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ABSTRACT:
PROVIDER: PRJNA640138 | ENA |
REPOSITORIES: ENA
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Project description:Circadian rhythms are central to optimal physiological functioning and their interruption contributes to the development of several chronic diseases. Alcohol (EtOH) intoxication disrupts circadian rhythms within liver, brain, and intestines, but it is unknown whether alcohol also disrupts components of the core clock in skeletal muscle. Female C57BL/6Hsd mice were randomized to receive either saline (control) or alcohol (EtOH) (5g/kg) via intraperitoneal injection at the start of the dark cycle (ZT12), and gastrocnemius was collected every 4hr from Control and EtOH treated mice for the next 48hr following isoflurane anesthetization. In addition, metyrapone was administered prior to alcohol intoxication in separate mice to determine whether the alcohol-induced increase in serum corticosterone contributed to circadian gene regulation. Finally, synchronized C2C12 myotubes were treated with alcohol (100mM) to assess the influence of centrally or peripherally mediated effects of alcohol on the muscle clock. Alcohol significantly disrupted the mRNA expression of Bmal1, Per1/2, and Cry1/2 in addition to perturbing the clock-controlled genes, Myod1, Dbp, Tef, and Bhlhe40 (p<0.05). Alcohol increased serum corticosterone levels and glucocorticoid target genes, Redd1 and Klf15, in muscle. Metyrapone decreased serum corticosterone in EtOH mice but did not normalize the mRNA expression of Per1, Cry1 and Cry2 and Myod1 which were altered by EtOH. Alcohol did not alter core clock gene expression (Bmal, Per1/2, Cry1/2) at 4, 8, and 12hrs post treatment in synchronized C2C12 myotubes. Therefore, binge alcohol disrupted genes of the core molecular clock independently of elevated serum corticosterone.
2021-09-10 | GSE183665 | GEO
Project description:Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL17 Receptor A (IL17ra-/-), or pharmacological blockade of IL17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice, and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL17A positively correlated with the alcohol use in excessive drinkers, and was further increased in patients with ALD as compared to healthy individuals. Our data suggest that IL17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL17A may provide a novel strategy for treatment of alcohol-induced pathology.
2020-04-07 | GSE137228 | GEO
Project description:The circadian transcriptional repressors cryptochromes 1 (Cry1) and 2 (Cry2) interact with the C-terminus of the glucocorticoid receptor (GR) and are required for transrepression in response to the synthetic GR ligand dexamethasone (Dex) in mouse embryonic fibroblasts. Dex induction of many genes was increased in Cry-deficient fibroblasts suggesting that cryptochromes oppose transactivation in addition to contributing to transrepression. In mice, genetic loss of Cry1 and/or Cry2 resulted in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced glucocorticoid suppression of the hypothalamic-pituitary-adrenal axis coupled with increased sensitivity to the hyperglycemic effects of glucocorticoid-mediated transactivation in the liver. Cry1 and Cry2 association with a GRE in the Pck1 promoter was stimulated by Dex, and Dex-induced transcription of pck1 was strikingly increased in Cry-deficient livers. Finally, cry1-/-;cry2-/- mice subjected to 8 weeks of chronic Dex treatment exhibited incomplete suppression of circulating corticosterone and greater glucose intolerance compared with wildtype littermates subjected to the same chronic treatment, consistent with enhanced transcriptional response to the synthetic glucocorticoid ligand. Total RNA was obtained from WT and Cry1/2 KO MEFs treated with Dexamethasone (1uM) or control EtOH for 16 hours.
2011-12-22 | E-GEOD-24469 | biostudies-arrayexpress
Project description:The circadian transcriptional repressors cryptochromes 1 (Cry1) and 2 (Cry2) interact with the C-terminus of the glucocorticoid receptor (GR) and are required for transrepression in response to the synthetic GR ligand dexamethasone (Dex) in mouse embryonic fibroblasts. Dex induction of many genes was increased in Cry-deficient fibroblasts suggesting that cryptochromes oppose transactivation in addition to contributing to transrepression. In mice, genetic loss of Cry1 and/or Cry2 resulted in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced glucocorticoid suppression of the hypothalamic-pituitary-adrenal axis coupled with increased sensitivity to the hyperglycemic effects of glucocorticoid-mediated transactivation in the liver. Cry1 and Cry2 association with a GRE in the Pck1 promoter was stimulated by Dex, and Dex-induced transcription of pck1 was strikingly increased in Cry-deficient livers. Finally, cry1-/-;cry2-/- mice subjected to 8 weeks of chronic Dex treatment exhibited incomplete suppression of circulating corticosterone and greater glucose intolerance compared with wildtype littermates subjected to the same chronic treatment, consistent with enhanced transcriptional response to the synthetic glucocorticoid ligand.
2011-12-22 | GSE24469 | GEO
Project description:The etiology of alcohol dependence is not completely understood. Increasing evidence reveals that gut microbiota dysbiosis is associated with certain psychiatric disorders, including alcoholism, through the 'microbiota-gut-brain' axis. The aims were to evaluate the effect of alcohol abuse on the gut microbiota, intestinal permeability and serum metabolic profile and to determine whether alcohol-induced alterations in gut microbiota are correlated with gut permeability and serum metabolic phenotype changes. 16S rRNA gene high-throughput sequencing and nontarget metabolomics techniques were applied in an alcohol-dependent rat model in the present study. The results showed that alcohol intake altered the composition and structure of the colonic microbiota, especially the relative abundance of the commensal microbes <i>Lachnospiraceae</i> and <i>Prevotellaceae</i>, which was significantly decreased. Alcohol-dependent rats developed gut leakiness and a serum metabolic phenotype disorder. The valine, leucine and isoleucine biosynthesis pathways and arginine and proline metabolism pathways were obviously influenced by alcohol intake. Moreover, alcohol consumption disturbed the brain's neurotransmitter homeostasis. The regression analysis showed that alcohol-induced colonic microbiota dysbiosis was strongly associated with increased intestinal permeability and serum metabolic phenotype and neurotransmitter disorders. These results revealed that gut microbiota dysbiosis and serum metabolites alteration might be a cofactor for developing of alcohol dependence. <b>IMPORTANCE</b> The gut microbiota dysbiosis is associated with certain psychiatric disorders through the 'microbiota-gut-brain' axis. Here we revealed that alcohol consumption induced the colonic microbiota dysbiosis, increased intestinal permeability, altered the serum metabolic phenotype in rats, and there were a strong correlation between gut microbiota dysbiosis and serum metabolites disorders. Thus, gut microbiota dysbiosis and serum metabolites alteration may be a cofactor for development of alcohol dependence.
2021-07-30 | MTBLS2688 | MetaboLights
Project description:Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regualtion
| PRJNA720407 | ENA
Project description:Progesterone (P4) acting through its cognate receptor, the progesterone receptor (PR), plays an important role in uterine physiology. The PR knockout (PRKO) mouse has demonstrated the importance of the P4-PR axis in the regulation of uterine function. To define the molecular pathways regulated by P4-PR in the mouse uterus, Affymetrix MG U74Av2 oligonucleotide arrays were used to identify alterations in gene expression after acute and chronic P4 treatments. In the analysis, retinoic acid metabolic genes, cytochrome P 450 26a1 (Cyp26a1), alcohol dehydrogenase 5, and aldehyde dehydrogenase 1a1 (Aldh1a1); kallikrein genes, Klk5 and Klk6; and specific transcription factors, GATA-2 and Cited2 [cAMP-corticosterone-binding protein/p300-interacting transactivator with glutamic acid (E) and aspartic acid (D)-rich tail], were validated as regulated by the P4-PR axis. Identification and analysis of these responsive genes will help define the role of PR in regulating uterine biology. Ovariectomized wild-type and progesterone receptor knockout mice were injected with either vehicle or 1 mg/mouse progesterone. The injections were repeated every 12 h, and groups of mice were killed 4 h after the first injection (acute P4 treatment) or 4 h after the fourth injection (chronic P4 treatment).
2012-08-06 | E-GEOD-39920 | biostudies-arrayexpress
Project description:Glucocorticoid receptor axis in lung cancer
| PRJNA669682 | ENA
Project description:Nevirapine, an antiretroviral used in the treatment of HIV, is associated with idiosyncratic drug-induced liver injury (IDILI), a potentially life-threatening adverse drug reaction. Its usage has decreased due to this concern, but it is still widely used in lower-resource settings. In general, the mechanisms underlying idiosyncratic drug reactions (IDRs) are poorly understood, but evidence indicates that most are immune-mediated. There is very limited understanding of the early immune response following administration of drugs associated with IDRs, which likely occurs due to reactive metabolite formation. In this work, we aimed to characterize the links between covalent binding of nevirapine, the development of an early immune response, and the subsequent liver injury using a mouse model. We describe initial attempts to characterize an early immune response to nevirapine followed by the discovery that nevirapine induced the release of corticosterone. Corticosterone release was partially associated with the degree of drug covalent binding in the liver, but was also likely mediated by additional mechanisms at higher drug doses. Transcriptomic analysis confirmed metabolic activation, glucocorticoid signaling, and decreased immune activation; GDF-15 also warrants further investigation as part of the immune response to nevirapine. Finally, glucocorticoid blockade preceding the first dose of nevirapine attenuated nevirapine-induced liver injury at 3 weeks, suggesting that acute glucocorticoid signaling is harmful in the context of nevirapine-induced liver injury. This work demonstrates that nevirapine induces acute corticosterone release, which contributes to delayed-onset liver injury. It also has implications for screening drug candidates for IDILI risk and preventing nevirapine-induced IDILI.
2024-04-15 | GSE255038 | GEO
Project description:Angelman Syndrome (AS) is a severe neurodevelopmental disorder, caused by the neuronal absence of the ubiquitin protein ligase E3A (UBE3A). UBE3A promotes ubiquitin-mediated protein degradation and functions as a transcriptional coregulator of nuclear hormone receptors, including the glucocorticoid receptor (GR). Previous studies showed anxiety-like behavior and hippocampal-dependent memory disturbances in AS mouse models. Hippocampal GR is an important regulator of the stress response and memory formation, and we therefore investigated whether the absence of UBE3A in AS mice disrupted GR signaling in the hippocampus. We first established a strong cortisol-dependent interaction between the GR ligand binding domain and a UBE3A nuclear receptor box in a high-throughput interaction screen. In vivo, we found that UBE3A-deficient AS mice displayed significantly more variation in circulating corticosterone levels throughout the day compared to wildtypes (WT), with low to undetectable levels of corticosterone at the trough of the circadian cycle. Additionally, we observed an enhanced transcriptomic response in the AS hippocampus following acute corticosterone treatment. Surprisingly, chronic corticosterone treatment showed less contrast between AS and WT mice in the hippocampus and liver transcriptomic responses. This suggests that UBE3A limits the acute stimulation of GR signaling, likely as a member of the GR transcriptional complex. Altogether, these data indicate that AS mice are more sensitive to acute glucocorticoid exposure in the brain compared to WT mice. This suggests that stress responsiveness is altered in AS which could lead to anxiety symptoms.
2022-12-23 | GSE221378 | GEO