Mechanisms Of Inflammatory Bowel Disease Research Articles

P-015 Impaired spermatogenesis in colitis: the role of interferon-γ mediated ferroptosis in sertoli cells by colitic CD4+ T cells

Abstract Study question Does colitis have an impact on spermatogenesis and what could be the potential mechanism? Summary answer Colitis causes sertoli cell ferroptosis and disrupts spermatogenesis in mice due to the migration of colitic CD4+ T cells that produce interferon-γ. What is known already In recent years, there has been a significant increase in rheumatic and inflammatory diseases. Epidemiological data reveals that dysregulated immune conditions can directly or indirectly impact male fertility and sexual function in patients of reproductive age. Inflammatory bowel disease (IBD), which encompasses Crohn’s disease and ulcerative colitis, is a chronic, recurring gastrointestinal inflammatory disorder characterized by bloody stools and weight loss. A study from a Swedish national cohort showed that IBD patients had diminished sperm fertility and increased sperm DNA fragmentation compared to healthy individuals. However, the precise mechanisms underlying male fertility problems in IBD remain unclear. Study design, size, duration In this study, C57BL/6 mice were kept under specific pathogen-free conditions. A murine colitis model that simulates human colitis histological features and symptoms was created using Dextran Sulfate Sodium (DSS). To establish the model, 2-2.5% DSS was added to the mice’s drinking water from days 0 to 7, followed by a three-day recovery period. Participants/materials, setting, methods Testis, epididymis and colon sections were stained with hematoxylin and eosin for histological analysis. The localization and phenotype of infiltrated lymphocytes in epididymis and testis were studied by immunostaining and flow cytometry. Sperm functions including motility, viability, and DNA integrity were assessed by standard assays. Iron, malondialdehyde, and reactive oxygen species (ROS) levels were analysed by commercial kit. Main results and the role of chance Colitis was found to impair male fertility in DSS-induced colitic mice, causing testis and epididymis tissue damage along with inflammatory cell infiltration. Colitis altered the immune cell phenotypes in the testis and epididymis. The proportion and absolute cell count of CD4+ T cells and CD19+ B cells increased after colon inflammation. Testicular sertoli cells in colitic mice exhibited ferroptosis, characterized by increased levels of iron deposition, malondialdehyde, and ROS. We assessed sperm parameters from the cauda epididymis of mice. Compared to the control group, there were significant reduction in sperm concentration, motility, viability and DNA integrity in the group with murine colitis induction. Consistently, we observed lower numbers of active pups from the fathers of the colitis group compared to control mice. CD4+ T cells with interferon-γ producing capabilities accumulated in the testes of colitis mice. Leukocyte flow cytometric analysis and parabiotic mouse model further demonstrated that colitis promoted pathogenic CD4+ T cells migration to the testis through circulation. The treatment of anti-CD4 antibody, anti-interferon-γ antibody or ferroptosis inhibitor can attenuate the colitis-associated testis pathologies. Limitations, reasons for caution Our study was conducted exclusively in mice. The pathogenic effect and the corresponding mechanism of colitis on male fertility in humans still needs to be confirmed. Wider implications of the findings Our team identified the mechanism linking dysregulated gut immune cell activity to testicular dysfunction. By identifying specific molecules on colitic immune cells, which allow their infiltration into the testis, may pave the way for a new therapeutic approach potentially improving the prognosis of colitis and related fertility impairments. Trial registration number not applicable

Cu,Zn,I-Doped Carbon Dots with Boosted Triple Antioxidant Nanozyme Activity for Treatment of DSS-Induced Colitis.

Nanozyme-mediated antioxidative therapy is a promising star for treating a myriad of important diseases through eliminating excessive reactive oxygen species (ROS) such as O2·- and H2O2, a critical mechanism for inflammatory bowel disease (IBD). This work provides a high biocompatibility iodine-copper-zinc covalent doped carbon dots (Cu,Zn,I-CDs) with the catalase (CAT)-, superoxide dismutase (SOD)- and glutathione peroxidase (GPx)-like catalytic activities for treating ulcerative colitis (UC) by scavenging overproduced ROS. We found that I dopant aids in counteracting the positive charge at Cu,Zn dopants brought on by low pH, enabling Cu,Zn,I-CDs to process strong triple antioxidant nanozyme activities rather than Cu,Zn-CDs. Vitro experiments displayed that the Cu,Zn,I-CDs could scavenge the excessive ROS to protect cellular against oxidative stress and reduce the expression of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6. In sodium dextran sulfate (DSS)-induced colitis mice models, Cu,Zn,I-CDs with excellent biocompatibility could effectively relieve the inflammation of the colon, containing the reduction of the colon length, the damaged epithelium, the infiltration of inflammatory cells, and upregulation of antioxidant genes. Therefore, the therapy of Cu,Zn,I-CD antioxidant nanozymes is an effective approach and provides a novel strategy for UC treatment.

Role of epigenetic mechanisms in inflammatory bowel disease

Role of epigenetic mechanisms in inflammatory bowel disease

Potential Regulatory Gene Network Associated with the Ameliorative Effect of Oat Antibacterial Peptides on Rat Colitis.

Oat protein is unstable in intestinal fluid digestion, and it is easily degraded by trypsin and chymotrypsin, producing low molecular weight peptides. Endopeptidase hydrolysis can improve the bioavailability of active peptides and avoid further digestion in the gastrointestinal tract. Antimicrobial peptides (AMPs) can effectively improve host immunity, but most related studies focus on physiology and ecology, and there are few reports on their molecular level. Therefore, in this article, oat peptides were prepared via the simulated digestion method in vitro, and the main metabolites and action factors affecting colitis were screened by using the multi-omics methods in a high-throughput mode to analyze the effect and mechanism of colitis. Firstly, oat antimicrobial peptides were prepared from cationic resin combined with HPLC, and the anti-inflammatory effects of antimicrobial peptides were analyzed in vitro through the use of human colon epithelial (HCoEpiC) anti-inflammatory cells. In vivo experiments using rats have verified that AMPs can effectively prevent colitis caused by dextran sodium sulfate (DSS), reduce intestinal inflammatory cell infiltration and glandular disappearance in the colon, and reduce the apoptosis rate of colon cells. Secondly, metabolomics and transcriptomics were combined to analyze the mechanism of preventing enteritis, and it was found that oat antimicrobial peptides can promote DAG diglycerol production and inhibit the activation of T helper cells (TH), resulting in the down-regulation of key factors in the main downstream pathways of TH1, TH2 and TH17, and inhibit the production of inflammatory cells. At the same time, AMP can activate the wnt pathway, improve the expression of key genes of wnt and frizzled, promote the generation of intestinal stem cells, facilitate the differentiation and repair of intestinal epithelial cells, and prevent the generation of enteritis. Finally, the underlying genetic regulatory network of the important pathway was constructed from the effect of AMP on rat colitis.

Epigenetic modification of m6A methylation: Regulatory factors, functions and mechanism in inflammatory bowel disease

Although the exact cause of inflammatory bowel disease (IBD) is still unknown, there is a lot of evidence to support the notion that it results from a combination of environmental factors, immune system issues, gut microbial changes, and genetic susceptibility. In recent years, the role of epigenetics in the pathogenesis of IBD has drawn increasing attention. The regulation of IBD-related immunity, the preservation of the intestinal epithelial barrier, and autophagy are all significantly influenced by epigenetic factors. The most extensive epigenetic methylation modification of mammalian mRNA among them is N6-methyladenosine (m6A). It summarizes the general structure and function of the m6A regulating factors, as well as their complex effects on IBD by regulating the intestinal mucous barrier, intestine mucosal immunity, epidermal cell death, and intestinal microorganisms.This paper provides key insights for the future identification of potential new targets for the diagnosis and treatment of IBD.

The NRF2/Keap1 pathway as a therapeutic target in inflammatory bowel disease.

Oxidative stress (OS) is an important pathophysiological mechanism in inflammatory bowel disease (IBD). However, clinical trials investigating compounds directly targeting OS in IBD yielded mixed results. The NRF2 (nuclear factor erythroid 2-related factor 2)/Keap1 (Kelch-like ECH-associated protein 1) pathway orchestrates cellular responses to OS, and dysregulation of this pathway has been implicated in IBD. Activation of the NRF2/Keap1 pathway may enhance antioxidant responses. Although this approach could help to attenuate OS and potentially improve clinical outcomes, an overview of human evidence for modulating the NRF2/Keap1 axis and more recent developments in IBD is lacking. This review explores the NRF2/Keap1 pathway as potential therapeutic target in IBD and presents compounds activating this pathway for future clinical applications.

Role of sphingosine 1-phosphate (S1P) in sepsis-associated intestinal injury.

Sphingosine-1-phosphate (S1P) is a widespread lipid signaling molecule that binds to five sphingosine-1-phosphate receptors (S1PRs) to regulate downstream signaling pathways. Sepsis can cause intestinal injury and intestinal injury can aggravate sepsis. Thus, intestinal injury and sepsis are mutually interdependent. S1P is more abundant in intestinal tissues as compared to other tissues, exerts anti-inflammatory effects, promotes immune cell trafficking, and protects the intestinal barrier. Despite the clinical importance of S1P in inflammation, with a very well-defined mechanism in inflammatory bowel disease, their role in sepsis-induced intestinal injury has been relatively unexplored. In addition to regulating lymphocyte exit, the S1P-S1PR pathway has been implicated in the gut microbiota, intestinal epithelial cells (IECs), and immune cells in the lamina propria. This review mainly elaborates on the physiological role of S1P in sepsis, focusing on intestinal injury. We introduce the generation and metabolism of S1P, emphasize the maintenance of intestinal barrier homeostasis in sepsis, and the protective effect of S1P in the intestine. We also review the link between sepsis-induced intestinal injury and S1P-S1PRs signaling, as well as the underlying mechanisms of action. Finally, we discuss how S1PRs affect intestinal function and become targets for future drug development to improve the translational capacity of preclinical studies to the clinic.

Hematopoietic stem cell transplantation for CYBB heterozygous mutation resulting in very early onset inflammatory bowel disease in children: a case report

BackgroundInflammatory bowel disease (IBD) is a heterogeneous group of disorders associated with environmental triggers and dysregulated immune responses resulting in chronic, recurrent intestinal inflammation. Very early-onset IBD (VEO-IBD) refers to patients with symptoms or diagnosis before the age of 6 years and is widely thought to be associated with monogenic mutations. Traditional drug therapy is often ineffective in this patient population, while hematopoietic stem cell transplantation (HSCT) represents the definitive cure for patients with gene mutations.Case presentationWe report a case of VEO-IBD associated with a monogenic mutation in a 2-year-old girl presenting mainly with gastrointestinal symptoms, including recurrent hematochezia and abdominal pain for more than 3 months. A gastroscopy revealed erosive gastritis and bulbar duodenitis, while a colonoscopy indicated erosive colitis. Abnormal results were obtained from the dihydrohodamine (DHR) assay and immunoglobulin testing. Whole-exome sequencing identified a heterozygous and de novo nonsense mutation (c.388 C > T; p.R130X) in the CYBB gene leading to deficiency of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) (encoded by CYBB), a critical component of phagocytes. HSCT was performed successfully, and the DHR assay showed that normal neutrophil function was restored. Six months after HSCT, clinical remission was observed, and a repeat colonoscopy revealed intestinal mucosal healing was attained.ConclusionsPatients with CYBB mutations often develop recurrent or severe bacterial or fungal infections, mostly in the lungs, skin, lymph nodes, and liver. Here, we report on a young female child with CYBB mutations presenting predominantly with gastrointestinal symptoms. This study explores the mechanisms of inflammatory bowel disease caused by a monogenic mutation in CYBB to improve early diagnosis and effective treatment rates of this patient population.

Differential Gene Expression Profiles Involved in the Inflammations Due to COVID-19 and Inflammatory Bowel Diseases and the Investigation of Predictive Biomarkers.

Gastrointestinal manifestations in COVID-19 were attributed to 74-86% of the hospitalised patients due to severe or prolonged pathogenesis. Though it is a respiratory disease, the impact it elicits on the gastrointestinal tract and brain are intense. Inflammatory bowel disease including Crohn's disease and ulcerative colitis are idiopathic inflammatory disorders of the gastrointestinal tract. The intrinsic mechanisms involved in gut inflammations due to a respiratory viral disease can be deciphered when the gene expression profiles of COVID-19 and IBD are compared. The current study utilises an integrated bioinformatics approach to unravel them. The publicly available gene expression profiles of colon transcriptomes infected with COVID-19, Crohn's disease and Ulcerative colitis were retrieved, integrated and analysed for the identification of differentially expressed genes. The inter-relational analysis along with gene annotation and pathway enrichment detailed the functional and metabolic pathways of the genes during normal and diseased conditions. The protein-protein interactions deduced from the STRING database and the identified hub genes predicted potential biomarker candidates for COVID-19, Crohn's disease and ulcerative colitis. The inflammatory response pathways were upregulated and enrichment of chemokine signalling, altered lipid metabolism, coagulation and complement cascades were seen in all three conditions along with impaired transport mechanisms. CXCL11, MMP10, and CFB are predicted to be overexpressed biomarkers, whilst GUCA2A, SLC13A2, CEACAM, and IGSF9 as downregulated novel biomarker candidates for colon inflammations. The three miRNAs hsa-miR-16-5p, hsa-miR-21-5p, and hsa-miR-27b-5p exhibited significant interactions with the upregulated hub genes and four long non-coding RNAs NEAT1, KCNQ1OT1, and LINC00852 capable of regulating miRNA were also predicted. This study offers significant information on the underlying molecular mechanisms of inflammatory bowel disease with identification of potential biomarkers.

Colitis induced by PD-1 inhibitor combined with platinum-containing dual drug chemotherapy in Lewis mice and its mechanism.

To explore the occurrence and possible mechanism of colitis in Lewis mice treated with PD-1 inhibitor combined with platinum-containing dual drug chemotherapy. A Lewis lung cancer model of C57BL/6 mice was established, randomly divided into the treatment group (group C, PD-1 inhibitor + Carboplatin (CARB) + Pemetrexed (PEM)) and model group (group B, normal saline), and a control group (group A, normal saline) was set up. Observe the changes in tumor-free weight, tumor volume, disease activity index (DAI), colon histopathology, identify serum interleukin (IL)-10, interferon (IFN)-γ, the expression of claudin-1, and occludin mRNA in the colon in each animals. Compared with group A, the tumor-free weight of mice in B decreased (P < 0.001), the content of IL-10 in serum increased (P < 0.01), the content of IFN-γ in serum decreased (P < 0.01). Compared with group B, the transplanted tumor volume in C was reduced (P < 0.05), DAI scores of D4 (P < 0.001), and D7 (P < 0.001) were increased, colonic histopathology analysis showed that colitis occurred, serum IL-10 content was decreased (P < 0.05), IFN-γ content was increased (P < 0.05), and the mRNA expression of claudin-1 (P < 0.05) and occludin (P < 0.05) was reduced. This treatment can inhibit the growth of transplanted tumors but will cause colitis in Lewis mice. The impairment of intestinal barrier function following administration cause an imbalance in the expression of pro-inflammatory and anti-inflammatory factors in the colon, thus causing colitis.

Amelioration of colitis progression by ginseng-derived exosome-like nanoparticles through suppression of inflammatory cytokines

BackgroundDamage to the healthy intestinal epithelial layer and regulation of the intestinal immune system, closely interrelated, are considered pivotal parts of the curative treatment for inflammatory bowel disease (IBD). Plant-based diets and phytochemicals can support the immune microenvironment in the intestinal epithelial barrier for a balanced immune system by improving the intestinal microecological balance and may have therapeutic potential in colitis. However, there have been only a few reports on the therapeutic potential of plant-derived exosome-like nanoparticles (PENs) and the underlying mechanism in colitis. This study aimed to assess the therapeutic effect of PENs from Panax ginseng, ginseng-derived exosome-like nanoparticles (GENs), in a mouse model of IBD, with a focus on the intestinal immune microenvironment. MethodTo evaluate the anti-inflammatory effect of GENs on acute colitis, we treated GENs in Caco2 and lipopolysaccharide (LPS) -induced RAW 264.7 macrophages and analyzed the gene expression of pro-inflammatory cytokines and anti-inflammatory cytokines such as TNF-α, IL-6, and IL-10 by real-time PCR (RT-PCR). Furthermore, we further examined bacterial DNA from feces and determined the alteration of gut microbiota composition in DSS-induced colitis mice after administration of GENs through 16S rRNA gene sequencing analysis. ResultGENs with low toxicity showed a long-lasting intestinal retention effect for 48 h, which could lead to effective suppression of pro-inflammatory cytokines such as TNF-α and IL-6 production through inhibition of NF-κB in DSS-induced colitis. As a result, it showed longer colon length and suppressed thickening of the colon wall in the mice treated with GENs. Due to the amelioration of the progression of DSS-induced colitis with GENs treatment, the prolonged survival rate was observed for 17 days compared to 9 days in the PBS-treated group. In the gut microbiota analysis, the ratio of Firmicutes/Bacteroidota was decreased, which means GENs have therapeutic effectiveness against IBD. Ingesting GENs would be expected to slow colitis progression, strengthen the gut microbiota, and maintain gut homeostasis by preventing bacterial dysbiosis. ConclusionGENs have a therapeutic effect on colitis through modulation of the intestinal microbiota and immune microenvironment. GENs not only ameliorate the inflammation in the damaged intestine by downregulating pro-inflammatory cytokines but also help balance the microbiota on the intestinal barrier and thereby improve the digestive system.

Identification of hub genes and potential molecular mechanisms associated with inflammatory bowel diseases using meta-analysis of gene expression data

Inflammatory bowel diseases (IBDs), which primarily include Crohn's disease (CD) and ulcerative colitis (UC), are chronic recurrent diseases of the gastrointestinal tract with increasing prevalence and incidence worldwide. In this study, we aimed to identify key factor genes that control the progression of inflammatory bowel disease, identify common and unique nodal genes, examine gene-protein interactions, assess current advances in the published literature on inflammatory bowel disease, and examine the impact of various biological pathways. Gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. We performed gene expression analysis to identify deferentially expressed genes. Subsequently, GO and KEGG pathway enrichment analyzes and protein-protein interaction network analyzes (PPI) of DEGs were performed. Text mining was used to examine the frequency of genes in the published IBD literature. Four GEO databases (GSE156044, GSE159751, GSE159008, and GSE102746) were downloaded from GEO databases. A total of 368 DEGs were identified. The results of GO term analysis showed that DEGs were mainly involved in the activity of cytokine receptors, integral components of the plasma membrane, and cytokine-mediated signaling. KEGG pathway analysis showed that DEGs were mainly enriched in bile secretion, mineral absorption, and cytokine-cytokine receptor interaction. The results of PPI analysis showed that about 10 genes were the key genes for the occurrence of CED. Text mining revealed the existence of 399 genes associated with CED. Our results suggest a possible link between CED and other diseases such as triple negative breast cancer (TNBC) and lung adenocarcinoma (LUAD), and provide new insights into the mechanisms of inflammatory bowel disease and new treatment targets.

An orally administered gold nanocluster with ROS scavenging for inflammatory bowel disease treatment

Oxidative stress that is induced by excessive reactive oxygen species (ROS) is considered to be a key pathophysiological mechanism of inflammatory bowel disease (IBD), and restoring redox homeostasis in the inflammatory region by eliminating ROS is an effective way to treat IBD. Herein, ultrasmall Au25 nanoclusters (Au25 NCs) were synthesized using a simple improved protocol, which has good physiological stability and biosafety and can be noninvasively monitored by clinical computed tomography (CT) after oral administration. Au25 NCs can eliminate ROS such as ABTS radicals, superoxide free radicals (•O2−), and hydroxyl free radicals (•OH), upregulate the expression level of antioxidant enzymes, inhibit the expression of proinflammatory cytokines, and finally interrupt the inflammatory circuit of IBD to achieve the effective prevention and delayed treatment of IBD. This work will demonstrate the protective effect of Au25 NCs on IBD in living animals, which suggests a new nanomedicine strategy for IBD treatment.

Targeting IL12/23 in ulcerative colitis: update on the role of ustekinumab.

As our comprehension of the pathogenic mechanisms of inflammatory bowel disease (IBD) increases, the therapeutic armamentarium for its treatment can expand, and novel target therapies join the treatment pipeline. Interleukin (IL)-12 and IL23 are two key cytokines responsible for promoting and perpetuating bowel inflammation in IBD. Ustekinumab is a monoclonal antibody directed against the shared p40 subunit of both cytokines, and it was recently approved for the treatment of ulcerative colitis (UC). In the pivotal phase III UNIFI trial, ustekinumab showed a superiority over placebo in both clinical and endoscopic outcomes; furthermore, it was characterized by a favorable safety profile, with a similar rate of adverse events as compared with placebo. Recent evidence from real-life experiences have started accumulating, generally confirming the effectiveness and safety figures emerged from the registration studies. However, most of these observational studies enrolled multirefractory patients; moreover, comparative data with other target therapies are lacking, leaving physicians without clear indications about the appropriate positioning of ustekinumab in the therapeutic pipeline for UC. This review examines the basis of targeting IL12-23 in UC therapy and summarizes the data from both clinical trials and real-life studies, to highlight the main evidence already available and the research gaps that need to be filled for the optimal usage of ustekinumab in UC.

В лабиринтах патогенеза воспалительных заболеваний кишечника: эволюция микробиологической теории

Traditionally, the search of the causes and study of the development mechanisms of inflammatory bowel diseases have been of great interest over the past decades. Previously, attention was focused on the genetic and immunological aspects of this group of diseases. At the same time, numerous studies are currently focused on the study of the intestinal microbiome, which is associated with the supposition that IBD develops as a result of the interaction of environmental factors, microbiome and the immune system in genetically susceptible individuals. This supposition was confirmed in a number of studies in which mutations were found in the genes that regulate the interaction between the microbiome and the immune system of IBD patients. The article discusses the role of the intestinal microbiome in IBD and various factors that can influence it, such as smoking, hygiene, diet, and use of antibacterial drugs.

Anti-Inflammatory Effects of Curcumin in the Inflammatory Diseases: Status, Limitations and Countermeasures.

Curcumin is a natural compound with great potential for disease treatment. A large number of studies have proved that curcumin has a variety of biological activities, among which anti-inflammatory effect is a significant feature of it. Inflammation is a complex and pervasive physiological and pathological process. The physiological and pathological mechanisms of inflammatory bowel disease, psoriasis, atherosclerosis, COVID-19 and other research focus diseases are not clear yet, and they are considered to be related to inflammation. The anti-inflammatory effect of curcumin can effectively improve the symptoms of these diseases and is expected to be a candidate drug for the treatment of related diseases. This paper mainly reviews the anti-inflammatory effect of curcumin, the inflammatory pathological mechanism of related diseases, the regulatory effect of curcumin on these, and the latest research results on the improvement of curcumin pharmacokinetics. It is beneficial to the further study of curcumin and provides new ideas and insights for the development of curcumin anti-inflammatory preparations.

Gryllus bimaculatus Extract Protects against Lipopolysaccharide-Derived Inflammatory Response in Human Colon Epithelial Caco-2 Cells.

Simple SummaryInflammatory bowel disease (IBD), a potentially life-threatening disease, is characterized by increased tight junction permeability and overproduction of proinflammatory cytokines. The long-term administration of recognized chemotherapeutic agents can cause serious potential side effects. As such, increasing attention has been paid to natural, low-toxicity products with anti-inflammatory properties for treating IBD. We assessed the potential utility of the edible cricket species Gryllus bimaculatus for anti-inflammatory and cytoprotective effects in the human epithelial cell line Caco-2, following treatment with an inflammatory lipopolysaccharide stimulus. We found that aqueous ethanolic G. bimaculatus extract (AE-GBE) treatment increased cell viability and significantly reduced inflammatory mediators. Moreover, AE-GBE significantly reduced inflammatory cytokine expression levels, intestinal epithelial permeability, and related tight junction protein expression levels. In conclusion, AE-GBE can protect epithelial cells from lipopolysaccharide-induced impaired barrier integrity by increasing tight junction proteins and preventing various inflammatory mediators. These results may be used to pursue further use of natural insect extracts in treating IBD.Increased tight junction permeability and overproduction of proinflammatory cytokines are crucial pathophysiological mechanisms in inflammatory bowel disease (IBD). This study evaluated anti-inflammatory effects of aqueous ethanolic Gryllus bimaculatus extract (AE-GBE) against intestinal permeability on lipopolysaccharide (LPS)-treated Caco-2 cells. Treatment with AE-GBE increased cell viability and significantly reduced inflammatory mediators such as nitric oxide and LPS-induced reactive oxidative stress. LPS increased the expression levels of iNOS, Cox-2, and 4-hydroxylnonenal; however, these levels were attenuated by AE-GBE treatment. Moreover, the mRNA and protein expression levels of the inflammatory cytokines TNFα, IL-6, IL-1β, and IFNγ were increased by LPS, but were significantly reduced by AE-GBE treatment. Intestinal epithelial permeability and the related expression of the proteins Zoula ocludence-1, occludin, and claudin-1 was increased by LPS treatment, and this effect was significantly reduced by AE-GBE treatment. The reduction in AMPK phosphorylation in LPS-treated Caco-2 cells was reversed in activation by co-treatment with AE-GBE. In conclusion, AE-GBE can protect epithelial cells from LPS-induced impaired barrier integrity by increasing tight junction proteins and preventing various inflammatory mediators. Thus, AE-GBE has the potential to improve inflammation-related diseases, including IBD, by inhibiting excessive production of inflammation-inducing mediators.

Superoxide Dismutase 3-Transduced Mesenchymal Stem Cells Preserve Epithelial Tight Junction Barrier in Murine Colitis and Attenuate Inflammatory Damage in Epithelial Organoids.

Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory bowel disease (IBD) have not been uncovered. Therefore, in the present study, we investigated whether SOD3 can protect intestinal cells or organoids from inflammation-mediated epithelial damage. Cells or mice were treated with SOD3 protein or SOD3-transduced mesenchymal stem cells (MSCs). Caco-2 cells or intestinal organoids stimulated with pro-inflammatory cytokines were used to evaluate the protective effect of SOD3 on epithelial junctional integrity. Dextran sulfate sodium (DSS)-induced colitis mice received SOD3 or SOD3-transduced MSCs (SOD3-MSCs), and were assessed for severity of disease and junctional protein expression. The activation of the mitogen-activated protein kinase (MAPK) pathway and elevated expression of cytokine-encoding genes decreased in TNF-α-treated Caco-2 cells or DSS-induced colitis mice when treated with SOD3 or SOD3-MSCs. Moreover, the SOD3 supply preserved the expression of tight junction (ZO-1, occludin) or adherence junction (E-cadherin) proteins when inflammation was induced. SOD3 also exerted a protective effect against cytokine- or ROS-mediated damage to intestinal organoids. These results indicate that SOD3 can effectively alleviate enteritis symptoms by maintaining the integrity of epithelial junctions and regulating inflammatory- and oxidative stress.

Differential gene expression analysis of dasatinib-induced colitis in a patient with chronic myeloid leukemia followed for 3\xa0years: a case report

BackgroundDasatinib is a second-generation tyrosine kinase inhibitor (TKI) developed for treatment of patients with chronic myeloid leukemia (CML). The drug has been shown to act as a potent multikinase inhibitor by blocking not only the BCR-ABL1 gene sequence but also the SRC kinase family, though unexpected adverse events such as pleural effusion have recently been reported in patients undergoing treatment with dasatinib. Hemorrhagic colitis is a unique gastrointestinal adverse events associated with dasatinib and its pathogenesis remains poorly understood.Case presentationWe report here a case of dasatinib-induced asymptomatic colitis in a patient with CML, who showed no exacerbation in careful observations and maintained deep molecular response (DMR) during a 3-year period. In addition, we performed transcriptome analysis of inflamed colonic mucosa specimens to clarify the possible mechanism of colitis that develops in association with dasatinib administration. Our results demonstrated that differential gene expression, especially lymphocyte-associated genes and chemokines, is substantially involved in inflammation of colonic mucosa in affected patients.ConclusionDasatinib induces immune-mediated colitis following lymphocyte infiltration.

Head-to-head comparison of biological drugs for inflammatory bowel disease: from randomized controlled trials to real-world experience.

During past years, the increasing knowledge of molecular mechanisms of inflammatory bowel disease (IBD) have led to the development of several targeted biological therapies. This great expansion of available medical options has prompted the need for comparative data between drugs. For years, given that most randomized controlled trials (RCTs) were performed only versus placebo, this demand has clashed with the absence of head-to-head trials comparing two or more treatments. The quality of evidence coming from real-world experience was low overall, so it was extremely difficult to clarify the correct positioning of the biologicals inside the therapeutic algorithms for IBD. Fortunately, times are changing: head-to-head comparative RCTs have been conducted or are ongoing, and the methodological quality of real-world studies is gradually increasing, mainly thanks to a higher rate of application of statistical methods capable of reducing the selection bias, such as the propensity score. In this evolving scenario, the increasing number of comparative RCTs is providing high-quality data for a correct drug positioning in IBD. In parallel, real-world observational studies are supporting the data coming from RCTs, and covering those comparisons not performed in the RCT setting. We believe that there is moderate evidence already available to support clinicians in the correct choice between different biologicals, and data will certainly be more robust in the near future.