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Project description:Impaired bile secretion promotes hepatobiliary injury in Sickle Cell Disease.
| PRJNA541984 | ENA
Project description:Background and aimsHepatic crisis is an emergent complication affecting patients with sickle cell disease (SCD); however, the molecular mechanism of sickle cell hepatobiliary injury remains poorly understood. Using the knock-in humanized mouse model of SCD and SCD patient blood, we sought to mechanistically characterize SCD-associated hepato-pathophysiology applying our recently developed quantitative liver intravital imaging, RNA sequence analysis, and biochemical approaches.Approach and resultsSCD mice manifested sinusoidal ischemia, progressive hepatomegaly, liver injury, hyperbilirubinemia, and increased ductular reaction under basal conditions. Nuclear factor kappa B (NF-κB) activation in the liver of SCD mice inhibited farnesoid X receptor (FXR) signaling and its downstream targets, leading to loss of canalicular bile transport and altered bile acid pool. Intravital imaging revealed impaired bile secretion into the bile canaliculi, which was secondary to loss of canalicular bile transport and bile acid metabolism, leading to intrahepatic bile accumulation in SCD mouse liver. Blocking NF-κB activation rescued FXR signaling and partially ameliorated liver injury and sinusoidal ischemia in SCD mice.ConclusionsThese findings identify that NF-κB/FXR-dependent impaired bile secretion promotes intrahepatic bile accumulation, which contributes to hepatobiliary injury of SCD. Improved understanding of these processes could potentially benefit the development of therapies to treat sickle cell hepatic crisis.
| S-EPMC7923682 | biostudies-literature
Project description:Bile acid diarrhoea is a chronic condition caused by increased delivery of bile acids to the colon. The underlying mechanisms remain to be elucidated. To investigate genes involved in bile acid diarrhoea, systems-level analyses were employed on a rat bile acid diarrhoea model. Twelve male Wistar Munich rats, housed in metabolic cages, were fed either control or bile acid-mixed (1% w/w) diets for ten days. Food intake, water intake, urine volume, bodyweight and faecal output were monitored daily. After euthanasia, colonic epithelial cells were isolated using calcium-chelation and processed for systems-level analyses, i.e. RNA-sequencing transcriptomics and mass spectrometry proteomics. Bile acid-fed rats suffered diarrhoea, indicated by increased drinking, faeces weight and faecal water content compared with control rats. Urine output was unchanged. With bile acid-feeding, RNA-sequencing revealed 204 increased and 401 decreased mRNAs; mass spectrometry 183 increased and 111 decreased proteins. Among the altered genes were genes associated with electrolyte and water transport (including Slc12a7, Clca4 and Aqp3) and genes associated with bile acid transport (Slc2b1, Abcg2, Slc51a, Slc51b and Fabps). Correlation analysis showed a significant positive correlation (Pearson’s r=0.28) between changes in mRNA-expression and changes in protein-expression. However, caution must be exercised in making a direct correlation between experimentally determined transcriptomes and proteomes. Genes associated with bile acid transport responded to bile acid-feeding, suggesting that colonic bile acid transport occur by regulated protein facilitated mechanisms rather than passive diffusion. In addition, the study provides annotated rat colonic epithelial cell transcriptome and proteome with response to bile acid-feeding.
2024-05-10 | GSE174249 | GEO
Project description:Rationale. Sickle cell cardiomyopathy is characterized by prolonged QTc, myocardial fibrosis, diastolic dysfunction, and vulnerability to ventricular tachycardia (VT). Based on previous reports, IL-18 mediates cardiac fibrosis and its promoter SNPs are associated with sudden cardiac death in a non-sickle population. We, therefore, hypothesized that IL-18 may mediate cardiomyopathy and VT in sickle cell disease. Findings. Sickle cell patients with evidence of myocardial fibrosis demonstrated greater IL18 expression. Patients with higher IL18 gene expression levels also exhibited increased QTc intervals and overall mortality. A novel SNP within IL-18, rs5744285, was associated with both QTc and IL-18 expression levels. Similar to sickle cell patients, sickle mice demonstrated increased cardiac fibrosis and prolonged action potential duration (APD) associated with higher VT inducibility. Administration of exogenous IL-18 acutely ex vivo to hearts resulted in increased triggered activity and VTs while inhibition of IL-18 resulted in reduced cardiac NFkB expression, fibrosis, and dysfunction in sickle mice. Conclusions. IL-18 is associated with prolonged QTc, myocardial fibrosis, and mortality in sickle cell patients, and prolonged APD associated with heightened VT susceptibility in sickle mice. Inhibition of IL-18 improves cardiac function, in part, via NFκB. Inflammatory cytokines contribute to the development of sickle cardiomyopathy and inducible VT.
2018-10-31 | GSE89373 | GEO
Project description:To analyze expression of inflammatory cytokines in Exhaled Breath Condensates from pediatric patients with sickle cell disease, asthma, sickle cell disease and asthma, and controls
2020-05-08 | GSE150056 | GEO
Project description:Tolerance of gut commensals to bile salt exposure is an important feature for their survival in and colonization of the intestinal environment. A transcriptomic approach was employed to study the response of Bifidobacterium breve UCC2003 to bile, allowing the identification of a number of bile-induced genes with a range of predicted functions. The potential role of a selection of these bile-inducible genes in bile protection was determined by heterologous expression in Lactococcus lactis with subsequent characterization of the recombinant strains. Genes coding for three transport systems belonging to the MFS superfamily, Bbr_0838, Bbr_0832 and Bbr_1756, and three ABC-type transporters, Bbr_0406-0407, Bbr_1804-1805 and Bbr_1826-1827, along with the dps gene Bbr_0016, were thus analyzed. L. lactis cells expressing selected transporters exhibited enhanced resistance and survival to bile. In addition, L. lactis cells expressing the Dps protein also demonstrated a higher resistance to bile. This work significantly improves our understanding as to how bifidobacteria respond to and survives bile exposure.
2011-12-16 | GSE31032 | GEO
Project description:Decreased bile secretion in rodents by either ligation of the common bile duct or induction of cirrhosis causes changes in the small intestine, including bacterial overgrowth and translocation across the mucosal barrier. Oral administration of bile acids inhibits these effects. The genes regulated by FXR in ileum suggested that it might contribute to the enteroprotective actions of bile acids. To test this hypothesis, mice were administered either GW4064 or vehicle for 2 days and then subjected to bile duct ligation (BDL) or sham operation. After 5 days, during which GW4064 or vehicle treatment was continued, the mice were killed and their intestines were analyzed for FXR target gene expression.
2012-09-12 | GSE40821 | GEO
Project description:Decreased bile secretion in rodents by either ligation of the common bile duct or induction of cirrhosis causes changes in the small intestine, including bacterial overgrowth and translocation across the mucosal barrier. Oral administration of bile acids inhibits these effects. The genes regulated by FXR in ileum suggested that it might contribute to the enteroprotective actions of bile acids. To test this hypothesis, mice were administered either GW4064 or vehicle for 2 days and then subjected to bile duct ligation (BDL) or sham operation. After 5 days, during which GW4064 or vehicle treatment was continued, the mice were killed and their intestines were analyzed for FXR target gene expression. Mice were treated with or without FXR ligand GW4064 for 2 days prior to bile duct ligation surgery and for 5 days after surgery. After 5 days the mice were sacrificed and the ileum collected and processed for gene expression analysis. Gene expression in the ilium from each sample group was assayed in duplicate using Affymetrix Mouse Genome 430A 2.0 Gene Chips.
2012-09-12 | E-GEOD-40821 | biostudies-arrayexpress
Project description:Enteric pathogens have developed several resistance mechanisms to survive the antimicrobial action of bile. We investigated the transcriptional profile of Vibrio cholerae O1 El Tor strain C6706 under virulence gene inducing conditions, in the presence and absence of bile. Microarray analysis revealed that the expression of 119 genes was affected by bile. The mRNA levels of genes encoding proteins involved in transport was increased in the presence of bile, whereas mRNA levels of genes encoding proteins involved in pathogenesis and chemotaxis was decreased. This study identified genes encoding transcriptional regulators from the TetR family (vexR and breR) and multidrug efflux pumps from the RND superfamily (vexB and vexD [here renamed breB]) that were induced in response to bile. Further analysis regarding vexAB and breAB expression in the presence of various antimicrobial compounds established that vexAB was induced in the presence of bile, SDS or novobiocin, whereas induction of breAB was specific to bile. BreR is a direct repressor of the breAB promoter and is able to autoregulate its own expression, as demonstrated by transcriptional and electrophoretic mobility shift assays (EMSA). Expression of breR and breAB is induced in the presence of the bile salts cholate, deoxycholate or chenodeoxycholate and EMSA showed that deoxycholate is able to abolish formation of BreR-PbreR complexes. We propose that deoxycholate is able to interact with BreR and induce a conformational change that will interfere with its DNA binding ability resulting in breAB and breR expression. These results provide new insight into a transcriptional regulator and a transport system that likely play an essential role in the ability of Vibrio cholerae to resist the action of bile in the host. Keywords: Vibrio cholerae response to bile Three independent experiments were performed for the microarray analysis. From each experiment, RNA was obtained from four different time points and was prepared for hybridization, therefore, a total of 3 slides were analyzed per time point. The growth conditions were as follows; C6706 str2 was grown 15 h in LB medium at 30 degrees C with aeration. The cultures were then diluted 100-fold into AKI medium with, or without, 0.4% crude bile (high bile concentration) and were grown at 37degrees C for 3.5 h stationary followed by 2 h with aeration to induce virulence gene expression. Then the cultures were diluted 100-fold into AKI medium with, or without, 0.02% crude bile (low bile concentration) and were grown at 37 degrees C for 2 h stationary. Samples were obtained from 4 different time points: 2, 4, and 5.5 h from the high bile cultures, and at 2 h from the low bile cultures.
2010-06-05 | E-GEOD-6468 | biostudies-arrayexpress