Effect and molecular mechanism of Honeysuckle-Rhizoma coptidis in the treatment of periprosthetic joint infection based on molecular docking and network pharmacology

doi:10.3969/j.issn.2095-4344.3870

Abstract

Abstract: BACKGROUND: Studies have shown that various monomers of Honeysuckle and Rhizoma coptidis are effective in the treatment of periprosthetic joint infections. There are many studies on the individual effects of Honeysuckle and Rhizoma coptidis, but the common pharmacological mechanism of Honeysuckle and Rhizoma coptidis is rarely reported.
OBJECTIVE: To explore the potential effective components, targets and action mechanisms of Honeysuckle-Rhizoma coptidis in the treatment of periprosthetic joint infection based on molecular docking network pharmacology.
METHODS: The effective components and target genes of Honeysuckle and Rhizoma coptidis were screened by traditional Chinese medicine system pharmacology database and analysis platform. The GeneCards and On-line Mendelian Inheritance in Man were used to obtain the targets for periprosthetic joint infection. The intersection of the two was taken to obtain the Honeysuckle, Rhizoma coptidis-periprosthetic joint infection disease intersection target. The protein-protein interaction (PPI) network was constructed through the STRING database, and the “CytoNCA” plug-in in Cytoscape 3.7.2 software was used for topology analysis and core target screening of the PPI network. Afterwards, through Cytoscape 3.7.2 software, the network of “traditional Chinese medicine - active component -intersection target-disease”, “active component -intersection target” and “pathway -enrichment gene” was constructed. DAVID was used to analyze the Gene Ontology (GO) function of the intersection target and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The affinity between the active components and the target was verified by molecular docking.
RESULTS AND CONCLUSION: (1) Through data screening, 14 effective components and 183 corresponding targets of Honeysuckle, 9 effective components of Rhizoma coptidis and 158 corresponding targets were obtained for periprosthetic joint infection. (2) In addition, 286 genes related to periprosthetic joint infection and 37 genes related to drug and disease were obtained. 17 core genes (such as interleukin 6) were screened by PPI network. (3) GO function enrichment showed that there were 59 biological functions of Honeysuckle-Rhizoma coptidis in the treatment of periprosthetic infection, including 44 biological processes, 6 cellular components and 9 molecular functions. (4) A total of 17 signal pathways were screened by enrichment of KEGG pathway. (5) The results of molecular docking showed that quercetin, luteolin, and kaempferol had good affinity with interleukin 6, matrix metalloproteinase 9 and interleukin 1β. (6) Results verified that Honeysuckle-Rhizoma coptidis is characterized by multiple effective compounds (such as quercetin and luteolin), multiple action pathways (such as Chagas disease and Toll-like receptor signaling pathway) and multiple target genes (such as prostaglandin-endoperoxide synthase 2 and interleukin 6) in the treatment of periprosthetic infection. These compounds, target genes and pathways can coordinate the therapeutic effect of drugs. In addition, quercetin was also found as a potential active ingredient, which provides a new direction and new idea for further research.

Key words: joint, traditional Chinese medicine, prosthesis, Honeysuckle, Rhizoma coptidis, infection, network pharmacology, molecular docking, signal pathway, gene

CLC Number:

Zhang Haitao, Chen Jinlun, Zhu Xingyang, Zeng Huiliang, Li Jie, Sun Xiaobo, Qi Xinyu, Zeng Jianchun, Zeng Yirong. Effect and molecular mechanism of Honeysuckle-Rhizoma coptidis in the treatment of periprosthetic joint infection based on molecular docking and network pharmacology[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(21): 3360-3367.

Figures/Tables 12

References

[1] KAPADIA BH, BERG RA, DALEY JA, et al. Periprosthetic joint infection. Lancet. 2016;387(10016):386-394.
[2] PARVIZI J, ZMISTOWSKI B, ADELI B. Periprosthetic joint infection: treatment options. Orthopedics. 2010;33(9):659.
[3] 李兆合.五味消毒饮治疗关节置换术后金黄色葡萄球菌感染机理窥探[J].中医学报,2012,27(5):613-614.
[4] 吴娇,王聪,海川.金银花中的化学成分及其药理作用研究进展[J].中国实验方剂学杂志,2019,25(4):225-234.
[5] 庄丽,张超,阿里穆斯.金银花的药理作用与临床应用研究进展[J].辽宁中医杂志,2013,40(2):378-380.
[6] SI L, LI P, LIU X, et al. Chinese herb medicine against Sortase A catalyzed transformations, a key role in gram-positive bacterial infection progress. J Enzyme Inhib Med Chem. 2016;31(sup1):184-196.
[7] LI X, MOTWANI M, TONG W, et al. Huanglian, a Chinese herbal extract, inhibits cell growth by suppressing the expression of cyclin B1 and inhibiting CDC2 kinase activity in human cancer cells. Mol Pharmacol. 2000;58(6):1287-1293.
[8] 盖晓红,刘素香,任涛.黄连的化学成分及药理作用研究进展[J].中草药,2018,20(49):4919.
[9] 王清,朱萱萱,张赤兵,等.金银花提取物抗菌作用的实验研究[J].中国医药导刊,2008,10(9):1428-1430.
[10] 张庆莲,黄娟,邵单炫,等.黄连抗菌作用研究进展[J].中医药信息, 2019;36(5):125-127.
[11] 徐森楠,庄莉,翟园园,等.基于网络药理学研究二至丸防治骨质疏松症的物质基础与作用机制[J].中国药学杂志,2018,53(22): 1913-1920.
[12] RICCIARDI BF, MUTHUKRISHNAN G, MASTERS EA, et al. New developments and future challenges in prevention, diagnosis, and treatment of prosthetic joint infection. J Orthop Res. 2020;38(7): 1423-1435.
[13] SONG Z, BORGWARDT L, HØIBY N, et al. Prosthesis infections after orthopedic joint replacement: the possible role of bacterial biofilms. Orthop Rev (Pavia). 2013;5(2):65-71.
[14] Memariani H, Memariani M, Ghasemian A. An overview on anti-biofilm properties of quercetin against bacterial pathogens. World J Microbiol Biotechnol. 2019;35(9):143.
[15] Lv PC, Li HQ, Xue JY, et al. Synthesis and biological evaluation of novel luteolin derivatives as antibacterial agents. Eur J Med Chem. 2009;44(2):908-914.
[16] Wang Q, Xie M. Antibacterial activity and mechanism of luteolin on Staphylococcus aureus. Wei Sheng Wu Xue Bao. 2010;50(9):1180-1184.
[17] Liu MH, Otsuka N, Noyori K, et al. Synergistic effect of kaempferol glycosides purified from Laurus nobilis and fluoroquinolones on methicillin-resistant Staphylococcus aureus. Biol Pharm Bull. 2009; 32(3):489-492.
[18] García-Mediavilla V, Crespo I, Collado PS, et al. The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur J Pharmacol. 2007;557(2-3):221-229.
[19] Tan J, Wang J, Yang C, et al. Antimicrobial characteristics of Berberine against prosthetic joint infection-related Staphylococcus aureus of different multi-locus sequence types. BMC Complement Altern Med. 2019;19(1):218.
[20] Xie Y, Liu X, Zhou P. In vitro antifungal effects of berberine against candida spp. in planktonic and biofilm conditions. Drug Des Devel Ther. 2020;14:87-101.
[21] Lenski M, Scherer MA. Synovial IL-6 as inflammatory marker in periprosthetic joint infections. J Arthroplasty. 2014;29(6):1105-1109.
[22] Lee S, Kim B, Choi W, et al. Lack of association between pro-inflammatory genotypes of the interleukin-1 (IL-1B-31 C/+ and IL-1RN* 2/* 2) and gastric cancer/duodenal ulcer in Korean population. Cytokine. 2003;21(4):167-171.
[23] Quiney C, Billard C, Mirshahi P, et al. Hyperforin inhibits MMP-9 secretion by B-CLL cells and microtubule formation by endothelial cells. Leukemia. 2006;20(4):583-589.
[24] Sharma K, Ivy M, Block DR, et al. Comparative analysis of 23 synovial fluid biomarkers for hip and knee periprosthetic joint infection detection. J Orthop Res. 2020. doi: 10.1002/jor.24766.
[25] Ackmann T, Möllenbeck B, Gosheger G, et al. Comparing the diagnostic value of serum D-Dimer to CRP and IL-6 in the diagnosis of chronic prosthetic joint infection. J Clin Med. 2020;9(9):E2917.
[26] Rosenfeld Y, Shai Y. Lipopolysaccharide (Endotoxin)-host defense antibacterial peptides interactions: role in bacterial resistance and prevention of sepsis. Biochim Biophys Acta. 2006;1758(9):1513-1522.
[27] Covre LP, Devine OP, Garcia de Moura R, et al. Compartmentalized cytotoxic immune response leads to distinct pathogenic roles of natural killer and senescent CD8+ T cells in human cutaneous leishmaniasis. Immunology. 2020;159(4):429-440.
[28] Souza-Fonseca-Guimaraes F, Adib-Conquy M, Cavaillon J. Natural killer (NK) cells in antibacterial innate immunity: angels or devils? Mol Med. 2012;18(2):270-285.
[29] Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis. Ann Rev Med. 2000;51(1):207-229.
[30] Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14(5):329-342.
[31] Caradonna L, Amati L, Lella P, et al. Phagocytosis, killing, lymphocyte-mediated antibacterial activity, serum autoantibodies, and plasma endotoxins in inflammatory bowel disease. Am J Gastroenterol. 2000;95(6):1495-1502.
[32] Ellerin T, Rubin RH, Weinblatt ME. Infections and anti–tumor necrosis factor α therapy. Arthritis Rheum. 2003;48(11):3013-3022.
[33] Galliera E, Drago L, Vassena C, et al. Toll-like receptor 2 in serum: a potential diagnostic marker of prosthetic joint infection? J Clin Microbiol. 2014;52(2):620-623.
[34] Knapp S. Update on the role of Toll-like receptors during bacterial infections and sepsis. Wien Med Wochenschr. 2010;160(5-6):107-111.
[35] Koc M, Toprak A, Arikan H, et al. Toll-like receptor expression in monocytes in patients with chronic kidney disease and haemodialysis: relation with inflammation. Nephrol Dial Transplant. 2011;26(3): 955-963.