Restoring immune balance by targeting macrophage polarization is a potentially valuable therapeutic strategy for ulcerative colitis (UC). Dioscin is a steroidal saponin with potent anti-inflammatory, ...immunoregulatory, and hypolipidemic effects. This study examined the protective effect of Dioscin on UC in mice and explored the underlying mechanisms. Mice were induced colitis by dextran sulfate sodium (DSS) and concurrently treated with Dioscin oral administration. RAW264.7 cells were skewed to M1 macrophage polarization by lipopolysaccharide (LPS) and interferon-γ (INF-γ) in vitro, and received Dioscin treatment. The results showed that Dioscin ameliorated colitis in mice, reduced macrophage M1 polarization, but markedly promoted M2 polarization in mice colon. Dioscin inhibited mammalian target rapamycin complex 1 (mTORC1)/hypoxia-inducible factor-1α (HIF-1α) signaling and restrained glycolysis in RAW264.7; however, it activated mammalian target rapamycin complex 2 (mTORC2)/peroxisome proliferator-activated receptor-γ (PPAR-γ) signal and facilitated fatty acid oxidation (FAO). The modulation of mTORs signaling may inhibit M1, but promote M2 polarization. Furthermore, the effect of Dioscin on M2 polarization was neutralized by the FAO inhibitor Etomoxir and the mTORC2 inhibitor JR-AB2-011. In parallel, the inhibitory effect of Dioscin on M1 polarization was mitigated by the mTORC1 agonist L-leucine. Both JR-AB2-011 and L-leucine blocked the therapeutic effect of Dioscin in mice with UC. Therefore, Dioscin ameliorated UC in mice, possibly by restraining M1, while skewing M2 polarization of macrophages. Regulation of mTORC1/HIF-1α and mTORC2/PPAR-γ signals is a possible mechanism by which Dioscin inhibited aerobic glycolysis and promoted FAO of macrophages. In summary, Dioscin protected mice against DSS-induced UC by regulating mTOR signaling, thereby adjusting macrophage metabolism and polarization.
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Peroxisome proliferator-activated receptor γ (PPARγ) is an important member of the nuclear receptor superfamily. Previous studies have shown the satisfactory anti-inflammatory role of PPARγ in ...experimental colitis models, mainly through negatively regulating several transcription factors such as nuclear factor-κB (NF-κB). Therefore, regulating PPARγ and PPARγ-related pathways has great promise for treating ulcerative colitis (UC). In the present study, our objective was to explore the potential effect of naringin on dextran sulfate sodium (DSS) induced UC in mice and its involved potential mechanism. We found that naringin significantly relieved DSS-induced disease activities index (DAI), colon length shortening, and colonic pathological damage. Exploration of the potential mechanisms demonstrated that naringin significantly activated DSS-induced PPARγ and subsequently suppressed NF-κB activation. PPARγ inhibitor GW9662 largely abrogated the roles of naringin in vitro. Moreover, DSS induced the activation of mitogen-activated protein kinase (MAPK) and (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome was inhibited by naringin. Tight junction (TJ) architecture in naringin groups was also maintained by regulating zonula occludens-1 (ZO-1) expression. These results suggested that naringin may be a potential natural agent for protecting mice from DSS-induced UC.
Background & Aims Persistent activation of the inflammatory response contributes to the development of inflammatory bowel diseases, which increase the risk of colorectal cancer. We aimed to identify ...microRNAs that regulate inflammation during the development of ulcerative colitis (UC) and progression to colitis-associated colon cancer (CAC). Methods We performed a quantitative polymerase chain reaction analysis to measure microRNAs in 401 colon specimens from patients with UC, Crohn’s disease, irritable bowel syndrome, sporadic colorectal cancer, or CAC, as well as subjects without these disorders (controls); levels were correlated with clinical features and disease activity of patients. Colitis was induced in mice by administration of dextran sodium sulfate (DSS), and carcinogenesis was induced by addition of azoxymethane; some mice also were given an inhibitor of microRNA214 (miR214). Results A high-throughput functional screen of the human microRNAome found that miR214 regulated the activity of nuclear factor-κB. Higher levels of miR214 were detected in colon tissues from patients with active UC or CAC than from patients with other disorders or controls and correlated with disease progression. Bioinformatic and genome-wide profile analyses showed that miR214 activates an inflammatory response and is amplified through a feedback loop circuit mediated by phosphatase and tensin homolog (PTEN) and PDZ and LIM domain 2 (PDLIM2). Interleukin-6 induced signal transducer and activator of transcription 3 (STAT3)-mediated transcription of miR214. A miR214 chemical inhibitor blocked this circuit and reduced the severity of DSS-induced colitis in mice, as well as the number and size of tumors that formed in mice given azoxymethane and DSS. In fresh colonic biopsy specimens from patients with active UC, the miR214 inhibitor reduced inflammation by increasing levels of PDLIM2 and PTEN. Conclusions Interleukin-6 up-regulates STAT3-mediated transcription of miR214 in colon tissues, which reduces levels of PDLIM2 and PTEN, increases phosphorylation of AKT, and activates nuclear factor-κB. The activity of this circuit correlates with disease activity in patients with UC and progression to colorectal cancer.
We aimed to quantify the safety and effectiveness of vedolizumab (VDZ) when used for UC, and to identify predictors of response to treatment.
Retrospective review (May 2014-December 2016) of VICTORY ...Consortium data. Adults with follow-up after starting VDZ for clinically active UC were included. Primary effectiveness outcomes were cumulative rates of clinical remission (resolution of all UC-related symptoms) and endoscopic remission (Mayo endoscopic sub-score 0). Key secondary effectiveness outcomes included cumulative rates of corticosteroid-free remission and deep remission (clinical remission and endoscopic remission). Cox proportional hazard analyses were used to identify independent predictors of treatment effectiveness. Non-response imputation (NRI) sensitivity analyses were performed for effectiveness outcomes. Key safety outcomes were rates of serious infection, serious adverse events, and colectomy.
We included 321 UC patients (71% prior TNFα antagonist exposure, median follow-up 10 months). The 12-month cumulative rates of clinical remission and endoscopic remission were 51% and 41%, respectively. Corresponding rates for corticosteroid-free remission and deep remission were 37% and 30%, respectively. Using NRI, 12-month rates were 20% (n = 64/321) for clinical remission, 17% (n = 35/203) for endoscopic remission, 15% (n = 30/195) for corticosteroid-free remission, and 14% (n = 28/203) for deep remission. A majority of the patients without adequate follow-up at 12 months who were deemed non-responders using NRI had already achieved clinical remission (n = 70) or a significant clinical response (n = 36) prior to 12 months. VDZ discontinuation prior to 12 months was observed in 91 patients, for lack of response (n = 56), need for surgery (n = 29), or adverse event (n = 6). On multivariable analyses, prior exposure to a TNFα antagonist was associated with a reduced probability of achieving clinical remission (HR 0.53, 95% CI 0.38-0.75) and endoscopic remission (HR 0.51, 95% CI 0.29-0.88). Serious adverse events and serious infections were reported in 6% and 4% of patients, respectively. Overall cumulative rates of colectomy over 12 months were 13%, with lower rates observed in patients naive to TNFα antagonist therapy (2%) than those who had been exposed to TNFα antagonists (19%).
In this large real-world cohort we observed that VDZ was well tolerated and effective in achieving key clinical outcomes.
A complex mucosal barrier protects as the first line of defense the surface of the healthy intestinal tract from adhesion and invasion by luminal microorganisms.In this review,we provide an overview ...about the major components of this protective system as for example an intact epithelium,the synthesis of various antimicrobial peptides(AMPs)and the formation of the mucus layer.We highlight the crucial importance of their correct functioning for the maintenance of a proper intestinal function and the prevention of dysbiosis and disease.Barrier disturbances including a defective production of AMPs,alterations in thickness or composition of the intestinal mucus layer,alterations of pattern-recognition receptors,defects in the process of autophagy as well as unresolved endoplasmic reticulum stress result in an inadequate host protection and are thought to play a crucial role in the pathogenesis of the inflammatory bowel diseases Crohn’s disease and ulcerative colitis.
Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. ...Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 ...cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.
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•51 cell subsets in colon mucosa of 18 ulcerative colitis and 12 healthy individuals•M-like cells, inflammatory monocytes and fibroblasts, and CD8+IL-17+ T cells expand in disease•Oncostatin M circuit in inflammatory monocytes and fibroblasts may affect drug response•Co-expression of genes within cells allows inference of causal genes across risk loci
Single-cell analyses of colon biopsy specimens from patients with ulcerative colitis delineate how expression patterns and shifting cell populations may shape disease and drug resistance, and provide a framework for linking GWAS risk loci with specific cell types and functional pathways.
Ulcerative colitis Le Berre, Catherine; Honap, Sailish; Peyrin-Biroulet, Laurent
The Lancet (British edition),
08/2023, Letnik:
402, Številka:
10401
Journal Article
Recenzirano
Ulcerative colitis is a lifelong inflammatory disease affecting the rectum and colon to a variable extent. In 2023, the prevalence of ulcerative colitis was estimated to be 5 million cases around the ...world, and the incidence is increasing worldwide. Ulcerative colitis is thought to occur in people with a genetic predisposition following environmental exposures; gut epithelial barrier defects, the microbiota, and a dysregulated immune response are strongly implicated. Patients usually present with bloody diarrhoea, and the diagnosis is based on a combination of clinical, biological, endoscopic, and histological findings. The aim of medical management is, first, to induce a rapid clinical response and normalise biomarkers and, second, to maintain clinical remission and reach endoscopic normalisation to prevent long-term disability. Treatments for inducing remission include 5-aminosalicylic acid drugs and corticosteroids. Maintenance treatments include 5-aminosalicylic acid drugs, thiopurines, biologics (eg, anti-cytokines and anti-integrins), and small molecules (Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators). Although the therapeutic options are expanding, 10-20% of patients still require proctocolectomy for medically refractory disease. The keys to breaking through this therapeutic ceiling might be the combination of therapeutics with precision and personalised medicine.
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