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  • 1
    In: Digestion, S. Karger AG, Vol. 84, No. 2 ( 2011), p. 156-167
    Abstract: 〈 i 〉 Background/Aims: 〈 /i 〉 The non-lysosomal glucosylceramidase, β-glucosidase (Gba2), hydrolyzes glucosylceramide to glucose and ceramide (Cer). Cer is a potent second-messenger lipid that plays an important role in signaling cascades involved in apoptosis. The aim of this study was to investigate whether Gba2 knock-out (Gba2 〈 sup 〉 –/– 〈 /sup 〉 ) affects the extent of dextran sulfate sodium (DSS)-induced colitis in mice. 〈 i 〉 Methods: 〈 /i 〉 Acute colitis was induced in wild-type (WT) and Gba2 〈 sup 〉 –/– 〈 /sup 〉 mice by administration of 2% DSS in drinking water. After 7 days, mice underwent colonoscopy and were sacrificed. 〈 i 〉 Results: 〈 /i 〉 Both DSS-treated WT (n = 10) and Gba2 〈 sup 〉 –/– 〈 /sup 〉 (n = 12) mice showed elevated histological and endoscopic scores compared to respective H 〈 sub 〉 2 〈 /sub 〉 O controls (n = 9 each). However, no significant differences between the DSS groups were detected. Flow cytometric analysis of propidium iodide staining, cleavage of caspases-3 and -8, indicative for apoptosis, as well as Cer levels were not altered in DSS-treated WT or Gba2 〈 sup 〉 –/– 〈 /sup 〉 mice. Gba2 〈 sup 〉 –/– 〈 /sup 〉 resulted in slightly decreased expression of glucocerebrosidase (Gba1) as well as in upregulation of proteins being involved in cellular regeneration, such as STAT3 (signal transducer and activator of transcription), JNK and iNOS, upon DSS treatment. 〈 i 〉 Conclusion: 〈 /i 〉 We demonstrate that Gba2 〈 sup 〉 –/– 〈 /sup 〉 does not affect the extent of DSS-induced inflammation in mice, however, it might be involved in tissue regeneration in response to toxic agents.
    Type of Medium: Online Resource
    ISSN: 0012-2823 , 1421-9867
    RVK:
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    Language: English
    Publisher: S. Karger AG
    Publication Date: 2011
    detail.hit.zdb_id: 1482218-0
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  • 2
    In: Inflammatory Intestinal Diseases, S. Karger AG, Vol. 6, No. 2 ( 2021), p. 87-100
    Abstract: 〈 b 〉 〈 i 〉 Introduction: 〈 /i 〉 〈 /b 〉 Intestinal fibrosis, characterized by excessive deposition of extracellular matrix proteins, is a common and severe clinical complication of inflammatory bowel disease (IBD). However, the mechanisms underlying fibrosis remain elusive, and currently, there are limited effective pharmacologic treatments that target the development of fibrosis. Hypoxia is one of the key microenvironmental factors influencing intestinal inflammation and has been linked to fibrosis. 〈 b 〉 〈 i 〉 Objective: 〈 /i 〉 〈 /b 〉 In the present study, we sought to elucidate the impact of hypoxia on fibrotic gene expression in the intestinal mucosa. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 Human volunteers, IBD patients, and dextran sulphate sodium-treated mice were exposed to hypoxia, and colonic biopsies were collected. The human intestinal epithelial cell line Caco-2, human THP-1 macrophages, and primary human gut fibroblasts were subjected to hypoxia, and changes in fibrotic gene expression were assessed. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Human volunteers subjected to hypoxia presented reduced transcriptional levels of fibrotic and epithelial-mesenchymal transition markers in the intestinal mucosa. IBD patients showed a trend towards a decrease in tissue inhibitor of metalloproteinase 1 protein expression. In mice, hypoxic conditions reduced the colonic expression of several collagens and matrix metalloproteinases. Hypoxic Caco-2 cells, THP-1 cells, and primary gut fibroblasts showed a significant downregulation in the expression of fibrotic and tissue remodelling factors. 〈 b 〉 〈 i 〉 Conclusions: 〈 /i 〉 〈 /b 〉 Stabilization of hypoxia-inducible factors might represent a novel therapeutic approach for the treatment of IBD-associated fibrosis.
    Type of Medium: Online Resource
    ISSN: 2296-9403 , 2296-9365
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2021
    detail.hit.zdb_id: 2817967-5
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  • 3
    In: Inflammatory Intestinal Diseases, S. Karger AG, Vol. 6, No. 3 ( 2021), p. 140-153
    Abstract: 〈 b 〉 〈 i 〉 Background and Aims: 〈 /i 〉 〈 /b 〉 Local extracellular acidification is associated with several conditions, such as ischemia, cancer, metabolic disease, respiratory diseases, and inflammatory bowel disease (IBD). Several recent studies reported a link between IBD and a family of pH-sensing G protein-coupled receptors. Our previous studies point to an essential role for OGR1 (GPR68) in the modulation of intestinal inflammation and fibrosis. In the current study, we evaluated the effects of a novel OGR1 inhibitor in murine models of colitis. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 The effects of a novel small-molecule OGR1 inhibitor were assessed in the acute and chronic dextran sulfate sodium (DSS) murine models of colitis. Macroscopic disease indicators of intestinal inflammation were evaluated, and epithelial damage and immune cell infiltration and proliferation were assessed by immunohistochemistry. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 The OGR1 inhibitor ameliorated clinical parameters in acute and chronic DSS-induced colitis. In mice treated with the OGR1 inhibitor, endoscopy showed no thickening and normal vascularity, while fibrin was not detected. Histopathological findings revealed a decrease in severity of colonic inflammation in the OGR1 inhibitor group when compared to vehicle-DSS controls. In OGR1 inhibitor-treated mice, staining for the macrophage marker F4/80 and cellular proliferation marker Ki-67 revealed a reduction of infiltrating macrophages and slightly enhanced cell proliferation, respectively. This was accompanied by a reduction in pro-inflammatory cytokines, TNF and IL-6, and the fibrosis marker TGF-β1. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 This is the first report providing evidence that a pharmacological inhibition of OGR1 has a therapeutic effect in murine colitis models. Our data suggest that targeting proton-sensing OGR1 using specific small-molecule inhibitors may be a novel therapeutic approach for the treatment of IBD.
    Type of Medium: Online Resource
    ISSN: 2296-9403 , 2296-9365
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2021
    detail.hit.zdb_id: 2817967-5
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  • 4
    In: Cardiology, S. Karger AG, Vol. 97, No. 1 ( 2002), p. 29-36
    Abstract: 〈 i 〉 Background: 〈 /i 〉 Experimental studies have shown an activation of the angiotensin-converting enzyme (ACE) system as a response to endothelial injury. Recent publications have elucidated the hypothesis that the ACE gene polymorphism may influence the level of late luminal loss after coronary stent implantation. It is still unclear whether the polymorphism of the angiotensin gene is a major predictor of the extent of neointimal hyperplasia. In this multicenter study, we therefore tested the relationship between the ACE gene polymorphism and the restenosis rate after coronary stent implantation. 〈 i 〉 Methods: 〈 /i 〉 As a substudy of the optimization with intracoronary ultrasound (ICUS) to reduce stent restenosis (OPTICUS) study, we analyzed ACE serum levels and the ACE gene polymorphism in 154 patients at 9 different centers. All patients underwent elective coronary stent implantation in a stenosis of a major coronary vessel. Balloon inflations were repeated until a satisfactory result was achieved in on-line quantitative coronary angiography or ICUS fulfilling the OPTICUS study criteria. After follow-up of 6 months, all patients underwent reangiography under identical projections as the baseline procedure. A blinded quantitative analysis of the initial procedure as well as the follow-up examinations were performed by an independent core laboratory. ACE gene polymorphism and ACE serum activity were measured at the 6-month follow-up in a double-blinded setting. 〈 i 〉 Results: 〈 /i 〉 With respect to the ACE gene polymorphism, there were three subgroups: DD genotype (48 patients), ID (83 patients) and II (23 patients). The subgroups did not differ in regard to age, gender, extent of coronary artery disease, stenosis length, initial degree of stenosis or degree of stenosis after stent implantation. In all, 39 patients (25.3%) had significant restenosis: 12 DD patients (25.0%), 18 ID patients (21.7%) and 9 II patients (39.1%) (odds ratio 2.164, 95% confidence interval 0.853–5.493). We obtained the following results for ACE serum levels: 0.53 µmol/l/s in the DD subgroup, 0.29 µmol/l/s in the ID subgroup and 0.09 µmol/l/s in the II subgroup (p 〈 0.001). Multivariate logistic regression analysis of the influence of ACE gene polymorphism on the restenosis rate after coronary stent implantation adjusted for lesion length ( 〉 12 mm), ACE inhibitor or hydroxymethylglutaryl coenzyme A reductase (CSE) inhibitor treatment, age, male gender, diabetes mellitus, hypertension, high cholesterol, family history, smoking and three-vessel disease did not uncover any statistic significance. 〈 i 〉 Conclusions: 〈 /i 〉 In contrast to other study groups, we were unable to disclose that the DD polymorphism of the ACE gene was associated with a higher rate of restenosis after coronary stent implantation in this multicenter study. In addition, patients with higher ACE serum levels did not show a higher restenosis rate in this trial. We conclude that the pathogenesis of restenosis is a multifactorial process involving various genetic and nongenetic factors.
    Type of Medium: Online Resource
    ISSN: 0008-6312 , 1421-9751
    RVK:
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2002
    detail.hit.zdb_id: 1482041-9
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