Olanzapine suppresses mPFC-norepinephrine releasing to alleviate CLOCK-induced cancer stemness under chronic stress
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1119202 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29258439_1.fastq.gz | Fastqsanger.gz | |||
| SRR29258439_2.fastq.gz | Fastqsanger.gz | |||
| SRR29258440_1.fastq.gz | Fastqsanger.gz | |||
| SRR29258440_2.fastq.gz | Fastqsanger.gz | |||
| SRR29258441_1.fastq.gz | Fastqsanger.gz |
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Project description:We identify a new mechanism by which OLZ ameliorates chronic stress-enhanced tumorigenesis and chemoresistance. OLZ reversed chronic stress-enhanced lung tumorigenesis and anxiety-like behaviors by suppressing neuro-activity in the mPFC and reducing norepinephrine (NE) releasing. To investigate the mechanism of NE in cancer stemness we performed RNA-seq of the NCI-H1299 cells under NE treatment and found that NE activated β2-adrenoceptor (ADRB2)-mediated cAMP-PKA-CREB pathway to transactivate CLOCK that further sustains cancer stemness.
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Project description:Male Sprague-Dawley albino rats (Charles River) initially weighting approximately 200 grams were randomly assigned to one of the following: 1) olanzapine (2 mg/kg/day, I.P.) (N=20) or 2) Saline (N=20) and administered olanzapine or saline for 21 days. Frontal cortex (N=4/group) was dissected and homogenized for microarray, QPCR and western blotting following previous methods (Fatemi et al. 2003; Brooks et al. 2003). RNA isolation, cDNA preparation, microarray hybridization and QPCR followed previous methods (Brooks et al. 2003). Keywords = olanzapine Keywords = frontal cortex Keywords: repeat sample
2007-04-10 | GSE2547 | GEO
Project description:Antipsychotic drugs are commonly used to treat psychosis, mood disorders, and anxiety. While there is indirect evidence that some component of the antipsychotic effect of these drugs may involve modulation of dopamine transmission, their mechanism of action is poorly understood. We hypothesized that antipsychotic drugs mediate their effects via epigenetic modulation. Here we tested the effect of an antipsychotic, olanzapine, on the methylation status of genes following chronic treatment. These effects have been revealed through significantly increased (p<0.01) DNA methylation of genes involved in dopaminergic and non-dopaminergic pathways including the glutamatergic, GABAergic, cholinergic, neuregulin and ErbB signaling pathways. The affected genes included GLS in hippocampus, NR1 in cerebellum and GLUD1 and NR2B in liver. Further, from a set of genes in the 22q11.2 micro-deletions that has been previously implicated in psychosis, 22 genes showed increased methylation following olanzapine treatment. Ingenuity Pathway Analysis (IPA) revealed that chronic olanzapine treatment significantly affected several important pathways such as CREB and CDK5 signaling (p=1.4E-05). Also, DNA replication, recombination and repair, cellular movement and cell cycle have been identified as the top networks affected by olanzapine. The results suggest that these downstream effects, aside from D2 blockade, may play a critical role in the biological actions of antipsychotics. These include altered expressions of relevant genes involved in GABAergic, glutamatergic, cholinergic, neuregulin and ErbB signaling pathways. Epigenetic mechanisms involving changes in DNA methylation could, therefore, explain the delay and individualized non-specificity of biological effects of olanzapine. The results also suggest that DNA methylation may play a role in the process of therapeutic efficacy of olanzapine by altering the transcriptome via tissue-specific methylation of genes involved in schizophrenia signaling pathways. comparison of olanzapine treated rats vs. control rats for genome-wide DNA methylation changes
2013-11-22 | E-GEOD-52615 | biostudies-arrayexpress
Project description:Antipsychotic drugs are commonly used to treat psychosis, mood disorders, and anxiety. While there is indirect evidence that some component of the antipsychotic effect of these drugs may involve modulation of dopamine transmission, their mechanism of action is poorly understood. We hypothesized that antipsychotic drugs mediate their effects via epigenetic modulation. Here we tested the effect of an antipsychotic, olanzapine, on the methylation status of genes following chronic treatment. These effects have been revealed through significantly increased (p<0.01) DNA methylation of genes involved in dopaminergic and non-dopaminergic pathways including the glutamatergic, GABAergic, cholinergic, neuregulin and ErbB signaling pathways. The affected genes included GLS in hippocampus, NR1 in cerebellum and GLUD1 and NR2B in liver. Further, from a set of genes in the 22q11.2 micro-deletions that has been previously implicated in psychosis, 22 genes showed increased methylation following olanzapine treatment. Ingenuity Pathway Analysis (IPA) revealed that chronic olanzapine treatment significantly affected several important pathways such as CREB and CDK5 signaling (p=1.4E-05). Also, DNA replication, recombination and repair, cellular movement and cell cycle have been identified as the top networks affected by olanzapine. The results suggest that these downstream effects, aside from D2 blockade, may play a critical role in the biological actions of antipsychotics. These include altered expressions of relevant genes involved in GABAergic, glutamatergic, cholinergic, neuregulin and ErbB signaling pathways. Epigenetic mechanisms involving changes in DNA methylation could, therefore, explain the delay and individualized non-specificity of biological effects of olanzapine. The results also suggest that DNA methylation may play a role in the process of therapeutic efficacy of olanzapine by altering the transcriptome via tissue-specific methylation of genes involved in schizophrenia signaling pathways.
2013-11-22 | GSE52615 | GEO
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Project description:Background: The goal of this study was to determine the transcriptional consequences of norepinephrine transporter (NET) gene deletion in noradrenergic neuron differentiation. The norepinephrine transporter (NET) is the target of powerful mind-altering substances, such as tricyclic antidepressants and the drug of abuse, cocaine. NET function in adult noradrenergic neurons of the peripheral and central nervous systems is that of a scavenger that internalizes norepinephrine from the synaptic cleft. By contrast, norepinephrine (NE) transport has a different role in embryogenesis. It promotes differentiation of neural crest cells and locus ceruleus progenitors into noradrenergic neurons, whereas NET inhibitors, such as the tricyclic antidepressant desipramine and the drug of abuse, cocaine, inhibit noradrenergic differentiation. While NET structure und regulation of NET function is well described, little is known about downstream targets of NE transport. Results: We have determined by long serial analysis of gene expression (LongSAGE) the gene expression profiles of in vitro differentiating wild type and norepinephrine transporter-deficient (NETKO) neural crest derivatives. Comparison analyses with the wild type library (GSM 105765) have identified a number of important differentially expressed genes, including genes relevant to noradrenergic neuron differentiation and to the phenotype of NETKO mice. Furthermore we have identified novel differentially expressed genes. Conclusions: Loss of NET function during embryonic development deregulates signaling pathways that are critically involved in neural crest formation and noradrenergic neuron differentiation. The library was constructed from total RNA of 60 neural crest culture at culture day 7. The neural tubes were dissected from E9.5 embryos that lack the norepinephrine transporter gene.
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Project description:To explore the effects of long-term olanzapine treatment on gene expression in the lateral septum of female mice, we conducted a study using female C57BL/6 mice fed with olanzapine-supplemented chow for 12 weeks. The treated mice exhibited significant weight gain and lipid alterations compared to the control group. Subsequently, RNA-seq was performed on the lateral septum brain regions of both the treated and control mice, followed by gene expression profiling to analyze the data.
2024-07-03 | GSE268867 | GEO
Project description:Olanzapine is considered to induce dyslipidemia as an adversary effect in clinical practice. Critically, raised low-density lipoprotein levels and lowered high-density lipoprotein levels in the blood of patients are detected. The present study utilized three independent sources of clinical big data to analyze the drugs potent to prevent olanzapine-induced dyslipidemia, and vitamin D was found to be effective. To clarify the molecular mechanism of the influence of olanzapine and vitamin D, the culture of three cholesterol metabolism-related cells of mice, primary hepatocyte, primary adipocyte, and C2C12 cells (myocyte) were introduced to treat with olanzapine and vitamin D primary metabolites like calcifediol and calcitriol. RNA-seq was performed on these three types of cells to uncover the direct effects of olanzapine and vitamin D in cholesterol metabolism.
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Project description:Chronic pain is a major health care problem with great social and economic consequences. Although the medial prefrontal cortex (mPFC) and the thalamus have been implicated in regulating pain, whether and how these regions may involve in pain chronification process have remained largely unknown. Here, we show that Foxp2+ neurons in mPFC, which are corticothalamic (CT) neurons representing the major mPFC output to thalamus, are deactivated in chronic inflammatory pain. Interestingly, prolonged, but not short-term, inactivation of the Foxp2+ neurons in mPFC increases the sensitivity to noxious stimulations. Conversely, chemogenetic activation of this neuronal cluster induces robust antinociceptive effects in both naïve mice and mice with chronic inflammatory pain. Furthermore, we found that the mPFC Foxp2+ neurons project to several thalamic relay nuclei and that activation of the mPFC to the parataenial nucleus of thalamus (PTN) circuit relieves pain. Finally, RNA-seq of the mPFC Foxp2+ neurons revealed that many genes related to neuronal activity are dysregulated in mice with chronic inflammatory pain. Collectively, our studies revealed that Foxp2+ neurons in mPFC that project to thalamus play a critical role in somatosensory processing and pain chronification.
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