基于网络药理学探讨骨碎补治疗骨质疏松症的作用机制
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摘要
目的:探讨骨碎补治疗骨质疏松(OP)的作用机制。方法:采用中药系统药理学成分分析平台(BATMAN-TCM)数据库获得骨碎补的活性化合物及其作用靶点,再通过GeneCards数据库获得相关化合物靶点,取两者交集得到骨碎补作用靶点。通过TTD、DrugBank、OMIM、GAD、PharmGKB、CTD数据库获得OP疾病相关靶点,与骨碎补作用靶点取交集后获得骨碎补-OP疾病交集靶点。运用STRING在线数据库构建蛋白相互作用(PPI)网络,再通过Cytoscape 3.6.1软件进行分析获得关键靶点,并进行可视化展示。借助DAVID在线工具进行交集靶点的基因本体论(GO)分析。通过在线分析工具KOBAS进行KEGG通路富集分析,筛选出显著富集的通路(P<0.05)。通过MCC算法进行关键基因的筛选。结果:共获得骨碎补活性化合物7个,骨碎补-OP疾病交集靶点136个。GO分析结果显示,上述交集靶点的生物途径主要包括化学反应、类固醇代谢过程、细胞对化学刺激的应答等;细胞组分主要包括细胞外间隙、胞外区部分、细胞质等;分子功能主要有血红素结合、四吡咯结合、单氧酶活性等。KEGG通路富集结果显示,上述靶点主要与骨代谢、内分泌、炎症、肿瘤、细胞凋亡等信号通路相关。通过MCC算法筛选得到关键基因30个,包括ALB、AKT1、JUN等(P≤1.96×10~(-9))。结论:骨碎补治疗OP的作用机制呈多靶点、多系统的特性,除了影响骨代谢相关途径还可影响体内多种代谢途径。
OBJECTIVE: To investigate the mechanism of Drynariae rhizoma in the treatment of osteoporosis(OP).METHODS:The active compounds and targets of D. rhizoma were obtained by using Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine(BATMAN-TCM database). The targets of relevant compounds were also obtained by GeneCards database,and targets of D. rhizoma were obtained by the combination of the two. The disease targets corresponding toOP were obtained by using TTD, DrugBank, OMIM, GAD, PharmGKB and CTD database. The D. rhizoma-OP disease intersection targets were obtained after intersecting with the target of D. rhizoma. PPI network was constructed by STRING online database,analyzed by using Cytoscape 3.6.1 software to obtain key targets and showed by network visualization. Gene ontology(GO)analysis of drug-disease intersection target were conducted by DAVID online tools. KEGG pathway enrichment analysis was conducted by KOBAS online tools to screen the significant enrichment pathway(P<0.05). The key genes were screened by MCC algorithm. RESULTS:There were 7 active compounds of D. rhizoma 136 intersection targets of D. rhizoma-OP disease. GO analysis results showed that the biological function of intersection target mainly included chemical reaction,steroid metabolic process as well as cellular response to chemical stimulus and so on; cell composition mainly included extracellular space,extracellular area and cytoplasm;molecular functions included heme binding,tetrapyrrole binding and monooxygenase activity,etc.KEGG pathway enrichment showed that above targets were mainly related to bone metabolism,endocrinology,inflammation,tumor,apoptosis,etc. Thirty key genes(such as ALB,AKT1,JUN,etc.,P≤1.96 × 10~(-9)) were screened by MCC algorithm.CONCLUSIONS:The mechanism of action of D. rhizoma in the treatment of OP is in multi-target and multi-system manner. In addition to influencing the related pathways of bone metabolism,it can also affect various metabolic pathways in vivo.
OBJECTIVE: To investigate the mechanism of Drynariae rhizoma in the treatment of osteoporosis(OP).METHODS:The active compounds and targets of D. rhizoma were obtained by using Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine(BATMAN-TCM database). The targets of relevant compounds were also obtained by GeneCards database,and targets of D. rhizoma were obtained by the combination of the two. The disease targets corresponding toOP were obtained by using TTD, DrugBank, OMIM, GAD, PharmGKB and CTD database. The D. rhizoma-OP disease intersection targets were obtained after intersecting with the target of D. rhizoma. PPI network was constructed by STRING online database,analyzed by using Cytoscape 3.6.1 software to obtain key targets and showed by network visualization. Gene ontology(GO)analysis of drug-disease intersection target were conducted by DAVID online tools. KEGG pathway enrichment analysis was conducted by KOBAS online tools to screen the significant enrichment pathway(P<0.05). The key genes were screened by MCC algorithm. RESULTS:There were 7 active compounds of D. rhizoma 136 intersection targets of D. rhizoma-OP disease. GO analysis results showed that the biological function of intersection target mainly included chemical reaction,steroid metabolic process as well as cellular response to chemical stimulus and so on; cell composition mainly included extracellular space,extracellular area and cytoplasm;molecular functions included heme binding,tetrapyrrole binding and monooxygenase activity,etc.KEGG pathway enrichment showed that above targets were mainly related to bone metabolism,endocrinology,inflammation,tumor,apoptosis,etc. Thirty key genes(such as ALB,AKT1,JUN,etc.,P≤1.96 × 10~(-9)) were screened by MCC algorithm.CONCLUSIONS:The mechanism of action of D. rhizoma in the treatment of OP is in multi-target and multi-system manner. In addition to influencing the related pathways of bone metabolism,it can also affect various metabolic pathways in vivo.
引文
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[30]YU H,JIANG L,WAN B,et al.The role of aryl hydrocarbon receptor in bone remodeling[J].Prog Biophys Mol Biol,2018.DOI:10.1016/j.pbiomolbio.2017.12.005.
[31]KIM WK,MELITON V,BOURQUARD N,et al.Hedgehog signaling and osteogenic differentiation in multipotent bone marrow stromal cells are inhibited by oxidative stress[J].J Cell Biochem,2010,111(5):1199-1209.
[32]CAI JQ,HUANG YZ,CHEN XH,et al.Sonic hedgehog enhances the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells[J].Cell Biol Int,2012,36(4):349-355.
[2]汪呈,曹宇,顾永清,等.骨质疏松治疗药物的研究进展[J].科学通报,2014,59(13):1209-1214.
[3]张智海,刘忠厚,李娜,等.中国人骨质疏松症诊断标准专家共识:第三稿:2014版[J].中国骨质疏松杂志,2014,20(9):1007-1010.
[4]郭鱼波,王丽丽,马如风,等.骨质疏松的中医病因病机分析及其中医药治疗的前景探讨[J].世界科学技术:中医药现代化,2015,17(4):768-772.
[5]丁小刚,覃勇,鄂建设,等.骨碎补总黄酮对老年性骨质疏松症患者血清骨钙素水平及骨密度影响[J].中国骨质疏松杂志,2013,19(5):519-521.
[6]AGUAYO-OROZCO A,AUDOUZE K,BRUNAK S,et al.In silico systems pharmacology to assess drug’s therapeutic and toxic effects[J].Curr Pharm Des,2016,22(46):6895-6902.
[7]CHENG F,HONG H,YANG S,et al.Individualized network-based drug repositioning infrastructure for precision oncology in the panomics era[J].Brief Bioinform,2017,18(4):682-697.
[8]ZHANG W,BAI Y,WANG Y,et al.Polypharmacology in drug discovery:a review from systems pharmacology perspective[J].Curr Pharm Des,2016,22(21):3171-3181.
[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]STELZER G,ROSEN N,PLASCHKES I,et al.The genecards suite:from gene data mining to disease genome sequence analyses[J].Curr Protoc Bioinformatics,2016,54:1-30.
[11]SHANNON P,MARKIEL A,OZIER O,et al.Cytoscape:a software environment for integrated models of biomolecular interaction networks[J].Genome Res,2003,13(11):2498-2504.
[12]MARTUCCI D,MASSEROLI M,PINCIROLI F.Gene ontology application to genomic functional annotation,statistical analysis and knowledge mining[J].Stud Health Technol Inform,2004,102:108-131.
[13]DENNIS G JR,SHERMAN BT,HOSACK DA,et al.DA-VID:database for annotation,visualization,and integrated discovery[J].Genome Biol,2003,4(9):R60.
[14]XIE C,MAO X,HUANG J,et al.KOBAS 2.0:a web server for annotation and identification of enriched pathways and diseases[J].Nucleic Acids Res,2011.DOI:10.1093/nar/gkr483.
[15]KANEHISA M,GOTO S.KEGG:kyoto encyclopedia of genes and genomes[J].Nucleic Acids Res,2000,28(1):27-30.
[16]KANEHISA M,FURUMICHI M,TANABE M,et al.KEGG:new perspectives on genomes,pathways,diseases and drugs[J].Nucleic Acids Res,2017,45(D1):D353-D361.
[17]邱冬妮,潘峰,谭希,等.基于网络药理学探讨补肾强督治偻方治疗强直性脊柱炎的作用机理[J].中医杂志,2018,59(2):151-155.
[18]CHIN CH,CHEN SH,WU HH,et al.cytoHubba:identifying hub objects and sub-networks from complex interactome[J].BMC Syst Biol,2014,8(Suppl 4):S11.
[19]李烨,童杰,周衍晶,等.补肾壮骨中药抗骨质疏松有效成分及其药理作用研究进展[J].中国中药杂志,2015,40(6):1038-1043.
[20]匡立华,贾庆运,谭国庆,等.骨碎补防治骨质疏松症的研究进展[J].中国骨质疏松杂志,2015,21(8):1000-1004.
[21]宋渊,李盛华,何志军.骨碎补含药血清对成骨细胞增殖、成骨的影响[J].中国骨质疏松杂志,2014,20(2):125-128.
[22]KAY AM,SIMPSON CL,STEWART JJ.The role of AGE/RAGE signaling in diabetes-mediated vascular calcification[J].J Diabetes Res,2016.DOI:10.1155/2016/6809703.
[23]KARNER CM,LONG F.Wnt signaling and cellular metabolism in osteoblasts[J].Cell Mol Life Sci,2017,74(9):1649-1657.
[24]ZENG HC,BAE Y,DAWSON BC,et al.MicroRNAmiR-23a cluster promotes osteocyte differentiation by regulating TGF-beta signalling in osteoblasts[J].Nat Commun,2017.DOI:10.1038/ncomms15000.
[25]QUERQUES F,CANTILENA B,COZZOLINO C,et al.Angiotensin receptorⅠstimulates osteoprogenitor proliferation through TGFbeta-mediated signaling[J].J Cell Physiol,2015,230(7):1466-1474.
[26]CHAKRAVORTY N,HAMLET S,JAIPRAKASH A,et al.Pro-osteogenic topographical cues promote early activation of osteoprogenitor differentiation via enhanced TGF-beta,Wnt,and Notch signaling[J].Clin Oral Implants Res,2014,25(4):475-486.
[27]XU L,KONG Q.Research progress of key signaling pathways in osteoblast differentiation and bone formation regulation[J].Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi,2014,28(12):1484-1489.
[28]DENG ZL,SHARFF KA,TANG N,et al.Regulation of osteogenic differentiation during skeletal development[J].Front Biosci,2008,13:2001-2021.
[29]WANG C,INZANA JA,MIRANDO AJ,et al.NOTCHsignaling in skeletal progenitors is critical for fracture repair[J].J Clin Invest,2016,126(4):1471-1481.
[30]YU H,JIANG L,WAN B,et al.The role of aryl hydrocarbon receptor in bone remodeling[J].Prog Biophys Mol Biol,2018.DOI:10.1016/j.pbiomolbio.2017.12.005.
[31]KIM WK,MELITON V,BOURQUARD N,et al.Hedgehog signaling and osteogenic differentiation in multipotent bone marrow stromal cells are inhibited by oxidative stress[J].J Cell Biochem,2010,111(5):1199-1209.
[32]CAI JQ,HUANG YZ,CHEN XH,et al.Sonic hedgehog enhances the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells[J].Cell Biol Int,2012,36(4):349-355.