| 1. |
- Sotak, Matus, et al.
(författare)
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Intestinal sodium/glucose cotransporter 3 expression is epithelial and downregulated in obesity.
- 2021
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Ingår i: Life sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 267
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to determine whether the sodium/glucose cotransporter family member SGLT3, a proposed glucose sensor, is expressed in the intestine and/or kidney, and if its expression is altered in mouse models of obesity and in humans before and after weight-loss surgery.We used in-situ hybridization and quantitative PCR to determine whether the Sglt3 isoforms 3a and 3b were expressed in the intestine and kidney of C57, leptin-deficient ob/ob, and diabetic BTBR ob/ob mice. Western blotting and immunohistochemistry were also used to assess SGLT3 protein levels in jejunal biopsies from obese patients before and after weight-loss Roux-en-Y gastric bypass surgery (RYGB), and in lean healthy controls.Sglt3a/3b mRNA was detected in the small intestine (duodenum, jejunum and ileum), but not in the large intestine or kidneys of mice. Both isoforms were detected in epithelial cells (confirmed using intestinal organoids). Expression of Sglt3a/3b mRNA in duodenum and jejunum was significantly lower in ob/ob and BTBR ob/ob mice than in normal-weight littermates. Jejunal SGLT3 protein levels in aged obese patients before Roux-en-Y gastric bypass (RYGB) were lower than in lean individuals, but substantially upregulated 6months post-RYGB.Our study shows that Sglt3a/3b is expressed primarily in epithelial cells of the small intestine in mice. Furthermore, we observed an association between intestinal mRNA Sglt3a/3b expression and obesity in mice, and between jejunal SGLT3 protein levels and obesity in humans. Further studies are required to determine the possible role of SGLT3 in obesity.
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| 2. |
- Berglund, Martin, 1979, et al.
(författare)
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Gender dependent importance of IRAK-1 in dextran sulfate sodium induced colitis
- 2009
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Ingår i: Cellular Immunology. - : Elsevier BV. - 1090-2163 .- 0008-8749. ; 259:1, s. 27-32
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Tidskriftsartikel (refereegranskat)abstract
- Toll-like receptor (TLR) signaling is important for the induction of pro-inflammatory cytokines and interferon (IFN)-inducible genes in response to bacterial and viral challenge. Interleukin-1 receptor-associated kinase-1 (IRAK-1) is a signaling kinase situated downstream of the adapter protein myeloid differentiation factor 88 (MyD88) in the TLR intracellular signaling cascade and is required for normal signal transduction through this pathway. We investigated the importance of IRAK-1 in intestinal inflammation by using the dextran sulfate sodium (DSS)-colitis model. We show that IRAK-1 deficient mice are protected against systemic signs of inflammation, i.e., weight loss and spleen enlargement compared to wild-type controls irrespective of gender. However, IRAK-1(-/y) males but not IRAK-1(-/-) females display significant protection against colitis and thymic atrophy compared to wild-type mice. Our results indicate a gender specific effect of IRAK-1 in the DSS-induced colitis, an interesting finding since the Irak-1 gene is located on the X-chromosome and several inflammatory diseases have a gender dependent incidence.
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| 3. |
- Fredin, Maria Fritsch, 1970, et al.
(författare)
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Dextran sulfate sodium-induced colitis generates a transient thymic involution--impact on thymocyte subsets.
- 2007
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Ingår i: Scandinavian journal of immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 65:5, s. 421-9
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Tidskriftsartikel (refereegranskat)abstract
- One of the most widely used animal models for inflammatory bowel disease (IBD) is the dextran sulfate sodium (DSS)-induced colitis. We have previously reported that 5 days administration of DSS in C57Bl/6J mice induces a colonic inflammation that progresses into chronicity after DSS removal, whereas in BALB/cJ mice the inflammation resolves within 4 weeks post-DSS. Here we show that both thymic size and thymocyte numbers dramatically decreased in the acute phase of inflammation in C57Bl/6 mice, 7 days after DSS withdrawal. Mature, CD4(+) and CD8(+) single positive (SP) CD69(lo) CD62L(hi) thymocytes were enriched in these mice, accompanied by a major decrease in the number of immature double positive (DP) thymocytes. However, the different maturation stages within the DP thymocyte subset were unchanged between healthy and inflamed C57Bl/6J mice. Interestingly, as the inflammation progressed into the chronic phase, the thymus recovered and 2 weeks after the acute inflammatory phase all the thymic parameters investigated in this study were restored to normal. In contrast, BALB/cJ mice only develop mild thymic alterations. Nevertheless, we found that within the double negative (DN) thymocytes an increased frequency and also total numbers of CD44(+) CD25(-) (DN1) cells correlated with the severity of colitis, and that the frequency of CD44(-) CD25(-) (DN4) thymocytes decreased proportionally in the acute phase in BALB/cJ mice. Our observations suggest that the thymic effects are intimately connected to the intestinal inflammatory response in colitis regardless of the inflammatory stimuli.
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| 4. |
- Fredin, Maria Fritsch, 1970
(författare)
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Dynamic changes in T cell compartments and new approaches in evaluating DSS induced and Gai2 deficient colitis
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to increase the understanding of the immunopathology of Inflammatory Bowel Disease (IBD). The first aim was to elucidate how the thymus and the gut epithelium were affected by colitis. The second aim was to investigate new ways of assessing and monitoring colitis. Two mouse models of colitis were used, the dextran sodium sulfate (DSS) induced model and the Gai2 deficient (Gai2-/-) mouse model, which spontaneously develops colitis. These two models were compared throughout the study. Colitis-induced changes were analysed in thymocytes and intestinal intraepithelial lymphocytes (IEL). To monitor and evaluate colitis, cultures of mouse and human colonic tissue were set up and the colon wall thickness was measured by micro-Computed Tomography (micro-CT). During acute DSS induced colitis, the thymocytes were shifted towards a more mature phenotype, with loss of double positive (DP) thymocytes, paralleled by an increase in the absolute number of double negative (DN1) thymocytes. These changes were transient and returned to normal as the mice recovered or progressed into the chronic phase. In colitic Gai2-/- mice, CD4+ IELs increased in the large intestine, while CD4+CD8aa+ DP IELs increased in the small intestine. The dynamic changes in thymocyte and IEL composition demonstrates that colitis affect other T cell compartments than the colon. Thymic involution and the increase in immature DN1 thymocytes during acute colitis may result in an increased export of immature T cells to the gut. The different responses in the small and large intestine during colitis suggest that the two microenvironments induce either an uncontrolled inflammation in the large intestine or suppression in the small intestine. Approximately 75% of the genes detected in DSS induced and Gai2-/- colitic mice were similarly regulated in ex vivo cultures and in vivo, and belonged to cytokines and T and B cell markers. A similar gene profile was obtained in human UC ex vivo cultures compared to mouse. Measurements of the colon wall in DSS treated mice demonstrated a significantly thicker colon wall during the acute phase of colitis compared to healthy controls, and correlated to the macroscopic scoring of colitis. The similar gene expression profile in mouse and human cultures and the finding that colon wall thickness can be used to identify responding animals support the relevance of these systems in monitoring colitis and evaluating new substances for the treatment of IBD. Finally, this study points to the fact that chemically induced and spontaneously developing mouse models of colitis have several characteristics in common, such as thymic involution and expression of similar immune-related genes during colitis.
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| 5. |
- Fredin, Maria Fritsch, 1970, et al.
(författare)
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Predicting and monitoring colitis development in mice by micro-computed tomography
- 2008
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Ingår i: Inflammatory Bowel Diseases. - : Oxford University Press (OUP). - 1078-0998 .- 1536-4844. ; 14:4, s. 491-499
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Computed tomography (CT) has been developed as a tool for monitoring human inflammatory bowel disease (IBD). The aim of this study was to evaluate colon wall thickness as a noninvasive marker in the dextran sodium sulfate (DSS) mouse model of colitis using micro-CT. METHODS: Mice were examined by micro-CT 1, 2, or 4 times between day 0 (d0) and d26 after induction of colitis to document the kinetics of changes in colon wall thickness and its relation to colitis development. RESULTS: DSS-treated mice displayed a significantly thicker colon wall at all timepoints (days 5, 8, 12, 19, and 26) investigated compared to healthy controls. Colon wall thickness showed a good correlation to the macroscopic grading of colitis (r = 0.81). The increase in colon wall thickness occurred mainly during the acute phase of colitis (between days 5 and 12) and did not progress much further in the chronic phase of colitis (d26). Colon wall thickness at d26 was thereby predicted by measurements at d12. All mice did not respond equally to DSS and this difference was manifest during the first 2 weeks of colitis, providing an important tool in stratifying responders from nonresponders. CONCLUSIONS: While the potential impact of handling and anesthesia should be considered on repeated micro-CT, irradiation exposure during repeated micro-CT did not affect the development of colitis. Thus, the results suggest that micro-CT can be used for monitoring and prediction of the inflammatory response in mouse colitis in future therapeutic studies.
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| 6. |
- Fredin, Maria Fritsch, 1970, et al.
(författare)
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The application and relevance of ex vivo culture systems for assessment of IBD treatment in murine models of colitis
- 2008
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 58:3-4, s. 222-231
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the relevance of mouse ex vivo cultures as a first screening model for new therapeutic agents of Inflammatory Bowel Disease (IBD). Two murine models (dextran sodium sulphate (DSS)-induced colitis and Gαi2-deficient mice) and two anti-inflammatory agents (methyl-prednisolone and the proteasome inhibitor MG132) were evaluated. The in vivo effects of methyl-prednisolone were assessed in both models. Ex vivo colonic tissue from both mouse models were cultured in the presence or absence of the drugs and TaqMan Low-Density arrays were used to assess the regulation of inflammatory genes before and after drug treatment. Colitis induced a similar inflammatory gene profile in both mouse models in in vivo studies and in ex vivo cultures. The differences encountered reflected the different phases of colitis in the models, e.g. innate cytokine/chemokine profile in the DSS model and T cell related markers in Gαi2-deficient mice. After steroid treatment, a similar pattern of genes was suppressed in the two mouse models. We confirmed the suppression of inflammatory gene expression for IL-1β, IL-6 and iNOS in ex vivo and in vivo colons from both mouse models by quantitative RT-PCR. Importantly, the inflammatory responses in the murine ex vivo culture system reflected the in vivo response in the inflamed colonic tissue as assessed by changes in inflammatory gene expression, suggesting that the murine culture system can be used for validation of future IBD therapies.
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