[1]张雪,徐彬,刘又文,等.基于网络药理学方法分析股骨头坏死愈胶囊治疗股骨头坏死的潜在靶点及作用机制[J].中医正骨,2022,34(01):1-7.
　ZHANG Xue,XU Bin,LIU Youwen,et al.Analysis of potential targets and mechanism of action of Gugutou Huaisiyu Capsule(股骨头坏死愈胶囊)for treatment of osteonecrosis of femoral head using network pharmacology approach[J].The Journal of Traditional Chinese Orthopedics and Traumatology,2022,34(01):1-7.
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基于网络药理学方法分析股骨头坏死愈胶囊治疗股骨头坏死的潜在靶点及作用机制()
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《中医正骨》[ISSN:1001-6015/CN:41-1162/R]

卷:
第34卷
期数:
2022年01期
页码:
1-7
栏目:
基础研究
出版日期:
2022-01-20

文章信息/Info

Title:
Analysis of potential targets and mechanism of action of Gugutou Huaisiyu Capsule(股骨头坏死愈胶囊)for treatment of osteonecrosis of femoral head using network pharmacology approach
作者:
张雪1; 徐彬2; 刘又文1; 李无阴1; 张虹1; 岳辰1
(1.河南省洛阳正骨医院/河南省骨科医院,河南 洛阳 471002; 2.浙江省立同德医院,浙江 杭州 310012)
Author(s):
ZHANG Xue1; XU Bin2; LIU Youwen1; LI Wuyin1; ZHANG Hong1; YUE Chen1
1.Luoyang Orthopedic-Traumatological Hospital,Luoyang 471002,Henan,China;2.Tongde Hospital of Zhejiang Province,Hangzhou 310012,Zhejiang,China
关键词:
股骨头坏死;  股骨头坏死愈胶囊;  网络药理学;  靶点;  药物作用机制
Keywords:
femur head necrosis;  Gugutouhuaisiyu capsule;  network pharmacology;  target;  mechanism of drug action
摘要:
目的:分析股骨头坏死愈胶囊治疗股骨头坏死(osteonecrosis of femoral head,ONFH)的潜在靶点及作用机制。方法:通过中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)和中医药百科全书(encyclopedia of traditional Chinese medicine,ETCM)数据库检索、筛选股骨头坏死愈胶囊的有效成分和靶点。在GeneCards数据库中检索ONFH相关基因,从GEO数据库下载包含ONFH基因数据的GSE74089数据集获取ONFH差异表达基因,并通过与已获取的股骨头坏死愈胶囊药物靶点基因取交集,筛选股骨头坏死愈胶囊治疗ONFH的关键靶点。利用Cytoscape软件、STRING数据库及已筛选出的股骨头坏死愈胶囊有效成分和关键靶点,构建药物-成分-靶点蛋白互作网络。利用R软件对筛选出的关键靶点基因进行GO功能富集分析和KEGG通路富集分析,挖掘关键靶点的生物学功能和通路信息。利用Cytoscape软件和STRING数据库构建关键靶点蛋白互作网络,筛选股骨头坏死愈胶囊治疗ONFH的核心靶点。结果:从TCMSP和ETCM数据库中共筛选出股骨头坏死愈胶囊的有效成分203个、靶点592个。在GeneCards数据库中检索到ONFH相关基因2033个,在GEO数据库GSE74089数据集获得ONFH差异表达基因8178个。将ONFH相关基因、ONFH差异表达基因及药物靶点基因取交集后,获得股骨头坏死愈胶囊治疗ONFH的关键靶点57个。构建的药物-成分-靶点蛋白互作网路包含200个节点和500条边,蛋白互作网络显示137个药物有效成分与57个关键靶点有对应关系。GO功能富集分析结果显示,关键靶点的基因功能主要涉及激素反应、氧供反应、免疫系统过程调节、骨细胞调节、骨小梁形成、骨重塑调节、骨化调节、软骨发育及骨合成过程等; KEGG信号通路富集分析结果显示,关键靶点的主要信号通路包括缺氧诱导因子1(hypoxia-inducible factor 1,HIF-1)信号通路、核转录因子-κB(nuclear factor-κB,NF-κB)信号通路、鞘脂信号通路、p53信号通路、钙信号通路、精氨酸和脯氨酸代谢信号通路。构建的关键靶点蛋白互作网络显示,肿瘤坏死因子(tumor necrosis factor,TNF)为具有最高度值的关键靶点,即核心靶点。结论:股骨头坏死愈胶囊治疗ONFH的潜在靶点为TNF,其作用机制可能为通过HIF-1、NF-κB、p53等信号通路,参与激素反应、氧供反应、免疫系统过程调节及骨形成调节等生物学过程。
Abstract:
Objective:To explore the potential targets and mechanism of action of Gugutou Huaisiyu Capsule(股骨头坏死愈胶囊,GHC)in treatment of osteonecrosis of femoral head(ONFH).Methods:The active ingredients and action targets of GHC were screened by retrieving Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and Encyclopedia of Traditional Chinese Medicine(ETCM).The ONFH-related genes were searched out from GeneCards database,and the ONFH-related differentially expressed genes(DEGs)were obtained from the microarray dataset GSE74089 downloaded from the Gene Expression Omnibus(GEO)database.The key targets of GHC for treatment of ONFH were selected through overlapping ONFH-related genes,ONFH-related DEGs with the obtained drug target genes of GHC.The drug-ingredient-target network was built by using Cytoscape software and STRING database based on the active ingredients and key targets of GHC.The GO function and KEGG pathway enrichment analysis were performed on key target genes respectively by using R software to dig biological functions and pathways of the key targets.The protein-protein interaction(PPI)network of the key targets was built by using Cytoscape software and STRING database for screening the core targets of GHC for treatment of ONFH.Results:Two hundred and three active ingredients and 592 targets of GHC were screened out from TCMSP and ETCM,and 2033 ONFH-related genes and 8178 ONFH-related DEGs were obtained from GeneCards and GEO database respectively.Fifty-seven key targets of GHC for treatment of ONFH were obtained through overlapping ONFH-related genes,ONFH-related DEGs with the drug target genes of GHC.The drug-ingredient-target network diagram consists of 200 nodes and 500 edges,and the PPI network illustrated the corresponding connections between 137 active ingredients and 57 key targets.The results of GO function enrichment analysis suggested that the key targets were mainly involved in the response to hormone,response to oxygen level,regulation of immune system process,regulation of osteocytes,bone trabecula morphogenesis,regulation of bone remodeling,regulation of ossification,cartilage development and osteogenesis.The results of KEGG signaling pathway enrichment analysis indicated that the key targets were mainly enriched in hypoxia-inducible factor 1(HIF-1),nuclear factor-κB(NF-κB),sphingolipid,p53,calcium,arginine and proline metabolism signaling pathways.The PPI network of the key targets demonstrated that the tumor necrosis factor(TNF)with the highest value acted as the core target.Conclusion:TNF is the potential target of GHC in treatment of ONFH.It may participate in the responses to hormones and oxygen level and the regulation of immune system process and ossification through the signaling pathways of HIF-1,NF-κB and p53.

参考文献/References:

[1] 魏秋实,何伟,张庆文,等.股骨头坏死中医证型分布规律的文献研究和系统评价[J].中华关节外科杂志(电子版),2013,7(3):369-372.
[2] 朱蜀云,杨康,王巍,等.股骨头坏死中医治法应用分析[J].中医正骨,2020,32(1):40-42.
[3] 谭旭仪,刘又文,高书图,等.股骨头坏死愈胶囊对股骨头坏死患者血液流变学的影响[J].中成药,2014,36(10):2227-2228.
[4] 刘又文,王玉辉,贾宇东,等.股骨头坏死愈胶囊对兔激素性股骨头坏死血清骨钙素与降钙素的影响[J].世界中西医结合杂志,2014,9(3):248-250.
[5] ZHANG R,ZHU X,BAI H,et al.Network pharmacology databases for traditional Chinese medicine:review and assessment[J].Front Pharmacol,2019,10:123.
[6] 夏天卫,李若颀,环大维,等.基于网络药理学方法探究补肾活血汤治疗激素性股骨头坏死的作用机制[J].中医正骨,2020,32(3):14-20.
[7] MUTIJIMA E,DE MAERTELAER V,DEPREZ M,et al.The apoptosis of osteoblasts and osteocytes in femoral head osteonecrosis:its specificity and its distribution[J].Clin Rheumatol,2014,33(12):1791-1795.
[8] LI D,HU Q,TAN G,et al.Erythropoietin enhances bone repair effects via the hypoxia-inducible factor signal pathway in glucocorticoid-induced osteonecrosis of the femoral head[J].Am J Med Sci,2018,355(6):597-606.
[9] ZUO G L,ZHANG L F,QI J,et al.Activation of HIFa pathway in mature osteoblasts disrupts the integrity of the osteocyte/canalicular network[J].PLoS One,2015,10(3):266.
[10] WU J,YAO L,WANG B,et al.Tao-Hong-Si-Wu decoction ameliorates steroid-induced avascular necrosis of the femoral head by regulating the HIF-1α pathway and cell apoptosis[J].Biosci Trends,2016,10(5):410-417.
[11] ZHANG Z,DAI F,CHENG P,et al.Pitavastatin attenuates monocyte activation in response to orthopedic implant-derived wear particles by suppressing the NF-κB signaling pathway[J].Mol Med Rep,2015,12(5):6932-6938.
[12] QU Y,LIU Y,LI R.FSTL1 promotes inflammatory reaction and cartilage catabolism through interplay with NFκB signaling pathways in an in vitro ONFH model[J].Inflammation,2019,42(4):1491-1503.
[13] PEI J,FAN L,NAN K,et al.Excessive activation of TLR4/NF-κB interactively suppresses the canonical Wnt/β-catenin pathway and induces SANFH in SD rats[J].Sci Rep,2017,7(1):11928.
[14] ZHANG F,PENG W,ZHANG J,et al.P53 and parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head[J].Cell Death Dis,2020,11(1):42.
[15] LIU Y,JIANG W,LIU S,et al.Combined effect of tnf-α polymorphisms and hypoxia on steroid-induced osteonecrosis of femoral head[J].Int J Clin Exp Pathol,2015,8(3):3215-3219.
[16] WANG L M,ZHAO N,ZHANG J,et al.Tumor necrosis factor-alpha inhibits osteogenic differentiation of pre-osteoblasts by downregulation of EphB4 signaling via activated nuclear factor-kappaB signaling pathway[J].J Periodontal Res,2018,53(1):66-72.
[17] SAMARA S,KOLLIA P,DAILIANA Z,et al.Predictive role of cytokine gene polymorphisms for the development of femoral head osteonecrosis[J].Dis Markers,2012,33(4):215-221.
[18] FANG B,WANG D,ZHENG J,et al.Involvement of tumor necrosis factor alpha in steroid-associated osteonecrosis of the femoral head:friend or foe?[J].Stem Cell Res Ther,2019,10(1):5.
[19] LI J K,CHENG L,ZHAO Y P,et al.ADAMTS-7 exhibits elevated expression in cartilage of osteonecrosis of femoral head and has a positive correlation with TNF-α and NF-κB P65[J/OL].Mediators Inflamm,2015[2021-04-01].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310498.
[20] PENG W,DONG W,ZHANG F,et al.Effects of transplantation of FGF-2-transfected MSCs and XACB on TNF-α expression with avascular necrosis of the femoral head in rabbits[J].Biosci Rep,2019,39(4):765.

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备注/Memo

备注/Memo:
基金项目:国家自然科学基金项目(82074472,81804126)
通讯作者:刘又文 E-mail:liuyouwen543@sina.com
更新日期/Last Update: 1900-01-01