Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease, and Gegen Qinlian Decoction (GQD), a Chinese botanical formula, has exhibited beneficial efficacy against UC. However, the mechanisms underlying the effect of GQD still remain to be elucidated. In this study, network pharmacology approach and molecular docking in silico were applied to uncover the potential multicomponent synergetic effect and molecular mechanisms. The targets of ingredients in GQD were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Bioinformatics Analysis Tool for Molecular mechANism of TCM (BATMAN-TCM) database, while the UC targets were retrieved from Genecards, therapeutic target database (TTD) and Online Mendelian Inheritance in Man (OMIM) database. The topological parameters of Protein-Protein Interaction (PPI) data were used to screen the hub targets in the network. The possible mechanisms were investigated with gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking was used to verify the binding affinity between the active compounds and hub targets. Network pharmacology analysis successfully identified 77 candidate compounds and 56 potential targets. The targets were further mapped to 20 related pathways to construct a compound-target-pathway network and an integrated network of GQD treating UC. Among these pathways, PI3K-AKT, HIF-1, VEGF, Ras, and TNF signaling pathways may exert important effects in the treatment of UC via inflammation suppression and anti-carcinogenesis. In the animal experiment, treatment with GQD and sulfasalazine (SASP) both ameliorated inflammation in UC. The proinflammatory cytokines (TNF-α, IL-1β, and IL-6) induced by UC were significantly decreased by GQD and SASP. Moreover, the protein expression of EGFR, PI3K, and phosphorylation of AKT were reduced after GQD and SASP treatment, and there was no significance between the GQD group and SASP group. Our study systematically dissected the molecular mechanisms of GQD on the treatment of UC using network pharmacology, as well as uncovered the therapeutic effects of GQD against UC through ameliorating inflammation via downregulating EGFR/PI3K/AKT signaling pathway and the pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6.
Highlights
Ulcerative colitis (UC), a subcategory of inflammatory bowel disease (IBD), is an idiopathic chronic inflammatory disorder of intestinal mucosa or lamina propria (Torres, et al, 2012)
In the network pharmacology study, we found that many active components, prediction targets and pathways related to gegen qinlian decoction (GQD) were involved in the inflammation, angiogenesis, cell proliferation and apoptosis, which are closely related to cell carcinogenesis in UC
From the integrated drug target prediction, pathway enrichment analysis and in vivo experiment, the results demonstrated that the effective downregulation of the expression of epidermal growth factor receptor erbB1 (EGFR), phosphoinositide 3-kinase (PI3K), and p-serine/threonine-protein kinase akt-1 (AKT) by the administration of GQD and SASP may contribute to ameliorating UC
Summary
Ulcerative colitis (UC), a subcategory of inflammatory bowel disease (IBD), is an idiopathic chronic inflammatory disorder of intestinal mucosa or lamina propria (Torres, et al, 2012). With continuous infiltration of immune cells and repeated stimulation of epithelial cells in intestinal mucosa, a risk of tumor initiation on UC has dramatically increased (Rubin et al, 2012). The options of medication depend on the severity of disease, while 5-Aminosalicylate and corticosteroids are recommended for mild to moderate UC (Bressler et al, 2015). Up to now no regular method is fit for every patient, and patients may require multiple and integral treatment modalities to achieve best therapeutic effect. This happened to coincide with the theory of traditional Chinese medicine (TCM) based on the comprehensive and individual medicinal system
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