Molecular targets and mechanism of Bushen Huoxue Decoction in treating osteonecrosis of the femoral head: an analysis based on network pharmacology and protein module

doi:10.3969/j.issn.2095-4344.3914

Abstract

Abstract: BACKGROUND: Studies have shown that Bushen Huoxue Decoction has a very active role in treating osteonecrosis of the femoral head (ONFH), but the chemical ingredients contained in the compound are more complicated. The action mechanism and pharmacological mechanism of the compound underlying the treatment of ONFH at the molecular level are not yet clear. Therefore, network pharmacology and protein module analyses are used to explain the potential active ingredients and molecular mechanism of Bushen Huoxue Decoction, and provide a certain theoretical basis for the later development of new drugs and better clinical application in the treatment of ONFH.
OBJECTIVE: Through network pharmacology and protein module analysis to explore the molecular targets and mechanisms of Bushen Huoxue Decoction in the treatment of ONFH.
METHODS: The compounds and their targets in Carthamus tinctorius, Angelica sinensis, Cistanche deserticola, Cornus officinalis, Chinese wolfberry, dodder, Radix Rehmanniae, Eucommia ulmoides, myrrh, Fructus psoraleae and Fructus psoraleae in Bushen Huoxue Decoction were searched by TCMSP and TCMID databases, and the related targets of ONFH were predicted by GeneCards and CTD databases. The drug-meridian-compound-target network was constructed by Cytoscape3.7.2, the protein-protein interaction network was constructed and analyzed by STRING database, and the key protein modules were analyzed by Metascape database. Gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were carried out by using DAVID database.
RESULTS AND CONCLUSION: A total of 167 active components and 151 action targets of Bushen Huoxue Decoction were screened, with peroxisome proliferator-activated receptor, vascular endothelial growth factor A, tumor necrosis factor and epidermal growth factor receptor as key targets. There were 8 817 related targets of ONFH, 128 proteins in the protein-protein interaction core network, and 5 protein modules. A total of 289 GO biological processes were obtained, and 110 related signal pathways were obtained by enrichment and screening of KEGG pathway, including estrogen, phosphoinositide-3 kinase/protein kinase, cyclic adenosine phosphate, Wnt signaling, tumor necrosis factor and mitogen-activated protein kinase. These pathways were associated with the occurrence and development of ONFH. The results show that Bushen Huoxue Decoction may treat ONFH by regulating cell metabolism, proliferation and apoptosis, lipid metabolism and promoting angiogenesis, which is the result of the interaction of multi-components, multi-targets and multi-pathways.

Key words: bone, femur, traditional Chinese medicine, network pharmacology, protein, factor, target, pathway, mechanism

CLC Number:

Liu Yuan, Liu Jinbao, Xu Bo, Zhang Jingzhou, Li Gang. Molecular targets and mechanism of Bushen Huoxue Decoction in treating osteonecrosis of the femoral head: an analysis based on network pharmacology and protein module[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(17): 2703-2710.

Figures/Tables 9

References

[1] 虹霖,侯德才,魏波,等.基于筋骨并重理论中医内治法联合髓芯减压+人工骨植骨术治疗股骨头缺血性坏死[J].长春中医药大学学报,2020,36(2):402-405.
[2] 李盛华,邓昶,周明旺,等.中医药防治股骨头坏死临床应用现状[J].中国中医药信息杂志,2018,25(6):137-140.
[3] 曾宪峰,王进东,梁鼎天,等.补肾活血汤联合西医治疗早中期非创伤性股骨头缺血坏死(肾虚血瘀)随机平行对照研究[J].实用中医内科杂志,2019,33(5):38-41.
[4] 滕加文.补肾活血汤治疗股骨头缺血性坏死45例[J].山东中医药大学学报,2011 ,35(1):36-37.
[5] 张翔,吴泱,董晓俊,等.补肾活血方调控兔激素性股骨头坏死APN-AMPK信号通路的实验研究[J].中国中西医结合杂志,2019,39(10):1234-1239.
[6] LIU JF, HU AN, ZAN JF, et al. Network pharmacology deciphering mechanisms of volatiles of granule for the treatment of Alzheimer’s disease. Evid Based Complement Alternat Med. 2019;2019: 7826769.
[7] NIU B, ZHANG H, LI C, et al. Network pharmacology study on the active components of and the mechanism of their effect against cerebral ischemia. Drug Des Devel Ther. 2019;13:3009-3019.
[8] 宗阳,丁美林,贾可可,等.基于网络药理学和分子对接法探寻达原饮治疗新型冠状病毒肺炎(COVID-19)活性化合物的研究[J].中草药,2020,51(4):836-844.
[9] URSU O, RAYAN A, GOLDBLUM A, et al. Understanding drug-likeness. Wires Comput Mol Sci. 2011;1(5):760-781.
[10] UNIPROT CONSORTIUM T. UniProt: the universal protein knowledgebase. Nucleic Acids Res. 2018;46(5):2699.
[11] 《中华人民共和国药典》中药材名称与中药饮片名称对照表[J].西部中医药, 2017,30(03):21, 50.
[12] STELZER G, ROSEN N, PLASCHKES I, et al. The Genecards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinformatics. 2016;54:1.30.1-1.30.33.
[13] DAVIS AP, GRONDIN CJ, JOHNSON RJ, et al. The Comparative Toxicogenomics Database: update 2019. Nucleic Acids Res. 2019;47(D1):D948-D954.
[14] SZKLARCZYK D, GABLE AL, LYON D, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607-D613.
[15] BADER GD. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics. 2003;4:2.
[16] ZHOU Y, ZHOU B, PACHE L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523.
[17] HUANG DA W, SHERMAN BT. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44-57.
[18] 韦明照,李宏宇.股骨头缺血性坏死基因治疗的研究进展[J].中国临床新医学, 2020,13(3):305-309.
[19] 卞伟,杨丽,孙宏,等.槲皮素对骨髓间充质干细胞增殖和骨向分化的影响[J].中药药理与临床,2016,32(5):27-30.
[20] 桂志鹏. 槲皮素对软骨细胞的生物学调控及其机理研究[D].上海:上海交通大学,2018.
[21] RAYALAM S, DELLA-FERA MA. Phytochemicals and regulation of the adipocyte life cycle. J Nutr Biochem. 2008; 19:717-726.
[22] 孙卉,滕浩,杜密英,等.槲皮素降脂减肥机制研究进展[J].食品工业科技,2019, 40(16):349-353,362.
[23] 周爱珍,王蕾,程斌.淫羊藿醇提工艺及醇提物对软骨细胞保护作用的研究[J].中国中药杂志,2020,45(5):1097-1104.
[24] 瞿晶田,王家龙,柴士伟,等.补骨脂素和补骨脂酚舒张血管的作用机制研究[J].中国药房,2019,30(24):3364-3368.
[25] 李洪波,魏云鹏,杨芳,等.补骨脂素对大鼠骨髓间充质干细胞成骨分化的影响[J].解剖科学进展,2020,26(1):18-21,26.
[26] MA W, XIN K, CHEN K, et al. Relationship of common variants in VEGFA gene with osteonecrosis of the femoral head: a Han Chinese population based association study. Sci Rep. 2018;8:16221.
[27] 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? Stem Cell Res Ther. 2019;10:5.
[28] BASAL O, ATAY T, CIRIS İM. Epidermal growth factor (EGF) promotes bone healing in surgically induced osteonecrosis of the femoral head (ONFH). Bosn J Basic Med Sci. 2018;18:352-360.
[29] 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;477:1800-1812.
[30] 温玉琴.研究揭示Wnt/β-连锁蛋白信号传导控制FOXC2表达的机制[J].广东药科大学学报,2018,34(5):553.
[31] 史东梅,董明,陆颖,等.PI3K/Akt信号通路与骨破坏:问题与机制[J].中国组织工程研究,2020,24(23):3716-3722.
[32] WU F, JIAO J, LIU F, et al. Hypermethylation of Frizzled1 is associated with Wnt/β-catenin signaling inactivation in mesenchymal stem cells of patients with steroid-associated osteonecrosis. Exp Mol Med. 2019;51:1-9.
[33] 李莉莉,钟佩茹.非创伤性股骨头坏死发病相关因素及信号通路机制的研究进展[J].医学综述,2018,24(1):22-27.
[34] HAN Y, SI M, ZHAO Y, et al. Progranulin protects against osteonecrosis of the femoral head by activating ERK1/2 pathway. Inflammation 2017;40:946-955.
[35] 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.