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  1. Article ; Online: Common Genetic Variants in the Bile Acid Synthesis Enzyme CYP7A1 Are Associated With Severe Primary Bile Acid Diarrhea.

    Balesaria, Sara / Pattni, Sanjeev S / Johnston, Ian M / Nolan, Jonathan D / Appleby, Richard N / Walters, Julian R F

    Gastroenterology

    2022  Volume 163, Issue 2, Page(s) 517–519.e2

    MeSH term(s) Bile Acids and Salts ; Cholesterol 7-alpha-Hydroxylase/metabolism ; Diarrhea/genetics ; Humans ; Lipogenesis
    Chemical Substances Bile Acids and Salts ; CYP7A1 protein, human (EC 1.14.14.23) ; Cholesterol 7-alpha-Hydroxylase (EC 1.14.14.23)
    Language English
    Publishing date 2022-05-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80112-4
    ISSN 1528-0012 ; 0016-5085
    ISSN (online) 1528-0012
    ISSN 0016-5085
    DOI 10.1053/j.gastro.2022.05.005
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  2. Article ; Online: Altered enterohepatic circulation of bile acids in Crohn's disease and their clinical significance: a new perspective.

    Nolan, Jonathan D / Johnston, Ian M / Walters, Julian R F

    Expert review of gastroenterology & hepatology

    2013  Volume 7, Issue 1, Page(s) 49–56

    Abstract: The role of bile acids (BA) extends far beyond lipid digestion and cholesterol metabolism. The transcriptional regulation of multiple genes within the liver and intestine are under their influence. BA exert these effects through binding and activating ... ...

    Abstract The role of bile acids (BA) extends far beyond lipid digestion and cholesterol metabolism. The transcriptional regulation of multiple genes within the liver and intestine are under their influence. BA exert these effects through binding and activating receptors in much the same way as endocrine hormones. The farnesoid X receptor (FXR) is the intracellular transcription factor for BA; TGR5 is the cell-surface receptor. The main target genes of FXR are those involved in BA and cholesterol metabolism. Yet more recently, FXR has also been shown to influence and promote certain protective pathways within the liver. These pathways are being harnessed by semisynthetic BAs in Phase II and III clinical trials. FXR activation within the intestine is also associated with similar protective pathways. This article examines the consequences of altered FXR activation in the context of BA malabsorption in Crohn's disease and the potential benefits of FXR agonists in Crohn's disease.
    MeSH term(s) Animals ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacology ; Bile Acids and Salts/metabolism ; Crohn Disease/drug therapy ; Crohn Disease/immunology ; Crohn Disease/metabolism ; Cytokines/metabolism ; Drug Design ; Enterohepatic Circulation ; Fibroblast Growth Factors/metabolism ; Gastrointestinal Agents/chemistry ; Gastrointestinal Agents/pharmacology ; Humans ; Inflammation Mediators/metabolism ; Intestinal Absorption ; Intestines/drug effects ; Intestines/metabolism ; Ligands ; Liver/drug effects ; Liver/metabolism ; Receptors, Cytoplasmic and Nuclear/agonists ; Receptors, Cytoplasmic and Nuclear/metabolism ; Signal Transduction
    Chemical Substances Anti-Inflammatory Agents ; Bile Acids and Salts ; Cytokines ; FGF19 protein, human ; Gastrointestinal Agents ; Inflammation Mediators ; Ligands ; Receptors, Cytoplasmic and Nuclear ; farnesoid X-activated receptor ; Fibroblast Growth Factors (62031-54-3)
    Language English
    Publishing date 2013-01
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2481021-6
    ISSN 1747-4132 ; 1747-4124
    ISSN (online) 1747-4132
    ISSN 1747-4124
    DOI 10.1586/egh.12.66
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  3. Article ; Online: Azathioprine with Allopurinol Is a Promising First-Line Therapy for Inflammatory Bowel Diseases.

    van Liere, Elsa L S A / Bayoumy, Ahmed B / Mulder, Chris J J / Warner, Ben / Hayee, Bu / Mateen, Bilal A / Nolan, Jonathan D / de Boer, Nanne K H / Anderson, Simon H C / Ansari, Azhar R

    Digestive diseases and sciences

    2021  Volume 67, Issue 8, Page(s) 4008–4019

    Abstract: Background: Beneficial response to first-line immunosuppressive azathioprine in patients with inflammatory bowel disease (IBD) is low due to high rates of adverse events. Co-administrating allopurinol has been shown to improve tolerability. However, ... ...

    Abstract Background: Beneficial response to first-line immunosuppressive azathioprine in patients with inflammatory bowel disease (IBD) is low due to high rates of adverse events. Co-administrating allopurinol has been shown to improve tolerability. However, data on this co-therapy as first-line treatment are scarce.
    Aim: Retrospective comparison of long-term effectiveness and safety of first-line low-dose azathioprine-allopurinol co-therapy (LDAA) with first-line azathioprine monotherapy (AZAm) in patients with IBD without metabolite monitoring.
    Methods: Clinical benefit was defined as ongoing therapy without initiation of steroids, biologics or surgery. Secondary outcomes included CRP, HBI/SCCAI, steroid withdrawal and adverse events.
    Results: In total, 166 LDAA and 118 AZAm patients (median follow-up 25 and 27 months) were evaluated. Clinical benefit was more frequently observed in LDAA patients at 6 months (74% vs. 53%, p = 0.0003), 12 months (54% vs. 37%, p = 0.01) and in the long-term (median 36 months; 37% vs. 24%, p = 0.04). Throughout follow-up, AZAm patients were 60% more likely to fail therapy, due to a higher intolerance rate (45% vs. 26%, p = 0.001). Only 73% of the effective AZA dose was tolerated in AZAm patients, while LDAA could be initiated and maintained at its target dose. Incidence of myelotoxicity and elevated liver enzymes was similar in both cohorts, and both conditions led to LDAA withdrawal in only 2%. Increasing allopurinol from 100 to 200-300 mg/day significantly lowered liver enzymes in 5/6 LDAA patients with hepatotoxicity.
    Conclusions: Our poor AZAm outcomes emphasize that optimization of azathioprine is needed. We demonstrated a long-term safe and more effective profile of first-line LDAA. This co-therapy may therefore be considered standard first-line immunosuppressive.
    MeSH term(s) Allopurinol/adverse effects ; Azathioprine/adverse effects ; Drug Therapy, Combination ; Humans ; Immunosuppressive Agents/adverse effects ; Inflammatory Bowel Diseases/chemically induced ; Inflammatory Bowel Diseases/drug therapy ; Mercaptopurine/therapeutic use ; Retrospective Studies ; Treatment Outcome
    Chemical Substances Immunosuppressive Agents ; Allopurinol (63CZ7GJN5I) ; Mercaptopurine (E7WED276I5) ; Azathioprine (MRK240IY2L)
    Language English
    Publishing date 2021-11-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 304250-9
    ISSN 1573-2568 ; 0163-2116
    ISSN (online) 1573-2568
    ISSN 0163-2116
    DOI 10.1007/s10620-021-07273-y
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  4. Article: Novel associations of bile acid diarrhoea with fatty liver disease and gallstones: a cohort retrospective analysis.

    Appleby, Richard N / Nolan, Jonathan D / Johnston, Ian M / Pattni, Sanjeev S / Fox, Jessica / Walters, Julian Rf

    BMJ open gastroenterology

    2017  Volume 4, Issue 1, Page(s) e000178

    Abstract: Background: Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), ... ...

    Abstract Background: Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), obesity and hypertriglyceridaemia. The aim of this study was to identify further associations of BAD.
    Methods: A cohort of patients with chronic diarrhoea who underwent
    Findings: Of 578 patients, 303 (52%) had BAD, defined as a SeHCAT 7d retention value <15%, with 179 (31%) having primary BAD. 425 had an alanine aminotransferase (ALT) recorded, 184 had liver imaging and 176 had both. Overall, SeHCAT values were negatively associated with ALT (r
    Interpretation: The diagnosis of BAD is associated with fatty liver disease and with gallstones. The reasons for these associations require further investigation into potential metabolic causes.
    Language English
    Publishing date 2017-10-26
    Publishing country England
    Document type Journal Article
    ISSN 2054-4774
    ISSN 2054-4774
    DOI 10.1136/bmjgast-2017-000178
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  5. Article ; Online: Diarrhea in Crohn’s disease: investigating the role of the ileal hormone fibroblast growth factor 19.

    Nolan, Jonathan D / Johnston, Ian M / Pattni, Sanjeev S / Dew, Tracy / Orchard, Timothy R / Walters, Julian R F

    Journal of Crohn's & colitis

    2015  Volume 9, Issue 2, Page(s) 125–131

    Abstract: Background: Bile acids [BA] are usually reabsorbed by the terminal ileum, but this process is frequently abnormal in Crohn’s disease [CD]. BA malabsorption occurs, and excess colonic BA cause secretory diarrhea. Furthermore, the hormone fibroblast ... ...

    Abstract Background: Bile acids [BA] are usually reabsorbed by the terminal ileum, but this process is frequently abnormal in Crohn’s disease [CD]. BA malabsorption occurs, and excess colonic BA cause secretory diarrhea. Furthermore, the hormone fibroblast growth factor 19 [FGF19] is synthesized in the ileum in response to BA absorption and regulates BA synthesis. We hypothesized that reduced serum FGF19 levels will be associated with diarrheal symptoms and disease activity in both ileal resected[IR-CD] and non-resected CD [NR-CD] patients.
    Methods: Fasting serum FGF19 levels were measured in 58 patients [23 IR-CD patients and 35NR-CD patients]. Disease activity was assessed using the Harvey Bradshaw Index and C-reactive protein [CRP]. Stool frequency, Bristol Stool Form Scale and length of previous ileal resection were recorded. FGF19 levels were also compared with healthy and diarrhea control patients.
    Results: FGF19 levels were inversely correlated with ileal resection length in IR-CD patients[r = -0.54, p = 0.02]. In NR-CD patients, median FGF19 levels were significantly lower in patients with active disease compared with inactive disease [103 vs. 158 pg/ml, p = 0.04] and in those with symptoms of diarrhea compared with those without [86 vs. 145 pg/ml, p = 0.035]. FGF19 levels were inversely correlated with stool frequency, Bristol stool form and CRP in NR-CD patients with ileal disease.
    Conclusions: Reduced FGF19 levels are associated with ileal resection, diarrhea and disease activity. FGF19 may have utility as a biomarker for functioning ileum in CD. This study supports a potential role of FGF19 in guiding treatments for diarrhea in Crohn’s disease.
    MeSH term(s) Adult ; Aged ; Biomarkers/metabolism ; Biopsy ; Crohn Disease/complications ; Crohn Disease/metabolism ; Crohn Disease/pathology ; Diarrhea/etiology ; Female ; Fibroblast Growth Factors/physiology ; Humans ; Ileum/metabolism ; Ileum/pathology ; Male ; Middle Aged ; Prospective Studies
    Chemical Substances Biomarkers ; FGF19 protein, human ; Fibroblast Growth Factors (62031-54-3)
    Language English
    Publishing date 2015-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2390120-2
    ISSN 1876-4479 ; 1873-9946
    ISSN (online) 1876-4479
    ISSN 1873-9946
    DOI 10.1093/ecco-jcc/jju022
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  6. Article ; Online: Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids.

    Zhang, Justine H / Nolan, Jonathan D / Kennie, Sarah L / Johnston, Ian M / Dew, Tracy / Dixon, Peter H / Williamson, Catherine / Walters, Julian R F

    American journal of physiology. Gastrointestinal and liver physiology

    2013  Volume 304, Issue 10, Page(s) G940–8

    Abstract: Fibroblast growth factor 19 (FGF19) is proposed to be a negative feedback regulator of hepatic bile acid (BA) synthesis. We aimed to clarify the distribution of FGF19 expression in human intestine and to investigate induction in a novel explant system. ... ...

    Abstract Fibroblast growth factor 19 (FGF19) is proposed to be a negative feedback regulator of hepatic bile acid (BA) synthesis. We aimed to clarify the distribution of FGF19 expression in human intestine and to investigate induction in a novel explant system. Ileal and colonic mucosal biopsies were obtained at endoscopy and analyzed for FGF19 transcript expression. Primary explants were incubated with physiological concentrations of various BA for up to 6 h, and expression of FGF19 and other genes was determined. FGF19 transcripts were detected in ileum but were unquantifiable in colon. No loss of FGF19 mRNA occurred as a consequence of the explant system. Ileal FGF19 transcript expression was induced 350-fold by 50 μM chenodeoxycholate (CDCA, n = 24, P < 0.0001) and 161-fold by 50 μM glycochenodeoxycholate (GCDCA, n = 12, P = 0.0005). The responses of other genes to CDCA or GCDCA (50 μM) were smaller: median increases of ileal bile acid binding protein, organic solute transporter-α and -β, and short heterodimer partner were 2.4- to 4.0-fold; apical membrane sodium bile acid transporter and farnesoid X receptor (FXR) showed little change. The EC50 for FGF19 transcript induction by CDCA was 20 μM. FGF19 protein concentrations were significantly higher in the culture fluid from BA-stimulated explants. FGF19 induction with cholate was 81% of that found with CDCA, but deoxycholate (40%) and lithocholate (4%) were significantly less potent. The synthetic FXR agonist obeticholic acid was much more potent than CDCA with a 70-fold FGF19 stimulation at 1 μM. We concluded that FGF19 expression in human ileum is very highly responsive to BA. Changes in FGF19 induction are a potential mechanism involved in disorders of BA homeostasis.
    MeSH term(s) Adult ; Bile Acids and Salts/metabolism ; Bile Acids and Salts/pharmacology ; Biopsy ; Chenodeoxycholic Acid/pharmacology ; Colon/metabolism ; DNA, Complementary/biosynthesis ; DNA, Complementary/genetics ; Enterohepatic Circulation/physiology ; Enzyme-Linked Immunosorbent Assay ; Fibroblast Growth Factors/biosynthesis ; Gene Expression/drug effects ; Glycochenodeoxycholic Acid/pharmacology ; Humans ; Ileum/drug effects ; Ileum/metabolism ; Organ Culture Techniques ; RNA/genetics ; RNA/isolation & purification ; Real-Time Polymerase Chain Reaction ; Receptors, Cytoplasmic and Nuclear/drug effects ; Stimulation, Chemical
    Chemical Substances Bile Acids and Salts ; DNA, Complementary ; FGF19 protein, human ; Receptors, Cytoplasmic and Nuclear ; farnesoid X-activated receptor (0C5V0MRU6P) ; Chenodeoxycholic Acid (0GEI24LG0J) ; Fibroblast Growth Factors (62031-54-3) ; RNA (63231-63-0) ; Glycochenodeoxycholic Acid (640-79-9)
    Language English
    Publishing date 2013-03-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 603840-2
    ISSN 1522-1547 ; 0193-1857
    ISSN (online) 1522-1547
    ISSN 0193-1857
    DOI 10.1152/ajpgi.00398.2012
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  7. Article ; Online: Characterizing Factors Associated With Differences in FGF19 Blood Levels and Synthesis in Patients With Primary Bile Acid Diarrhea.

    Johnston, Ian M / Nolan, Jonathan D / Pattni, Sanjeev S / Appleby, Richard N / Zhang, Justine H / Kennie, Sarah L / Madhan, Gaganjit K / Jameie-Oskooei, Sina / Pathmasrirengam, Shivani / Lin, Jeremy / Hong, Albert / Dixon, Peter H / Williamson, Catherine / Walters, Julian R F

    The American journal of gastroenterology

    2016  Volume 111, Issue 3, Page(s) 423–432

    Abstract: Objectives: Chronic diarrhea caused by primary bile acid diarrhea (PBAD) is a common condition. We have previously shown PBAD is associated with low fasting serum levels of the ileal hormone, fibroblast growth factor 19 (FGF19). FGF19 is a negative ... ...

    Abstract Objectives: Chronic diarrhea caused by primary bile acid diarrhea (PBAD) is a common condition. We have previously shown PBAD is associated with low fasting serum levels of the ileal hormone, fibroblast growth factor 19 (FGF19). FGF19 is a negative regulator of hepatic bile acid synthesis and is stimulated by farnesoid X receptor agonists, which produce symptomatic improvement in PBAD. We aimed to assess possible causes for low serum FGF19 in patients with PBAD.
    Methods: Patients with PBAD, defined by reduced (75)Se-labelled homocholic acid taurine (SeHCAT) retention, and idiopathic diarrhea controls had measurements of fasting lipids and fasting/post-prandial FGF19 serum profiles. Specific functional variants in candidate genes were investigated in exploratory studies. In further groups, basal and bile acid-stimulated transcript expression was determined in ileal biopsies and explant cultures by quantitative PCR.
    Results: FGF19 profiles in PBAD patients included low fasting and meal-stimulated responses, which were both strongly correlated with SeHCAT. A subgroup of 30% of PBAD patients had fasting hypertriglyceridemia and higher FGF19. No clear significant differences were found for any genetic variant but there were borderline associations with FGFR4 and KLB. SeHCAT retention significantly correlated with the basal ileal transcript expression of FGF19 (rs=0.59, P=0.03) and apical sodium-dependent bile acid transporter (ASBT) (rs=0.49, P=0.04), and also with the degree of stimulation by chenodeoxycholic acid at 6 h for transcripts of FGF19 (median 184-fold, rs=0.50, P=0.02) and ileal bile acid binding protein (IBABP) (median 2.2-fold, rs=0.47, P=0.04). Median stimulation of FGF19 was lower in patients with SeHCAT retention <10% (P=0.01).
    Conclusions: These studies demonstrate a complex, multifactorial etiology of PBAD, including impairments in ileal FGF19 expression and responsiveness.
    MeSH term(s) Adult ; Bile Acids and Salts/biosynthesis ; Body Mass Index ; Diarrhea/blood ; Diarrhea/diagnosis ; Diarrhea/etiology ; Female ; Fibroblast Growth Factors/blood ; Fibroblast Growth Factors/genetics ; Humans ; Ileum/metabolism ; Ileum/pathology ; Male ; Membrane Proteins/genetics ; Middle Aged ; Receptor, Fibroblast Growth Factor, Type 4/genetics ; Receptors, Cytoplasmic and Nuclear/genetics ; Selenium Radioisotopes/pharmacology ; Statistics as Topic ; Taurocholic Acid/analogs & derivatives ; Taurocholic Acid/pharmacology ; Triglycerides/blood
    Chemical Substances Bile Acids and Salts ; FGF19 protein, human ; KLB protein, human ; Membrane Proteins ; Receptors, Cytoplasmic and Nuclear ; Selenium Radioisotopes ; Triglycerides ; farnesoid X-activated receptor ; Taurocholic Acid (5E090O0G3Z) ; Fibroblast Growth Factors (62031-54-3) ; 23-seleno-25-homotaurocholic acid (75018-70-1) ; FGFR4 protein, human (EC 2.7.10.1) ; Receptor, Fibroblast Growth Factor, Type 4 (EC 2.7.10.1)
    Language English
    Publishing date 2016-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 390122-1
    ISSN 1572-0241 ; 0002-9270
    ISSN (online) 1572-0241
    ISSN 0002-9270
    DOI 10.1038/ajg.2015.424
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