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  1. Article ; Online: Tofacitinib-Induced Modulation of Intestinal Adaptive and Innate Immunity and Factors Driving Cellular and Systemic Pharmacokinetics.

    Texler, Bernhard / Zollner, Andreas / Reinstadler, Vera / Reider, Simon J / Macheiner, Sophie / Jelusic, Barbara / Pfister, Alexandra / Watschinger, Christina / Przysiecki, Nicole / Tilg, Herbert / Oberacher, Herbert / Moschen, Alexander R

    Cellular and molecular gastroenterology and hepatology

    2021  Volume 13, Issue 2, Page(s) 383–404

    Abstract: Objective: By interfering with multiple cytokines, human Janus kinase inhibitors (JAKis) are of growing importance in the treatment of malignant and inflammatory conditions. Although tofacitinib has demonstrated efficacy as the first-in-class JAKi in ... ...

    Abstract Objective: By interfering with multiple cytokines, human Janus kinase inhibitors (JAKis) are of growing importance in the treatment of malignant and inflammatory conditions. Although tofacitinib has demonstrated efficacy as the first-in-class JAKi in ulcerative colitis many aspects concerning its mode of action and pharmacokinetics remain unresolved.
    Design: We studied tofacitinib's impact on various primary human innate and adaptive immune cells. In-depth in vivo studies were performed in dextran sodium sulfate-induced colitis in mice. Immune populations were characterized by flow cytometry and critical transcription factors and effector cytokines were analyzed. Pharmacokinetics of tofacitinib was studied by liquid chromatography-tandem mass spectrometry.
    Results: Tofacitinib inhibited proliferation in CD4
    Conclusions: We provide a detailed analysis of the cell-specific immune-suppressive effects of the JAKis tofacitinib on innate and adaptive immunity and reveal that intestinal inflammation critically impacts tofacitinib's pharmacokinetics in mice. Furthermore, we describe an unappreciated mechanism-namely induction of equilibrative nucleoside transporters-enhancing baseline cellular uptake that can be inhibited pharmaceutically.
    MeSH term(s) Animals ; CD8-Positive T-Lymphocytes ; Immunity, Innate ; Mice ; Piperidines/pharmacology ; Pyrimidines/pharmacology
    Chemical Substances Piperidines ; Pyrimidines ; tofacitinib (87LA6FU830)
    Language English
    Publishing date 2021-10-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2819778-1
    ISSN 2352-345X ; 2352-345X
    ISSN (online) 2352-345X
    ISSN 2352-345X
    DOI 10.1016/j.jcmgh.2021.09.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Prebiotic Effects of Partially Hydrolyzed Guar Gum on the Composition and Function of the Human Microbiota—Results from the PAGODA Trial

    Reider, Simon J / Moosmang, Simon / Tragust, Judith / Trgovec-Greif, Lovro / Tragust, Simon / Perschy, Lorenz / Przysiecki, Nicole / Sturm, Sonja / Tilg, Herbert / Stuppner, Hermann / Rattei, Thomas / Moschen, Alexander R

    Nutrients. 2020 Apr. 28, v. 12, no. 5

    2020  

    Abstract: 1) Background: Alterations in the structural composition of the human gut microbiota have been identified in various disease entities along with exciting mechanistic clues by reductionist gnotobiotic modeling. Improving health by beneficially modulating ...

    Abstract (1) Background: Alterations in the structural composition of the human gut microbiota have been identified in various disease entities along with exciting mechanistic clues by reductionist gnotobiotic modeling. Improving health by beneficially modulating an altered microbiota is a promising treatment approach. Prebiotics, substrates selectively used by host microorganisms conferring a health benefit, are broadly used for dietary and clinical interventions. Herein, we sought to investigate the microbiota-modelling effects of the soluble fiber, partially hydrolyzed guar gum (PHGG). (2) Methods: We performed a 9 week clinical trial in 20 healthy volunteers that included three weeks of a lead-in period, followed by three weeks of an intervention phase, wherein study subjects received 5 g PHGG up to three times per day, and concluding with a three-week washout period. A stool diary was kept on a daily basis, and clinical data along with serum/plasma and stool samples were collected on a weekly basis. PHGG-induced alterations of the gut microbiota were studied by 16S metagenomics of the V1–V3 and V3–V4 regions. To gain functional insight, we further studied stool metabolites using nuclear magnetic resonance (NMR) spectroscopy. (3) Results: In healthy subjects, PHGG had significant effects on stool frequency and consistency. These effects were paralleled by changes in α- (species evenness) and β-diversity (Bray–Curtis distances), along with increasing abundances of metabolites including butyrate, acetate and various amino acids. On a taxonomic level, PHGG intake was associated with a bloom in Ruminococcus, Fusicatenibacter, Faecalibacterium and Bacteroides and a reduction in Roseburia, Lachnospiracea and Blautia. The majority of effects disappeared after stopping the prebiotic and most effects tended to be more pronounced in male participants. (4) Conclusions: Herein, we describe novel aspects of the prebiotic PHGG on compositional and functional properties of the healthy human microbiota.
    Keywords Bacteroides ; Roseburia ; Ruminococcus ; acetates ; amino acids ; blood serum ; butyrates ; clinical trials ; feces ; frequency ; functional properties ; germ-free animals ; guar gum ; humans ; intestinal microorganisms ; males ; metabolites ; metagenomics ; models ; nuclear magnetic resonance spectroscopy ; nutrients ; prebiotics ; soluble fiber
    Language English
    Dates of publication 2020-0428
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    Note NAL-light
    ZDB-ID 2518386-2
    ISSN 2072-6643
    ISSN 2072-6643
    DOI 10.3390/nu12051257
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: Prebiotic Effects of Partially Hydrolyzed Guar Gum on the Composition and Function of the Human Microbiota-Results from the PAGODA Trial.

    Reider, Simon J / Moosmang, Simon / Tragust, Judith / Trgovec-Greif, Lovro / Tragust, Simon / Perschy, Lorenz / Przysiecki, Nicole / Sturm, Sonja / Tilg, Herbert / Stuppner, Hermann / Rattei, Thomas / Moschen, Alexander R

    Nutrients

    2020  Volume 12, Issue 5

    Abstract: 1) Background: Alterations in the structural composition of the human gut microbiota have been identified in various disease entities along with exciting mechanistic clues by reductionist gnotobiotic modeling. Improving health by beneficially modulating ...

    Abstract (1) Background: Alterations in the structural composition of the human gut microbiota have been identified in various disease entities along with exciting mechanistic clues by reductionist gnotobiotic modeling. Improving health by beneficially modulating an altered microbiota is a promising treatment approach. Prebiotics, substrates selectively used by host microorganisms conferring a health benefit, are broadly used for dietary and clinical interventions. Herein, we sought to investigate the microbiota-modelling effects of the soluble fiber, partially hydrolyzed guar gum (PHGG). (2) Methods: We performed a 9 week clinical trial in 20 healthy volunteers that included three weeks of a lead-in period, followed by three weeks of an intervention phase, wherein study subjects received 5 g PHGG up to three times per day, and concluding with a three-week washout period. A stool diary was kept on a daily basis, and clinical data along with serum/plasma and stool samples were collected on a weekly basis. PHGG-induced alterations of the gut microbiota were studied by 16S metagenomics of the V1-V3 and V3-V4 regions. To gain functional insight, we further studied stool metabolites using nuclear magnetic resonance (NMR) spectroscopy. (3) Results: In healthy subjects, PHGG had significant effects on stool frequency and consistency. These effects were paralleled by changes in α- (species evenness) and β-diversity (Bray-Curtis distances), along with increasing abundances of metabolites including butyrate, acetate and various amino acids. On a taxonomic level, PHGG intake was associated with a bloom in
    MeSH term(s) Acetates/metabolism ; Bacteroides/isolation & purification ; Butyrates/metabolism ; Dietary Fiber/administration & dosage ; Dietary Fiber/pharmacology ; Faecalibacterium/isolation & purification ; Feces/microbiology ; Female ; Galactans/administration & dosage ; Galactans/pharmacology ; Gastrointestinal Microbiome/drug effects ; Healthy Volunteers ; Humans ; Hydrolysis ; Male ; Mannans/administration & dosage ; Mannans/pharmacology ; Plant Gums/administration & dosage ; Plant Gums/pharmacology ; Prebiotics ; Ruminococcus/isolation & purification ; Solubility
    Chemical Substances Acetates ; Butyrates ; Dietary Fiber ; Galactans ; Mannans ; Plant Gums ; Prebiotics ; guar gum (E89I1637KE)
    Language English
    Publishing date 2020-04-28
    Publishing country Switzerland
    Document type Clinical Trial ; Journal Article
    ZDB-ID 2518386-2
    ISSN 2072-6643 ; 2072-6643
    ISSN (online) 2072-6643
    ISSN 2072-6643
    DOI 10.3390/nu12051257
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Faecal Biomarkers in Inflammatory Bowel Diseases: Calprotectin Versus Lipocalin-2-a Comparative Study.

    Zollner, Andreas / Schmiderer, Andreas / Reider, Simon J / Oberhuber, Georg / Pfister, Alexandra / Texler, Bernhard / Watschinger, Christina / Koch, Robert / Effenberger, Maria / Raine, Tim / Tilg, Herbert / Moschen, Alexander R

    Journal of Crohn's & colitis

    2020  Volume 15, Issue 1, Page(s) 43–54

    Abstract: Background and aims: Faecal biomarkers, particularly calprotectin [FCAL], have become important diagnostic and monitoring tools in inflammatory bowel diseases [IBD]. As FCAL is mainly produced by neutrophils, we hypothesised that faecal lipocalin-2 [ ... ...

    Abstract Background and aims: Faecal biomarkers, particularly calprotectin [FCAL], have become important diagnostic and monitoring tools in inflammatory bowel diseases [IBD]. As FCAL is mainly produced by neutrophils, we hypothesised that faecal lipocalin-2 [FLCN2], also expressed by intestinal epithelial cells [IEC], could be beneficial in specific clinical situations.
    Methods: We compared clinical and endoscopic activity-related correlations between FCAL and FLCN2, assayed from the same sample, in a cohort of 132 patients (72 Crohn's disease [CD]) and 40 controls. A detailed analysis of cellular origins was done by confocal microscopy and flow cytometry. To evaluate the potential to detect low-grade inflammation, we studied faecal and tissue concentrations in a cohort with clinical, endoscopic, and histological remission.
    Results: There was an excellent correlation between FCAL and FLCN2 [rS = 0.87, p <0.001] and comparable sensitivity and specificity to predict clinical and endoscopic disease activity, with optimal thresholds for endoscopic activity of 73.4 and 1.98 µg/g in ulcerative colitis [UC] and 78.4 and 0.56 µg/g in Crohn's disease for FCAL and FLCN2, respectively. Strong co-expression of both proteins was observed in granulocytes and macrophages. IECs expressed LCN2 but not CAL. In our IBD cohort in deep remission neither FCAL nor FLCN2 was different from controls; yet mucosal LCN2 but not CAL expressions remained elevated in the rectum of UC and the ileum of CD patients.
    Conclusions: This study corroborates the diagnostic equivalence of FLCN2 and FCAL in IBD. In remission, persistent mucosal overexpression renders LCN2 an attractive candidate for molecular inflammation warranting further investigation.
    MeSH term(s) Biomarkers/analysis ; Colitis, Ulcerative/immunology ; Colitis, Ulcerative/pathology ; Colitis, Ulcerative/therapy ; Colonoscopy/methods ; Crohn Disease/immunology ; Crohn Disease/pathology ; Crohn Disease/therapy ; Feces/chemistry ; Female ; Gene Expression Profiling/methods ; Humans ; Ileum/immunology ; Ileum/pathology ; Inflammation/metabolism ; Intestinal Mucosa/metabolism ; Intestinal Mucosa/pathology ; Leukocyte L1 Antigen Complex/analysis ; Lipocalin-2/analysis ; Male ; Rectum/immunology ; Rectum/pathology ; Remission Induction ; Sensitivity and Specificity ; Severity of Illness Index
    Chemical Substances Biomarkers ; Leukocyte L1 Antigen Complex ; Lipocalin-2
    Language English
    Publishing date 2020-06-19
    Publishing country England
    Document type Comparative Study ; Journal Article
    ZDB-ID 2390120-2
    ISSN 1876-4479 ; 1873-9946
    ISSN (online) 1876-4479
    ISSN 1873-9946
    DOI 10.1093/ecco-jcc/jjaa124
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6634: Show issues Location:
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  5. Article ; Online: Lipocalin 2 Protects from Inflammation and Tumorigenesis Associated with Gut Microbiota Alterations.

    Moschen, Alexander R / Gerner, Romana R / Wang, Jun / Klepsch, Victoria / Adolph, Timon E / Reider, Simon J / Hackl, Hubert / Pfister, Alexandra / Schilling, Johannes / Moser, Patrizia L / Kempster, Sarah L / Swidsinski, Alexander / Orth Höller, Dorothea / Weiss, Günter / Baines, John F / Kaser, Arthur / Tilg, Herbert

    Cell host & microbe

    2016  Volume 19, Issue 4, Page(s) 455–469

    Abstract: High mucosal and fecal concentrations of the antimicrobial siderophore-binding peptide Lipocalin-2 (Lcn2) are observed in inflammatory bowel disease. However, Lcn2 function in chronic intestinal inflammation remains unclear. Here, we demonstrate that ... ...

    Abstract High mucosal and fecal concentrations of the antimicrobial siderophore-binding peptide Lipocalin-2 (Lcn2) are observed in inflammatory bowel disease. However, Lcn2 function in chronic intestinal inflammation remains unclear. Here, we demonstrate that Lcn2 protects from early-onset colitis and spontaneous emergence of right-sided colonic tumors resulting from IL-10 deficiency. Exacerbated inflammation in Lcn2(-/-)/Il10(-/-) mice is driven by IL-6, which also controls tumorigenesis. Lcn2(-/-)/Il10(-/-) mice exhibit profound alterations in gut microbial composition, which contributes to inflammation and tumorigenesis, as demonstrated by the transmissibility of the phenotype and protection conferred by antibiotics. Specifically, facultative pathogenic Alistipes spp. utilize enterobactin as iron source, bloom in Lcn2(-/-)/Il10(-/-) mice, and are sufficient to induce colitis and right-sided tumors when transferred into Il10(-/-) mice. Our results demonstrate that Lcn2 protects against intestinal inflammation and tumorigenesis associated with alterations in the microbiota.
    MeSH term(s) Animals ; Bacteroides/growth & development ; Carcinogenesis ; Colitis/genetics ; Colitis/immunology ; Colitis/microbiology ; Colitis/pathology ; Gastrointestinal Microbiome ; Humans ; Inflammation ; Interleukin-10/genetics ; Interleukin-10/immunology ; Interleukin-6/genetics ; Interleukin-6/immunology ; Intestinal Neoplasms/genetics ; Intestinal Neoplasms/immunology ; Intestinal Neoplasms/microbiology ; Intestinal Neoplasms/pathology ; Lipocalin-2/genetics ; Lipocalin-2/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout
    Chemical Substances Interleukin-6 ; Lipocalin-2 ; Interleukin-10 (130068-27-8)
    Language English
    Publishing date 2016-04-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2278004-X
    ISSN 1934-6069 ; 1931-3128
    ISSN (online) 1934-6069
    ISSN 1931-3128
    DOI 10.1016/j.chom.2016.03.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6578: Show issues Location:
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