The Experts below are selected from a list of 33621 Experts worldwide ranked by ideXlab platform

Michael J. Meaney - One of the best experts on this subject based on the ideXlab platform.

  • epigenetic regulation of the Glucocorticoid Receptor in human brain associates with childhood abuse
    Nature Neuroscience, 2009
    Co-Authors: Patrick O Mcgowan, Michael J. Meaney, Moshe Szyf, Aya Sasaki, Ana C Dalessio, Sergiy Dymov, Benoit Labonte, Gustavo Turecki
    Abstract:

    Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of Glucocorticoid Receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific Glucocorticoid Receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of Glucocorticoid Receptor mRNA, as well as mRNA transcripts bearing the Glucocorticoid Receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A–inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal Glucocorticoid Receptor expression.

  • early environmental regulation of hippocampal Glucocorticoid Receptor gene expression characterization of intracellular mediators and potential genomic target sites
    Annals of the New York Academy of Sciences, 2004
    Co-Authors: Ian C G Weaver, Josie Diorio, Jonathan R Seckl, Moshe Szyf, Michael J. Meaney
    Abstract:

    Abstract: Environmental conditions in early life permanently alter the development of Glucocorticoid Receptor gene expression in the hippocampus and hypothalamic-pituitary-adrenal responses to acute or chronic stress. In part, these effects can involve an activation of ascending serotonergic pathways and subsequent changes in the expression of transcription factors that might drive Glucocorticoid Receptor expression in the hippocampus. This paper summarizes the evidence in favor of these pathways as well as recent studies describing regulatory targets within the chromatin structure of the promoter region of the rat hippocampal Glucocorticoid Receptor gene.

  • Serotonin regulates hippocampal Glucocorticoid Receptor expression via a 5-HT7 Receptor.
    Brain research. Developmental brain research, 2002
    Co-Authors: Patricia Laplante, Josie Diorio, Michael J. Meaney
    Abstract:

    Glucocorticoid Receptor expression in primary hippocampal cell cultures was significantly increased with either 10 mM 8-bromo cAMP, 50 nM 5-carboxamidotryptamine (5-CT), a potent 5-HT7 Receptor agonist, or 100 nM 5-HT. The effect of 5-HT or 5-CT was blocked with methiothepin or by a protein kinase A inhibitor, but not pindolol. These results suggest that the effects of 5-HT on hippocampal GR expression is mediated by a 5-HT7 Receptor.

  • early environmental regulation of hippocampal Glucocorticoid Receptor gene expression characterization of intracellular mediators and potential genomic target sites
    Molecular and Cellular Endocrinology, 2001
    Co-Authors: Ian C G Weaver, Josie Diorio, Jonathan R Seckl, Moshe Szyf, Patricia La Plante, Shelley Weaver, Angel Parent, Shakti Sharma, Karen E Chapman, Michael J. Meaney
    Abstract:

    Environmental conditions in early life permanently alter the development of Glucocorticoid Receptor gene expression in the hippocampus and hypothalamic-pituitary-adrenal responses to acute or chronic stress. In part, these effects can involve an activation of ascending serotonergic pathways and subsequent changes in the expression of transcription factors that might drive Glucocorticoid Receptor expression in the hippocampus. This paper summarizes the evidence in favor of these pathways as well as recent studies describing regulatory targets on the promoter region of the rat hippocampal Glucocorticoid Receptor gene.

Béla Bohus - One of the best experts on this subject based on the ideXlab platform.

  • Antisense to the Glucocorticoid Receptor in hippocampal dentate gyrus reduces immobility in forced swim test
    European Journal of Pharmacology, 1996
    Co-Authors: S. Mechiel Korte, Bauke Buwalda, Stephan D. Bouman, E. Ronald De Kloet, Béla Bohus
    Abstract:

    Immobility time of rats in the forced swim test was reduced after bilateral infusion of an 18-mer antisense phosphorothioate oligodeoxynucleotide targeted to the Glucocorticoid Receptor mRNA into the dentate gyrus of the hippocampus. Vehicle-, sense- and scrambled sequence-treated animals spent significantly more time immobile than antisense-treated animals during the initial test. Immunolabeling of the Glucocorticoid Receptor in brain sections demonstrated a reduced expression of Glucocorticoid Receptor proteins in antisense-treated dentate gyrus compared to the contralateral sense-treated dentate gyrus or contralateral scrambled sequence-treated dentate gyrus. During the initial test the time spent on immobility was also reduced when rats were treated with the Glucocorticoid Receptor antagonist RU38486 (17β-hydroxy-11β-(4-dimethylamino-phenyl)17α-(1-propynyl)estra-4,9-diene-3 -one)) 6 h (but not 1 h) earlier. These results demonstrate the participation of Glucocorticoid Receptors in the expression of immobility in a forced swim test during the initial test.

John A. Cidlowski - One of the best experts on this subject based on the ideXlab platform.

  • Generating diversity in Glucocorticoid Receptor signaling: mechanisms, Receptor isoforms, and post-translational modifications
    2020
    Co-Authors: Danielle Duma, John A. Cidlowski
    Abstract:

    Abstract Glucocorticoids are necessary for life after birth and regulate numerous homeostatic functions in man, including glucose homeostasis, protein catabolism, skeletal growth, respiratory function, inflammation, development, behavior, and apoptosis. In a clinical setting, they are widely used as anti-inflammatory agents to control both acute and chronic inflammation. Unfortunately, owing to their broad range of physiological actions, patients treated with Glucocorticoids for long periods of time experience a variety of serious side effects, including metabolic syndrome, bone loss, and psychiatric disorders including depression, mania, and psychosis. Our understanding of how one hormone or drug regulates all of these diverse processes is limited. Recent studies have shown that multiple Glucocorticoid Receptor isoforms are produced from one gene via combinations of alternative mRNA splicing and alternative translation initiation. These isoforms possess unique tissue distribution patterns and transcriptional regulatory profiles. Owing to variation in the N-terminal and C-terminal length of Glucocorticoid Receptor isoforms, different post-translational modifications including ubiquitination, phosphorylation, and sumoylation are predicted, contributing to the complexity of Glucocorticoid signaling. Furthermore, increasing evidence suggests that unique Glucocorticoid Receptor isoform compositions within cells could determine the cell-specific response to Glucocorticoids. In this review, we will outline the recent advances made in the characterization of the transcriptional activity and the selective regulation of apoptosis by the various Glucocorticoid Receptor isoforms

  • estrogen deficiency promotes hepatic steatosis via a Glucocorticoid Receptor dependent mechanism in mice
    Cell Reports, 2018
    Co-Authors: Matthew Quinn, Melania Ronfani, John A. Cidlowski
    Abstract:

    Glucocorticoids (GCs) are master regulators of systemic metabolism. Intriguingly, Cushing's syndrome, a disorder of excessive GCs, phenocopies several menopause-induced metabolic pathologies. Here, we show that the Glucocorticoid Receptor (GR) drives steatosis in hypogonadal female mice because hepatocyte-specific GR knockout mice are refractory to developing ovariectomy-induced steatosis. Intriguingly, transcriptional profiling revealed that ovariectomy elicits hepatic GC hypersensitivity globally. Hypogonadism-induced GC hypersensitivity results from a loss of systemic but not hepatic estrogen (E2) signaling, given that hepatocyte-specific E2 Receptor deletion does not confer GC hypersensitivity. Mechanistically, enhanced chromatin recruitment and ligand-dependent hyperphosphorylation of GR underlie ovariectomy-induced Glucocorticoid hypersensitivity. The dysregulated Glucocorticoid-mediated signaling present in hypogonadal females is a product of increased follicle-stimulating hormone (FSH) production because FSH treatment in ovary-intact mice recapitulates Glucocorticoid hypersensitivity similar to hypogonadal female mice. Our findings uncover a regulatory axis between estradiol, FSH, and hepatic Glucocorticoid Receptor signaling that, when disrupted, as in menopause, promotes hepatic steatosis.

  • hes1 is a master regulator of Glucocorticoid Receptor dependent gene expression
    Science Signaling, 2013
    Co-Authors: Javier Revollo, Nick Z Lu, Mahita Kadmiel, Maheer Gandhavadi, Robert H. Oakley, John A. Cidlowski
    Abstract:

    Hairy and enhancer of split-1 (HES1) is a basic helix-loop-helix transcription factor that is a key regulator of development and organogenesis. However, little is known about the role of HES1 after birth. Glucocorticoids, primary stress hormones that are essential for life, regulate numerous homeostatic processes that permit vertebrates to cope with physiological challenges. The molecular actions of Glucocorticoids are mediated by Glucocorticoid Receptor–dependent regulation of nearly 25% of the genome. Here, we established a genome-wide molecular link between HES1 and Glucocorticoid Receptors that controls the ability of cells and animals to respond to stress. Glucocorticoid signaling rapidly and robustly silenced HES1 expression. This Glucocorticoid-dependent repression of HES1 was necessary for the Glucocorticoid Receptor to regulate many of its target genes. Mice with conditional knockout of HES1 in the liver exhibited an expanded Glucocorticoid Receptor signaling profile and aberrant metabolic phenotype. Our results indicate that HES1 acts as a master repressor, the silencing of which is required for proper Glucocorticoid signaling.

  • Glucocorticoid Receptor signaling in health and disease
    Trends in Pharmacological Sciences, 2013
    Co-Authors: Mahita Kadmiel, John A. Cidlowski
    Abstract:

    Glucocorticoids are steroid hormones regulated in a circadian and stress-associated manner to maintain various metabolic and homeostatic functions that are necessary for life. Synthetic Glucocorticoids are widely prescribed drugs for many conditions including asthma, chronic obstructive pulmonary disease (COPD), and inflammatory disorders of the eye. Research in the past few years has begun to unravel the profound complexity of Glucocorticoid signaling and has contributed remarkably to improved therapeutic strategies. Glucocorticoids signal through the Glucocorticoid Receptor (GR), a member of the superfamily of nuclear Receptors, in both genomic and non-genomic ways in almost every tissue in the human body. In this review, we provide an update on Glucocorticoid Receptor signaling and highlight the role of GR signaling in physiological and pathophysiological conditions in the major organ systems in the human body.

  • selective regulation of bone cell apoptosis by translational isoforms of the Glucocorticoid Receptor
    Molecular and Cellular Biology, 2007
    Co-Authors: Nick Z Lu, Jennifer B Collins, Sherry F Grissom, John A. Cidlowski
    Abstract:

    Glucocorticoids are widely used in the treatment of inflammatory and other diseases. However, high-dose or chronic administration often triggers troublesome side effects such as metabolic syndrome and osteoporosis. We recently described that one Glucocorticoid Receptor gene produces eight translational Glucocorticoid Receptor isoforms that have distinct gene-regulatory abilities. We show here that specific, but not all, Glucocorticoid Receptor isoforms induced apoptosis in human osteosarcoma U-2 OS bone cells. Whole human genome microarray analysis revealed that the majority of the Glucocorticoid target genes were selectively regulated by specific Glucocorticoid Receptor isoforms. Real-time PCR experiments confirmed that proapoptotic enzymes necessary for cell death, granzyme A and caspase-6, were induced by specific Glucocorticoid Receptor isoforms. Chromatin immunoprecipitation assays further suggested that Glucocorticoid Receptor isoform-dependent induction of proapoptotic genes was likely due to selective coregulator recruitment and chromatin modification. Interestingly, the capabilities to transrepress proinflammatory genes were similar among Glucocorticoid Receptor isoforms. Together, these findings provide new evidence that translational Glucocorticoid Receptor isoforms can elicit distinct Glucocorticoid responses and may be useful for the development of safe Glucocorticoids with reduced side effects.

Ilse M. Beck - One of the best experts on this subject based on the ideXlab platform.

  • selective Glucocorticoid Receptor modulation new directions with non steroidal scaffolds
    Pharmacology & Therapeutics, 2015
    Co-Authors: Nora Sundahl, Jolien Bridelance, Karolien De Bosscher, Claude Libert, Ilse M. Beck
    Abstract:

    Abstract Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the Glucocorticoid Receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective Glucocorticoid Receptor agonists (SEGRAs) or selective Glucocorticoid Receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the Glucocorticoid Receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective Glucocorticoid Receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the Glucocorticoid Receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective Glucocorticoid Receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling Glucocorticoid-mediated side effects as well as Glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective Glucocorticoid Receptor therapies.

  • differential cytokine profiles upon comparing selective versus classic Glucocorticoid Receptor modulation in human peripheral blood mononuclear cells and inferior turbinate tissue
    PLOS ONE, 2015
    Co-Authors: Ilse M. Beck, Koen Van Crombruggen, Gabriele Holtappels, Francois Daubeuf, Nelly Frossard, Claus Bachert, Karolien De Bosscher
    Abstract:

    Background Glucocorticoid Receptor agonists, particularly classic Glucocorticoids, are the mainstay among treatment protocols for various chronic inflammatory disorders, including nasal disease. To steer away from steroid-induced side effects, novel GR modulators exhibiting a more favorable therapeutic profile remain actively sought after. Currently, the impact of 2(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride a plant-derived selective Glucocorticoid Receptor modulator named compound A, on cytokine production in ex vivo human immune cells and tissue has scarcely been evaluated.

Ian C G Weaver - One of the best experts on this subject based on the ideXlab platform.