Abstract
Background: Rheumatoid Arthritis (RA) is a chronic autoimmune disease that can lead to joint pain and disability, and seriously impact patients' quality of life. Strychni Semen combined with Atractylodes Macrocephala koidz (SA) have pronounced curative effect on RA, and there is no poisoning of Strychni Semen (SS). However, its pharmacological mechanisms are still unclear.
Objective: In this study, we aimed to investigate the pharmacological mechanisms of Strychni Semen combined with Atractylodes Macrocephala Koidz (SA) for the treatment of RA.
Methods: We used network pharmacology to screen the active components of SA and predict the targets and pathways involved. Results originating from network pharmacology were then verified by animal experiments.
Results: Network pharmacology identified 81 active ingredients and 141 targets of SA; 2640 disease- related genes were also identified. The core targets of SA for the treatment of RA included ALB, IL-6, TNF and IL-1β. A total of 354 gene ontology terms were identified by Gene ontology (GO) enrichment analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results showed that SA was closely associated with TNF signaling pathways in the treatment of RA. Furthermore, according to the predicted results of network pharmacology, we established a rat model of Adjuvant Arthritis (AA) for in vivo experiments. Analysis showed that each treatment group led to an improvement in paw swelling, immune organ coefficient and synovial tissue morphology in AA rats to different degrees, inhibit the expression levels of IL-1β, TNF-α and IL-6, upregulated the levels of Fas, Bax and Caspase 3, down-regulated the expression levels of Fas-L, Bcl-2 and p53.
Conclusion: SA has an anti-RA effect, the mechanism underlying the therapeutic action of SA in AA rats was related to the regulation of apoptosis signaling pathways.
Graphical Abstract
[1]
Xia, Z.B.; Meng, F.R.; Fang, Y.X.; Wu, X.; Zhang, C.W.; Liu, Y.; Liu, D.; Li, G.Q.; Feng, F.B.; Qiu, H.Y. Inhibition of NF-κB signaling pathway induces apoptosis and suppresses proliferation and angiogenesis of human fibroblast-like synovial cells in rheumatoid arthritis. Medicine, 2018, 97(23), e10920.
[http://dx.doi.org/10.1097/MD.0000000000010920] [PMID: 29879032]
[http://dx.doi.org/10.1097/MD.0000000000010920] [PMID: 29879032]
[2]
Yin, G.; Wang, Y.; Cen, X.; Yang, M.; Liang, Y.; Xie, Q. Lipid peroxidation-mediated inflammation promotes cell apoptosis through activation of NF-κB pathway in rheumatoid arthritis synovial cells. Mediators Inflamm., 2015, 2015, 1-10.
[http://dx.doi.org/10.1155/2015/460310] [PMID: 25741130]
[http://dx.doi.org/10.1155/2015/460310] [PMID: 25741130]
[3]
Scherer, H.U.; Häupl, T.; Burmester, G.R. The etiology of rheumatoid arthritis. J. Autoimmun., 2020, 110, 102400.
[http://dx.doi.org/10.1016/j.jaut.2019.102400] [PMID: 31980337]
[http://dx.doi.org/10.1016/j.jaut.2019.102400] [PMID: 31980337]
[4]
Birch, J.T., Jr; Bhattacharya, S. Emerging trends in diagnosis and treatment of rheumatoid arthritis. Prim. Care, 2010, 37(4), 779-792.
[http://dx.doi.org/10.1016/j.pop.2010.07.001] [PMID: 21050958]
[http://dx.doi.org/10.1016/j.pop.2010.07.001] [PMID: 21050958]
[5]
Littlejohn, E.A.; Monrad, S.U. Early diagnosis and treatment of rheumatoid arthritis. Prim. Care, 2018, 45(2), 237-255.
[http://dx.doi.org/10.1016/j.pop.2018.02.010] [PMID: 29759122]
[http://dx.doi.org/10.1016/j.pop.2018.02.010] [PMID: 29759122]
[6]
Lu, Y.; Gao, N. Research progress on pharmacological activities of Strychnos nux-vomica L. and methods of synergism and attenuation. Shanghai J. Tradit. Chinese Med., 2019, 53(5), 93-97.
[7]
Sun, Z.; Cao, L. Study on the qiqing compatibility of strychni semen based on pharmacological effect. Pharmacol. Clinic. Chinese Mater. Medica., 2020, 36(2), 257-262.
[8]
Liang, X.; Chen, T.; Tang, Y.; Cao, Y. Study on the compatibility of nux vomica and baizhu on immune mechanism in rats with arthritis. Chinese J. Basic Med. Tradit. Chinese Med., 2015, 21(8), 949-951.
[9]
Liang, X.; Chen, T.; Cao, Y.; Tang, Y. Effects of nux vomica alone and compatibility of nux vomica and largehead atractylodes rhizome on adjuvant arthritis rats. Zhonghua Zhongyiyao Zazhi, 2016, 31(1), 235-238.
[10]
Yan, S.; Cai, B.; Zhang, Z. Application progress of network pharmacology in traditional chinese medicine research. J. Nanjing Uni. Tradit. Chinese Med., 2021, 37(1), 156-160.
[11]
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.
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[12]
Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res., 2021, 49(D1), D1388-D1395.
[http://dx.doi.org/10.1093/nar/gkaa971] [PMID: 33151290]
[http://dx.doi.org/10.1093/nar/gkaa971] [PMID: 33151290]
[13]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[14]
Wang, X.; Shen, Y.; Wang, S.; Li, S.; Zhang, W.; Liu, X.; Lai, L.; Pei, J.; Li, H. PharmMapper 2017 update: A web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res., 2017, 45(W1), W356-W360.
[http://dx.doi.org/10.1093/nar/gkx374] [PMID: 28472422]
[http://dx.doi.org/10.1093/nar/gkx374] [PMID: 28472422]
[15]
UniProt Consortium. UniProt: A worldwide hub of protein knowledge. Nucleic Acids Res., 2019, 47(D1), D506-D515.
[http://dx.doi.org/10.1093/nar/gky1049] [PMID: 30395287]
[http://dx.doi.org/10.1093/nar/gky1049] [PMID: 30395287]
[16]
PCAWG transcriptome core group, Calabrese, C.; Davidson, N. R.; Demircioğlu, D.; Fonseca, N. A.; He, Y.; Kahles, A.; Lehmann, K. V.; Liu, F.; Shiraishi, Y.; Soulette, C. M.; Urban, L.; Greger, L.; Li, S.; Liu, D.; Perry, M. D.; Xiang, Q.; Zhang, F.; Zhang, J.; Bailey, P.; Erkek, S.; Hoadley, K. A.; Hou, Y., Huska, M. R.; Kilpinen, H.; Korbel, J. O.; Marin, M. G.; Markowski, J.; Nandi, T.; Pan-Hammarström, Q.; Pedamallu, C. S.; Siebert, R.; Stark, S. G.; Su, H.; Tan, P.; Waszak, S.M.; Yung, C.; Zhu, S.; Awadalla, P.; Creighton, C. J.; Meyerson, M.; Ouellette, B. F. F.; Wu, K.; Yang,H.; PCAWG transcriptome working group; Brazma, A.; Brooks, A. N.; Göke, J.; Rätsch, G.; Schwarz, R. F.; Stegle, O.; Zhang, Z. PCAWG consortium genomic basis for RNA alterations in cancer. Nature., 2020, 578, 129-136.
[http://dx.doi.org/10.1038/s41586-020-1970-0] [PMID: 7054216]
[http://dx.doi.org/10.1038/s41586-020-1970-0] [PMID: 7054216]
[17]
Wang, Y.; Zhang, S.; Li, F.; Zhou, Y.; Zhang, Y.; Wang, Z.; Zhang, R.; Zhu, J.; Ren, Y.; Tan, Y.; Qin, C.; Li, Y.; Li, X.; Chen, Y.; Zhu, F. Therapeutic target database 2020: Enriched resource for facilitating research and early development of targeted therapeutics. Nucleic Acids Res., 2020, 48(D1), D1031-D1041.
[PMID: 31691823]
[PMID: 31691823]
[18]
Wishart, D.S.; Feunang, Y.D.; Guo, A.C.; Lo, E.J.; Marcu, A.; Grant, J.R.; Sajed, T.; Johnson, D.; Li, C.; Sayeeda, Z.; Assempour, N.; Iynkkaran, I.; Liu, Y.; Maciejewski, A.; Gale, N.; Wilson, A.; Chin, L.; Cummings, R.; Le, D.; Pon, A.; Knox, C.; Wilson, M. DrugBank 5.0: A major update to the DrugBank database for 2018. Nucleic Acids Res., 2018, 46(D1), D1074-D1082.
[http://dx.doi.org/10.1093/nar/gkx1037] [PMID: 29126136]
[http://dx.doi.org/10.1093/nar/gkx1037] [PMID: 29126136]
[19]
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]
[http://dx.doi.org/10.1093/nar/gky1131] [PMID: 30476243]
[20]
Huang, D.W.; Sherman, B.T.; Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc., 2009, 4(1), 44-57.
[http://dx.doi.org/10.1038/nprot.2008.211] [PMID: 19131956]
[http://dx.doi.org/10.1038/nprot.2008.211] [PMID: 19131956]
[21]
Urman, A.; Taklalsingh, N.; Sorrento, C.; McFarlane, I.M. Inflammation beyond the joints: Rheumatoid arthritis and cardiovascular disease. Scifed. J. Cardiol., 2018, 2(3), 1000019.
[22]
Figus, F.A.; Piga, M.; Azzolin, I.; McConnell, R.; Iagnocco, A. Rheumatoid arthritis: Extra-articular manifestations and comorbidities. Autoimmun. Rev., 2021, 20(4), 102776.
[http://dx.doi.org/10.1016/j.autrev.2021.102776] [PMID: 33609792]
[http://dx.doi.org/10.1016/j.autrev.2021.102776] [PMID: 33609792]
[23]
Yan, H.; Yu, J.; Zhang, X.; An, Y.; Xue, Y. Research progress of apoptosis protein in the pathogenesis of rheumatoid arthritis. Rheumatism Arthritis., 2021, 10(5), 69-72.
[24]
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.
[http://dx.doi.org/10.3390/biom9120795] [PMID: 31795133]
[http://dx.doi.org/10.3390/biom9120795] [PMID: 31795133]
[25]
Hu, W.; Fu, W.; Wei, X.; Yang, Y.; Lu, C.; Liu, Z. A network pharmacology study on the active ingredients and potential targets of Tripterygium wilfordii hook for treatment of rheumatoid arthritis. Evid. Based Complement. Alternat. Med., 2019, 2019, 1-15.
[http://dx.doi.org/10.1155/2019/5276865] [PMID: 31118961]
[http://dx.doi.org/10.1155/2019/5276865] [PMID: 31118961]
[26]
Guo, Q.; Mao, X.; Zhang, Y.; Meng, S.; Xi, Y.; Ding, Y.; Zhang, X.; Dai, Y.; Liu, X.; Wang, C.; Li, Y.; Lin, N. Guizhi-Shaoyao-Zhimu decoction attenuates rheumatoid arthritis partially by reversing inflammation-immune system imbalance. J. Transl. Med., 2016, 14(1), 165.
[http://dx.doi.org/10.1186/s12967-016-0921-x] [PMID: 27277474]
[http://dx.doi.org/10.1186/s12967-016-0921-x] [PMID: 27277474]
[27]
Chen, T.; Zhang, P.; Cheng, Y. Research progress on determination method, dryness and pharmacological action of Rhizoma Atractylodis. Zhongchengyao, 2020, 44(06), 1902-1905.
[28]
Yao, Z.; Chen, W.; Yang, Z.; Jiang, C.; Li, N.; Guo, Y.; Wang, D.; Liu, C. Research progress in Atractylodes macrocephala and predictive analysis on Q-marker. Chin. Tradit. Herbal Drugs, 2019, 50(19), 4796-4807.
[29]
Wang, S.; Sun, Y.; Li, C.; Lu, Q. Research progress of stigmasterol. China Pharmaceut., 2019, 28(23), 96-98.
[30]
Wu, L.; Li, J.; Zhang, T.; Tao, F.; Liu, W. Discussion on anti-inflammatory effect of stigmasterol based on network pharmacology and cell experiment. Zhongchengyao, 2022, 44(2), 609-615.
[31]
Yin, W.; Wang, T.S.; Yin, F.Z.; Cai, B.C. Analgesic and anti-inflammatory properties of brucine and brucine N-oxide extracted from seeds of Strychnos nux-vomica. J. Ethnopharmacol., 2003, 88(2-3), 205-214.
[http://dx.doi.org/10.1016/S0378-8741(03)00224-1] [PMID: 12963144]
[http://dx.doi.org/10.1016/S0378-8741(03)00224-1] [PMID: 12963144]
[32]
Xu, J.; Chen, J.; Cai, B. Advances in studies on brucine. Zhongguo Xin Yao Zazhi, 2009, 18(3), 213-216, 221.
[33]
Xie, B.; Tang, W.; Wang, X. Research progress on chemical constituents and pharmacological effects of Strychnos nux -vomica. J. Pharm. Res., 2014, (10), 603-606.
[34]
Mateen, S.; Zafar, A.; Moin, S.; Khan, A.Q.; Zubair, S. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin. Chim. Acta., 2016, 455, 161-171.
[http://dx.doi.org/10.1016/j.cca.2016.02.010] [PMID: 26883280]
[http://dx.doi.org/10.1016/j.cca.2016.02.010] [PMID: 26883280]
[35]
Favalli, E.G. Understanding the role of interleukin-6 (IL-6) in the joint and beyond: A comprehensive review of IL-6 inhibition for the management of rheumatoid arthritis. Rheumatol. Ther., 2020, 7(3), 473-516.
[http://dx.doi.org/10.1007/s40744-020-00219-2] [PMID: 32734482]
[http://dx.doi.org/10.1007/s40744-020-00219-2] [PMID: 32734482]
[36]
Zhao, Z.; Xu, J.; Wang, R.; Xu, L. Expression and significance of NLRP3 inflammasome and its downstream factors IL-1β/IL-18 in synovium of rheumatoid arthritis. Chinese J. Clinic. Exp. Pathol., 2019, 35(5), 534-538.
[37]
Cabal-Hierro, L.; Lazo, P.S. Signal transduction by tumor necrosis factor receptors. Cell. Signal., 2012, 24(6), 1297-1305.
[http://dx.doi.org/10.1016/j.cellsig.2012.02.006] [PMID: 22374304]
[http://dx.doi.org/10.1016/j.cellsig.2012.02.006] [PMID: 22374304]
[38]
Wertz, I.E. TNFR1-activated NF-κB signal transduction: Regulation by the ubiquitin/proteasome system. Curr. Opin. Chem. Biol., 2014, 23, 71-77.
[http://dx.doi.org/10.1016/j.cbpa.2014.10.011] [PMID: 25461388]
[http://dx.doi.org/10.1016/j.cbpa.2014.10.011] [PMID: 25461388]
[39]
Benderska, N.; Chakilam, S.; Hugle, M.; Ivanovska, J.; Gandesiri, M.; Schulze-Luhrmann, J.; Bajbouj, K.; Croner, R.; Schneider-Stock, R. Apoptosis signalling activated by TNF in the lower gastrointestinal tract--review. Curr. Pharm. Biotechnol., 2012, 13(11), 2248-2258.
[http://dx.doi.org/10.2174/138920112802501971] [PMID: 21605069]
[http://dx.doi.org/10.2174/138920112802501971] [PMID: 21605069]
[40]
Chu, W.M. Tumor necrosis factor. Cancer Lett., 2013, 328(2), 222-225.
[http://dx.doi.org/10.1016/j.canlet.2012.10.014] [PMID: 23085193]
[http://dx.doi.org/10.1016/j.canlet.2012.10.014] [PMID: 23085193]
[41]
Ma, Y.; Jiang, Z.; Jin, Y.; Miao, Q.; Zhang, C.; Zhang, L. Gene ontology analysis of the TNF signaling pathway in early orthodontic tooth movement of rats with peri-odontitis. J. Dent. Prevent. Treat., 2019, 27(11), 695-702.
[42]
Calmon-Hamaty, F.; Audo, R.; Combe, B.; Morel, J.; Hahne, M. Targeting the Fas/FasL system in rheumatoid arthritis therapy: Promising or risky? Cytokine, 2015, 75(2), 228-233.
[http://dx.doi.org/10.1016/j.cyto.2014.10.004] [PMID: 25481649]
[http://dx.doi.org/10.1016/j.cyto.2014.10.004] [PMID: 25481649]
[43]
Wang, M.; Su, P. The role of the Fas/FasL signaling pathway in environmental toxicant-induced testicular cell apoptosis: An update. Syst. Biol. Reprod Med., 2018, 64(2), 93-102.
[http://dx.doi.org/10.1080/19396368.2017.1422046] [PMID: 29299971]
[http://dx.doi.org/10.1080/19396368.2017.1422046] [PMID: 29299971]
[44]
Kiraz, Y.; Adan, A.; Kartal Yandim, M.; Baran, Y. Major apoptotic mechanisms and genes involved in apoptosis. Tumour Biol., 2016, 37(7), 8471-8486.
[http://dx.doi.org/10.1007/s13277-016-5035-9] [PMID: 27059734]
[http://dx.doi.org/10.1007/s13277-016-5035-9] [PMID: 27059734]
[45]
Xu, X.; Lai, Y.; Hua, Z.C. Apoptosis and apoptotic body: Disease message and therapeutic target potentials. Biosci. Rep., 2019, 39(1), BSR20180992.
[http://dx.doi.org/10.1042/BSR20180992] [PMID: 30530866]
[http://dx.doi.org/10.1042/BSR20180992] [PMID: 30530866]
[46]
Abd El-Rahman, R.S.; Suddek, G.M.; Gameil, N.M.; El-kashef, H.A. Protective potential of MMR vaccine against complete Freund’s adjuvant-induced inflammation in rats. Inflammopharmacology, 2011, 19(6), 343-348.
[http://dx.doi.org/10.1007/s10787-011-0094-4] [PMID: 22081121]
[http://dx.doi.org/10.1007/s10787-011-0094-4] [PMID: 22081121]
[47]
Choudhary, N.; Bhatt, L.K.; Prabhavalkar, K.S. Experimental animal models for rheumatoid arthritis. Immunopharmacol. Immunotoxicol., 2018, 40(3), 193-200.
[http://dx.doi.org/10.1080/08923973.2018.1434793] [PMID: 29433367]
[http://dx.doi.org/10.1080/08923973.2018.1434793] [PMID: 29433367]
