Underlying targets and mechanism of Taohong Siwu Decoction in prosthetic joint infection on network pharmacology

doi:10.3969/j.issn.2095-4344.4012

Abstract

Abstract: BACKGROUND: Taohong Siwu Decoction has a good effect in the treatment of periprosthetic infection after joint replacement, and can improve the function of joint movement. However, most present studies focus on the antibacterial effect of single drug and its components in the prescription, and there is little research on the compound and other mechanisms.
OBJECTIVE: To explore the mechanism of Taohong Siwu Decoction in the treatment of periprosthetic joint infection.
METHODS: Ingredients and target genes of Semen Persicae, Carthami Flos, Rehmanniae Radix Praeparata, Paeoniae Radix Alba, Angelicae Sinensis Radixand and Chuanxiong Rhizoma were screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Periprosthetic joint infection-related target genes were obtained from the human gene database (GeneCards). Cytoscape3.7.2 was used for constructing a “Drug-Ingredient-Target-Disease” network. The key target genes were introduced into the STRING to construct protein-protein interaction network. We analyzed the mechanism by Kyoto Encyclopedia of Genes and Genomes and Gene Ontology biological enrichment analysis.
RESULTS AND CONCLUSION: (1) Totally 15 active components, such as quercetin, luteolin and kaempferol, were screened from Taohong Siwu Decoction, which acted on 34 key genes, such as vascular endothelial growth factor A, tumor necrosis factor, and interleukin-6. (2) Gene Ontology function enrichment showed that the biological process and function of Taohong Siwu Decoction were concentrated in positive regulation of biological process, response to chemical stimulus, response to stress, and regulation of apoptosis. (3) Kyoto Encyclopedia of Genes and Genomes pathway enrichment showed that the treatment of periprosthetic joint infection by Taohong Siwu Decoction mainly involved pathways in cancer, AGE-RAGE signaling pathway, fluid shear stress and atherosclerosis, inflammatory bowel disease and cytokine-cytokine receptor interaction pathway. (4) Through the study of network pharmacology, it is found that Taohong Siwu Decoction could treat periprosthetic joint infection by inhibiting bacterial growth and improving hemorheology, which provided a preliminary theoretical basis for the application of “activating circulation and removing blood stasis” in periprosthetic joint infection and a new idea for subsequent experiments.

Key words: joint replacement, prosthesis, traditional Chinese medicine, Taohong Siwu Decoction, periprosthetic infection, network pharmacology, signal pathway

CLC Number:

Yuan Jiawei, Zhang Haitao, Jie Ke, Cao Houran, Zeng Yirong. Underlying targets and mechanism of Taohong Siwu Decoction in prosthetic joint infection on network pharmacology[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(9): 1428-1433.

Figures/Tables 6

2.1 桃红四物汤活性成分和靶基因在 TCMSP 数据库检索关键词“桃仁”“红花”“熟地”“当归”“白芍”“川芎”分别得到 68，189，76，125，85，189个活性成分。再以 OB>30%和 DL>0.18 进行筛选，分别得到23，22，2，2，13，7个有效活性成分，并选择“Related Targets”，筛选药物有效活性成分所对应的靶基因，除外无法找到相关靶基因的药物活性成分后，分别得到桃仁139个靶基因、红花449个靶基因、熟地34个靶基因、当归65个靶基因、白芍123个靶基因、川芎42个靶基因。 2.2 假体周围感染相关基因在 GeneCards 数据库检索“Prosthetic Joint Infection”，共筛选出927个假体周围感染相关基因，然后分别取桃红四物汤各药物相对应靶点的交集，得到桃仁5个、红花69个、当归3个、川芎4个、白芍16个活性成分治疗假体周围感染的靶基因，而熟地有效成分的靶基因未能与假体周围感染相关基因找到交集。 2.3 “药物-成分-靶点-疾病”网络利用蛋白质数据库UniProt转换成对应的基因名称，并将上述治疗假体周围感染相关靶基因与药物活性成分进行映射，建立药物活性成分与假体周围感染相关靶基因之间的对应关系，得到与治疗假体周围感染相关的桃仁19个、红花17个、当归2个、白芍8个、川芎6个活性成分，熟地未取到，见表1。将桃仁5个、红花69个、当归3个、川芎4个、白芍16个治疗假体周围感染的靶基因合并去重后，得到34个关键靶基因。将桃仁、红花、白芍、当归、川芎与对应活性成分、活性成分与关键靶基因、关键靶基因与假体周围感染对应关系导入到Cytoscape，建立“药物-成分-靶点-疾病”网络，见图1。并使用插件“CentiScape”计算“Degree”，其值表示链接该节点的边数，值越大，表明该节点与其他节点的相互作用越广泛，在网络中起到重要的枢纽作用。“Degree”前五位的是quercetin(槲皮素)为28、luteolin(木犀草素)为19、kaempferol(山奈酚)为12、baicalein(黄芩苷)为9、beta-sitosterol(β-谷甾醇)为8。"

References

[1] KURTZ S, ONGK, LAU E, et al. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030.J Bone Joint Surg Am. 2007; 89(4):780-785.
[2] ONG KL, KURTZ SM, LAU E, et al. Prosthetic joint infection risk after total hip arthroplasty in the Medicare population.J Arthroplasty.2009;24:105-109.
[3] KURTZ SM, ONG KL, LAU E, et al. Prosthetic joint infection risk after TKA in the Medicare population. Clin Orthop Relat Res.2010;468:52-56.
[4] DALE H, FENSTAD AM, HALLAN G, et al. Increasing risk of prosthetic joint infection after total hip arthroplasty.Acta Orthop.2012;83(5):449-458.
[5] PHILLIPS JE, CRANE TP, NOY M, et al. The incidence of deep prosthetic infections in a specialist orthopaedic hospital: a 15-year prospective survey.J Bone Joint Surg Br. 2006;88(7):943-948.
[6] HORAN TC, ANDRUS M, DUDECK MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting.Am J Infect Control.2008;36(5):309-332.
[7] REZAPOOR M, PARVIZI J. Prevention of periprosthetic joint infection.J Arthroplasty. 2015;30:902-907.
[8] PARVIZI J, SHOHAT N, GEHRKE T. Prevention of periprostheticjoint infection: new guidelines.Bone Joint J.2017;99-b: 3-10.
[9] 俞杰,张树喜,王虎,等.加味桃红四物汤合生肌膏治疗创面感染临床观察[J].中国中医骨伤科,1997, 5(4):18-21.
[10] 邓煜,曹林虎,白新文桃红四物汤合五味消毒饮加减预防全髋关节置换术后假体周围感染临床研究[J]. 实用中医药杂志,2018,34(10):1143-1145.
[11] 李红,王新磊,吕书政.桃红四物汤对髋关节置换术患者髋关节功能的影响[J].中国中医药信息杂志, 2018,25(10):31-34.
[12] XIE C, MAO X, HUANG J, et al. KOBAS 2.0:a web server for annotation and identification of enriched pathways and diseases.Nucleic Acids Res. 2011;39:W316-W322.
[13] Jin-Hyung Lee, Joo-Hyeon Park, Hyun Seob Cho, et al. Anti-biofilm activities of quercetin and tannic acid against Staphylococcus aureus. Biofouling. 2013;29(5): 491-499.
[14] AMIN MU, KHURRAM M, KHATTAK B, et al. Antibiotic additive and synergistic action of rutin,morin and quercetin against methicillin resistant Staphylococcus aureus.BMC Complement Altern Med. 2015;15:59.
[15] ZHANG T, QIU Y, LUO Q, et al. The Mechanism by Which Luteolin Disrupts the Cytoplasmic Membrane of Methicillin-Resistant Staphylococcus aureus.J Phys.Chem.B. 2018;122:1427-1438.
[16] AMIN MU, MUHAMMAD K, ALI KT, et al. Effects of Luteolin and Quercetin in Combination with Some Conventional Antibiotics against Methicillin-Resistant Staphylococcus aureus.Int J Mol Sci.2016;17:1947.
[17] MING D, WANG D, CAO F, et al. Kaempferol Inhibits the Primary Attachment Phase of Biofilm Formation in Staphylococcus aureus.Front Microbiol.2017;8:2263.
[18] CHEN Y, LIU T, WANG K, et al. Baicalein Inhibits Staphylococcus aureus Biofilm Formation and the Quorum Sensing System In Vitro.PLoS One.2016;11(4): e0153468.
[19] DEIRMENGIAN C, KARDOS K, KILMARTIN P, et al. Diagnosing periprosthetic joint infection:has the era of the biomarker arrived? Clin Orthop Relat Res. 2014; 472(11):3254-3262.
[20] NOHA THARWAT ABOU EL-KHIER, ABD EL-RHMAN EL GANAINY, ADHAM ELGEIDY, et al. Assessment of interleukin-6 and other inflammatory markers in the diagnosis of Egyptian patients with periprosthetic joint infection.Egypt J Immunol.2013;20(2):93-99.
[21] VARLEY CD, DEODHAR AA, EHST BD, et al.Persistence of Staphylococcus aureus colonization among individuals with immune-mediated inflammatory diseases treated with TNF-a inhibitor therapy.Rheumatology.2014;53:332-337.
[22] FALANGA V. Wound healing and its impairment in the diabetic foot.Lancet. 2005; 366(9498):1736-1743.
[23] WINSTEL V, MISSIAKAS D, SCHNEEWIND O, et al. Staphylococcus aureus targets the purine salvage pathway to kill phagocytes.Proc Natl Acad Sci U S A. 2018;115:6846-6851.
[24] KIM H, KIM HS, PARK WJ, et al. Inhibitory Effect of Lactobacillus plantarum Extracts on HT-29 Colon Cancer Cell Apoptosis Induced by Staphylococcus aureus and Its Alpha-Toxin.J Microbiol Biotechnol.2015;25:1849-1855.
[25] HE Y, SONG M, ZHANG Y, et al. Whole-genome regulation analysis of histone H3 lysin 27 trimethylation in subclinical mastitis cows infected by Staphylococcus aureus.BMC Genomics.2016;17:565.
[26] XUE J, RAI V, SINGER D, et al. Advanced glycation end product recognition by the receptor for AGEs.Structure.2011;19:722-732.
[27] 戴涟生,叶俊星,杨志刚,等.髋关节置换术后感染对血液流变学、ApoE及皮质醇的影响[J].中国老年学杂志,2019,39(20):5005-5009.
[28] TAMTAJI OR, MILAJERDI A, DADGOSTAR E, et al. The Effects of Quercetin Supplementation on Blood Pressures and Endothelial Function Among Patients with Metabolic Syndrome and Related Disorders:A Systematic Review and Meta-analysis of Randomized Controlled Trials.Curr Pharm Des.2019;25(12):1372-1384.
[29] CHEN Y, DEUSTER P. Comparison of quercetin and dihydroquercetin:antioxidant-independent actions on erythrocyte and platelet membrane.Chem Biol Interact. 2009;182:7-12.
[30] CHOI JH, KIM KJ, KIM S. Comparative Effect of Quercetin and Quercetin-3-O-β-d-Glucoside on Fibrin Polymers,Blood Clots,and in Rodent Models.J Biochem Mol Toxicol.2016;30(11):548-558.
[31] HERNÁNDEZ G, BOLLINI A, MENGARELLI G. Protective effect of quercetin against in vitro erythrocyte rheology alterations produced by arsenic.Clin Hemorheol Microcirc. 2015;59(4):355-364.
[32] 谢兴文,李建国,黄晋,等.血管内皮生长因子防治骨质疏松的研究进展[J].中国骨质疏松杂志,2019, 25(7):1030-1033.
[33] 钱洲曜,王勇平.血管内皮生长因子有望成为加速骨折愈合的全新治疗手段[J].中国组织工程研究,2020, 23(17):2759-2769.
[34] 王辉,林松娟,刘源.慢性阻塞性肺疾病患者血清血管内皮生长因子水平变化及其临床意义[J].临床合理用药杂志,2012,5(7):7-8.
[35] GONG W, ZHANG N, CHENG G, et al. Rehmannia glutinosa Libosch Extracts Prevent Bone Loss and Architectural Deterioration and Enhance Osteoblastic Bone Formation by Regulating the IGF-1/PI3K/mTOR Pathway in Streptozotocin-Induced Diabetic Rats.Int J Mol Sci.2019;20:3964.
[36] 葛慧芳,孙明飞,叶佳,等.川芎醇提物抗氧化活性及抗食源性致病菌特性分析[J].食品工业科技,2019, 40(10):127-132.
[37] 胡屹屹,何孔旺,俞正玉.青藤碱、吴茱萸碱和川芎嗪抗细菌内毒素作用及其机制研究[J].南京农业大学学报,2012,35(1):103-107.