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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Integrated Bioinformatic Analysis and Experimental Validation to Reveal the Mechanisms of Xinfeng Capsule against Rheumatoid Arthritis

Author(s): Xiaochuang Liu, Yuanyuan Wang*, Yanyan Zhang*, Hui Jiang, Xingxing Huo and Rui Liu

Volume 26, Issue 12, 2023

Published on: 03 March, 2023

Page: [2161 - 2169] Pages: 9

DOI: 10.2174/1386207326666230127151049

Price: $65

Abstract

Background: Xinfeng capsule (XFC) is a well-known drug against rheumatoid arthritis (RA). However, the combination mechanisms of XFC on RA remain unclear.

Objective: The purpose of this study is to explore the mechanisms of XFC against RA in terms of compounds, targets, and signaling pathways via network pharmacology.

Methods: The bioactive compounds and potential targets of XFC were extracted from TCMSP and BATMAN-TCM database, and the putative RA-related targets were determined from the DisGeNET, PHGKB, PharmGKB, and CTD database. The approach of protein-protein interaction, gene ontology analysis, and kyoto encyclopedia of genes and genomes pathway enrichment analysis were constructed, respectively. In animal experiments, we evaluated the expression of core targets.

Results: We found that XFC handled 30 active compounds and 131 common target genes. Among them, mairin, folic acid, cholesterol, and triptolide in XFC were selected as the central active compounds against RA. The mechanisms of XFC on RA which concerned critical targets were protein kinase B (AKT1) and tumor necrosis factor (TNF). In vivo, we found that the expression levels of AKT1 and TNF in the modeling group were significantly increased but reversed by XFC.

Conclusion: The combination mechanisms of XFC were elucidated in terms of components and targets and signaling pathways, which may be related to inhibiting the proliferation of synovial cells and inflammation.

Graphical Abstract

[1]
Josef, S. Rheumatoid arthritis. Lancet, 2016, 388, 2023-2038.
[2]
Rheumatoid arthritis–a molecular understanding. Ann. Intern. Med., 2002, 136(12), 902-922.
[3]
Yue, S.; Jian, L.; Yonghe, C. Effects of Xinfeng capsule on the Fas/FasL-mediated apoptotic pathway in patients with rheumatoid arthritis. J. Tradit. Chin. Med., 2018, 38(4), 601-609.
[http://dx.doi.org/10.1016/S0254-6272(18)30893-8] [PMID: 32186086]
[4]
Jiang, H.; Liu, J.; Wang, T.; Gao, J.; Sun, Y.; Huang, C.; Meng, M.; Qin, X. Mechanism of xinfeng capsule on adjuvant-induced arthritis via analysis of urinary metabolomic profiles. Autoimmune Dis., 2016, 2016, 1-10.
[http://dx.doi.org/10.1155/2016/5690935] [PMID: 26989506]
[5]
Cao, Y.X.; Huang, D.; Liu, J.; Zong, R.K.; Wan, L.; Huang, C.B.; Zhang, W.D.; Wang, Y. A novel chinese medicine, xinfeng capsule, modulates proinflammatory cytokines via regulating the toll-like receptor 4 (TLR4)/Mitogen-Activated Protein Kinase (MAPK)/Nuclear Kappa B (NF-κB) signaling pathway in an adjuvant arthritis rat model. Med. Sci. Monit., 2019, 25, 6767-6774.
[http://dx.doi.org/10.12659/MSM.916317] [PMID: 31495827]
[6]
Xu, X.; Bi, J.; Ping, L.; Li, P.; Li, F. A network pharmacology approach to determine the synergetic mechanisms of herb couple for treating rheumatic arthritis. Drug Des. Devel. Ther., 2018, 12, 967-979.
[http://dx.doi.org/10.2147/DDDT.S161904] [PMID: 29731604]
[7]
Szklarczyk, D.; Gable, A.L.; Lyon, D.; Junge, A.; Wyder, S.; Huerta-Cepas, J.; Simonovic, M.; Doncheva, N.T.; Morris, J.H.; Bork, P.; Jensen, L.J.; Mering, C. 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.
[http://dx.doi.org/10.1093/nar/gky1131] [PMID: 30476243]
[8]
Ru, J.; Li, P.; Wang, J.; Zhou, W.; Li, B.; Huang, C.; Li, P.; Guo, Z.; Tao, W.; Yang, Y.; Xu, X.; Li, Y.; Wang, Y.; Yang, L. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J. Cheminform., 2014, 6(1), 13-18.
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[9]
Piñero, J.; Bravo, À.; Queralt-Rosinach, N.; Gutiérrez-Sacristán, A.; Deu-Pons, J.; Centeno, E.; García-García, J.; Sanz, F.; Furlong, L.I. DisGeNET: A comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res., 2017, 45(D1), D833-D839.
[http://dx.doi.org/10.1093/nar/gkw943] [PMID: 27924018]
[10]
Yu, W.; Gwinn, M.; Dotson, W.D.; Green, R.F.; Clyne, M.; Wulf, A.; Bowen, S.; Kolor, K.; Khoury, M.J. A knowledge base for tracking the impact of genomics on population health. Genet. Med., 2016, 18(12), 1312-1314.
[http://dx.doi.org/10.1038/gim.2016.63] [PMID: 27280867]
[11]
Barbarino, J.M.; Whirl-Carrillo, M.; Altman, R.B.; Klein, T.E. PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip. Rev. Syst. Biol. Med., 2018, 10(4), e1417-e1429.
[http://dx.doi.org/10.1002/wsbm.1417] [PMID: 29474005]
[12]
Davis, A.P.; Grondin, C.J.; Johnson, R.J.; Sciaky, D.; McMorran, R.; Wiegers, J.; Wiegers, T.C.; Mattingly, C.J. The comparative toxicogenomics database: Update 2019. Nucleic Acids Res., 2019, 47(D1), D948-D954.
[http://dx.doi.org/10.1093/nar/gky868] [PMID: 30247620]
[13]
Liu, Z.; Guo, F.; Wang, Y.; Li, C.; Zhang, X.; Li, H.; Diao, L.; Gu, J.; Wang, W.; Li, D.; He, F. BATMAN–TCM: A bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine. Sci. Rep., 2016, 6(1), 21146-21155.
[http://dx.doi.org/10.1038/srep21146] [PMID: 26879404]
[14]
Szklarczyk, D.; Santos, A.; von Mering, C.; Jensen, L.J.; Bork, P.; Kuhn, M. STITCH 5: Augmenting protein–chemical interaction networks with tissue and affinity data. Nucleic Acids Res., 2016, 44(D1), D380-D384.
[http://dx.doi.org/10.1093/nar/gkv1277] [PMID: 26590256]
[15]
Huang, R.; Guo, F.; Li, Y.; Liang, Y.; Li, G.; Fu, P.; Ma, L. Activation of AMPK by triptolide alleviates nonalcoholic fatty liver disease by improving hepatic lipid metabolism, inflammation and fibrosis. Phytomedicine, 2021, 92, 153739.
[http://dx.doi.org/10.1016/j.phymed.2021.153739] [PMID: 34592488]
[16]
Tang, B.; Zhu, J.; Zhang, B.; Wu, F.; Wang, Y.; Weng, Q.; Fang, S.; Zheng, L.; Yang, Y.; Qiu, R.; Chen, M.; Xu, M.; Zhao, Z.; Ji, J. Therapeutic potential of triptolide as an anti-inflammatory agent in dextran sulfate sodium-induced murine experimental colitis. Front. Immunol., 2020, 11, 592084.
[http://dx.doi.org/10.3389/fimmu.2020.592084] [PMID: 33240279]
[17]
Wang, J.; Zhao, Q. Betulinic acid inhibits cell proliferation, migration, and inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes. J. Cell. Biochem., 2019, 120(2), 2151-2158.
[http://dx.doi.org/10.1002/jcb.27523] [PMID: 30367550]
[18]
Li, R.; Li, Y.; Liang, X.; Yang, L.; Su, M.; Lai, K.P. Network Pharmacology and bioinformatics analyses identify intersection genes of niacin and COVID-19 as potential therapeutic targets. Brief. Bioinform., 2021, 22(2), 1279-1290.
[http://dx.doi.org/10.1093/bib/bbaa300] [PMID: 33169132]
[19]
Gong, B.; Kao, Y.; Zhang, C.; Sun, F.; Zhao, H. Systematic investigation of scutellariae barbatae herba for treating hepatocellular carcinoma based on network pharmacology. Evid. Based Complement. Alternat. Med., 2018, 2018, 1-12.
[http://dx.doi.org/10.1155/2018/4365739] [PMID: 30584453]
[20]
Zamanpoor, M. The genetic pathogenesis, diagnosis and therapeutic insight of rheumatoid arthritis. Clin. Genet., 2019, 95(5), 547-557.
[http://dx.doi.org/10.1111/cge.13498] [PMID: 30578544]
[21]
Lee, I.T.; Lin, C.F.; Huang, Y.L.; Chong, K.Y.; Hsieh, M.F.; Huang, T.H.; Cheng, C.Y. Protective mechanisms of resveratrol derivatives against TNF-α-induced inflammatory responses in rat mesangial cells. Cytokine, 2019, 113, 380-392.
[http://dx.doi.org/10.1016/j.cyto.2018.10.008] [PMID: 30389230]
[22]
Hellmann, J.; Tang, Y.; Zhang, M.J.; Hai, T.; Bhatnagar, A.; Srivastava, S.; Spite, M. Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation. Prostaglandins Other Lipid Mediat., 2015, 116-117, 49-56.
[http://dx.doi.org/10.1016/j.prostaglandins.2015.01.001] [PMID: 25619459]
[23]
Dougan, M.; Dranoff, G.; Dougan, S.K. IL–3, and IL–5 family of cytokines: Regulators of inflammation. Immunity, 2019, 50(4), 796-811.
[http://dx.doi.org/10.1016/j.immuni.2019.03.022] [PMID: 30995500]
[24]
Bi, X.; Guo, X.H.; Mo, B.Y.; Wang, M.L.; Luo, X.Q.; Chen, Y.X.; Liu, F.; Olsen, N.; Pan, Y.F.; Zheng, S.G. LncRNA PICSAR promotes cell proliferation, migration and invasion of fibroblast-like synoviocytes by sponging miRNA-4701-5p in rheumatoid arthritis. EBioMedicine, 2019, 50, 408-420.
[http://dx.doi.org/10.1016/j.ebiom.2019.11.024] [PMID: 31791845]
[25]
Zhang, Q.; Liu, J.; Zhang, M.; Wei, S.; Li, R.; Gao, Y.; Peng, W.; Wu, C. Apoptosis induction of fibroblast–like synoviocytes is an important molecular–mechanism for herbal medicine along with its active components in treating rheumatoid arthritis. Biomolecules, 2019, 9(12), 795-823.
[http://dx.doi.org/10.3390/biom9120795] [PMID: 31795133]
[26]
Yang, J.; Zhao, S.; Yang, X.; Zhang, H.; Zheng, P.; Wu, H. Inhibition of B-cell apoptosis is mediated through increased expression of Bcl-2 in patients with rheumatoid arthritis. Int. J. Rheum. Dis., 2016, 19(2), 134-140.
[http://dx.doi.org/10.1111/1756-185X.12706] [PMID: 26176566]
[27]
Kuo, W.T.; Shen, L.; Zuo, L.; Shashikanth, N.; Ong, M.L.D.M.; Wu, L.; Zha, J.; Edelblum, K.L.; Wang, Y.; Wang, Y.; Nilsen, S.P.; Turner, J.R. Inflammation–induced occludin downregulation limits epithelial apoptosis by suppressing caspase–3 expression. Gastroenterology, 2019, 157(5), 1323-1337.
[http://dx.doi.org/10.1053/j.gastro.2019.07.058] [PMID: 31401143]
[28]
Chen, J.; Zhou, Y.; Mueller-Steiner, S.; Chen, L.F.; Kwon, H.; Yi, S.; Mucke, L.; Gan, L. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J. Biol. Chem., 2005, 280(48), 40364-40374.
[http://dx.doi.org/10.1074/jbc.M509329200] [PMID: 16183991]
[29]
Hentzen, N.B.; Mogaki, R.; Otake, S.; Okuro, K.; Aida, T. Intracellular photoactivation of caspase–3 by molecular glues for spatiotemporal apoptosis induction. J. Am. Chem. Soc., 2020, 142(18), 8080-8084.
[http://dx.doi.org/10.1021/jacs.0c01823] [PMID: 32275408]
[30]
Liu, Q.; Chen, T.; Chen, G.; Li, N.; Wang, J.; Ma, P.; Cao, X. Immunosuppressant triptolide inhibits dendritic cell-mediated chemoattraction of neutrophils and T cells through inhibiting Stat3 phosphorylation and NF-κB activation. Biochem. Biophys. Res. Commun., 2006, 345(3), 1122-1130.
[http://dx.doi.org/10.1016/j.bbrc.2006.05.024] [PMID: 16713992]
[31]
Zhang, H.; Chen, W. Interleukin 6 inhibition by triptolide prevents inflammation in a mouse model of ulcerative colitis. Exp. Ther. Med., 2017, 14(3), 2271-2276.
[http://dx.doi.org/10.3892/etm.2017.4778] [PMID: 28962154]
[32]
Yu, W.G.; Shen, Y.; Wu, J.Z.; Gao, Y.B.; Zhang, L.X. Madecassoside impedes invasion of rheumatoid fibroblast-like synoviocyte from adjuvant arthritis rats via inhibition of NF- κ B-mediated matrix metalloproteinase-13 expression. Chin. J. Nat. Med., 2018, 16(5), 330-338.
[http://dx.doi.org/10.1016/S1875-5364(18)30064-5] [PMID: 29860993]
[33]
Xiong, Y.; Yan, Y.; Li, Y. RETRACTED: Tripterine alleviates LPS-induced inflammatory injury by up-regulation of miR-146a in HaCaT cells. Biomed. Pharmacother., 2018, 105, 798-804.
[http://dx.doi.org/10.1016/j.biopha.2018.05.008] [PMID: 29913408]
[34]
Jiang, H.; Qin, X.J.; Li, W.P.; Ma, R.; Wang, T.; Li, Z.Q. LncRNAs expression in adjuvant-induced arthritis rats reveals the potential role of LncRNAs contributing to rheumatoid arthritis pathogenesis. Gene, 2016, 593(1), 131-142.
[http://dx.doi.org/10.1016/j.gene.2016.08.012] [PMID: 27511374]
[35]
Jiang, D.L.; Liu, Y.Y.; Sun, R.Y.; Chen, S.; Di, W. NLRP3 inflammasome and its role in inflammation–related diseases. Chin. Bull. Life Sci., 2017, 29, 898-907.
[36]
Su, M.; Cao, J.; Huang, J.; Liu, S.; Im, D.; Yoo, J.W.; Jung, J. The in vitro and in vivo anti–inflammatory effects of a phthalimide PPAR–γ agonist. Mar. Drugs, 2017, 15(1), 7.
[http://dx.doi.org/10.3390/md15010007] [PMID: 28054961]
[37]
Korbecki, J.; Bobiński, R.; Dutka, M. Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors. Inflamm. Res., 2019, 68(6), 443-458.
[http://dx.doi.org/10.1007/s00011-019-01231-1] [PMID: 30927048]
[38]
Ingawale, D.K.; Mandlik, S.K. New insights into the novel anti–inflammatory mode of action of glucocorticoids. Immunopharmacol. Immunotoxicol., 2020, 42(2), 59-73.
[http://dx.doi.org/10.1080/08923973.2020.1728765]
[39]
Sawada, H.; Suda, M.; Rokutanda, R.; Kobayashi, D.; Mitsumasa, K.; Okada, M. Concomitant use of intravenous methylprednisolone to increase retention rate of abatacept in rheumatoid arthritis. Rheumatol. Int., 2018, 38(10), 1825-1831.
[http://dx.doi.org/10.1007/s00296-018-4115-0] [PMID: 30054716]
[40]
Mota, L.M.H.; Kakehasi, A.M.; Gomides, A.P.M.; Duarte, A.L.B.P.; Cruz, B.A.; Brenol, C.V.; de Albuquerque, C.P.; Castelar Pinheiro, G.R.; Laurindo, I.M.M.; Pereira, I.A.; Bertolo, M.B.; Ubirajara Silva de Souza, M.P.G.; de Freitas, M.V.C.; Louzada-Júnior, P.; Xavier, R.M.; Giorgi, R.D.N. 2017 recommendations of the Brazilian Society of Rheumatology for the pharmacological treatment of rheumatoid arthritis. Adv. Rheumatol., 2018, 58(1), 2.
[http://dx.doi.org/10.1186/s42358-018-0005-0] [PMID: 30657071]
[41]
Chen, Z.; Bozec, A.; Ramming, A.; Schett, G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat. Rev. Rheumatol., 2019, 15(1), 9-17.
[http://dx.doi.org/10.1038/s41584-018-0109-2] [PMID: 30341437]
[42]
Yang, P.; Qian, F.Y.; Zhang, M.F.; Xu, A.L.; Wang, X.; Jiang, B.P.; Zhou, L.L. Th17 cell pathogenicity and plasticity in rheumatoid arthritis. J. Leukoc. Biol., 2019, 106(6), 1233-1240.
[http://dx.doi.org/10.1002/JLB.4RU0619-197R] [PMID: 31497905]

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