Abstract
Objectives Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. This study was designed to uncover the healing effect of friedelin, a bioactive compound against UC through bioinformatics of network pharmacology and experimental verification of UC model mice. Materials and Methods Targets of friedelin and potential mechanism of friedelin on UC were predicted through target searching, PPI network establishing, and enrichment analyzing. We explored effects of friedelin on dextran sulfate sodium (DSS)-induced colitis. Severity of UC was investigated by body weight, disease activity index (DAI), and length of the colon. Inflammation severity was examined by determination of proinflammatory and anti-inflammatory cytokines. The numbers of autophagosome around the epithelial cells were observed by autophagy inhibition via a transmission electron microscope. The expressions of autophagy-related ATG5 protein and AMPK-mTOR signaling pathway were determined by immunofluorescence staining. Results In this study, 17 potential targets of friedelin and 1111 UC-related targets were identified. 10 therapeutic targets of friedelin against UC were acquired from overlapped targets of UC and friedelin. PPI network construction filtered 14 core targets through target amplification and confidence enhancement. The results of molecular docking showed that the docking scores of the top 5 active targets were higher than the threshold values. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out, showing friedelin alleviates UC through anti-inflammatory pathways and molecular function of autophagy. Subsequently, animal-based experiments revealed the intraperitoneal injection of friedelin ameliorated DSS-induced body weight loss, DAI decrease, colon length shortening and colonic pathological damage with lower myeloperoxidase and proinflammatory cytokines (IL-1β and IL-6) and higher IL-10 levels, and more autophagosomes in transmission electron microscope results. The AMPK-mTOR signaling pathway plays important role in the friedelin's effect in autophagy as KEGG pathway result and experiment verification. Furthermore, the 3 ma validated the role of autophagy as an improvement in the friedelin's pharmacologic effect to UC model mice. Conclusions Friedelin ameliorated DSS-induced colitis in mice through of inflammatory inhibition and regulation of autophagy.
Highlights
Ulcerative colitis (UC) and Crohn’s disease (CD), which both belong to chronic inflammation of the intestine, are the two main subtypes of inflammatory bowel disease (IBD) in clinical work [1]. e epidemiology of IBD is changing throughout the world at the turn of the 21st century. e incidence is stabilizing in western countries; incidence rates in newly industrialized countries have been increasing quickly, attributing to rapid socioeconomic development [2]. e main feature of UC is a recurrence cycle with mucosal ulceration and diffuse colonic inflammation [3]
Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to predict the mechanism of friedelin against UC
Discussion e conventional therapy for UC is mainly based on the anti-inflammatory medicine. e anti-inflammatory drug research for UC was initiated in lab and further extended to clinical in the past decades
Summary
Ulcerative colitis (UC) and Crohn’s disease (CD), which both belong to chronic inflammation of the intestine, are the two main subtypes of inflammatory bowel disease (IBD) in clinical work [1]. e epidemiology of IBD is changing throughout the world at the turn of the 21st century. e incidence is stabilizing in western countries; incidence rates in newly industrialized countries have been increasing quickly, attributing to rapid socioeconomic development [2]. e main feature of UC is a recurrence cycle with mucosal ulceration and diffuse colonic inflammation [3]. Ulcerative colitis (UC) and Crohn’s disease (CD), which both belong to chronic inflammation of the intestine, are the two main subtypes of inflammatory bowel disease (IBD) in clinical work [1]. E main feature of UC is a recurrence cycle with mucosal ulceration and diffuse colonic inflammation [3]. Several immune cells and immune-regulatory proteins participate in the disturbance of intestine immune system, which accounts for activation and augmentation of inflammation cascade in UC. The intestinal epithelial cells are the first barrier of any intestinal disease. Ese cells released a variety of proinflammatory cytokines which caused the injury of the colon Once the epithelial cells are damaged by external injury, such as excessive stress, mechanical damage, and chemical stimulation, the intestinal pathogens may enter the intestinal tract, trigger antigen presenting cells, and transform the immature T cells into differentiated effector T cells, for example, 1, 2, 17, and natural killer T cells [5]. ese cells released a variety of proinflammatory cytokines which caused the injury of the colon
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