Journal of Traditional Chinese Medicine >
Efficacy of active ingredients in Qingdai (Indigo Naturalis) on ulcerative colitis: a network pharmacology-based evaluation
Received date: 2021-11-29
Accepted date: 2022-02-11
Online published: 2023-01-10
Supported by
Mechanism of Chang-An Decotion in Neuropeptide Spexin related GSK-3 β Regulating Intestinal Nerve Immune Network in Ulcerative Colitis(2018A030310614);Mchanism of Chang-An Decotion in Intestinal Mucosal Immunity of Ulcerative Colitis on Exocrine Mediated Rab27(81903963);Mchanism of Chang-An decotion of Ulcerative Colitis on Exocrine Mediated GSK-3 β Regulating Th17/Treg in Ulcerative Colitis(2017KQNCX045)
OBJECTIVE: To elucidate the protective effect of Qingdai (Indigo Naturalis, QD) on ulcerative colitis (UC) by means of in silico and in vivo approaches.
METHODS: A systems pharmacology analysis was per-formed to predict the active components of QD whereas the putative biological targets of QD against UC were obtained through target fishing, network cons-truction and enrichment analyses. Meanwhile, we examined the ameliorative effect of QD in a mouse model of dextran sulfate sodium (DSS)-induced colitis. During the 10-day experiment, the control and diseased mice were given with oral gavages of QD (1.3 g raw herbs·kg-1·d-1) or 5‐aminosalicylic acid (5-ASA, 100 mg·kg-1·d-1) every day. The underlying pharma-cological mechanisms of QD in UC were determined using polymerase chain reaction tests, histological staining, enzyme-linked immunoassays, and Western blotting analysis.
RESULTS: Searching from various network pharmacology databases, 29 compounds were identified in QD. According to the screening criteria suggested by TCMSP (i.e. OB ≥ 30% and DL ≥ 0.18), nine of them were considered the active ingredients that contribute to the ameliorative effects of QD on different mouse models of colitis. Most importantly, the protective effect of QD on DSS-induced colitis was significantly associated with modulations of the expression levels of glycogen synthase kinase 3-β (Gsk3-β) and forkhead box p3 (Foxp3), which are widely considered as important regulators of excessive inflammatory responses.
CONCLUSIONS: The results of this study provide solid scientific evidence for the use of QD or its core active components in the clinical management of UC.
Yue LI , Shuting WEN , Runyuan ZHAO , Dongmei FAN , Dike ZHAO , Fengbin LIU , Hong MI . Efficacy of active ingredients in Qingdai (Indigo Naturalis) on ulcerative colitis: a network pharmacology-based evaluation[J]. Journal of Traditional Chinese Medicine, 2023 , 43(1) : 124 -133 . DOI: 10.19852/j.cnki.jtcm.2023.01.011
| 1 | Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet 2017; 389: 1756-70. |
| 2 | Doherty G, Katsanos KH, Burisch J, et al. European crohn's and colitis organisation topical review on treatment withdrawal ['exit strategies'] in inflammatory bowel disease. J Crohns Colitis 2018; 12: 17-31. |
| 3 | Zhao L, Zhang S, He P. Mechanistic understanding of herbal therapy in inflammatory bowel disease. Curr Pharm Des 2017; 23: 5173-79. |
| 4 | Yang Y, Zhang Z, Li S, Ye X, Li X, He K. Synergy effects of herb extracts: pharmacokinetics and pharmacodynamic basis. Fitoterapia 2014; 92: 133-47. |
| 5 | Shimada F, Yoshimatsu Y, Sujino T, Fukuda T, Naganuma M, Kanai T. Su473 natural history after the induction therapy in uc patients with indigo naturalis. Gastroenterology 2021; 160: S-708. |
| 6 | Antonio-Cisneros CM, Dávila-Jiménez MM, Elizalde-González MP, García-Díaz E. Tio2 immobilized on manihot carbon: Optimal preparation and evaluation of its activity in the decomposition of indigo carmine. Int J Mol Sci 2015; 16: 1590-612. |
| 7 | Li S. Framework and practice of network-based studies for Chinese herbal formula. Zhong Xi Yi Jie He Xue Bao 2007; 5: 489-93. |
| 8 | Ru J, Li P, Wang J, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014; 6: 13. |
| 9 | Liu Z, Guo F, Wang Y, et al. Batman-TCM: a bioinformatics analysis tool for molecular mechanism of Traditional Chinese Medicine. Sci Rep 2016; 6: 21146. |
| 10 | Xue R, Fang Z, Zhang M, Yi Z, Wen C, Shi T. TCMID: Traditional Chinese Medicine integrative database for herb molecular mechanism analysis. Nucleic Acids Res 2013; 41: D1089-95. |
| 11 | Daina A, Michielin O, Zoete V. Swisstargetprediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 2019; 47: W357-64. |
| 12 | Liu X, Ouyang S, Yu B, et al. Pharmmapper server: a web server for potential drug target identification using pharmacophore mapping approach. Nucleic Acids Res 2010; 38: W609-14. |
| 13 | Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13: 2498-504. |
| 14 | Hamosh A, Scott AF, Amberger J, Bocchini C, Valle D, McKusick VA. Online mendelian inheritance in man (omim), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res 2002; 30: 52-5. |
| 15 | Yang H, Qin C, Li YH, et al. Therapeutic target database update 2016: enriched resource for bench to clinical drug target and targeted pathway information. Nucleic Acids Res 2016; 44: D1069-74. |
| 16 | Thorn CF, Klein TE, Altman RB. Pharmgkb: the pharmacogenomics knowledge base. Methods Mol Biol 2013; 1015: 311-20. |
| 17 | Kim J, So S, Lee HJ, Park JC, Kim JJ, Lee H. Digsee: disease gene search engine with evidence sentences (version cancer). Nucleic Acids Res 2013; 41: W510-7. |
| 18 | Mandloi S, Chakrabarti S. Palm-ist: pathway assembly from literature mining--an information search tool. Sci Rep 2015; 5: 10021. |
| 19 | Liu Y, Liang Y, Wishart D. Polysearch2: a significantly improved text-mining system for discovering associations between human diseases, genes, drugs, metabolites, toxins and more. Nucleic Acids Res 2015; 43: W535-42. |
| 20 | de Leeuw N, Dijkhuizen T, Hehir-Kwa JY, et al. Diagnostic interpretation of array data using public databases and internet sources. Hum Mutat 2012; 33: 930-40. |
| 21 | Szklarczyk D, Morris JH, Cook H, et al. The string database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 2017; 45: D362-8. |
| 22 | Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho JK. Role of cytokines in inflammatory bowel disease. World J Gastroenterol 2008; 14: 4280-8. |
| 23 | Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF. Scurfin (foxp3) acts as a repressor of transcription and regulates t cell activation. J Biol Chem 2001; 276: 37672-9. |
| 24 | Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory t cells. Nat Immunol 2003; 4: 330-6. |
| 25 | Naganuma M. Treatment with indigo naturalis for inflammatory bowel disease and other immune diseases. Immunol Med 2019; 42: 16-21. |
| 26 | Leclerc S, Garnier M, Hoessel R, et al. Indirubins inhibit glycogen synthase kinase-3 beta and cdk5/p25, two protein kinases involved in abnormal tau phosphorylation in alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors? J Biol Chem 2001; 276: 251-60. |
| 27 | Eisenbrand G, Hippe F, Jakobs S, Muehlbeyer S. Molecular mechanisms of indirubin and its derivatives: Novel anticancer molecules with their origin in traditional Chinese phytomedicine. J Cancer Res Clin Oncol 2004; 130: 627-35. |
| 28 | Xiao HT, Peng J, Wen B, et al. Indigo naturalis suppresses colonic oxidative stress and th1/th 17 responses of dss-induced colitis in mice. Oxid Med Cell Longev 2019;2019: 9480945. |
| 29 | Hofmann C, Dunger N, Sch?lmerich J, Falk W, Obermeier F. Glycogen synthase kinase 3-β: a master regulator of toll-like receptor-mediated chronic intestinal inflammation. Inflamm Bowel Dis 2010; 16: 1850-8. |
| 30 | Whittle BJ, Varga C, Pósa A, Molnár A, Collin M, Thiemermann C. Reduction of experimental colitis in the rat by inhibitors of gly-cogen synthase kinase-3beta. Br J Pharmacol 2006; 147: 575-82. |
| 31 | Beurel E, Grieco SF, Jope RS. Glycogen synthase kinase-3 (gsk3): regulation, actions, and diseases. Pharmacol Ther 2015; 148: 114-31. |
| 32 | Elson CO, Cong Y, Weaver CT, et al. Monoclonal anti-interleukin 23 reverses active colitis in a t cell-mediated model in mice. Gastroenterology 2007; 132: 2359-70. |
| 33 | Takahashi-Yanaga F. Activator or inhibitor? Gsk-3 as a new drug target. Biochem Pharmacol 2013; 86: 191-9. |
| 34 | Cortés-Vieyra R, Bravo-Pati?o A, Valdez-Alarcón JJ, Juárez MC, Finlay BB, Baizabal-Aguirre VM. Role of glycogen synthase kinase-3 beta in the inflammatory response caused by bacterial pathogens. J Inflamm (Lond) 2012; 9: 23. |
| 35 | Mi H, Liu FB, Li HW, Hou JT, Li PW. Anti-inflammatory effect of chang-an-shuan on tnbs-induced experimental colitis in rats. BMC Complement Altern Med 2017; 17: 315. |
| 36 | Harada K, Shimoda S, Sato Y, Isse K, Ikeda H, Nakanuma Y. Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis. Clin Exp Immunol 2009; 157: 261-70. |
| 37 | Graham JA, Fray M, de Haseth S, et al. Suppressive regulatory t cell activity is potentiated by glycogen synthase kinase 3{beta} inhibition. J Biol Chem 2010;285: 32852-59. |
| 38 | Cosmi L, Santarlasci V, Maggi L, Liotta F, Annunziato F. Th17 plasticity: pathophysiology and treatment of chronic inflammatory disorders. Curr Opin Pharmacol 2014; 17: 12-6. |
| 39 | Romagnani S, Maggi E, Liotta F, Cosmi L, Annunziato F. Properties and origin of human th17 cells. Mol Immunol 2009; 47: 3-7. |
| 40 | Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. The phenotype of human th17 cells and their precursors, the cytokines that mediate their differentiation and the role of th17 cells in inflammation. Int Immunol 2008; 20: 1361-8. |
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