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Concept: Glucocorticoid receptor

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Generalized glucocorticoid resistance is characterized by impaired cortisol signaling, resulting from mutations of the glucocorticoid receptor (GR) gene NR3C1. The objective of our study was to identify the causative mutation in a patient with clinical manifestations compatible with generalized glucocorticoid resistance and to determine the functional consequences of the mutation. The possible occurrence of NR3C1 mutations in a selected group of hypertensive subjects with low plasma renin and aldosterone levels was also explored.

Concepts: DNA, Genetics, Evolution, Hypertension, Cortisol, Nuclear receptor, Mineralocorticoid receptor, Glucocorticoid receptor

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A newly discovered negative glucocorticoid response element (nGRE) mediates DNA-dependent transrepression by the glucocorticoid receptor (GR) across the genome and has a major role in immunosuppressive therapy. The nGRE differs dramatically from activating response elements, and the mechanism driving GR binding and transrepression is unknown. To unravel the mechanism of nGRE-mediated transrepression by the GR, we characterized the interaction between GR and an nGRE in the thymic stromal lymphopoietin (TSLP) promoter. We show using structural and mechanistic approaches that nGRE binding is a new mode of sequence recognition by human GR and that nGREs prevent receptor dimerization through a unique GR-binding orientation and strong negative cooperativity, ensuring the presence of monomeric GR at repressive elements.

Concepts: Immune system, Transcription factor, Nuclear receptor, Glucocorticoid receptor, Selective glucocorticoid receptor agonist, Response element, Hormone response element, Transrepression

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How the glucocorticoid receptor (GR) activates some genes while potently repressing others remains an open question. There are three current models for suppression: transrepression via GR tethering to AP-1/NF-κB sites, direct GR association with inhibitory elements (nGREs), and GR recruitment of the corepressor GRIP1. To gain insights into GR suppression, we used genomic analyses and genome-wide profiling of GR, p65, and c-Jun in LPS-stimulated macrophages. We show that GR mediates both activation and repression at tethered sites, GREs, and GRIP1-bound elements, indicating that motif classification is insufficient to predict regulatory polarity of GR binding. Interestingly, sites of GR repression utilize GRIP1’s corepressor function and display reduced histone acetylation. Together, these findings suggest that while GR occupancy confers hormone responsiveness, the receptor itself may not participate in the regulatory effects. Furthermore, transcriptional outcome is not established by sequence but is influenced by epigenetic regulators, context, and other unrecognized regulatory determinants.

Concepts: DNA, Gene, Genetics, Gene expression, Histone, Histone deacetylase, Regulation, Glucocorticoid receptor

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BACKGROUND: Increased circulating glucocorticoids are features of both aging and Alzheimer’s disease (AD), and increased glucocorticoids accelerate the accumulation of AD pathologies. Here, we analyzed the effects of the glucocorticoid receptor antagonist mifepristone (RU486) in the 3xTg-AD mouse model at an age where hippocampal damage leads to high circulating corticosterone levels. METHODS: The effects of mifepristone were investigated in 3xTg-AD mice using a combination of biochemical, histological, and behavior analyses. RESULTS: Mifepristone treatment rescues the pathologically induced cognitive impairments and markedly reduces amyloid beta (Aβ)-load and levels, as well as tau pathologies. Analysis of amyloid precursor protein (APP) processing revealed concomitant decreases in both APP C-terminal fragments C99 and C83 and the appearance of a larger 17-kDa C-terminal fragment. Hence, mifepristone induces a novel C-terminal cleavage of APP that prevents it being cleaved by α- or β-secretase, thereby precluding Aβ generation in the central nervous system; this cleavage and the production of the 17-kDa APP fragment was generated by a calcium-dependent cysteine protease. In addition, mifepristone treatment also reduced the phosphorylation and accumulation of tau, concomitant with reductions in p25. Notably, deficits in cyclic-AMP response element-binding protein signaling were restored with the treatment. CONCLUSIONS: These preclinical results point to a potential therapeutic role for mifepristone as an effective treatment for AD and further highlight the impact the glucocorticoid system has as a regulator of Aβ generation.

Concepts: Alzheimer's disease, Central nervous system, Nervous system, Protein, Brain, Signal transduction, Receptor, Glucocorticoid receptor

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Glucocorticoids (GCs) potentially regulate the proliferation, differentiation, and premature senescence of bone marrow mesenchymal stem/stromal cells (MSCs). In the present study we investigated the effects mediated by endogenous GCs and the effects of an antagonist of the glucocorticoid receptor, RU486, on the proliferative and differentiation capabilities of MSCs using an ovariectomized (OVX) animal model. Following ovariectomy and a decrease in systemic estradiol levels, the serum concentration of corticosterone is significantly increased in OVX rats. Compared to sham-operated controls, the total superoxide dismutase (SOD) activity in serum of OVX rats and the proliferation of their MSCs are significantly reduced. Furthermore, the osteogenic differentiation capabilities of OVX rat MSCs are significantly decreased, while adipogenic capabilities tend to increase. Subcutaneous administration of RU486 effectively increases the population and proliferative capacity of the MSCs in OVX rats. RU486 treatment also improves osteogenic capabilities and down-regulates adipogenic capabilities of MSCs. These results strongly indicate that the elevated levels of endogenous GCs induced by estrogen depletion might accelerate the premature senescence of MSCs and reduce their proliferative and osteogenic differentiation capabilities, while the blockage of the effects of endogenous GCs may restore their capabilities. These responses could potentially be developed to protect the capabilities of MSCs from oxidative stress-induced premature senescence and extend their lifespan in patients with advancing age and estrogen depletion. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Concepts: Bone, Stem cell, Mesenchymal stem cell, Bone marrow, Superoxide dismutase, Receptor, Estradiol, Glucocorticoid receptor

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In monogamous mammals, fathers play an important role in the development of the brain and typical behavior in offspring, but the exact nature of this process is not well understood. In particular, little research has addressed whether the presence or absence of paternal care alters levels of hippocampal glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF), and basal levels of serum corticosterone (CORT) and adrenocorticotropin (ACTH). Here, we explore this concept using socially monogamous mandarin voles (Microtus mandarinus), a species in which fathers display high levels of paternal care toward their pups. Our immunohistochemical study shows that paternal deprivation (PD) significantly decreased levels of GR and BDNF protein in the CA1 and CA2/3 of the hippocampus. In the dental gyrus, decreases in GR and BDNF induced by PD were evident in females but not in males. Additionally, Elisa results show that PD significantly up-regulated levels of serum CORT and ACTH in females, but not males. These findings demonstrate that paternal deprivation alters HPA axis activity in a sex-specific way. The changes in stress hormones documented here may be associated with alteration in hippocampal BDNF and GR levels. © 2014 S. Karger AG, Basel.

Concepts: Brain, Cerebrum, Cortisol, Neurotrophin, Brain-derived neurotrophic factor, Nerve growth factor, Adrenal cortex, Glucocorticoid receptor

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The H (hypothalamic)-P (pituitary)-I (interrenal) axis plays a critical role in the fish stress response and is regulated by several factors. Cadmium (Cd) is one of the most toxic heavy metals in the world, but its effects on the H-P-I axis of teleosts are largely unknown. Using rare minnow (Gobiocypris rarus) as an experimental animal, we found that Cd only disrupted the secretion and synthesis of cortisol. Neither hormones at the H or P level nor the expressions of their receptor genes (corticotropin-releasing hormone receptor (CRHR) and melanocortin receptor 2, (MC2R)) were affected. Steroidogenic acute regulator (StAR), CYP11A1 and CYP11B1, which encode the key enzymes in the cortisol synthesis pathway, were significantly up-regulated in the kidney (including the head kidney). The level of 11β-HSD2, which is required for the conversion of cortisol to cortisone, was increased in the kidney, intestine, brain, and hepatopancreas, whereas the expression of 11β-HSD1, which encodes the reverse conversion enzyme, was increased in the gill, kidney and almost unchanged in other tissues. The enzyme activity concentration of 11βHSD2 was increased in the kidney as well. The level of glucocorticoid receptor (GR) decreased in the intestine, gill and muscle, and the key GR regulator FK506 binding protein5 (FKBP5) was up-regulated in the GR-decreased tissues, whereas the level of nuclear receptor co-repressor 1 (NCoR1), another GR regulator remained almost unchanged. Thus, GR, FKBP5 and 11β-HSD2 may be involved in Cd-induced cortisol disruption.

Concepts: Protein, Signal transduction, Metabolism, Enzyme, Hormone, Glucocorticoid, Cortisol, Glucocorticoid receptor

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Adrenal crisis is a life-threatening emergency contributing to the excess mortality of patients with adrenal insufficiency. Studies in patients on chronic replacement therapy for adrenal insufficiency have revealed an incidence of 5 - 10 adrenal crises per 100 patient years and suggest a mortality from adrenal crisis of 0.5 per 100 patient years. Patients with adrenal crisis typically present with profoundly impaired well-being, hypotension, nausea and vomiting, and fever responding well to parenteral hydrocortisone administration. Infections are the major precipitating cause of adrenal crisis. Lack of increased cortisol concentrations during infection enhances pro-inflammatory cytokine release and sensitivity to the toxic effects of these cytokines (e.g. tumor necrosis factor alpha). Furthermore, pro-inflammatory cytokines may impair glucocorticoid receptor function aggravating glucocorticoid deficiency. Treatment of adrenal crisis is simple and highly effective consisting of intravenous hydrocortisone (initial bolus of 100 mg followed by 200 mg over 24 h as continuous infusion) and 0.9 % saline (1000 ml within the first hour). Prevention of adrenal crisis requires appropriate hydrocortisone dose adjustments to stressful medical procedures (e.g. major surgery) and other stressful events (e.g. infection). Patient education is key for such dose adjustments but current education concepts are not sufficiently effective. Thus improved education strategies are needed. Every patient should carry an emergency card and should be provided with an emergency kit for parenteral hydrocortisone self-administration. A hydrocortisone pen would hold great potential to lower the current barriers to hydrocortisone self-injection. Improved patient education and measures to facilitate parenteral hydrocortisone self-administration in impending crisis are expected to significantly reduce morbidity and mortality from adrenal crisis.

Concepts: Cytokine, Hormone, Aldosterone, Cortisol, Tumor necrosis factor-alpha, Adrenal cortex, Glucocorticoid receptor, Adrenal insufficiency

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The current study examined the long-term effects of neonatal amygdala (Neo-A) lesions on brain corticotropin-releasing factor (CRF) systems and hypothalamic-pituitary-adrenal (HPA) axis function of male and female prepubertal rhesus monkeys. At 12-months-old, CSF levels of CRF were measured and HPA axis activity was characterized by examining diurnal cortisol rhythm and response to pharmacological challenges. Compared with controls, Neo-A animals showed higher cortisol secretion throughout the day, and Neo-A females also showed higher CRF levels. Hypersecretion of basal cortisol, in conjunction with blunted pituitary-adrenal responses to CRF challenge, suggest HPA axis hyperactivity caused by increased CRF hypothalamic drive leading to downregulation of pituitary CRF receptors in Neo-A animals. This interpretation is supported by the increased CRF CSF levels, suggesting that Neo-A damage resulted in central CRF systems overactivity. Neo-A animals also exhibited enhanced glucocorticoid negative feedback, as reflected by an exaggerated cortisol suppression following dexamethasone administration, indicating an additional effect on glucocorticoid receptor (GR) function. Together these data demonstrate that early amygdala damage alters the typical development of the primate HPA axis resulting in increased rather than decreased activity, presumably via alterations in central CRF and GR systems in neural structures that control its activity. Thus, in contrast to evidence that the amygdala stimulates both CRF and HPA axis systems in the adult, our data suggest an opposite, inhibitory role of the amygdala on the HPA axis during early development, which fits with emerging literature on “developmental switches” in amygdala function and connectivity with other brain areas.

Concepts: Amygdala, Hypothalamus, Hormone, Cortisol, Primate, Rhesus Macaque, Monkeys in space, Glucocorticoid receptor

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OBJECTIVE Differential effects of maternal and paternal posttraumatic stress disorder (PTSD) have been observed in adult offspring of Holocaust survivors in both glucocorticoid receptor sensitivity and vulnerability to psychiatric disorder. The authors examined the relative influences of maternal and paternal PTSD on DNA methylation of the exon 1F promoter of the glucocorticoid receptor (GR-1F) gene (NR3C1) in peripheral blood mononuclear cells and its relationship to glucocorticoid receptor sensitivity in Holocaust offspring. METHOD Adult offspring with at least one Holocaust survivor parent (N=80) and demographically similar participants without parental Holocaust exposure or parental PTSD (N=15) completed clinical interviews, self-report measures, and biological procedures. Blood samples were collected for analysis of GR-1F promoter methylation and of cortisol levels in response to low-dose dexamethasone, and two-way analysis of covariance was performed using maternal and paternal PTSD as main effects. Hierarchical clustering analysis was used to permit visualization of maternal compared with paternal PTSD effects on clinical variables and GR-1F promoter methylation. RESULTS A significant interaction demonstrated that in the absence of maternal PTSD, offspring with paternal PTSD showed higher GR-1F promoter methylation, whereas offspring with both maternal and paternal PTSD showed lower methylation. Lower GR-1F promoter methylation was significantly associated with greater postdexamethasone cortisol suppression. The clustering analysis revealed that maternal and paternal PTSD effects were differentially associated with clinical indicators and GR-1F promoter methylation. CONCLUSIONS This is the first study to demonstrate alterations of GR-1F promoter methylation in relation to parental PTSD and neuroendocrine outcomes. The moderation of paternal PTSD effects by maternal PTSD suggests different mechanisms for the intergenerational transmission of trauma-related vulnerabilities.

Concepts: DNA, Gene expression, Epigenetics, Cortisol, DNA methylation, Posttraumatic stress disorder, PTSD, Glucocorticoid receptor