Current Computer-Aided Drug DesignCurrent Computer-Aided Drug DesignCurrent Computer-Aided Drug Design1573-40991875-6697Bentham Science64395810.2174/1573409919666230420083102ChemistryResearch ArticleEvaluation of the Mechanism of Sinomenii Caulis in Treating Ulcerative Colitis based on Network Pharmacology and Molecular DockingTianJuaninfo@benthamscience.netYangChanggenginfo@benthamscience.netWangYuninfo@benthamscience.netZhouCanlininfo@benthamscience.netLife Science and Technology School, Lingnan Normal University0103202420319520707012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://rjeid.com/1573-4099/article/view/643958

Background:Studies have indicated that Sinomenii Caulis (SC) has several physiological activities, such as anti-inflammatory, anti-cancer, immunosuppression, and so on. SC is currently widely used in the treatment of rheumatoid arthritis, skin disease, and other diseases. However, the mechanism of SC in the treatment of ulcerative colitis (UC) remains unclear.

Aims:To predict the active components of SC and determine the mechanism of SC on UC.

Methods:Active components and targets of SC were screened and obtained by TCMSP, PharmMapper, and CTD databases. The target genes of UC were searched from GEO (GSE9452), and DisGeNET databases. Based on the String database, Cytoscape 3.7.2 software, and David 6.7 database, we analyzed the relationship between SC active components and UC potential targets or pathways. Finally, identification of SC targets in anti-UC by molecular docking. GROMACS software was used to perform molecular dynamics simulations of protein and compound complexes and to perform free energy calculations.

Results:Six main active components, 61 potential anti-UC gene targets, and the top 5 targets with degree value are IL6, TNF, IL1β, CASP3, and SRC. According to GO enrichment analysis, the vascular endothelial growth factor receptor and vascular endothelial growth factor stimulus may be relevant biological processes implicated in the treatment of UC by SC. The KEGG pathway analysis result was mainly associated with the IL-17, AGE-RAGE, and TNF signaling pathways. Based on molecular docking results, beta-sitosterol, 16-epi-Isositsirikine, Sinomenine, and Stepholidine are strongly bound to the main targets. Molecular dynamics simulation results showed that IL1B/beta-sitosterol and TNF/16-epi-Isositsirikine binding was more stable.

Conclusion:SC can play a therapeutic role in UC through multiple components, targets, and pathways. The specific mechanism of action needs to be further explored.

Sinomenii Caulisulcerative colitisnetwork pharmacologymolecular dockingoxidative stressinflammation.Fumery, M; Singh, S; Dulai, P; Gower-Rousseau, C; Peyrin-Biroulet, L; Sandborn, W Natural history of adult ulcerative colitis in population-based cohorts: A systematic review. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2018, 16, 343-56.Ulcerative colitis. Nat. Rev. Dis. Primers, 2020, 6(1), 73. doi: 10.1038/s41572-020-00215-4 PMID: 32913215Ng, S.C.; Shi, H.Y.; Hamidi, N.; Underwood, F.E.; Tang, W.; Benchimol, E.I.; Panaccione, R.; Ghosh, S.; Wu, J.C.Y.; Chan, F.K.L.; Sung, J.J.Y.; Kaplan, G.G. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies. Lancet, 2017, 390(10114), 2769-2778. doi: 10.1016/S0140-6736(17)32448-0 PMID: 29050646Kamm, M.A. Rapid changes in epidemiology of inflammatory bowel disease. Lancet, 2017, 390(10114), 2741-2742. doi: 10.1016/S0140-6736(17)32669-7 PMID: 29050647Ng, S.C.; Kaplan, G.G.; Tang, W.; Banerjee, R.; Adigopula, B.; Underwood, F.E.; Tanyingoh, D.; Wei, S.C.; Lin, W.C.; Lin, H.H.; Li, J.; Bell, S.; Niewiadomski, O.; Kamm, M.A.; Zeng, Z.; Chen, M.; Hu, P.; Ong, D.; Ooi, C.J.; Ling, K.L.; Miao, Y.; Miao, J.; Janaka de Silva, H.; Niriella, M.; Aniwan, S.; Limsrivilai, J.; Pisespongsa, P.; Wu, K.; Yang, H.; Ng, K.K.; Yu, H.H.; Wang, Y.; Ouyang, Q.; Abdullah, M.; Simadibrata, M.; Gunawan, J.; Hilmi, I.; Lee Goh, K.; Cao, Q.; Sheng, H.; Ong-Go, A.; Chong, V.H.; Ching, J.Y.L.; Wu, J.C.Y.; Chan, F.K.L.; Sung, J.J.Y. Population density and risk of inflammatory bowel disease: A prospective population-based study in 13 Countries or regions in Asia-Pacific. Am. J. Gastroenterol., 2019, 114(1), 107-115. doi: 10.1038/s41395-018-0233-2 PMID: 30177785Zhou, T.; Sheng, Y.; Guan, H.; Meng, R.; Wang, Z. Cost-effectiveness analysis of vedolizumab compared with infliximab in Anti-TNF-α-Naïve patients with moderate-to-severe ulcerative colitis in China. Front. Public Health, 2021, 9, 704889. doi: 10.3389/fpubh.2021.704889 PMID: 34490187Huang, J.; Zhang, J.; Ma, J.; Ma, J.; Liu, J.; Wang, F.; Tang, X. Inhibiting ferroptosis: A novel approach for ulcerative colitis therapeutics. Oxid. Med. Cell. Longev., 2022, 2022, 9678625. doi: 10.1155/2022/9678625 PMID: 35378823Ungaro, R.C.; Limketkai, B.N.; Jensen, C.B.; Allin, K.H.; Agrawal, M.; Ullman, T.; Colombel, J.F.; Jess, T. Stopping 5-aminosalicylates in patients with ulcerative colitis starting biologic therapy does not increase the risk of adverse clinical outcomes: analysis of two nationwide population-based cohorts. Gut, 2019, 68(6), 977-984. doi: 10.1136/gutjnl-2018-317021 PMID: 30420398Cao, S.Y.; Ye, S.J.; Wang, W.W.; Wang, B.; Zhang, T.; Pu, Y.Q. Progress in active compounds effective on ulcerative colitis from Chinese medicines. Chin. J. Nat. Med., 2019, 17(2), 81-102. doi: 10.1016/S1875-5364(19)30012-3 PMID: 30797423Wang, L.J.; Jiang, Z.M.; Xiao, P.T.; Sun, J.B.; Bi, Z.M.; Liu, E.H. Identification of anti-inflammatory components in Sinomenii Caulis based on spectrum-effect relationship and chemometric methods. J. Pharm. Biomed. Anal., 2019, 167, 38-48. doi: 10.1016/j.jpba.2019.01.047 PMID: 30738242Kim, S.; Shoemaker, B.A.; Bolton, E.E.; Bryant, S.H. Finding potential multitarget ligands using PubChem. Methods Mol. Biol., 2018, 1825, 63-91. doi: 10.1007/978-1-4939-8639-2_2 PMID: 30334203Cheng, F.; Kovács, I.A.; Barabási, A.L. Network-based prediction of drug combinations. Nat. Commun., 2019, 10(1), 1197. doi: 10.1038/s41467-019-09186-x PMID: 30867426Tao, Q.; Du, J.; Li, X.; Zeng, J.; Tan, B.; Xu, J.; Lin, W.; Chen, X. Network pharmacology and molecular docking analysis on molecular targets and mechanisms of Huashi Baidu formula in the treatment of COVID-19. Drug Dev. Ind. Pharm., 2020, 46(8), 1345-1353. doi: 10.1080/03639045.2020.1788070 PMID: 32643448Shen, Z.H.; Zhu, C.X.; Quan, Y.S.; Yang, Z.Y.; Wu, S.; Luo, W.W.; Tan, B.; Wang, X.Y. Relationship between intestinal microbiota and ulcerative colitis: Mechanisms and clinical application of probiotics and fecal microbiota transplantation. World J. Gastroenterol., 2018, 24(1), 5-14. doi: 10.3748/wjg.v24.i1.5 PMID: 29358877Zhao, X.X.; Peng, C.; Zhang, H.; Qin, L.P. Sinomenium acutum: A review of chemistry, pharmacology, pharmacokinetics, and clinical use. Pharm. Biol., 2012, 50(8), 1053-1061. doi: 10.3109/13880209.2012.656847 PMID: 22775422Shou, X.; Wang, Y.; Zhang, X.; Zhang, Y.; Yang, Y.; Duan, C.; Yang, Y.; Jia, Q.; Yuan, G.; Shi, J.; Shi, S.; Cui, H.; Hu, Y. Network pharmacology and molecular docking analysis on molecular mechanism of qingzi zhitong decoction in the treatment of ulcerative colitis. Front. Pharmacol., 2022, 13, 727608. doi: 10.3389/fphar.2022.727608 PMID: 35237152Zhou, Y.; Liu, H.; Song, J.; Cao, L.; Tang, L.; Qi, C. Sinomenine alleviates dextran sulfate sodium induced colitis via the Nrf2/NQO 1 signaling pathway. Mol. Med. Rep., 2018, 18(4), 3691-3698. doi: 10.3892/mmr.2018.9378 PMID: 30106158Tan, Y.Y.; Ding, Y.; Zheng, X.; Dai, G.J.; Zhang, S.M.; Yang, X.; Xu, D.C.; Chen, P.; Zhang, J.M.; Ma, J.Z.; Li, M.; Huang, S.C.; Liu, Y.; Zhang, Y.T.; Xing, H.; Ding, K.; Ding, Y.J. Ding’s herbal enema treats dextran sulfate sodium induced colitis in mice by regulating the gut microbiota and maintaining the Treg/Th17 cell balance. Exp. Ther. Med., 2021, 22(6), 1368. doi: 10.3892/etm.2021.10802 PMID: 34659514Xiong, L.; Yang, L. Effects of alkaloid sinomenine on levels of IFN-γ, IL-1β, TNF-α and IL-6 in a rat renal allograft model. Immunotherapy, 2012, 4(8), 785-791. doi: 10.2217/imt.12.80 PMID: 22947007Li, Y.; Duan, Z.; Tian, Y.; Liu, Z.; Wang, Q. A novel perspective and approach to intestinal octreotide absorption: Sinomenine-mediated reversible tight junction opening and its molecular mechanism. Int. J. Mol. Sci., 2013, 14(6), 12873-12892. doi: 10.3390/ijms140612873 PMID: 23787475Yu, Q.; Zhu, S.; Zhou, R.; Yi, F.; Bing, Y.; Huang, S.; Wang, Z.; Wang, C.; Xia, B. Effects of sinomenine on the expression of microRNA-155 in 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice. PLoS One, 2013, 8(9), e73757. doi: 10.1371/journal.pone.0073757 PMID: 24066068Ubeda, A.; Montesinos, C.; Payá, M.; Alcaraz, M.J. Iron-reducing and free-radical-scavenging properties of apomorphine and some related benzylisoquinolines. Free Radic. Biol. Med., 1993, 15(2), 159-167. doi: 10.1016/0891-5849(93)90055-Y PMID: 8397141Alattar, A; Alshaman, R; Al-Gayyar, M Therapeutic effects of sulforaphane in ulcerative colitis: Effect on antioxidant activity, mitochondrial biogenesis and DNA polymerization. Redox report : Communications in free radical research, 2022, 27, 128-38.Mukhopadhyay, S.; El-Sayed, A.; Handy, G.A.; Cordell, G.A. Catharanthus alkaloids XXXVII. 16-Epi-Z-isositsirikine, a monomeric indole alkaloid with antineoplastic activity from Catharanthus roseus and Rhazya stricta. J. Nat. Prod., 1983, 46(3), 409-413. doi: 10.1021/np50027a019 PMID: 6619887Guimbaud, R.; Bertrand, V.; Chauvelot-Moachon, L.; Quartier, G.; Vidon, N.; Giroud, J.P.; Couturier, D.; Chaussade, S. Network of inflammatory cytokines and correlation with disease activity in ulcerative colitis. Am. J. Gastroenterol., 1998, 93(12), 2397-2404. doi: 10.1111/j.1572-0241.1998.00694.x PMID: 9860399Lacruz-Guzmán, D.; Torres-Moreno, D.; Pedrero, F.; Romero-Cara, P.; García-Tercero, I.; Trujillo-Santos, J.; Conesa-Zamora, P. Influence of polymorphisms and TNF and IL1β serum concentration on the infliximab response in Crohn’s disease and ulcerative colitis. Eur. J. Clin. Pharmacol., 2013, 69(3), 431-438. doi: 10.1007/s00228-012-1389-0 PMID: 22960943West, N.R.; McCuaig, S.; Franchini, F.; Powrie, F. Emerging cytokine networks in colorectal cancer. Nat. Rev. Immunol., 2015, 15(10), 615-629. doi: 10.1038/nri3896 PMID: 26358393Zhang, Y.; Zhang, Y.; Zhao, Y.; Wu, W.; Meng, W.; Zhou, Y.; Qiu, Y.; Li, C. Protection against ulcerative colitis and colorectal cancer by evodiamine via anti inflammatory effects. Mol. Med. Rep., 2022, 25(5), 188. doi: 10.3892/mmr.2022.12704 PMID: 35362542Xu, Z; Zhang, X; Lu, R; Zhang, D; Zou, T Mechanism of fructus mume pills underlying their protective effects in rats with acetic acid-inducedulcerative colitis via the regulation of inflammatory cytokines and the VEGF-PI3K/Akt-eNOS signaling pathway. Evidence-based complementary and alternative medicine : eCAM, 2022, 4621131.Tesoriere, L.; Attanzio, A.; Allegra, M.; Gentile, C.; Livrea, M.A. Indicaxanthin inhibits NADPH oxidase (NOX)-1 activation and NF-κB-dependent release of inflammatory mediators and prevents the increase of epithelial permeability in IL-1β-exposed Caco-2 cells. Br. J. Nutr., 2014, 111(3), 415-423. doi: 10.1017/S0007114513002663 PMID: 23931157Can, G.; Ayvaz, S.; Can, H. Karaboğa, İ; Demirtaş, S.; Akşit, H.; Yılmaz, B.; Korkmaz, U.; Kurt, M.; Karaca, T. The efficacy of tyrosine kinase inhibitor dasatinib on colonic mucosal damage in murine model of colitis. Clin. Res. Hepatol. Gastroenterol., 2016, 40(4), 504-516. doi: 10.1016/j.clinre.2015.12.006 PMID: 26823039Seok Yang, W.; Lee, J.; Woong Kim, T.; Hye Kim, J.; Lee, S.; Hee Rhee, M.; Hong, S.; Youl Cho, J. Src/NF-κB-targeted inhibition of LPS-induced macrophage activation and dextran sodium sulphate-induced colitis by Archidendron clypearia methanol extract. J. Ethnopharmacol., 2012, 142(1), 287-293. doi: 10.1016/j.jep.2012.04.026 PMID: 22537838Zhang, X.; Deng, Q.H.; Deng, J.H.; Wang, S.J.; Chen, Q. Lovastatin derivative dehydrolovastatin ameliorates ulcerative colitis in mice by suppressing NF-κB and inflammatory cytokine expression. Korean J. Physiol. Pharmacol., 2020, 24(2), 137-147. doi: 10.4196/kjpp.2020.24.2.137 PMID: 32140037Ding, Y; Chen, M; Wang, Q; Gao, L; Feng, Y Integrating pharmacology and microbial network analysis with experimental validation to reveal the mechanism of composite sophora colon-soluble capsule against ulcerative colitis. Evidence-based complementary and alternative medicine : eCAM, 2020, 9521073.Fukami, K.; Yamagishi, S.; Okuda, S. Role of AGEs-RAGE system in cardiovascular disease. Curr. Pharm. Des., 2014, 20(14), 2395-2402. doi: 10.2174/13816128113199990475 PMID: 23844818Moura, F.A.; Goulart, M.O.F.; Campos, S.B.G.; da Paz Martins, A.S. The close interplay of nitro-oxidative stress, advanced glycation end products and inflammation in inflammatory bowel diseases. Curr. Med. Chem., 2020, 27(13), 2059-2076. doi: 10.2174/0929867325666180904115633 PMID: 30182837Schliemann, M.; Bullinger, E.; Borchers, S.; Allgöwer, F.; Findeisen, R.; Scheurich, P. Heterogeneity reduces sensitivity of cell death for TNF-Stimuli. BMC Syst. Biol., 2011, 5(1), 204. doi: 10.1186/1752-0509-5-204 PMID: 22204418Frey, M.R.; Edelblum, K.L.; Mullane, M.T.; Liang, D.; Polk, D.B. The ErbB4 growth factor receptor is required for colon epithelial cell survival in the presence of TNF. Gastroenterology, 2009, 136(1), 217-226. doi: 10.1053/j.gastro.2008.09.023 PMID: 18973758