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  • 1
    Online Resource
    Online Resource
    Mucosal and faecal neutrophil gelatinase-associated lipocalin as potential biomarkers for collagenous colitis
    Springer Science and Business Media LLC ; 2021
    In:  Journal of Gastroenterology Vol. 56, No. 10 ( 2021-10), p. 914-927
    Details
    In: Journal of Gastroenterology, Springer Science and Business Media LLC, Vol. 56, No. 10 ( 2021-10), p. 914-927
    Abstract: Collagenous colitis (CC) is an inflammatory bowel disease where chronic diarrhoea is the main symptom. Diagnostic markers distinguishing between CC and other causes of chronic diarrhoea remain elusive. This study explores neutrophil gelatinase-associated lipocalin (NGAL) and its mRNA lipocalin2 ( LCN2 ) as histological and faecal disease markers in CC. Methods NGAL/ LCN2 were studied in colonic biopsies from CC patients before and during budesonide treatment using RNA sequencing ( n  = 9/group), in situ hybridization (ISH) ( n  = 13–22/group) and immunohistochemistry (IHC) ( n  = 14–25/group). Faecal samples from CC ( n  = 3–28/group), irritable bowel syndrome diarrhoea (IBS-D) ( n  = 14) and healthy controls (HC) ( n  = 15) were assayed for NGAL and calprotectin. Results NGAL/ LCN2 protein and mRNA expression were upregulated in active CC vs HC, and vs paired samples of treated CC in clinical remission. IHC and ISH localized increased NGAL/ LCN2 mainly to epithelium of active CC, compared to almost absence in HC and treated CC. In contrast, calprotectin was solely expressed in immune cells. Despite great individual differences, faecal NGAL was significantly increased in active CC compared to HC, IBS-D and treated CC and had high test sensitivity. Faecal calprotectin levels were variably increased in active CC, but the values remained below usual clinical cut-offs. Conclusion NGAL/ LCN2 is upregulated in the epithelium of active CC and reduced during budesonide-induced clinical remission to the level of HC and IBD-S. This was reflected in NGAL faecal concentrations. We propose NGAL as an IHC marker for disease activity in CC and a potential faecal biomarker discriminating CC from HC and IBS-D.
    Type of Medium: Online Resource
    ISSN: 0944-1174 , 1435-5922
    URL: Article
    DOI: 10.1007/s00535-021-01814-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1473159-9
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  • 2
    Online Resource
    Online Resource
    Table_1.xlsx
    Frontiers Media SA ; 2023
    In:  Frontiers in Immunology Vol. 14 ( 2023-1-27)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 14 ( 2023-1-27)
    Abstract: The epithelium in the colonic mucosa is implicated in the pathophysiology of various diseases, including inflammatory bowel diseases and colorectal cancer. Intestinal epithelial organoids from the colon (colonoids) can be used for disease modeling and personalized drug screening. Colonoids are usually cultured at 18-21% oxygen without accounting for the physiological hypoxia in the colonic epithelium (3% to & lt;1% oxygen). We hypothesize that recapitulating the in vivo physiological oxygen environment (i.e., physioxia) will enhance the translational value of colonoids as pre-clinical models. Here we evaluate whether human colonoids can be established and cultured in physioxia and compare growth, differentiation, and immunological responses at 2% and 20% oxygen. Methods Growth from single cells to differentiated colonoids was monitored by brightfield images and evaluated with a linear mixed model. Cell composition was identified by immunofluorescence staining of cell markers and single-cell RNA-sequencing (scRNA-seq). Enrichment analysis was used to identify transcriptomic differences within cell populations. Pro-inflammatory stimuli induced chemokines and Neutrophil gelatinase-associated lipocalin (NGAL) release were analyzed by Multiplex profiling and ELISA. Direct response to a lower oxygen level was analyzed by enrichment analysis of bulk RNA sequencing data. Results Colonoids established in a 2% oxygen environment acquired a significantly larger cell mass compared to a 20% oxygen environment. No differences in expression of cell markers for cells with proliferation potential (KI67 positive), goblet cells (MUC2 positive), absorptive cells (MUC2 negative, CK20 positive) and enteroendocrine cells (CGA positive) were found between colonoids cultured in 2% and 20% oxygen. However, the scRNA-seq analysis identified differences in the transcriptome within stem-, progenitor- and differentiated cell clusters. Both colonoids grown at 2% and 20% oxygen secreted CXCL2, CXCL5, CXCL10, CXCL12, CX3CL1 and CCL25, and NGAL upon TNF + poly(I:C) treatment, but there appeared to be a tendency towards lower pro-inflammatory response in 2% oxygen. Reducing the oxygen environment from 20% to 2% in differentiated colonoids altered the expression of genes related to differentiation, metabolism, mucus lining, and immune networks. Conclusions Our results suggest that colonoids studies can and should be performed in physioxia when the resemblance to in vivo conditions is important.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2023.1095812
    DOI: 10.3389/fimmu.2023.1095812.s001
    DOI: 10.3389/fimmu.2023.1095812.s002
    DOI: 10.3389/fimmu.2023.1095812.s003
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2606827-8
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  • 3
    Online Resource
    Online Resource
    Intestinal Epithelial Cells Express Immunomodulatory ISG15 During Active Ulcerative Colitis and Crohn’s Disease
    Oxford University Press (OUP) ; 2020
    In:  Journal of Crohn's and Colitis Vol. 14, No. 7 ( 2020-07-30), p. 920-934
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 14, No. 7 ( 2020-07-30), p. 920-934
    Abstract: Intestinal epithelial cells [IECs] secrete cytokines that recruit immune cells to the mucosa and regulate immune responses that drive inflammation in inflammatory bowel disease [IBD] . However, experiments in patient-derived IEC models are still scarce. Here, we aimed to investigate how innate immunity and IEC-specific pattern recognition receptor [PRR] signalling can be involved in an enhanced type I interferon [IFN] gene signature observed in colon epithelium of patients with active IBD, with a special focus on secreted ubiquitin-like protein ISG15. Methods Gene and protein expression in whole mucosa biopsies and in microdissected human colonic epithelial lining, in HT29 human intestinal epithelial cells and primary 3D colonoids treated with PRR-ligands and cytokines, were detected by transcriptomics, in situ hybridisation, immunohistochemistry, western blots, and enzyme-linked immunosorbent assay [ELISA]. Effects of IEC-secreted cytokines were examined in human peripheral blood mononuclear cells [PBMCs] by multiplex chemokine profiling and ELISA. Results The type I IFN gene signature in human mucosal biopsies was mimicked in Toll-like receptor TLR3 and to some extent tumour necrosis factor [TNF]-treated human IECs. In intestinal biopsies, ISG15 expression correlated with expression of the newly identified receptor for extracellular ISG15, LFA-1 integrin. ISG15 was expressed and secreted from HT29 cells and primary 3D colonoids through both JAK1-pSTAT-IRF9-dependent and independent pathways. In experiments using PBMCs, we show that ISG15 releases IBD-relevant proinflammatory cytokines such as CXCL1, CXCL5, CXCL8, CCL20, IL1, IL6, TNF, and IFNγ. Conclusions ISG15 is secreted from primary IECs upon extracellular stimulation, and mucosal ISG15 emerges as an intriguing candidate for immunotherapy in IBD.
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjaa022
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2389631-0
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