Project description:we assessed characteristic molecular and proteomic signatures in rat liver treated with drugs (pyrazinamide, ranitidine, enalapril, carbamazepine, and chlorpromazine) that are known to cause DILI in humans. In the present study, we assessed the characteristic gene expression signature for DILI in a rat model. Rats were administered representative drugs that are already known to induce DILI in humans and transcriptomic changes in rat liver were analyzed. The representative drugs, which induce three types (hepatocellular, mixed, and cholestatic) of DILI, that were used in this study were pyrazinamide (PZA, 150~1500 mg/kg), ranitidine (RAN, 209.5~2095 mg/kg), enalapril (ENA, 148.65~1486.5 mg/kg), carbamazepine (CBZ, 97.85~978.5 mg/kg), and chlorpromazine (CPZ, 7.1~71 mg/kg).
Project description:Experimental autoimmune uveitis (EAU) in Lewis rats is a model for the clinical heterogeneity of human uveitis. The autoantigens inducing disease in the rat are also seen in human disease. Depending upon the specific autoantigen used, the experimental disease course can be either monophasic or relapsing/remitting and appears to be dictated by the T cell effector phenotype elicited. We investigated potential differences between monophasic and relapsing/remitting effector T cells using transcriptomic profiling and pathway analysis. RNA samples isolated from three independent T cell lines derived from each specificity where analyzed by microarrays. Microarray data was used to obtain transcriptomic changes reflecting signal transduction pathway dysregulation. Keywords: Two group comparison Comparison of two types of cell lines of two different antigen specificities.
Project description:In this study we show that the exposure to genotoxicants (10 nM camptothecin and 20 µM Olaparib) affects embryo development in a stage-dependent manner with early stages being the most sensitive to DNA damage. The transcriptomic and proteomic patterns changed significantly after exposure to genotoxicants compared to the control. Camptothecin and Olaparib downregulated metabolic pathways and developmental processes. Additionally, the exposure to genotoxicants led to upregulation of cell proliferation, neural precursor cell proliferation, generation of neurons, taxis and locomotion. Protein patterns were altered as well by DNA damage. The results of this study indicate that there is a strong correlation between phenotype formation and changes in transcriptomic and proteomic profiles.
Project description:To investigate the molecular mechanism of F toxicity on glial cells we have performed a large transcriptomic and proteomic analysis over to two relevant fluoride doses. U87 glial-like cells were exposed to 0,095µg/mL and 0.22µg/ml for 10 days to mimic a chronic exposure to fluoride. A total of 62 genes and 209 genes were modulated after exposure to 0.095 and 0.22µg/ml respectively. The number of proteins modulates were 20 and 10 respectively. Gene Ontology annotation revealed changes on cellular metabolism and cell death regulation pathways such as MAPK and ERK1/ERK2. Proteomics analysis have confirmed changes on energy metabolism and revealed changes on cytoskeleton components.
Project description:A challenge for advancing approaches to liver regeneration is loss of functional differentiation capacity when hepatocyte progenitors are maintained in culture. Recent lineage-tracing studies have shown that mature hepatocytes (MHs) convert to an immature state during chronic liver injury, and we investigated whether this conversion could be recapitulated in vitro and if such converted cells could represent a source of expandable hepatocytes. We report that a cocktail of small molecules, Y-27632, A-83-01 and CHIR99021, can convert rat and mouse MHs in vitro into proliferative bipotent cells, which we term chemically induced liver progenitors (CLiPs). CLiPs can differentiate into both MHs and biliary epithelial cells that can form functional ductal structures. CLiPs in long-term culture did not lose their proliferative capacity or their hepatic differentiation ability, and rat CLiPs were shown to extensively repopulate chronically injured liver tissue. Thus our study advances the goals of liver regenerative medicine. Transcriptomic analyses for freshly isolated MHs and cells cultured for the designated periods with or without YAC stimulation (Matrix 1). Transcriptomic analysis for CLiPs which underwent hepatic induction (Matrix 2). Transcriptomic comparison of hepatic inducibility between CLiPs at early passage and those at late passages (Matrix 3). Transcriptomic comparison between chimera-derived rat cells (designated as “2nd”) and primary rat MH-derived cells (designated as “1st”) (Matrix 4).
Project description:Experimental autoimmune uveitis (EAU) in Lewis rats is a model for the clinical heterogeneity of human uveitis. The autoantigens inducing disease in the rat are also seen in human disease. Depending upon the specific autoantigen used, the experimental disease course can be either monophasic or relapsing/remitting and appears to be dictated by the T cell effector phenotype elicited. We investigated potential differences between monophasic and relapsing/remitting effector T cells using transcriptomic profiling and pathway analysis. RNA samples isolated from three independent T cell lines derived from each specificity where analyzed by microarrays. Microarray data was used to obtain transcriptomic changes reflecting signal transduction pathway dysregulation. Keywords: Two group comparison
Project description:we assessed characteristic molecular and proteomic signatures in rat liver treated with drugs (pyrazinamide, ranitidine, enalapril, carbamazepine, and chlorpromazine) that are known to cause DILI in humans.
Project description:Liver represents one of the most important organs involved in the elimination of xenobiotic and potentially toxic substances. Cigarette smoke (CS) contains several compounds that exert biological effects and cause smoking related diseases. Although cigarette smoke is not directly hepatotoxic, a growing body of evidence suggests that CS may exacerbate chronic liver diseases. Here we integrated classical toxicological endpoints with molecular measurement and computational analysis approaches to investigate exposure effects on liver in an Apoe-/- mouse study. The mice were exposed to high concentrations of 3R4F reference CS (600 mg/m3 TPM, 29.9 mg/m3 nicotine), aerosol from a candidate modified risk tobacco product (MRTP), the Tobacco Heating System (THS) 2.2, or filtered air (Sham) for up to 8 months. After 2 months of CS exposure, some groups were either switched to the MRTP or underwent cessation. While clear signs of hepatotoxic effects were absent for any exposure group, the integrative analysis of proteomic and transcriptomic data showed a CS-dependent impairment of specific biological networks, such as lipid, xenobiotic, and iron homeostasis, which likely in turn mutually contribute to worsening of the oxidative stress. In contrast, most of these changes were absent in mice exposed to THS2.2, and in the cessation and in the switching groups. Our findings shed light on the complex biological response of the liver to CS exposure and support the benefits of switching to the tested heat-not-burn product, THS2.2.