Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ileal Na+-dependent bile acid transport was quantified in vitro as the uptake of 3H-taurocholate into brush-border membrane vesicles. Vesicles were prepared from ileal biopsies of 158 patients placed in 10 diagnostic categories. Active bile acid transport (expressed as picomoles taurocholate uptake per milligram brush-border membrane protein per 15 s, median and interquartile ranges indicated) did not differ significantly in 6 categories: irritable bowel syndrome (71, 35-97; n = 21), colon polyps (42, 30-89; n = 29), colitis (62, 33-91; n = 31), postvagotomy or postcholecystectomy (69, 37-97; n = 11), diarrhea without increased bile acid loss (58, 48-85; n = 12), and lack of gastrointestinal pathology (74, 45-103; n = 22). A decreased active bile acid transport was found in 3 categories: ileal disease (4, 1-36; n = 11), partial ileal resection (5, 1-35; n = 5), and constipation (41, 22-50; n = 8). Bile acid transport was increased in patients with bile acid-losing diarrhea with endoscopically and histologically normal ilea (111, 94-135; n = 8). These findings indicate that a low fecal bile acid loss, presumed to be present in constipated patients, is associated with a low Na+-dependent ileal bile acid transport and a high bile acid loss is associated with a high active bile acid transport. Ileal bile acid transport might be regulated by the availability of bile acids to the ileal enterocytes.
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PMID:Na+-dependent bile acid transport in the ileum: the balance between diarrhea and constipation. 229 90

G-protein-coupled receptors (GPCRs) constitute the largest family of membrane-bound proteins involved in translation of extracellular signals into intracellular responses. They regulate diverse physiological and pathophysiological processes, and hence, they are prime drug targets for therapeutic intervention. In spite of the recent advancements in membrane protein crystallography, limited information is available on the molecular signatures of activation of GPCRs. Although few studies have been reported for class A GPCRs, the activation mechanism of class B GPCRs remains unexplored. Corticotropin-releasing factor 1 receptor (CRF1R), a class B GPCR, is associated with various disease conditions including stress, anxiety, and irritable bowel syndrome. Here, we report the activation of CRF1R using accelerated molecular dynamics simulations of the apo receptor. The breakage of His155(2.50)-Glu209(3.50) and Glu209(3.50)-Thr316(6.42) interactions is found to be crucial in transition of the receptor to its active conformation. Compared to the inactive crystal structure, major structural rearrangements occurred in the intracellular region of the transmembrane (TM) domain upon activation: TM3 twisted away from TM2, and an opening of the G-protein binding site occurred as a result of the outward movements of TM5 and TM6 from the helical bundle. Further, an inward tilt of TM7 toward the helical core is observed at the extracellular side, in agreement with recent findings (Coin et al. Cell 2013, 155, 1258-1269), where it is proposed that this movement helps in establishing favorable interactions with peptide agonist. Moreover, different allosteric pathways in the inactive and active states are identified using the correlations in torsion angle space. The inactive state is found to be less dynamic as compared to the putative active state of the receptor. Results from the current study could present a model for class B GPCRs activation and aid in the design of CRF1R modulators against brain and metabolic disorders.
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PMID:Activation of corticotropin-releasing factor 1 receptor: insights from molecular dynamics simulations. 2560 3

Background: Microbial dysbiosis is closely associated with visceral hypersensitivity and is involved in the pathogenesis of irritable bowel syndrome (IBS), but the specific strains that play a key role have yet to be identified. Previous bioinformatic studies have demonstrated that Fusobacterium is a shared microbial feature between IBS patients and maternal separation (MS)-stressed rats. In this study, we assessed the potential role of Fusobacterium nucleatum (F. nucleatum) in the pathogenesis of IBS. Methods: Fecal samples of patients with diarrhea predominant-IBS (IBS-D) and healthy controls were obtained. An MS rat model was established to receive gavage of either F. nucleatum or normal saline. Visceral sensitivity was evaluated through colorectal distension test, and fecal microbiota was analyzed by 16S rRNA gene sequencing. F. nucleatum-specific IgA levels in fecal supernatants were assessed by western blotting. The antigen reacted with the specific IgA of F. nucleatum was identified by mass spectrometry and the construction of a recombinant Escherichia coli BL21 (DE3). Results: IBS-D patients showed a lower Shannon index and a higher abundance of Fusobacterium. The F. nucleatum-gavage was shown to exacerbate visceral hypersensitivity in MS rats, with both the F. nucleatum-gavage and MS causing a decreased Shannon index and a clear segregation of fecal microbiota. In addition, specific IgA against F. nucleatum was detected in fecal supernatants of both the F. nucleatum-gavaged rats and the IBS-D patients. The FomA protein, which is a major outer membrane protein of F. nucleatum, was confirmed to react with the specific IgA of F. nucleatum in fecal supernatants. Conclusion: Fusobacterium increased significantly in IBS-D patients, and F. nucleatum was involved in the pathogenesis of IBS by causing microbial dysbiosis and exacerbating visceral hypersensitivity in a colonization-independent manner. Meanwhile, F. nucleatum was found to induce an increase in specific secretory IgA through FomA.
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PMID:Fusobacterium nucleatum Causes Microbial Dysbiosis and Exacerbates Visceral Hypersensitivity in a Colonization-Independent Manner. 3273 92