Chinese Journal of Tissue Engineering Research ›› 2020, Vol. 24 ›› Issue (35): 5638-5643.doi: 10.3969/j.issn.2095-4344.2875
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Fan Yinuo1, Chen Minghai1, Li Weifeng1, Chen Lixin1, Wei Qiushi2, He Wei2, Chen Zhenqiu2
1First Clinical School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China; 2First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China
Received:
2020-01-04
Revised:
2020-01-05
Accepted:
2020-02-26
Online:
2020-12-18
Published:
2020-10-17
Contact:
Chen Zhenqiu, MD, Professor, Master’s supervisor, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China
About author:
Fan Yinuo, Master candidate, First Clinical School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China
Supported by:
CLC Number:
Fan Yinuo, Chen Minghai, Li Weifeng, Chen Lixin, Wei Qiushi, He Wei, Chen Zhenqiu. Mechanism of Qutan Zhuyu Decoction for osteonecrosis of the femoral head based on network pharmacology[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(35): 5638-5643.
2.2 祛痰逐瘀方治疗股骨头坏死潜在靶点的预测 通过TCMSP平台数据库检索得到OB>30%和DL>0.18的中药活性成分,并利用TCMSP平台获得这些活性成分对应的靶点基因,去除无效和重复的靶点后,共得到祛痰逐瘀方中活性成分靶点基因共124个。以Femur Head Necrosis为检索词,利用Genecard数据库平台,以筛选出股骨头坏死疾病的潜在作用靶点共1 357个;利用OMIM数据库平台得到股骨头坏死疾病的潜在作用靶点共101个。利用R语言绘制韦恩图(图1),得到疾病和中药活性成分的共同基因靶点61个,如NCOA2,PTGS1,ESR1,RELA,BCL2,CASP3,LDLR,PPARG,APOB,SREBF1等。提示祛痰逐瘀方主要作用于这些潜在靶点发挥治疗股骨头坏死的作用。 "
2.3 活性成分靶点-疾病靶点网络图的构建 祛痰逐瘀方治疗股骨头坏死相关的中药活性成分共34个,前10个为sitosterol,naringenin,5,7-dihydroxy-2-(3-hydroxy-4- methoxyphenyl)chroman-4-one,Citromitin,nobiletin,Cavidine,baicalein,beta-sitosterol,Stigmasterol,gondoic acid。将中药活性成分和二者的共同基因靶点导入Cytoscape软件进行可视化分析(图2)。其中八边形代表祛痰逐瘀方,菱形代表疾病,三角形代表中药活性成分,椭圆代表基因靶点。结果显示祛痰逐瘀方-股骨头坏死中连接度为靠前的活性分子为quercetin,baicalein,kaempferol,luteolin,nobiletin,beta-sitosterol,beta-carotene,naringenin,coniferin(最少者对应6个基因靶点,最高者对应42个基因靶点)。祛痰逐瘀方作用于股骨头坏死的相关靶基因共61个,其中连接度较多的关键靶点基因为NCOA2,CHRM3,PTGS1,CASP3,BCL2,AR,PPARG,CASP8。以上成分以及基因靶点是祛痰逐瘀方治疗股骨头坏死的重要活性成分和关键基因靶点,在祛痰逐瘀方治疗股骨头坏死中具有重要意义。 "
2.5 GO富集分析和KEGG通路分析 GO富集分析得到84个GO条目,列举生物学功能排名较靠前的20个条目(图5),主要为近端启动子序列特异性DNA结合(共14个靶点:NCOA2,ESR1,RELA,PPARG,SREBF1,AR,ESR2,HIF1A,FOSL1,AHRMYC,RB1,RUNX2,IRF1)、DNA结合转录活性调控(共13个靶点:ESR1,RELA,SREBF1,AR,RXRB,FOS,HIF1A,FOSL, MYC,NR1I3,PARP1,RUNX2,IRF1)、RNA聚合酶II近端启动子序列特异性DNA结合(共13个靶点:NCOA2,ESR1,RELA,PPARG,SREBF1,AR,ESR2,HIF1A,FOSL1,AHR,MYC,IRF1,RUNX2)、蛋白质异二聚化(共13个靶点:RELA,BCL2,PPARG,VEGFA,FOS,HIF1A,AHR,CAV1,CTNNB1,IKBKB,EGFR,RAF1,ERBB3)、染色质结合(共12个靶点:NCOA2,ESR1,RELA,PPARG,SREBF1,NCOA1,AR,FOS,CTNNB1,EGFR,PCNA,RUNX2)、泛素蛋白连接酶结合(共11个靶点RELA,BCL2,GSK3,HIF1A,CASP8,NFKBIA,MDM2,CHEK2,ERBB3)等多个生物学功能。表明祛痰逐瘀方可以通过参与多种生物学过程来发挥治疗股骨头坏死的作用。 "
KEGG通路富集分析得到120条信号通路(P < 0.05),列举排名较靠前的20个条目(图6),主要为甲状腺激素信号通路、白细胞介素17(IL-17)信号通路、内分泌抵抗、AGE-RAGE信号通路、细胞凋亡、缺氧诱导因子1(HIF-1)信号通路、PI3K-Akt信号通路等,除柱状图、点状图列出的通路外,还有血管内皮生长因子(VEGF)信号通路、p53信号通路、Th17细胞分化、TNF信号通路、细胞衰老、MAPK信号通路、Wnt信号通路、mTOR信号通路等值得关注。PI3K-Akt信号通路是KEGG通路富集分析中与股骨头坏死相关的分值最高、靶点最多的通路,以祛痰逐瘀方参与PI3K-Akt信号通路为例(图7),标记靶点代表祛痰逐瘀方中活性成分的关键基因靶点在PI3K-Akt信号通路中所参与的过程,这些基因靶点在PI3K-Akt信号通路中起着关键作用。这些表明祛痰逐瘀方可以通过参与多种通路协调发挥治疗股骨头坏死的作用,提示这些关键通路可以作为研究祛痰逐瘀方治疗股骨头坏死的方向。 "
KEGG通路富集分析得到120条信号通路(P < 0.05),列举排名较靠前的20个条目(图6),主要为甲状腺激素信号通路、白细胞介素17(IL-17)信号通路、内分泌抵抗、AGE-RAGE信号通路、细胞凋亡、缺氧诱导因子1(HIF-1)信号通路、PI3K-Akt信号通路等,除柱状图、点状图列出的通路外,还有血管内皮生长因子(VEGF)信号通路、p53信号通路、Th17细胞分化、TNF信号通路、细胞衰老、MAPK信号通路、Wnt信号通路、mTOR信号通路等值得关注。PI3K-Akt信号通路是KEGG通路富集分析中与股骨头坏死相关的分值最高、靶点最多的通路,以祛痰逐瘀方参与PI3K-Akt信号通路为例(图7),标记靶点代表祛痰逐瘀方中活性成分的关键基因靶点在PI3K-Akt信号通路中所参与的过程,这些基因靶点在PI3K-Akt信号通路中起着关键作用。这些表明祛痰逐瘀方可以通过参与多种通路协调发挥治疗股骨头坏死的作用,提示这些关键通路可以作为研究祛痰逐瘀方治疗股骨头坏死的方向。 "
[1] CHUGHTAI M, PIUZZI NS, KHLOPAS A, et al. An evidence-based guide to the treatment of osteonecrosis of the femoral head.Bone Joint J.2017;99-B(10):1267-1279.
[2] COHEN-ROSENBLUM A, CUI QJ. Osteonecrosis of the Femoral Head. Orthop Clin North Am. 2019;50(2):139-149.
[3] GAUTIER E, GANZ K, KRUGEL N, et al. Anatomy of the medial femoral circumflex artery and its surgical implications.J Bone Joint Surg.2000;82-B:679-683.
[4] LIU F, WANG W, YANG L, et al. An epidemiological study of etiology and clinical characteristics in patients with nontraumatic osteonecrosis of the femoral head.J Res Med Sci. 2017;22:15.
[5] TRIPATHY SK, GOYAL T, SEN RK. Management of femoral head osteonecrosis: Current concepts.Indian J Orthop.2015;49(1): 28-45.
[6] MOYA-ANGELER J, GIANAKOS A, VILLA J, et al. Current concepts on osteonecrosis of the femoral head.World World J Orthop. 2015;6(8):590-601.
[7] CHUGHTAI M, PIUZZI N, KHLOPAS A, et al. An evidence-based guide to the treatment of osteonecros is of the femoral head.Bone Joint J. 2017;99-B(10):1267-1279.
[8] MONT M, CHERIAN J, SIERRA R, et al. Nontraumatic osteonecrosis of the femoral head: Where dowe stand today? A ten-year update.J Bone Joint Surg Am. 2015;97(19):1604-1627.
[9] KOO K, KIM R, KO G, et al. Preventing collapse in early osteonecrosis of the femoral head. A randomised clinical trial of core decompression.J Bone Joint Surg Br. 1995;77(6):870-874.
[10] WRIGHT J, EINHORN T, HECKMAN J. Grades of recommendation.J Bone Joint Surg Am. 2005;87(9):1909-1910.
[11] WANG W, YU J, TAO X. Systemic lupus erythematosus complicated with femoral head ischemic necrosis treated by Chinese medicine therapy for activating blood and dredging collaterals method.Chin J Integr Med. 2011;17(2):105-110.
[12] LI C, SHEN L, YANG Y, et al.Effects of Modified Qing'e Pill on the expression of adiponectin, bone morphogenetic protein 2 and coagulation-related factors in patients with nontraumatic osteonecrosis of the femoral head.Chin J Integr Med. 2017;23(3): 183-189. [13] 李泰贤,陈志伟,薛志鹏,等.中老年股骨头坏死患者中医证候特点[J].中华中医药杂志,2019,34(4):1414-1418.
[14] 何伟.中西医结合骨伤科学[M].广州:广东高等教育出版社,2007-464.
[15] 包永生,谢文英,王俊月.二陈汤研究进展[J].中国实验方剂学杂志, 2019,25(23):9-18.
[16] 张东龙.桃红四物汤临床应用研究进展[J].辽宁中医药大学学报, 2014,16(11):217-219.
[17] 陈晓波,陈雷雷,洪郭驹,等.桃红四物汤对激素性股骨头坏死兔股骨头微结构的影响及其机制[J].山东医药,2017,57(32):5-9.
[18] 陈镇秋,何伟,魏秋实.“痰瘀同治”对酒精性股骨头坏死患者血液流变学及血脂水平的影响[J].中华中医药杂志,2012,27(1):246-248.
[19] 吴俊颖,张璐,谢铱子,等.基于网络药理学研究温胆汤治疗冠心病的作用机制[J].中国药房,2018,29(23):3227-3232.
[20] 赵炳聪,李亚鸿,解红霞.网络药理学在中药复方作用机制研究中的应用[J].中国中医药信息杂志,2020,27(3):133-136.
[21] 李晨睿,孟志远,牛银波,等.黄芩苷通过Wnt/β-catenin信号通路对大鼠骨髓间充质干细胞成骨分化的促进作用[J].中国药理学通报, 2015,31(7) :919-924.
[22] 刘彬,舒欣,葛怡坤,等.野黄芩苷对大鼠成骨细胞OPG、RANKL表达的影响[J].临床口腔医学杂志, 2017,33 (1):7-10.
[23] 宋红梅,魏迎辰,吴斌,等.温阳补肾方对兔激素性股骨头坏死组织RANKL/RANK/OPG通路的影响[J].中华中医药杂志,2016,31(1) : 302-305.
[24] 韦艳,陆艳玲,王荣荣,等.槲皮素对缺氧人肝癌细胞HepG2增殖及HIF-1α、VEGF的影响[J].武警医学, 2018,29(2):134-137.
[25] 肖洁,尹松梅,谢双锋,等.槲皮素调控AMPK活性诱导HL-60细胞自噬与凋亡[J].中山大学学报(医学科学版),2018,39 (4) :501-509.
[26] WYLES CC, PARADISE CR, HOUDEK MT, et al. CORR® ORS Richard A. Brand Award: Disruption in Peroxisome Proliferator- Activated Receptor-γ (PPARG) Increases Osteonecrosis Risk Through Genetic Variance and Pharmacologic Modulation.Clin Orthop Relat Res.2019;477(8):1800-1812.
[27] SONG Y, DU Z, REN M, et al. Association of gene variants of transcription factors PPARγ, RUNX2, Osterix genes and COL2A1, IGFBP3 genes with the development of osteonecrosis of the femoral head in Chinese population.Bone.2017;101:104-112.
[28] ZOU D, ZHANG K, YANG Y, et al. Th17 and IL-17 exhibit higher levels in osteonecrosis of the femoral head and have a positive correlation with severity of pain.Endokrynol Pol.2018;69(3): 283-290.
[29] 马剑雄,何伟伟,赵杰,等.股骨头坏死发病机制研究的最新进展[J].中国组织工程研究,2017,21(27):4397-4402.
[30] WHITE AP, VACCARO AR, HALL JA, et al. Clinical applications of BMP-7/OP-1 in fractures, nonunions and spinal fusion.Int Orthop. 2007;31:735-741.
[31] CAO QS, ZHANG T, ZHANG J. Correlation analysis of STAT3 and VEGF expression and eosinophil infiltration in nasal polyps.Eur Arch Otorhinolaryngol.2015;272:1955–1960.
[32] DAILIANA ZH, STEFANOU N, KHALDI L, et al. Vascular endothelial growth factor for the treatment of femoral head osteonecrosis: An experimental study in canines.World J Orthop. 2018;9(9):120-129.
[33] 王钰钢,范启明,汤亭亭.AMPK信号通路对骨代谢的调节作用[J].中国骨质疏松杂志,2014,20(3):322-326.
[34] ZHANG C, ZOU YL, MA J, et al. Apoptosis associated with Wnt/ β-catenin pathway leads to steroid-induced avascular necrosis of femoral head.BMC Musculoskelet.Disord.2015;16:132.
[35] 刘艳玲,李方兵,赵曦.Wnt信号通路在成骨细胞中的作用:成骨还是破骨?[J].中国组织工程研究,2014,18(33):5366-5371. [36] 宋世雷,陈跃平,章晓云.PI3K/AKT信号通路调控股骨头坏死的相关机制[J].中国组织工程研究,2020,24(3):408-415. |
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