Effects of Oltipraz on Gene Expression in the Livers of Wild-Type and Nrf2-null Mice
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ABSTRACT: Oltipraz is an activator of Nrf2 but is also an activator of other pathways including those mediated by constitutive activated receptor (CAR). To identify genes regulated by oltipraz that were Nrf2-dependent, we compared gene expression after exposure in wild-type and Nrf2-null mice. Wild-type or Nrf2-null mice were treated each day for 4 days with 75 mg/kg/day/day oltipraz in corn oil or corn oil alone. There were 4 biological replicates used for each of the 4 genotype-treatment groups. Gene expression in the livers of the mice was evaluated using Affymetrix mouse exon arrays (MoEx-1_0-st-v1).
Project description:Acute effects caused by the non-genotoxic carcinogen and peroxisome proliferator (PP) diethylhexylphthalate (DEHP) in the mouse liver Mice (n = 6) were dosed by oral gavage (10 ml/kg body weight) with the non-genotoxic carcinogen diethylhexylphthalate (DEHP), every 24 h for 3 days (1150 mg/kg/day), or with an equivalent volume of vehicle control (corn oil).
Project description:Provided later Pregnant Fisher 344 rats will be purchased from Charles River Laboratories, Inc. and delivered to CIIT on gestational day (GD) 7 (GD0 = day first vaginal plug positive). At gestational day 12 (GD12), the dams will be exposed once/day until GD20 to 50 mg/kg dibutyl phthalate (DBP) in corn oil vehicle via oral gavage. Each dose group will contain 4-6 vehicle control or phthalate treated dams. Groups of animals will be sacrificed at GD20, postnatal day (PND) 35, and PND90 for endpoint analysis. At GD20, treated and control animals will be examined for various endpoints including body weight, testicular histopathology, gene expression profile via microarray analysis, and anogenital distance (AGD). AGD (at parturition; PND1) and nipple number/location (at PND14 and day of sacrifice) will be determined on animals in the postnatal groups. At PND35 or 90, one male from each in utero corn oil vehicle or DBP exposed group will receive a second gavage of either corn oil or 500 mg/kg DBP. 6 hours after the second gavage, the following endpoints will be examined: 1) testis histopathology; 2) spermatid head quantification (PND90 only); 3) testis and body weights; 5) genome-wide gene expression (via microarray); and 6) germ cell apoptosis (TUNEL assay).
Project description:Oltipraz is an activator of Nrf2 but is also an activator of other pathways including those mediated by constitutive activated receptor (CAR). To identify genes regulated by oltipraz that were Nrf2-dependent, we compared gene expression after exposure in wild-type and Nrf2-null mice.
Project description:One month following airway injury with naphthalene (275mg/kg IP x1 in corn oil), total RNA was isolated from one lobe of the right lung (whole lung) from either Falcor-/- (null) or injured wild-type control mice.
Project description:Beneficial effects of long-chain omega-3 polyunsaturated fatty acids (n-3 FAs) are generally well-known from epidemiological studies, but the various mechanisms of action are not completely clarified. Regulation of gene expression is one known mechanism of action, but only very limited data of regulated pathways in humans after n-3 FA supplementation are available. Up to now, no studies compared gene expression changes after n-3 FA supplementation between normolipidemic and dyslipidemic subjects. Therefore, the aim of this study was to investigate the effects of n-3 FA administration on whole genome expression profiles in the blood of normo- and dyslipidemic subjects. We conducted an intervention study with normo- and dyslipidemic men aged between 29 and 51 years, which were subdivided into four groups with a balanced age distribution and randomized to either six fish oil capsules per day providing 1.5 g docosahexaenoic acid and 1.0 g eicosapentaenoic acid or corn oil capsules rich in linoleic acid per day for a period of 12 weeks. Venous blood samples were collected at baseline as well as after 4 hours, 1 week and 12 weeks of supplementation. For each investigation time point, the samples of each group were pooled together to minimize inter-individual variability. All subjects have successfully completed the study, but for the microarray experiments, nine subject samples were excluded. Therefore, the microarray experiments are based on the following group characteristics: normolipidemic fish oil group (FO-N): pool of nine RNAs from normolipidemic subjects supplemented with fish oil; normolipidemic corn oil group (CO-N): pool of six RNAs from normolipidemic subjects supplemented with corn oil; dyslipidemic corn oil group (CO-D): pool of eight RNAs from dyslipidemic subjects supplemented with corn oil; dyslipidemic fish oil group (FO-D): pool of nine RNAs from dyslipidemic subjects supplemented with fish oil.
Project description:The current study was designed to determine if dietary fatty acid concentration and composition affects the development and progression of nonalcoholic fatty liver disease. Male SD rats were overfed diets low (5%) or high (70%) fat diets via total enteral nutrition where the fat source was olive oil (monounsaturated), or corn oil (polyunsaturated). Overfeeding 5% corn oil produced little steatosis relative to feeding 5% olive oil. This was associated with lower fatty acid synthesis and reduced SREBP-c signaling in the 5% corn oil group. Overfeeding 70% fat diets increased steatosis and lead to increased liver necrosis in the 70% corn oil but not olive oil group. Increased injury after feeding polyunsaturated fat diets was linked to peroxidizability of hepatic free fatty acids and triglycerides and appearance of peroxidaized lipid products HETES and HODES previously linked to clinical nonalcoholic steatohepatitis. Male SD rats were overfed diets low (5%) or high (70%) fat diets via total enteral nutrition where the fat source was olive oil (monounsaturated) or corn oil (polyunsaturated).
Project description:Beneficial effects of long-chain omega-3 polyunsaturated fatty acids (n-3 FAs) are generally well-known from epidemiological studies, but the various mechanisms of action are not completely clarified. Regulation of gene expression is one known mechanism of action, but only very limited data of regulated pathways in humans after n-3 FA supplementation are available. Up to now, no studies compared gene expression changes after n-3 FA supplementation between normolipidemic and dyslipidemic subjects. Therefore, the aim of this study was to investigate the effects of n-3 FA administration on whole genome expression profiles in the blood of normo- and dyslipidemic subjects. We conducted an intervention study with normo- and dyslipidemic men aged between 29 and 51 years, which were subdivided into four groups with a balanced age distribution and randomized to either six fish oil capsules per day providing 1.5 g docosahexaenoic acid and 1.0 g eicosapentaenoic acid or corn oil capsules rich in linoleic acid per day for a period of 12 weeks. Venous blood samples were collected at baseline as well as after 4 hours, 1 week and 12 weeks of supplementation. For each investigation time point, the samples of each group were pooled together to minimize inter-individual variability. All subjects have successfully completed the study, but for the microarray experiments, nine subject samples were excluded. Therefore, the microarray experiments are based on the following group characteristics: normolipidemic fish oil group (FO-N): pool of nine RNAs from normolipidemic subjects supplemented with fish oil; normolipidemic corn oil group (CO-N): pool of six RNAs from normolipidemic subjects supplemented with corn oil; dyslipidemic corn oil group (CO-D): pool of eight RNAs from dyslipidemic subjects supplemented with corn oil; dyslipidemic fish oil group (FO-D): pool of nine RNAs from dyslipidemic subjects supplemented with fish oil. The twenty normolipidemic and the twenty dyslipidemic subjects were subdivided into two groups. Thus, a total of four groups with ten men per group passed through the study. To realize a comparable mean age between groups, the formation of groups was performed by stratified allocation according to subject's age. The four study groups were randomly assigned to different study products by an uninvolved collaborator. Subjects ingested either six FO or six corn oil (CO) capsules per day for a period of twelve weeks. The daily n-3 PUFA intake via FO capsules was 2.7 g (1.14 g DHA and 1.56 g EPA). The predominant FA of the CO capsules was the omega-6 (n-6) PUFA linoleic acid (LA, 18:2n-6). Thus, the daily LA intake via CO capsules was 3.05 g LA. The subjects were instructed to ingest the capsules together with food, three in the morning and three in the evening, and to maintain their usual exercise and dietary habits throughout the intervention time. As an exception, at the first intervention day, all six capsules were ingested at the same time in the morning after a standardised breakfast. During each visit, fasting blood samples were collected by venepuncture. Additionally, participants completed a questionnaire to obtain information about changes in medication, dietary (e.g., changes in weekly fish intake, preferred fish dishes or species, respectively) and lifestyle habits (e.g., physical activity), as well as the tolerability of the capsules. This record summarizes the results of 16 microarrays. The samples originate from whole blood of normo- and dyslipidemic subjects supplemented with either fish oil or corn oil for 4 h, 1 week and 12 weeks. Microarrays were hybridized in a loop design with one common reference using a dye-swap approach.
Project description:Many environmentally-relevant chemicals and drugs activate the nuclear receptor pregnane X receptor (PXR). Activation of PXR can lead to increases in liver weight in part through hepatocyte replication similar to a large number of compounds that activate other nuclear receptors such as the peroxisome proliferator-activated receptor alpha and the constitutive activated receptor (CAR). PXR controls the expression of a large battery of genes involved in xenobiotic metabolism. Identification of genes that are accurate predictors of PXR activation would be useful in high-throughput screens to assess potential toxicity and drug-drug interactions. Here, we identified PXR-dependent genes in the mouse liver after exposure to pregnenolone 16alpha-carbinonitrile (PCN), a chemical that is often used as a model PXR agonist. The animal studies were carried out at the University of Kansas Medical Center (Kansas City, KS) under federal guidelines for the use and care of laboratory animals and was approved by the KUMC Institutional Animal Care and Use Committee. Eight-week-old adult C57BL/6 mice were purchased from Jackson Laboratories (Bar Harbor, ME). Generation of the PXR-null mice was previously described (Staudinger et al., (2001), Proc Natl Acad Sci USA 98:3369M-bM-^@M-^S3374). PXR-null breeder pairs were engineered and backcrossed into the C57BL/6 background. Adult male wild-type mice and PXR-null mice were maintained on standard laboratory chow and were allowed food and water ad libitum. All mice were treated once a day i.p. with either vehicle (corn oil) or PCN at 400 mg/kg/day for 4 days. Livers were removed 24-hrs after the last dose. Portions of the livers were rapidly snap-frozen in liquid nitrogen and stored at -70M-BM-0C until analysis. Liver gene expression analysis was performed according to the Affymetrix recommended protocol using Affymetrix Mouse Genome 430 2.0 GeneChipsM-BM-.. Total RNA (5 M-NM-<g per sample) was labelled using the AffymetrixM-BM-. One-Cycle cDNA Synthesis protocol and hybridized to arrays as described by the manufacturer (AffymetrixM-BM-., Santa Clara, CA). Microarray hybridizations were conducted overnight at 45M-BM-0C while rotating in an Affymetrix hybridization oven. After 16 hours of hybridization, the cocktail was removed and the arrays were washed and stained in an Affymetrix GeneChipM-BM-. fluidics station 450 according to the Affymetrix-recommended protocol. Arrays were scanned on an Affymetrix GeneChipM-BM-. scanner. Four mice per group were examined.
Project description:The purpose of this study was to explore the mechanism of aerobic decay of whole-plant corn silage and the effect of Neolamarckia cadamba essential oil on aerobic stability of whole-plant corn silage. Firstly, the dynamic changes of temperature, microbial community and metabolite content after aerobic exposure of whole-plant corn silage were determined, and the main microbial species and mechanism leading to aerobic spoilage of whole-plant corn silage were analyzed. The N. cadamba essential oil was extracted from fresh N. cadamba leaves by steam distillation, and the minimal inhibitory concentration, antibacterial stability and bacteriostatic mechanism of N. cadamba essential oil against undesirable microorganisms in whole-plant corn silage were determined. According to the minimum inhibitory concentration of N. cadamba essential oil on undesirable microorganisms in silage, N. cadamba essential oil was added to whole-plant corn silage to explore the effect of N. cadamba essential oil on the aerobic stability of whole-plant corn silage.