78 research outputs found

    Effect of VSL#3 and dietary conjugated linoleic acid (CLA) supplementation on experimental <i>Helicobacter typhlonius</i>-induced colorectal cancer.

    No full text
    <p>Bacterial-free 129/SvEv and IL-10 gene deficient (IL-10−/−) 129/SvEv mice in a 129/SvEv background (n = 60) were treated with the VSL#3 probiotic (n = 20), CLA-supplemented (1 g/100 g) (n = 20) or control diets (n = 20) for 32 days and then were infected with <i>H. typhlonius</i> in order to develop experimental colorectal cancer associated with colitis. The disease activity index, a composite score reflecting clinical signs of the disease, was assessed daily for mice undergoing the DSS challenge (A). Colon, spleen and mesenteric lymph nodes (MLN) (B–D) were macroscopically scored for inflammation. Data are represented as mean ± standard error. Points with an asterisk are significantly different when compared to the control group (<i>P</i><0.05).</p

    VSL#3 and conjugated linoleic acid (CLA) modulate colonic gene expression.

    No full text
    <p>C57BL/6J mice (n = 60) were treated with the VSL#3 probiotic (n = 20), CLA-supplemented (1 g/100 g) (n = 20) or control diets (n = 20) for 32 days and challenged i.p. with azoxymethane (10 mg/kg) followed by 2% dextran sodium sulfate (DSS) in the drinking water for 7 days to induce colitis-associated colorectal cancer (CRC). Mice were euthanized on day 68. Expression of CD36 (A), cyclooxygenase 2 (COX2) (B), peroxisome proliferator-activated receptor γ (PPAR γ) (C) and angiostatin (D) were assessed by real-time quantitative PCR. Data are represented as mean ± standard error. Points with an asterisk are significantly different when compared to the control group (<i>P</i><0.05).</p

    Effect of VSL#3 and dietary conjugated linoleic acid (CLA) supplementation on experimental azoxymethane-induced colorectal cancer.

    No full text
    <p>C57BL/6J mice (n = 60) were treated with the VSL#3 probiotic (n = 20), CLA-supplemented (1 g/100 g) (n = 20) or control diets (n = 20) for 32 days and challenged i.p. with azoxymethane (10 mg/kg) followed by 2% dextran sodium sulfate (DSS) in the drinking water for 7 days to induce colitis-associated colorectal cancer (CRC). The disease activity index, a composite score reflecting clinical signs of the disease (i.e. perianal soiling, rectal bleeding, diarrhea, and piloerection) was assessed daily for mice undergoing the DSS challenge (A). Mice were euthanized on day 68. Colon and mesenteric lymph nodes (MLN) (B&C) were macroscopically scored for inflammation. Data are represented as mean ± standard error. Points with an asterisk are significantly different when compared to the control group (<i>P</i><0.05).</p

    Effect of the CLA and VSL#3 treatment on colon histopathology on experimental <i>Helicobacter typhlonius</i>-induced colorectal cancer.

    No full text
    <p>Bacterial-free 129/SvEv and IL-10 gene deficient (IL-10−/−) 129/SvEv mice in a 129/SvEv background (n = 60) were treated with the VSL#3 probiotic (n = 20), CLA-supplemented (1 g/100 g) (n = 20) or control diets (n = 20) for 32 days and then were infected with <i>H. typhlonius</i> in order to develop experimental colorectal cancer associated with colitis. After the necropsy, all specimens underwent blinded histological examination and were scored 1–4 on mucosal wall thickening (A), leukocyte infiltration (B), adenomas (C) and adenocarcinomas (D). Data are represented as mean ± standard error. Points with an asterisk are significantly different when compared to the control group (<i>P</i><0.05).</p

    VSL#3 and conjugated linoleic acid (CLA) modulate immune cell subsets in mesenteric lymph nodes (MLN), colonic lamina propria lymphocytes (LPL) and spleen.

    No full text
    <p>C57BL/6J mice (n = 60) were treated with the VSL#3 probiotic (n = 20), CLA-supplemented (1 g/100 g) (n = 20) or control diets (n = 20) for 32 days and challenged i.p. with azoxymethane (10 mg/kg) followed by 2% dextran sodium sulfate (DSS) in the drinking water for 7 days to induce colitis-associated colorectal cancer (CRC). Mice were euthanized on day 68. MLN (A–C), spleen (D) and LPL (E–F) from wild type mice were immunophenotyped to identify immune cells subsets by flow cytometry. Data are represented as mean ± standard error. Points with an asterisk are significantly different when compared to the control group (<i>P</i><0.05).</p

    An <i>N</i>,<i>N</i>‑Bis(benzimidazolylpicolinoyl)piperazine (BT-11): A Novel Lanthionine Synthetase C‑Like 2‑Based Therapeutic for Inflammatory Bowel Disease

    No full text
    Lanthionine synthetase C-like 2 (LANCL2), a novel therapeutic target for inflammatory and autoimmune diseases and diabetes, exerts anti-inflammatory and insulin-sensitizing effects. This study reports the first LANCL2-based therapeutics for inflammatory bowel disease (IBD). Analogues of <b>1</b> (ABA) and <b>2</b> (NSC61610) were screened by molecular docking, then synthesized and analyzed for binding to LANCL2 by surface plasmon resonance. Piperazine-1,4-diylbis­(6-benzo­[d]­imidazole-2-yl)­pyridine-2-yl)­methanone, <b>7</b>, was identified as the lead LANCL2-binding compound for treating IBD. The oral treatment with <b>7</b> (8 mg/kg/d) in a mouse model of IBD resulted in lowering the disease activity index, decreasing colonic inflammatory lesions by 4-fold, and suppressing inflammatory markers (e.g., TNF-α, and interferon-γ) in the gut. Furthermore, studies in LANCL2–/– mice demonstrated that loss of LANCL2 abrogated beneficial actions of <b>7</b>, suggesting high selectivity for the target. In conclusion, <b>7</b> merits continued development as a LANCL2-based, first-in-class orally active therapeutic for IBD

    image_1.PDF

    No full text
    <p>Interactions among the gut microbiome, dysregulated immune responses, and genetic factors contribute to the pathogenesis of inflammatory bowel disease (IBD). Nlrx1<sup>−/−</sup> mice have exacerbated disease severity, colonic lesions, and increased inflammatory markers. Global transcriptomic analyses demonstrate enhanced mucosal antimicrobial defense response, chemokine and cytokine expression, and epithelial cell metabolism in colitic Nlrx1<sup>−/−</sup> mice compared to wild-type (WT) mice. Cell-specificity studies using cre-lox mice demonstrate that the loss of NLRX1 in intestinal epithelial cells (IEC) recapitulate the increased sensitivity to DSS colitis observed in whole body Nlrx1<sup>−/−</sup> mice. Further, organoid cultures of Nlrx1<sup>−/−</sup> and WT epithelial cells confirm the altered patterns of proliferation, amino acid metabolism, and tight junction expression. These differences in IEC behavior can impact the composition of the microbiome. Microbiome analyses demonstrate that colitogenic bacterial taxa such as Veillonella and Clostridiales are increased in abundance in Nlrx1<sup>−/−</sup> mice and in WT mice co-housed with Nlrx1<sup>−/−</sup> mice. The transfer of an Nlrx1<sup>−/−</sup>-associated gut microbiome through co-housing worsens disease in WT mice confirming the contributions of the microbiome to the Nlrx1<sup>−/−</sup> phenotype. To validate NLRX1 effects on IEC metabolism mediate gut–microbiome interactions, restoration of WT glutamine metabolic profiles through either exogenous glutamine supplementation or administration of 6-diazo-5-oxo-l-norleucine abrogates differences in inflammation, microbiome, and overall disease severity in Nlrx1<sup>−/−</sup> mice. The influence NLRX1 deficiency on SIRT1-mediated effects is identified to be an upstream controller of the Nlrx1<sup>−/−</sup> phenotype in intestinal epithelial cell function and metabolism. The altered IEC function and metabolisms leads to changes in barrier permeability and microbiome interactions, in turn, promoting greater translocation and inflammation and resulting in an increased disease severity. In conclusion, NLRX1 is an immunoregulatory molecule and a candidate modulator of the interplay between mucosal inflammation, metabolism, and the gut microbiome during IBD.</p

    Simulated dynamics of mucosal immune response to <i>Clostridium difficile</i>.

    No full text
    <p>Modeling results following calibration and validation of the host response model in populations of (a) <i>C</i>. <i>difficile</i>, (b) protective commensal bacteria, (c) infection-exacerbating commensal bacteria, (d) lamina propria T helper 17 cells, (e) effector dendritic cells, (f) infiltrating neutrophils, (g) regulatory T cells, (h) tolerogenic dendritic cells and (i) activated macrophages. Lines represent simulation results, filled points represent experimental calibration data and unfilled points represent experimental validation data.</p

    <i>In silico</i> simulation of altered commensal bacteria regrowth during <i>Clostridium difficile</i> infection.

    No full text
    <p>Four cases were tested with variations to the inhibition of the commensal bacteria growth: inhibited by both neutrophils and inflamed epithelial cells (N and E_i), by only neutrophils (N), by only inflamed epithelial cells (E_i), and by neither (none). Resulting changes in species populations for each case are shown: (a) <i>baiCD</i>-containing commensal species, (b) <i>C</i>. <i>difficile</i>, (c) activated neutrophils, and (d) iTreg cells in the lamina propria.</p
    corecore