scholarly journals IL-10 Treatment Is Associated with Prohibitin Expression in the Crohn’s Disease Intestinal Fibrosis Mouse Model

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
C. Yuan ◽  
W.-X. Chen ◽  
J.-S. Zhu ◽  
N.-W. Chen ◽  
Y.-M. Lu ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Quantitative Polymerase Chain Reaction ◽  
Interleukin 10 ◽  
Colon Tissue ◽  
Intestinal Fibrosis ◽  
Murine Colitis ◽  
Inflammatory Bowel

Prohibitin, which can inhibit oxidative stress and mitochondrial dysfunction, has been shown to have significant anti-inflammatory activities. Here, we investigate the effects of altering prohibitin levels in affected tissues in the interleukin-10 knockout (IL-10KO) mouse model with intestinal fibrosis. The aim of this study is to investigate the effects of IL-10 on prohibitin and the role of prohibitin in intestinal fibrosis of murine colitis. After the mice were treated with IL-10, prohibitin expression and localization were evaluated in IL-10KO and wild-type (WT, 129/SvEv) mice. The colon tissue was then investigated and the potential pathogenic molecular mechanisms were further studied. Fluorescence-based quantitative polymerase chain reaction (FQ-PCR) and immunohistochemistry assays revealed a significant upregulation of prohibitin with IL-10 treatment. Furthermore, IL-10 decreases inflammatory cytokines and TGF-β1 in the IL-10KO model of Crohn’s disease and demonstrates a promising trend in decreasing tissue fibrosis. In conclusion, we hypothesize that IL-10 treatment is associated with increased prohibitin and would decrease inflammation and fibrosis in an animal model of Crohn’s disease. Interestingly, prohibitin may be a potential target for intestinal fibrosis associated with inflammatory bowel disease (IBD).

Pathogenic aspects and therapeutic avenues of intestinal fibrosis in Crohn's disease

2015 ◽  
Vol 129 (12) ◽  
pp. 1107-1113 ◽  
Author(s):  
Francesca Zorzi ◽  
Emma Calabrese ◽  
Giovanni Monteleone
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Current Knowledge ◽  
Experimental Models ◽  
Human Beings ◽  
Intestinal Fibrosis ◽  
Bowel Diseases ◽  
Ecm Extracellular Matrix ◽  
Inflammatory Bowel ◽  
Related Proteins

In Crohn's disease, one of the two major forms of inflammatory bowel diseases in human beings, persistent and chronic inflammation promotes fibrotic processes thereby facilitating formation of strictures, the most common indication for surgical intervention in this disorder. The pathogenesis of Crohn's disease-associated fibrosis is not fully understood, but variants of genes involved in the recognition of microbial components/products [e.g. CARD15 (caspase-activating recruitment domain 15) and ATG16L1 (autophagy-related 16-like 1)] are associated with this phenotype, and experimental evidence suggests that intestinal fibrosis results from an altered balance between deposition of ECM (extracellular matrix) and degradation of ECM by proteases. Studies have also contributed to identify the main phenotypic and functional alterations of cells involved in the fibrogenic process, as well as molecules that stimulate such cells to produce elevated amounts of collagen and other ECM-related proteins. In the present review, we assess the current knowledge about cellular and molecular mediators of intestinal fibrosis and describe results of recent studies aimed at testing the preventive/therapeutic effect of compounds in experimental models of intestinal fibrosis.

scholarly journals Moxibustion Inhibits the ERK Signaling Pathway and Intestinal Fibrosis in Rats with Crohn’s Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Xiaomei Wang ◽  
Yuan Lu ◽  
Luyi Wu ◽  
Chen Zhao ◽  
Chunbin Song ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Signaling Pathway ◽  
Pathological Process ◽  
Erk Signaling ◽  
Control Group ◽  
Mrna Levels ◽  
Colon Tissue ◽  
Intestinal Fibrosis ◽  
Mild Moxibustion

Intestinal fibrosis is the main pathological process in Crohn’s disease (CD); acupuncture and moxibustion can inhibit the process of fibrosis in CD rats, but the regulatory mechanism remains unknown. The present study observed the effect of moxibustion on the extracellular signal-regulated kinase (ERK) signaling pathway in the CD rat. The result shows that the phosphorylation of the Ras, Raf-1, MEK-1, and ERK-1/2 proteins and the expression of the corresponding mRNAs in the colon tissue of CD rat were significantly higher than the normal control group. Both treatments with mild moxibustion and with herb-separated moxibustion significantly reduced the expression of the Ras, Raf-1, MEK-1, and ERK-1/2 proteins and Ras and Raf-1 mRNA. MEK-1 and ERK-1/2 mRNA expression in each treatment group showed a downward trend, and the ERK-1/2 mRNA levels were significantly lower in the mild moxibustion group. It indicates that Ras, Raf-1, MEK-1, and ERK-1/2 are involved in the process of intestinal fibrosis in CD rats. Moxibustion can downregulate the abnormal expression of colonic Ras, Raf-1, MEK-1, and ERK-1/2 protein and mRNA levels in CD intestinal fibrosis in rats. Moxibustion may play a role in the treatment of CD intestinal fibrosis by regulating ERK signaling pathway.

scholarly journals Detection of Unspecified Inflammatory Bowel Disease, Crohn’s Disease and Ulcerative Colitis via Metabolite Analysis and Machine Learning

2021 ◽  
pp. 79-104
Author(s):  
Elliot Kim ◽  
Valentina L. Kouznetsova ◽  
Igor F. Tsigelny
Keyword(s):  
Machine Learning ◽  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Current Standard ◽  
Inflammatory Bowel ◽  
Accuracy Of Prediction

The current standard of inflammatory bowel disease (IBD), especially, Crohn’s disease (CD), diagnosis is set through an invasive endoscopy procedure. However, serum metabolites hold potential as useful biomarkers for non-invasive diagnosis and treatment of IBDs. The goal of this research was to elucidate the biomarkers including metabolites and genes related to IBDs, to show their distinguishing and common features, and to create a machine-learning (ML) model for recognition of each disease. We explored metabolic pathways and gene–metabolite networks related to unspecified-IBD (uIBD), Crohn’s diseaseand ulcerative colitis (UC). P38 MAPK, ERK1/2, AMPK, and proinsulin were found to be closely related to the pathology of IBDs. The best performing ML model, trained on filtered disease-specific metabolite datasets, was able to predict metabolite class with 92.17% accuracy. Through examination of IBD-related serum, significant relationships between the inputted metabolites and certain metabolic and signaling pathways were found, which can be pinpointed and used to increase accuracy of disease diagnoses. Development of a ML model including metabolites and their chemical descriptors made it possible to achieve considerable accuracy of prediction of the IBDs. Our results elucidate a large variety of metabolites, genes, and pathways that could be used for better understanding of IBDs’ molecular mechanisms.

scholarly journals DOP28 Understanding the molecular mechanisms of anti-TNF treatment failure in patients with Crohn’s disease: A pilot serum proteomic analysis of the PANTS cohort

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S067-S068
Author(s):  
S Lin ◽  
N Chanchlani ◽  
B M Invergo ◽  
M W Anderson ◽  
H M Guay ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Treatment Failure ◽  
Proteomic Analysis ◽  
Molecular Mechanisms ◽  
Area Under The Curve ◽  
Information Criterion ◽  
Drug Level ◽  
Interleukin 10 ◽  
Fibroblast Growth Factor 21

Abstract Background Proteomic biomarkers have been linked to anti-TNF treatment failure, but previous studies have been insufficiently powered to stratify associations by drug level. The Personalised Anti-TNF Therapy in Crohn’s disease (PANTS) is a prospective UK-wide study investigating treatment failure in 1610 anti-TNF naïve patients. We aimed to identify proteomic markers of treatment failure. Methods We sampled patients with primary non-response (PNR) (n = 223) and remission (n = 219) who had a baseline CRP ≥4 mg/l and/or calprotectin >100 µg/g. PNR was defined at week 14 as ongoing steroids, or both of HBI failed to fall by ≥3 points or to ≤4 and CRP failed to fall by ≥50% or to ≤3 mg/l. Non-remission at week 54 was defined as HBI >4 and CRP >3 mg/l and no steroids. Targeted serum proteomic analysis of 180 proteins using Olink Inflammation and Immune Response panels were performed. Mann–Whitney U tests were used to identify baseline proteins that predicted PNR and non-remission. Sub-group analyses stratified by drug level were undertaken. Pharmacokinetic (PK) failure was defined as PNR with low drug level (infliximab level <2 mg/l, adalimumab level <6 mg/l) and pharmacodynamic (PD) failure as PNR despite adequate drug level. Significant proteins were entered into multivariable logistic regression models and Bayesian information criterion (BIC) with backward stepwise selection were used to build predictive models of treatment failure. We applied 10-fold cross-validation to test the models. P-values of < 0.05 were considered significant. Results Elevated fibroblast growth factor 21 (FGF21) (OR 1.3, CI 1.1–1.4, p = 3.4 × 10–5) and interleukin-10 receptor subunit α (IL10RA) (OR 1.6, CI 1.2–2.1, p = 6.3 × 10–4) predicted PNR (Figure 1). At week 14, FGF21 (OR 1.5, CI 1.3–1.9, p = 1.8 × 10–6) and IL10RA (OR 1.8, CI 1.3–2.3, p = 5.8 × 10–5) levels were also associated with PNR. Sub-group analyses showed baseline FGF21 (OR 1.4, CI 1.2–1.7, p = 2.0 × 10–4) predicted PK failure and that IL10-RA (OR 1.6, CI 1.1–2.2, p = 6.7 × 10–3) predicted PD failure (Figure 2). In separate models, non-remission at week 54 was predicted by baseline (FGF21; OR 1.3, CI 1.1–1.4, p = 1.4 × 10–4, IL10-RA; OR 1.5, CI 1.1–2.0, p = 3.6 × 10–3) and week 14 (FGF21; OR 1.4, CI 1.2–1.7, p = 3.6 × 10–4, IL10-RA; OR 1.7, CI 1.3–2.4, p = 1.7 × 10–4) FGF21 and IL10-RA levels. Model validation of baseline FGF21 and IL10-RA showed an area under the curve of 0.61 (CI 0.57–0.64) for PNR and 0.60 (CI 0.56–0.64) for non-remission at week 54. Conclusion Our study identified FGF-21 and IL10-RA as proteins of interest associated with PK and PD treatment failure, respectively. Functional studies to determine the molecular mechanism driving dysregulation of these proteins are required.

scholarly journals Medical management of Crohn’s disease: state of the art and future perspectives

2019 ◽  
Vol 13 (3) ◽  
pp. 152-160
Author(s):  
Fabio Salvatore Macaluso
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Molecular Mechanisms ◽  
Oral Route ◽  
New Drugs ◽  
Mediators Of Inflammation ◽  
Bowel Diseases ◽  
Intrinsic Complexity ◽  
Inflammatory Bowel

Over the past decade, the improvement in the understanding of the molecular mechanisms of Crohn’s disease (CD) led to the development of more targeted therapies, including biologics - i.e. monoclonal antibodies that selectively block key mediators of inflammation - and novel small molecule drugs - i.e. compounds with a molecular weight <1 kDa able to diffuse through cell membranes and then fit for the oral route of administration - which will enrich the therapeutic armamentarium of CD soon. In parallel with the expansion of the medical options, the therapeutic targets to be achieved in patients with CD have changed. In particular, we moved from the simple control of symptoms to more ambitious goals which aim to permanently extinguish the inflammation, even the subclinical one. As a consequence, the role of some of the conventional drugs which have been used in CD for several years, such as 5-aminosalicylates and conventional immunosuppressants, is becoming more limited in favor of these new drugs. This profound modification of CD therapy and the intrinsic complexity of the disease are relevant to the point that the management of inflammatory bowel diseases is gradually becoming a subspecialty in the field of gastroenterology or internal medicine.

scholarly journals Current Topics of the Mechanism of Intestinal Fibrosis in Crohn’s Disease

Immuno ◽  
2021 ◽  
Vol 1 (4) ◽  
pp. 574-582
Author(s):  
Yusuke Honzawa ◽  
Shuji Yamamoto ◽  
Makoto Okabe ◽  
Hiroshi Seno ◽  
Hiroshi Nakase
Keyword(s):  
Inflammatory Bowel Disease ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Detailed Analysis ◽  
Immune Cells ◽  
Bowel Disease ◽  
Tissue Repair ◽  
Inflammatory Process ◽  
Intestinal Fibrosis ◽  
Inflammatory Bowel

Intestinal fibrosis is one of the most common intestinal complications observed in inflammatory bowel disease, especially Crohn’s disease (CD). Intestinal fibrosis in CD is associated with chronic inflammation resulting from immunologic abnormalities and occurs as a form of tissue repair during the anti-inflammatory process. Various types of immune cells and mesenchymal cells, including myofibroblasts, are intricately involved in causing intestinal fibrosis. It is often difficult to treat intestinal fibrosis as intestinal stricture may develop despite treatment aimed at controlling inflammation. Detailed analysis of the pathogenesis of intestinal fibrosis is critical towards advancing the development of future therapeutic applications.

scholarly journals Gene Expression-Genotype Analysis ImplicatesGSDMA,GSDMB, andLRRC3Cas Contributors to Inflammatory Bowel Disease Susceptibility

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Jan Söderman ◽  
Linda Berglind ◽  
Sven Almer
Keyword(s):  
Inflammatory Bowel Disease ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Bowel Disease ◽  
Disease Susceptibility ◽  
Susceptibility Allele ◽  
Colon Tissue ◽  
Inflammatory Bowel ◽  
Related Proteins ◽  
Biological Foundation

To investigate the biological foundation of the inflammatory bowel disease (IBD), ulcerative colitis and Crohn’s disease, susceptibility locus rs2872507, we have investigated the expression of 13 genes using ileal and colonic biopsies from patients with IBD (inflamed and noninflamed mucosa) or from individuals without IBD (noninflamed mucosa). The susceptibility allele was consistently associated with reduced expression ofGSDMB(P= 4.1 × 10−3–7.2 × 10−10). The susceptibility allele was also associated with the increased expression ofGSDMA(P= 1.6 × 10−4) andLRRC3C(P= 7.8 × 10−6) in colon tissue from individuals without IBD and with the reduced expression ofPGAP3(IBD;P= 2.0 × 10−3) andZPBP2(Crohn’s disease;P= 7.7 × 10−4) in noninflamed ileum. Inflammation resulted in the reduced colonic expression ofERBB2,GRB7,MIEN1, andPGAP3(P= 1.0 × 10−4–1.0 × 10−9) and the increased colonic expression ofIKZF3andCSF3(P= 2.4 × 10−7–3.5 × 10−8). Based on our results and published findings onGSDMA,GSDMB,LRRC3C, and related proteins, we propose that this locus in part affects IBD susceptibility via effects on apoptosis and cell proliferation and believe this hypothesis warrants further experimental investigation.

scholarly journals Autophagy Stimulation as a Potential Strategy Against Intestinal Fibrosis

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1078 ◽  
Author(s):  
Jesus Cosin-Roger ◽  
Francisco Canet ◽  
Dulce C. Macias-Ceja ◽  
Laura Gisbert-Ferrándiz ◽  
Dolores Ortiz-Masiá ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Fibrosis ◽  
Murine Colitis ◽  
Pharmacological Stimulation ◽  
Primary Fibroblasts ◽  
Potential Strategy ◽  
Autophagy Inhibition ◽  
Stimulation Of ◽  
Inflammatory Effect

We recently observed reduced autophagy in Crohn’s disease patients and an anti-inflammatory effect of autophagy stimulation in murine colitis, but both anti- and pro-fibrotic effects are associated with autophagy stimulation in different tissues, and fibrosis is a frequent complication of Crohn’s disease. Thus, we analyzed the effects of pharmacological modulation of autophagy in a murine model of intestinal fibrosis and detected that autophagy inhibition aggravates, while autophagy stimulation prevents, fibrosis. These effects are associated with changes in inflammation and in collagen degradation in primary fibroblasts. Thus, pharmacological stimulation of autophagy may be useful against intestinal fibrosis.

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