Gauthier Santos (fieldlevel57)

NAFLD is a growing public health burden. However, the pathogenesis of NAFLD has not yet been fully elucidated and the importance of genetic factors has only recently been appreciated. Genomic studies have revealed a strong association between NAFLD progression and the I148M variant in PNPLA3. Nonetheless, very little is known about the mechanisms by which this gene and its variants can influence disease development. In order to investigate these mechanisms, we have developed an in vitro model that takes advantage of the unique properties of human induced pluripotent stem cells (hiPSC) and the CRISPR/CAS9 gene editing technology. We used isogenic human induced pluripotent stem cell (hiPSC) lines with either a knock-out (PNPLA3 ) of the PNPLA3 gene or with the I148M variant (PNPLA3 ) to model PNPLA3-associated NAFLD. The resulting hiPSCs were differentiated into hepatocytes, treated with either unsaturated or saturated free fatty acids to induce NAFLD-like phenotypes, and characterized by various functional, transcriptomic, and lipidomic assays. PNPLA3 hepatocytes showed higher lipid accumulation as well as an altered pattern of response to lipid-induced stress. Interestingly, loss of PNPLA3 also caused a reduction in xenobiotic metabolism and predisposed PNPLA3 cells to be more susceptible to ethanol- and methotrexate-induced toxicity. The PNPLA3 cells exhibited an intermediate phenotype between the wild type and PNPLA3 cells. Together, these results indicate that the I148M variant induces a loss of function predisposing to steatosis and increased susceptibility to hepatotoxins. Together, these results indicate that the I148M variant induces a loss of function predisposing to steatosis and increased susceptibility to hepatotoxins. Cyclosporine A (CyA) causes intrahepatic biliary stasis via inhibition of bile acid excretion through the bile salt export pump. selleck kinase inhibitor We report a case of a patient in whom ursodeoxycholic acid (UDCA) markedly promoted the absorption of microemulsion-formulated CyA. The patient was a 22-year-old Japanese man diagnosed with stage 3 aplastic anaemia. He was treated with CyA, and 2h post-dose (C2) was increased by UDCA. A remarkable interaction was observed between CyA and UDCA. This is a valuable finding for improving the treatment strategies for haematological disorders. A remarkable interaction was observed between CyA and UDCA. This is a valuable finding for improving the treatment strategies for haematological disorders. Accelerated-FEV -decline, defined as rate of decline in FEV > 64 ml/year, is a risk factor for asthma and chronic obstructive pulmonary disease in World Trade Center (WTC)-exposed firefighters. Accelerated-FEV -decline in this cohort is associated with elevated blood eosinophil concentrations, a mediator of Th-2 response. We hypothesized that an association exists between Th-2 biomarkers and FEV decline rate in those with accelerated-FEV -decline. Serum was drawn from Fire Department of the City of New York (FDNY) firefighters 1-6 months (early) (N = 816) and 12-13 years (late) (N = 983) after 9/11/2001. Th-2 biomarkers IL-4, IL-13, and IL-5 were assayed by multiplex Luminex. Individual FEV decline rates were calculated using spirometric measurements taken (1) between 9/11/2001 and 9/10/2020 for the early biomarker group and (2) between late measurement date and 9/10/2020 for the late biomarker group. Associations of early and late Th-2 biomarkers with subsequent FEV decline rates were aear. Drugs targeting the IL-4 pathway may improve lung function in this high-risk subgroup.Short and medium-chain fatty acids (SMCFAs) are known as essential metabolites found in gut microbiota that function as modulators in the development and progression of many inflammatory conditions as well as in the regulation