PubMed | Gastroenterology and Infectious Diseases, Czech Institute of Organic Chemistry And Biochemistry, Charles University and Palacky University
Type: | Journal: Toxicology letters | Year: 2016
The Pregnane X (PXR), Vitamin D (VDR) and Farnesoid X (FXR) nuclear receptors have been shown to be receptors of bile acids controlling their detoxification or synthesis. Chenodeoxycholic (CDCA) and lithocholic (LCA) acids are ligands of FXR and VDR, respectively, whereas 3-keto and acetylated derivates of LCA have been described as ligands for all three receptors. In this study, we hypothesized that oxidation or acetylation at position 3, 7 and 12 of bile acids DCA (deoxycholic acid), LCA, CA (cholic acid), and CDCA by detoxification enzymes or microbiome may have an effect on the interactions with bile acid nuclear receptors. We employed reporter gene assays in HepG2 cells, the TR-FRET assay with recombinant PXR and RT-PCR to study the effects of acetylated and keto bile acids on the nuclear receptors activation and their target gene expression in differentiated hepatic HepaRG cells. We demonstrate that the DCA 3,12-diacetate and CA 3,7,12-triacetate derivatives are ligands of PXR and DCA 3,12-diacetate induces PXR target genes such as CYP3A4, CYP2B6 and ABCB1/MDR1. In conclusion, we found that acetylated DCA and CA are potent ligands of PXR. Whether the acetylated bile acid derivatives are novel endogenous ligands of PXR with detoxification or physiological functions should be further studied in ongoing experiments.
Chamulitrat W.,Gastroenterology and Infectious Diseases |
Liebisch G.,University of Regensburg |
Xu W.,Hangzhou First Peoples Hospital |
Gan-Schreier H.,Gastroenterology and Infectious Diseases |
And 3 more authors.
Molecular Pharmacology | Year: 2013
Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a hepatoprotectant in inhibiting apoptosis, inflammation, and hyperlipidemia in mouse models of nonalcoholic steatohepatitis (NASH). We studied the ability of UDCA-LPE to inhibit palmitate (Pal)-induced apoptosis in primary hepatocytes and delineate cytoprotective mechanisms. We showed that lipoprotection by UDCA-LPE was mediated by cAMP and was associated with increases in triglycerides (TGs) and phospholipids (PLs). An inhibitor of cAMP-effector protein kinase A partially reversed the protective effects of UDCA-LPE. Lipidomic analyses of fatty acids and PL composition revealed a shift of lipid metabolism from saturated Pal to monounsaturated and polyunsaturated fatty acids, mainly, oleate, docosapentaenoate, and docosahexaenoate. The latter two ω-3 fatty acids were particularly found in phosphatidylcholine and phosphatidylserine pools. The catalysis of Pal by stearoyl-CoA desaturase-1 (SCD-1) is a known mechanism for the channeling of Pal away from apoptosis. SCD-1 protein was upregulated during UDCA-LPE lipoprotection. SCD-1 knockdown of Pal-treated cells showed further increased apoptosis, and the extent of UDCA-LPE protection was reduced. Thus, the major mechanism of UDCA-LPE lipoprotection involved a metabolic shift from toxic saturated toward cytoprotective unsaturated fatty acids in part via SCD-1. UDCA-LPE may thus be a therapeutic agent for treatment of NASH by altering distinct pools of fatty acids for storage into TGs and PLs, and the latter may protect lipotoxicity at the membrane levels. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
PubMed | Abdominal and Gastroenterology and Infectious Diseases
Type: Journal Article | Journal: Endoscopy international open | Year: 2015
Endoscopic Vacuum Therapy (EVT) has been reported as a novel treatment option for esophageal leakage. We present our results in the treatment of iatrogenic perforation with EVT in a case series of 10 patients.An open pore polyurethane drainage was placed either intracavitary through the perforation defect or intraluminal covering the defect zone. Application of vacuum suction with an electronic device (continuous negative pressure, -125mmHg) resulted in defect closure and internal drainage.Esophageal perforations were located from the cricopharyngeus (4/10) to the esophagogastric junction (2/10). EVT was feasible in all patients. Eight patients were treated with intraluminal EVT, one with intracavitary EVT, and one with both types of treatments. All perforations (100%) were healed in within a median of (3-7) days. No stenosis occurred, no complications were observed, and no additional operative treatment was necessary.Our study suggests that intraluminal EVT will play an important role in endoscopic management of esophageal perforation.