):49.
[25]LI IC,CHEN WP,CHEN YP,et al.Acute and developmental toxicity assessment of erincine A-enriched Hericium erinaceus mycelia in Sprague-Dawley rats.Drug and Chemical Toxicology,2018,41(4):459-464.
[26]WOLTERS N,SCHEMBECKER G,MERZ J.Erinacine C:Anovel approach to produce the secondary metabolite by submerged cultivation of Hericium erinaceus.Fungal Biology,2015,119(12):1334-1344.
[27]ZHOU LJ,MO YB,BU X,et al.Erinacine facilitates the opening of the mitochondrial permeability transition pore through the inhibition of the PI3K/Akt/GSK-3βsignaling pathway in human hepatocellular carcinoma.Cellular Physiology and Biochemistry,2018,50(3):851-867.
[28]CHEN CC,TZENG TT,CHEN CC,et al.Erinacine S,a rare sesterterpene from the mycelia of Hericium erinaceus.Journal of Natural Products,2016,79(2):438-441.
[29]KHAN MA,TANIA M,LIU R,et al.Hericium erinaceus:an edible mushroom with medicinal values.Journal of Complementary and Integrative Medicine,2013,10(1):1-6.
[30]YU H,CHEN J,XU X,et al.A systematic prediction of multiple drug-target interactions from chemical,genomic,and pharmacological data.PLoS One,2012,7(5):e37608.
[31]JEONG H,MASON SP,BARABáSI AL,et al.Lethality and centrality in protein networks.Nature,2001,411(6833):41-42.
[32]LIU J,JIANG M,LI Z,et al.A novel systems pharmacology method to investigate molecular mechanisms of Scutellaria barbata D.Don for non-small cell lung cancer.Frontiers in Pharmacology,2018,9:1473.
[33]NIEDERER S,SHER A.Quantitative systems pharmacology:modelling and simulating drug action in health and disease.Progress in Biophysics&Molecular Biology,2018,139:1-2.
[34]GLASS CK,SAIJO K.Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells.Nature Reviews Immunology,2010,10(5):365-376.
[35]VOLPATO D,HOLZGRABE U.Designing hybrids targeting the cholinergic system by modulating the muscarinic and nicotinic receptors:a concept to treat Alzheimer's disease.Molecules,2018,23(12):3230.
[36]FERREIRA-VIEIRA TH,GUIMARAES IM,SILVA FR,et al.Alzheimer's disease:targeting the cholinergic system.Current Neuropharmacology,2016,14(1):101-115.
[37]KAMKWALALA AR,NEWHOUSE PA.Beyond Acetylcholinesterase inhibitors:novel cholinergic treatments for Alzheimer's disease.Current Alzheimer Research,2017,14(4):377-392.
[38]HUANG C,ZHENG C,LI Y,et al.Systems pharmacology in drug discovery and therapeutic insight for herbal medicines.Briefings in Bioinformatics,2014,15(5):710-733.