Project description:Anti-proinflammatory cytokine therapies against interleukin (IL)-6 and tumor necrosis factor (TNF)-a are major advances in treating inflammatory diseases. We found that 2-deoxy-D-glucose (2-DG), a simple monosaccharide, attenuated IL-6 responses by inhibiting N-linked glycosylation of the IL-6 receptor gp130. Aglyco forms of gp130 failed to bind IL-6 and to activate downstream signals. 2-DG completely inhibited dextran sodium sulfate-induced inflammatory bowel disease that was partially dependent on IL-6.
Project description:Compromise of the intestinal barrier have been associated with a series of inflammatory conditions where the routine controls nutrient absorption and pathogens exclusion is lost to different degrees. The intestinal epithelial cells form a barrier of selective permeability which protects from invasion by the normal bacteria present in the gut. When the barrier is compromised, bacteria and their products can attack the cells and cause inflammation, which can (in severe cases) cause sepsis. Mesenteric lymph nodes play a crucial role in the immune response and are of particular importance in the study of Inflammatory Bowel Disease (IBD) patients due to their involvement in the disease process. To assess the efficiency of gut immune barrier, we collected the pre-nodal lymph from Inflammatory Bowel Disease (IBD) subjects and performed a comprehensive proteomic analysis. The current study is complementary extension of the proteomics signature found in DSS-induced colitis mouse model, providing an insight in the lymph composition, and associated biochemical changes, in the set of samples (n=6) recruited from the Inflammatory Bowel Disease (IBD), subjects undergoing intestinal resection. Following bottom-up analysis, the enrichment analysis – GO and Ingenuity pathway analysis (IPA) analysis identified several pathways pointing towards a damaging phenotype.
Project description:Expression profiling of human colon mucosa samples aquired from inflammatory bowel disease patients and healthy controls. Expression profiling was done using Illumina Human HT-12 arrays, and data analysis was performed using tools from the Bioconductor package
Project description:Inflammatory bowel disease (IBD) is a multiple-genes-involved chronic disease and current available targeted drugs for IBD only deliver moderate efficacy. Whether there is a single gene that systematically regulates IBD is not yet known. Here we showed that the expression of miR-146a in colon was elevated in Dextran Sulfate Sodium Salt (DSS)-induced IBD mice and patients with IBD. DSS induced dramatic body weight loss and much more rectal bleeding, shorter colon length and colitis in miR-146a knock-out mice than wild type (WT) mice. The miR-146a mimics alleviated DSS-induced symptoms in both DSS-induced miR-146a-/- and WT mice. Further RNA sequencing illustrated that deficiency of miR-146a de-repressed majority of DSS-induced IBD-related genes which cover multiple genetic regulatory networks in IBD, and supplement of miR-146a mimics inhibited expression of many IBD-related genes. DOI 10.3389/fimmu.2024.1366319
Project description:Ulcerative colitis (UC), a form of inflammatory bowel disease, is characterized by a Q7 recurrent and persistent nonspecific inflammatory response. Polydatin (PD), a natural stilbenoid polyphenol with potent properties, exhibits unexpected beneficial effects beyond its well-documented anti-inflammatory and antioxidant activities. In this study, we presented evidence that PD confers protection against dextran sodium sulfate (DSS)-induced ulcerative colitis. Our findings demonstrated that PD mitigated the DSS-induced increases in proinflammatory cytokines (IL-6, TNF-α, and IL-1β), alleviated colon length shortening, reduced morphological damage to the intestinal mucosa, and preserved tight junction proteins (TJ) occludin and Zonula occludens-1 (ZO-1) in both Caco-2 cells and murine models of colitis. Results from bulk RNA sequencing and differential gene analysis suggested a potential role for ferroptosis in the protective mechanisms of PD against UC. Further investigations revealed that PD modulated the expression levels of several ferroptosis-related proteins and transcription factors within the DSS-induced colitis model. Notably, treatment with PD enhanced nuclear translocation of Nrf2, which inhibits ferroptosis while ameliorating oxidative stress through upregulation of Slc7a11 and Gpx4 expression. Additionally, erastin—a known inducer of ferroptosis—reversed the protective effects conferred by PD in the DSS-induced colitis model by downregulating Slc7a11 expression. These findings underscore that PD protects against DSS-induced ulcerative colitis via the Nrf2/ Slc7a11/Gpx4 signaling axis, highlighting its potential as a novel therapeutic agent for UC.
Project description:A compromised pathology of the intestinal barrier have been associated with a series of inflammatory conditions where the routine controls nutrient absorption and pathogens exclusion is lost to different degrees. When the epithelial barrier is compromised, bacteria and their products can attack the cells and cause inflammation, sometime leading to sepsis. Studying the lymph peptidome in inflammatory bowel disease (IBD) can offer valuable insights into the underlying mechanisms, disease progression, and potential therapeutic targets. To assess the efficiency of gut immune barrier, we collected the pre-nodal lymph from Inflammatory Bowel Disease (IBD) subjects and performed a comprehensive peptidomic analysis. . The current study is complementary extension of the proteomics signature found in DSS-induced colitis mouse model, providing an insight in the lymph composition inclined to an inflammatory phenotype which was also mirrored by a unique set of peptidome/degradome. Furthermore, the identified peptides mapped to a wide range of intracellular and extracellular pathways, encompassing cellular stress, apoptosis, and extracellular matrix degradation related pathways. A significant fraction of peptides was also found to be derived from bacterial origin with a predicted binding affinity to different MHC I and MHC II human haplotypes.
Project description:Thrombospondin 1 (TSP-1) is an anti-angiogenic matricellular protein with regulatory functions in inflammation and cancer. The type 1 repeats (TSR) domains of TSP-1 have been shown to interact with a wide range of proteins that result in the anti-angiogenic and anti-tumor properties of TSP-1. To evaluate potential therapeutic effects of TSRs in inflammatory bowel disease, we conducted clinical, histological and gene microarray analyses on a mouse model of induced colitis. We used Affymetrix GeneChips to determine the changes in the genetic profile underlying TSR-treatment coincident with induction of colitis using DSS. We identified differentially expressed genes among the treatment groups. Using DSS (dextran sulfate sodium) to induce colitis, wild-type mice were simultaneously injected with either saline or one form of TSP-1 derived peptides, containing either the three domains of the TSR (3TSR), the two last domains (TSR2), or TSR2 with the RFK sequence (TSR2+RFK). Wt mice drinking water only was used as reference.