Animal models of ulcerative colitis and their application in drug research

The specific pathogenesis underlying inflammatory bowel disease is complex, and it is even more difficult to decipher the pathophysiology to explain for the similarities and differences between two of its major subtypes, Crohn’s disease and ulcerative colitis (UC). Animal models are indispensable to pry into mechanistic details that will facilitate better preclinical drug/therapy design to target specific components involved in the disease pathogenesis. This review focuses on common animal models that are particularly useful for the study of UC and its therapeutic strategy. Recent reports of the latest compounds, therapeutic strategies, and approaches tested on UC animal models are also discussed

A collaboration platform for enabling industrial symbiosis : towards creating a self-learning waste-to-resource database for recommending industrial symbiosis transactions using text analytics

Industrial Symbiosis (IS) adopts a collaborative approach, which aims to re-channel resources – traditionally considered spent and non-productive – towards alternative value-adding pathways. Empirically, the concept of IS has been rapidly implemented in practice through a facilitated approach, whereby businesses are engaged and “match-made” via a facilitating body. While recommending alternative pathways for companies to establish IS-based transactions is a long-standing practice, recent technological advancement has shifted the nature of this task from one that is based purely on human intellect and reasoning, towards one which leverages intelligent recommendation algorithms to provide relevant suggestions. Traditionally, these recommendation engines rely on manually populated knowledge bases that are not only labor-intensive to build but also costly to maintain. This work presents the creation of a self-learning waste-to-resource database supporting an IS recommendation system by utilizing text analytics techniques. We further demonstrate its practical application to support IS facilitating bodies in their core activity

Integrative analysis workflow for the structural and functional classification of C-type lectins

<p>Abstract</p> <p>Background</p> <p>It is important to understand the roles of C-type lectins in the immune system due to their ubiquity and diverse range of functions in animal cells. It has been observed that currently confirmed C-type lectins share a highly conserved domain known as the C-type carbohydrate recognition domain (CRD). Using the sequence profile of the CRD, an increasing number of putative C-type lectins have been identified. Hence, it is highly needed to develop a systematic framework that enables us to elucidate their carbohydrate (glycan) recognition function, and discover their physiological and pathological roles.</p> <p>Results</p> <p>Presented herein is an integrated workflow for characterizing the sequence and structural features of novel C-type lectins. Our workflow utilizes web-based queries and available software suites to annotate features that can be found on the C-type lectin, given its amino acid sequence. At the same time, it incorporates modeling and analysis of glycans - a major class of ligands that interact with C-type lectins. Thereafter, the results are analyzed together with context-specific knowledge to filter off unlikely predictions. This allows researchers to design their subsequent experiments to confirm the functions of the C-type lectins in a systematic manner.</p> <p>Conclusions</p> <p>The efficacy and usefulness of our proposed immunoinformatics workflow was demonstrated by applying our integrated workflow to a novel C-type lectin -CLEC17A - and we report some of its possible functions that warrants further validation through wet-lab experiments.</p

High Endogenous Expression of Chitinase 3-Like 1 and Excessive Epithelial Proliferation with Colonic Tumor Formation in MOLF/EiJ Mice

Colorectal cancer (CRC) development is mediated by uncontrolled survival and proliferation of tumor progenitor cells. Using animal models to identify and study host-derived factors that underlie this process can aid interventions in preventing tumor expansion and metastasis. In healthy steady states in humans and mice (e.g. C57BL/6 strain), colonic Chitinase 3-like 1 (CHI3L1) gene expression is undetectable. However, this expression can be induced during intestinal inflammation and tumorigenesis where CHI3L1 plays an important role in tissue restitution and cell proliferation. Here, we show that a wild-derived mouse strain MOLF/EiJ expresses high levels of colonic epithelial CHI3L1 at the steady state due to several nucleotide polymorphisms in the proximal promoter regions of the CHI3L1 gene. Interestingly, these mice spontaneously developed polypoid nodules in the colon with signs of immune cell infiltrations at steady state. The CHI3L1 positive colonic epithelial cells were highly proliferative and exhibited malignant transformation and expansion when exposed in vivo to azoxymethane, one of the well-known colonic carcinogens

Genome-wide gene expression profiling of the Angelman syndrome mouse with Ube3a mutation : from genotype to phenotype

Angelman syndrome (AS) is an inheritable neurodevelopmental disorder resulting from the loss of function of the ubiquitin E3A ligase (UBE3A). Clinical features of the disorder include severe mental retardation, motor incoordination and perpetual happy disposition. Associated features of AS include hypopigmentation and seizures. Despite many targets and interacting partners of UBE3A being identified, the detailed pathogenesis of the disorder, as well as how the lack of functional UBE3A upsets cellular homeostasis, remains vague. The aim of this project is to characterize the gene expression profile of the AS mouse model by performing a genome-wide microarray screening to identify differentially expressed genes and to unravel potential genotype-phenotype correlationship mechanisms. Results: Sixty-four differentially expressed genes (7 up-regulated and 57 down-regulated) in the AS mouse cerebellum were identified, which subsequent pathway analysis showed their involvement in 3 major networks including cell signaling, nervous system development and cell death. Representative genes (Fgf7, Glra1, Mc1r, Nr4a2, Slc5a7, Epha6) from each network were selected based on their functional relevance to AS and validated for their differential expression using qRT-PCR. The validation was extended towards the protein level using Western blot for Nr4a2 and Mc1r. Both showed reduction in their respective protein level in the mutant AS mouse.DOCTOR OF PHILOSOPHY (SBS

Chitin-binding domains of Escherichia coli ChiA mediate interactions with intestinal epithelial cells in mice with colitis

International audienceBackground and aims: Inducible chitinase 3-like-1 is expressed by intestinal epithelial cells (IECs) and adheres to bacteria under conditions of inflammation. We performed a structure-function analysis of the chitin-binding domains encoded by the chiA gene, which mediates the pathogenic effects of adherent invasive Escherichia coli (AIEC). Methods: We created AIEC (strain LF82) with deletion of chiA (LF82-Delta chiA) or that expressed chiA with specific mutations. We investigated the effects of infecting different IEC lines with these bacteria compared with nonpathogenic E coli; chitinase activities were measured using the colloidal chitin-azure method. Colitis was induced in C57/Bl6 mice by administration of dextran sodium sulfate, and mice were given 10(8) bacteria for 15 consecutive days by gavage. Stool/tissue samples were collected and analyzed. Results: LF82-Delta chiA had significantly less adhesion to IEC lines than LF82. Complementation of LF82-Delta chiA with the LF82 chiA gene, but not chiA from nonpathogenic (K12) E coli, increased adhesion. We identified 5 specific polymorphisms in the chitin-binding domain of LF82 chiA (at amino acids 362, 370, 378, 388, and 548) that differ from chiA of K12 and were required for LF82 to interact directly with IECs. This interaction was mediated by an N-glycosylated asparagine in chitinase 3-like-1 (amino acid 68) on IECs. Mice infected with LF82, or LF82-Delta chiA complemented with LF82 chiA, developed more severe colitis after administration of dextran sodium sulfate than mice infected with LF82-Delta chiA or LF82 that expressed mutant forms of chiA. Conclusions: AIEC adheres to an N-glycosylated chitinase 3-like-1 on IECs via the chitin-binding domain of chiA. This mechanism promotes the pathogenic effects of AIEC in mice with colitis

MOLF express high levels of CHI3L1 in the colon and polypoid area and associates with high immune cellular infiltrates.

<p>Two-color Immunofluorescence analysis was performed on colonic sections from six months old B6 and MOLF mice using anti-CHI3L1 and anti-F4/80 (<b>A</b>) -CD11b (<b>B</b>) or -CD4 (<b>C</b>) primary antibodies respectively.</p