An Investigation of the Mechanism of Rapid Relief of Ulcerative Colitis Induced by Five-flavor Sophora Flavescens Enteric-coated Capsules Based on Network Pharmacology

Author(s): Sizhen Gu, Yan Xue, Yuli Zhang, Kanjun Chen, Shigui Xue, Ji Pan, Yini Tang, Hui Zhu, Huan Wu, Danbo Dou*

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 23 , Issue 3 , 2020

Become EABM
Become Reviewer

Abstract:

Aim and Objective: Five-Flavor Sophora flavescens Enteric-Coated Capsules (FSEC) are the only proprietary Chinese medicine approved for the treatment of ulcerative colitis (UC) in China. Phase II and III clinical trials have shown that the curative effect of FSEC in relieving UC was not inferior to that of mesalazine granules and enteric-coated tablets, but its pharmacological mechanism is unclear. Therefore, the network pharmacology is used to reveal the more comprehensive effective components and targets of FSEC in the treatment of UC.

Methods: We screened the components of FSEC based on the TCMSP database, determined the action targets of these compounds through target fishing, and integrated the UC disease targets of several disease gene databases. The FSEC-UC composite targets were obtained by matching the two results, and then a PPI network was constructed to analyze the relationship between these targets, and the core targets were selected by topological correlation parameters. Finally, GO-BP and KEGG enrichment analyses were carried out using the clusterProfiler software package.

Results: One hundred and sixty active components of FSEC were identified and 77 targets were obtained. Of these, 30 core targets were the main targets of FESC in the treatment of UC. And quercetin, kaempferol, luteolin and mangiferin were regarded as the core active components of FSEC. The results screened by GO and KEGG enrichment analysis showed that FSEC played a comprehensive therapeutic role in immune recognition, anti-inflammation and antioxidation mainly through IL-17, TNF, Toll-like receptor, NF-kappa B, and Th17 cell differentiation.

Conclusion: The molecular mechanism of UC remission induced by FSEC was predicted by network pharmacology. These findings provide an important theoretical basis for further study of the effective substances and mechanism of FSEC in the treatment of UC.

Keywords: Five-flavor sophora flavescens enteric-coated capsules (FSEC), network pharmacology, ulcerative colitis, chinese medicine, active compounds, UC treatment.

[1]
Drakos, P.E.; Nagler, A.; Or, R. Case of Crohn’s disease in bone marrow transplantation. Am. J. Hematol., 1993, 43(2), 157-158.
[http://dx.doi.org/10.1002/ajh.2830430223] [PMID: 8342550]
[2]
Oyama, Y.; Craig, R.M.; Traynor, A.E.; Quigley, K.; Statkute, L.; Halverson, A.; Brush, M.; Verda, L.; Kowalska, B.; Krosnjar, N.; Kletzel, M.; Whitington, P.F.; Burt, R.K. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn’s disease. Gastroenterology, 2005, 128(3), 552-563.
[http://dx.doi.org/10.1053/j.gastro.2004.11.051] [PMID: 15765390]
[3]
Cassinotti, A.; Annaloro, C.; Ardizzone, S.; Onida, F.; Della Volpe, A.; Clerici, M.; Usardi, P.; Greco, S.; Maconi, G.; Porro, G.B.; Deliliers, G.L. Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn’s disease. Gut, 2008, 57(2), 211-217.
[http://dx.doi.org/10.1136/gut.2007.128694] [PMID: 17895357]
[4]
Jin, C.; Yujie, M. lianghu, H.; Qinghua, W.; Yunfeng, F.; Jianming, T., Effect of age on isolation and culture of human bone marrow mesenchymal stem cells. Journal of practical. Medicine (Baltimore), 2010, 26(20), 3694-3697.
[5]
Zhanqi, T.; Bo, Y.; Xinyuan, T.; Qin, G.; Bingyue, C.; Zhengjun, W. A multicenter, randomized, double-blind, controlled study of compound Sophora flavescens colon-coated capsule in the treatment of damp-heat ulcerative colitis Chinese Journal of Integrated traditional Chinese and Western Medicine, 2011, 31(02), 172-176.
[6]
Gong, Y.; Zha, Q.; Li, L.; Liu, Y.; Yang, B.; Liu, L.; Lu, A.; Lin, Y.; Jiang, M. Efficacy and safety of Fufangkushen colon-coated capsule in the treatment of ulcerative colitis compared with mesalazine: a double-blinded and randomized study. J. Ethnopharmacol., 2012, 141(2), 592-598.
[http://dx.doi.org/10.1016/j.jep.2011.08.057] [PMID: 21911045]
[7]
Qinglin, M.; Kaihong, Z.; Lidong, D.; Hailong, L.; Haijing, D.; Yuan, R. Network pharmacology study of Wumei Pill in the treatment of ulcerative colitis. Pharmacology and Clinic of traditional. Chin. Med., 2019, 35(02), 11-16.
[8]
Huang, S.J.; Mu, F.; Li, F.; Wang, W.J.; Zhang, W.; Lei, L.; Ma, Y.; Wang, J.W. Systematic Elucidation of the Potential Mechanism of Erzhi Pill against Drug-Induced Liver Injury via Network Pharmacology Approach. Evid. Based Complement. Alternat. Med., 2020, 20206219432
[http://dx.doi.org/10.1155/2020/6219432] [PMID: 31998398]
[9]
Li, J.; Qi, X.; Sun, Y.; Zhang, Y.; Chen, J. Comb. Chem. High Throughput Screen., 2020.
[10]
Gang, L.; Bo, X.; Xuezhen, L.; Shuaishuai, G.; Congmin, X.; Bozhao, Y.; Jiacheng, L. Study on the molecular mechanism of Epimedium against osteoporosis based on network pharmacology. Zhongguo Yaolixue Tongbao, 2018, 34(02), 267-273.
[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, 13.
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[12]
Xu, X.; Zhang, W.; Huang, C.; Li, Y.; Yu, H.; Wang, Y.; Duan, J.; Ling, Y. A novel chemometric method for the prediction of human oral bioavailability. Int. J. Mol. Sci., 2012, 13(6), 6964-6982.
[http://dx.doi.org/10.3390/ijms13066964] [PMID: 22837674]
[13]
P, W.; M, B. J.; M, D. G., Chemical similarity searching. JChem Inf Comput Sci. J. Chem. Inf. Model., 1998, 38(6), 983-996.
[14]
Suh, S.Y.; An, W.G. Systems Pharmacological Approach of Pulsatillae Radix on Treating Crohn’s Disease. Evid. Based Complement. Alternat. Med., 2017, 20174198035
[http://dx.doi.org/10.1155/2017/4198035] [PMID: 28659988]
[15]
Haibo, L.; Yong, P.; Luqi, H.; Peigen, X. A rapid targeting method of natural products based on PubChem database. Chin. Herb. Med., 2012, 43(11), 2099-2106.
[16]
Keiser, M.J.; Roth, B.L.; Armbruster, B.N.; Ernsberger, P.; Irwin, J.J.; Shoichet, B.K. Relating protein pharmacology by ligand chemistry. Nat. Biotechnol., 2007, 25(2), 197-206.
[http://dx.doi.org/10.1038/nbt1284] [PMID: 17287757]
[17]
Li, Y.H.; Yu, C.Y.; Li, X.X.; Zhang, P.; Tang, J.; Yang, Q.; Fu, T.; Zhang, X.; Cui, X.; Tu, G.; Zhang, Y.; Li, S.; Yang, F.; Sun, Q.; Qin, C.; Zeng, X.; Chen, Z.; Chen, Y.Z.; Zhu, F. Therapeutic target database update 2018: enriched resource for facilitating bench-to-clinic research of targeted therapeutics. Nucleic Acids Res., 2018, 46(D1), D1121-D1127.
[PMID: 29140520]
[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]
[19]
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]
[20]
UniProt Consortium, T. UniProt: the universal protein knowledgebase. Nucleic Acids Res., 2018, 46(5), 2699.
[http://dx.doi.org/10.1093/nar/gky092] [PMID: 29425356]
[21]
Szklarczyk, D.; Morris, J.H.; Cook, H.; Kuhn, M.; Wyder, S.; Simonovic, M.; Santos, A.; Doncheva, N.T.; Roth, A.; Bork, P.; Jensen, L.J.; von Mering, C. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res., 2017, 45(D1), D362-D368.
[http://dx.doi.org/10.1093/nar/gkw937] [PMID: 27924014]
[22]
Yu, G.; Wang, L.G.; Han, Y.; He, Q.Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5), 284-287.
[http://dx.doi.org/10.1089/omi.2011.0118] [PMID: 22455463]
[23]
Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, 13(11), 2498-2504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[24]
Missiuro, P.V.; Liu, K.; Zou, L.; Ross, B.C.; Zhao, G.; Liu, J.S.; Ge, H. Information flow analysis of interactome networks. PLOS Comput. Biol., 2009, 5(4)e1000350
[http://dx.doi.org/10.1371/journal.pcbi.1000350] [PMID: 19503817]
[25]
Raman, K.; Damaraju, N.; Joshi, G.K. The organisational structure of protein networks: revisiting the centrality-lethality hypothesis. Syst. Synth. Biol., 2014, 8(1), 73-81.
[http://dx.doi.org/10.1007/s11693-013-9123-5] [PMID: 24592293]
[26]
Tang, Y.; Li, M.; Wang, J.; Pan, Y.; Wu, F.X. CytoNCA: a cytoscape plugin for centrality analysis and evaluation of protein interaction networks. Biosystems, 2015, 127, 67-72.
[http://dx.doi.org/10.1016/j.biosystems.2014.11.005] [PMID: 25451770]
[27]
Liu, Y.; Xing, H.; Jiang, X.; Chen, Y.; Huang, M.; Yu, S. Network pharmacology-based preventive effect of XZF on cutaneous toxicities induced by EGFR inhibitor. Biomed. Pharmacother., 2020, 123109755
[http://dx.doi.org/10.1016/j.biopha.2019.109755] [PMID: 31926375]
[28]
Li, L.; Qiu, H.; Liu, M.; Cai, Y. A Network Pharmacology-Based Study of the Molecular Mechanisms of Shaoyao-Gancao Decoction in Treating Parkinson’s Disease. Interdiscip. Sci., 2020.
[http://dx.doi.org/10.1007/s12539-020-00359-7] [PMID: 32006382]
[29]
Guo, X.; Ji, J.; Feng, Z.; Hou, X.; Luo, Y.; Mei, Z. A network pharmacology approach to explore the potential targets underlying the effect of sinomenine on rheumatoid arthritis. Int. Immunopharmacol., 2020, 80106201
[http://dx.doi.org/10.1016/j.intimp.2020.106201] [PMID: 31972421]
[30]
Endale, M.; Park, S.C.; Kim, S.; Kim, S.H.; Yang, Y.; Cho, J.Y.; Rhee, M.H. Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NF-κB-induced inflammatory mediators production in RAW 264.7 cells. Immunobiology, 2013, 218(12), 1452-1467.
[http://dx.doi.org/10.1016/j.imbio.2013.04.019] [PMID: 23735482]
[31]
Han, M.; Song, Y.; Zhang, X. Quercetin Suppresses the Migration and Invasion in Human Colon Cancer Caco-2 Cells Through Regulating Toll-like Receptor 4/Nuclear Factor-kappa B Pathway. Pharmacogn. Mag., 2016, 12(Suppl. 2), S237-S244.
[http://dx.doi.org/10.4103/0973-1296.182154] [PMID: 27279714]
[32]
Sharma, V.; Nehru, B.; Munshi, A.; Jyothy, A. Antioxidant potential of curcumin against oxidative insult induced by pentylenetetrazol in epileptic rats. Methods Find. Exp. Clin. Pharmacol., 2010, 32(4), 227-232.
[http://dx.doi.org/10.1358/mf.2010.32.4.1452090] [PMID: 20508869]
[33]
Suresh, D.; Srinivasan, K. Tissue distribution & elimination of capsaicin, piperine & curcumin following oral intake in rats. Indian J. Med. Res., 2010, 131, 682-691.
[PMID: 20516541]
[34]
Tingyu, Y.; Yani, L.; Shaojun, S. Research Progress on the Regulation of Drug Metabolic enzymes by moving Endothelin. Chinese Medicine Division, 2016, 19(03), 555-559.
[35]
Park, M.Y.; Ji, G.E.; Sung, M.K. Dietary kaempferol suppresses inflammation of dextran sulfate sodium-induced colitis in mice. Dig. Dis. Sci., 2012, 57(2), 355-363.
[http://dx.doi.org/10.1007/s10620-011-1883-8] [PMID: 21901258]
[36]
Bian, Y.; Liu, P.; Zhong, J.; Hu, Y.; Fan, Y.; Zhuang, S.; Liu, Z. Kaempferol inhibits multiple pathways involved in the secretion of inflammatory mediators from LPS‑induced rat intestinal microvascular endothelial cells. Mol. Med. Rep., 2019, 19(3), 1958-1964.
[PMID: 30569099]
[37]
Nunes, C.; Almeida, L.; Barbosa, R.M.; Laranjinha, J. Luteolin suppresses the JAK/STAT pathway in a cellular model of intestinal inflammation. Food Funct., 2017, 8(1), 387-396.
[http://dx.doi.org/10.1039/C6FO01529H] [PMID: 28067377]
[38]
Li, Y.; Shen, L.; Luo, H. Luteolin ameliorates dextran sulfate sodium-induced colitis in mice possibly through activation of the Nrf2 signaling pathway. Int. Immunopharmacol., 2016, 40, 24-31.
[http://dx.doi.org/10.1016/j.intimp.2016.08.020] [PMID: 27569028]
[39]
Wu, D.; Wu, K.; Zhu, Q.; Xiao, W.; Shan, Q.; Yan, Z.; Wu, J.; Deng, B.; Xue, Y.; Gong, W.; Lu, G.; Ding, Y. Formononetin Administration Ameliorates Dextran Sulfate Sodium-Induced Acute Colitis by Inhibiting NLRP3 Inflammasome Signaling Pathway. Mediators Inflamm., 2018, 20183048532
[PMID: 29507526]
[40]
Dan, L.; Lu, G.; Zhanqi, T.; Shida, W.; Liang, Z. chen, Z., Effect of Wuwei Sophora flavescens enteric-coated capsule on inflammatory factors in mice with ulcerative colitis. Chinese. J. Tradit. Chin. Med., 2018, 33(10), 4719-4722.
[41]
Dan, L.; Lu, G.; Zhanqi, T. Effects of Wuwei Sophora flavescens enteric-coated capsule on caspase-1 and IL-1 β protein in mice with ulcerative colitis. Journal of PLA Medical College, 2018, 39(02), 140-143+149.
[42]
Jia, Z.; Lin, S.; Heng, F.; Rui, Z. Effect of compound Sophora flavescens colon-coated capsule on the activation of NF- κ B and STAT6 in intestinal mucosa of patients with ulcerative colitis. Shi Zhenguo Medicine, 2009, 20(08), 1884-1886.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 23
ISSUE: 3
Year: 2020
Page: [239 - 252]
Pages: 14
DOI: 10.2174/1386207323666200302121711

Article Metrics

PDF: 35
HTML: 4
EPUB: 1
PRC: 1