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Trancriptomic profiling of hepatocytes and mesenchymal cells of mice treated with phenobarbital for 2 weeks

ABSTRACT: Conventional notion regards the action of non-genotoxic carcinogens (NGC) an autonomous process largely confined to parenchymal cells. Here we aim to elucidate the role of the hepatic mesenchyme for the action of a prototypical NGC, phenobarbital (PB), an anti-epileptic drug.

ORGANISM(S): Mus musculus

PROVIDER: GSE68111 | GEO | 2017/07/12

SECONDARY ACCESSION(S): PRJNA281876

REPOSITORIES: GEO

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Trancriptomic profiling of hepatocytes and mesenchymal cells of rats treated with nongenotoxic carcinogens for up to 2 weeks

Project description:Conventional notion regards the action of non-genotoxic carcinogens (NGC) an autonomous process largely confined to parenchymal cells. Here we aim to elucidate the role of the hepatic mesenchyme for the action of two prototypical NGC, phenobarbital (PB), an anti-epileptic drug, and cyproterone acetate (CPA) a gestagen used in contraceptive pills.

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Project description:Drug addiction is a chronic relapsing brain disease. The alterations of glucose uptake and metabolism were found in the brain of drug addicts. Insulin mediates brain glucose metabolism and its abnormality could induce brain injury and cognitive impairment. Here, we established a rat model of phenobarbital addiction by 90 days dosed escalation and evaluated addiction-related symptoms. We also performed proteomic analysis of the function of the differentially expressed (DE) proteins via bioinformatics in brain tissues by LC-MS/MS on day 60 and 90 of phenobarbital or 0,5% CMC-Na (vehicle) administration. The results showed that phenobarbital addictive rats developed severe withdrawal symptoms after abstinence. Proteomics analysis showed that numerous DE proteins were enriched after phenobarbital administration; which CALM1, ARAF and Cbl proteins (related to insulin signaling pathway) were significantly downregulated on day 60 but no day 90; however, SLC27A3 and NF-kB1 proteins (related to insulin resistance) were significantly upregulated on day 90. Our data indicate that insulin signaling pathway and insulin resistance may play a role in the development of phenobarbital addiction and brain injury and the findings may have important clinical implication.

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Cross-platform toxicogenomics for the prediction of nongenotoxic hepatocarcinogenesis in rat (miRNA)

Project description:In this study we performed microarray-based molecular profiling of liver samples from Wistar rats exposed to genotoxic carcinogens (GC), nongenotoxic carcinogens (NGC) or non-hepatocarcinogens (NC) for up to 14 days. In contrast to previous toxicogenomics studies aimed at the inference of molecular signatures for assessing the potential and mode of compound carcinogenicity, we considered multi-level omics data. Besides evaluating the predictive power of signatures observed on individual biological levels, such as mRNA, miRNA and protein expression, we also introduced novel feature representations which capture putative molecular interactions or pathway alterations by integrating expression profiles across platforms interrogating different biological levels. Male Wistar rats were treated by oral gavage with the eight nongenotoxic hepatocarcinogens Phenobarbital sodium (PB), Piperonylbutoxide (PBO), Dehydroepiandrosterone (DHEA), Acetamide (AA), Methapyrilene HCl (MPy), Methylcarbamate (Mcarb), Diethylstilbestrol (DES) and Ethionine (ETH), the two genotoxic carcinogens C.I Direct Black (CIDB) and dimethylnitrosamine (DMN), the two non-hepatocarcinogens Cefuroxime (CFX) and Nifedipine (Nif), and the three compounds with undefined carcinogenic class Cyproterone acetate (CPA), Thioacetamid (TAA) and Wy-14643 (Wy). Depending on the administered compound, livers were taken after 3, 7, or 14 days for histopathological evaluation. From the five animals per treatment group three animals were selected based on the histopathological findings and subjected to molecular profiling using Affymetrix RG-230A arrays (mRNA expression), Agilent G4473A arrays (miRNA expression) and Zeptosens ZeptoMARK reverse arrays (protein expression).

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Cross-platform toxicogenomics for the prediction of nongenotoxic hepatocarcinogenesis in rat (mRNA)

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Cross-platform toxicogenomics for the prediction of nongenotoxic hepatocarcinogenesis in rat (protein)

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Effect of Phenobarbital on Rat Primary Hepatocytes.

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