Guillain-Barre syndrome (GBS) is an autoimmune disorder in which the bodys immune system attacks part of the peripheral nervous system with a greater variable clinical progression, severity, and outcome. Infectious agent as well as host factor are responsible for developing GBS. Glucocorticoids are the steroid hormones that bind with glucocorticoid receptor (GR) gene to decrement the immune reaction through down-regulating the cytokine responsible for cellular and humoral immune reaction and thus, polymorphisms in GR gene act as a factor to develop autoimmune disease. Hence, in the population of 71 patients with GBS and healthy controls of Bangladesh , five known SNPs of glucocorticoid receptor gene along with the haplotype patterns of genetic variations has been studied. The study supports to investigate the individual SNP as well as the haplotype that are related to the susceptibility of developing GBS and their role in disease outcome. During the course of this study, which includes 5 ...
TY - JOUR. T1 - Functional characterization of the natural human glucocorticoid receptor (hGR) mutants hGRαR477H and hGRαG679S associated with generalized glucocorticoid resistance. AU - Charmandari, Evangelia. AU - Kino, Tomoshige. AU - Ichijo, Takamasa. AU - Zachman, Keith. AU - Alatsatianos, Anton. AU - Chrousos, George P.. PY - 2006/4. Y1 - 2006/4. N2 - Background: Glucocorticoid resistance is often a result of mutations in the human glucocorticoid receptor α (hGRα) gene, which impair one or more of hGRαs functions. We investigated the molecular mechanisms through which two previously described mutant receptors, hGRαR477H and hGRαG679S, with amino acid substitutions in the DNA- and ligand-binding domains, respectively, affect glucocorticoid signal transduction. Methods and Results: In transient transfection assays, hGRαR477H displayed no transcriptional activity, whereas hGRαG679S showed a 55% reduction in its ability to stimulate the transcription of the glucocorticoid-responsive ...
1. Previous data demonstrate that the tricyclic antidepressant, desipramine, induces glucocorticoid receptor (GR) translocation from the cytoplasm to the nucleus in L929 cells and increases dexamethasone-induced GR-mediated gene transcription in L929 cells stably transfected with the mouse mammary tumour virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter gene (LMCAT cells) (Pariante et al., 1997). 2. To extend these findings, the present study has investigated the effects of 24 h coincubation of LMCAT cells with dexamethasone and amitriptyline, clomipramine, paroxetine, citalopram or fluoxetine. 3. All antidepressants, except fluoxetine, enhanced GR-mediated gene transcription, with clomipramine having the greatest effect (10 fold increase). Twenty-four hours coincubation of cells with desipramine, clomipramine or paroxetine, also enhanced GR function in the presence of cortisol, but not of corticosterone. 4. It is proposed that these effects are due to the antidepressants inhibiting the L929
TY - JOUR. T1 - Glucocorticoid receptor in polymorphonuclear leukocytes. T2 - A simple method for leukocyte glucocorticoid receptor characterization. AU - Murakami, Tohru. AU - Brandon, David. AU - Rodbard, David. AU - Loriaux, Donald (Lynn). AU - Lipsett, Mortimer B.. PY - 1979. Y1 - 1979. N2 - Glucocorticoid receptors of polymorphonuclear leukocytes (PMN) have been characterized and compared with those of mononuclear leukocytes (MNL). Cytosol receptors from PMN and MNL have similar binding affinities for [3H]-dexamethasone (Dex). nearly superimposable sedimentation profiles on sucrose density gradients, and similar elution patterns from DEAE-Sephadex. Thus, the glucocorticoid receptors of MNL and PMN have similar biochemical properties. We have developed a simple method for preparing leukocytes from 20 ml of blood to characterize and quantify the glucocorticoid receptor. The Scatchard analysis of [3H]-Dex binding to intact leukocytes shows a single class of binding sites; the apparent Kd was ...
Mouse anti Human glucocorticoid receptor antibody, clone 8E9 recognizes the human glucocorticoid receptor (GR), also known as Nuclear rece
TY - JOUR. T1 - The glucocorticoid receptor resource. AU - Danielsen, M.. AU - Martinez, E.. PY - 1996. Y1 - 1996. N2 - The glucocorticoid receptor resource focuses on the structure-function relationships of the glucocorticoid receptor. As well as links to sequence and bibliographic databases via the World Wide Web, the database contains sequence comparisons of receptors from different species and source information for glucocorticoid receptor clones, probes, cell lines and antibodies. The resource allows the electronic publication of essays, unpublished data and reviews on steroid receptors. These publications will not be reviewed or edited and should allow the rapid dissemination of information to the scientific community. The resource can be reached at: http://biochem1.basic-sci.georgetown.edu/grr/grr.html.. AB - The glucocorticoid receptor resource focuses on the structure-function relationships of the glucocorticoid receptor. As well as links to sequence and bibliographic databases via the ...
A L Southren, M O Dominguez, G G Gordon, E J Wenk, M R Hernandez, M W Dunn, B I Weinstein; Nuclear translocation of the cytoplasmic glucocorticoid receptor in the iris-ciliary body and adjacent corneoscleral tissue of the rabbit following topical administration of various glucocorticoids. A rapid screening method for glucocorticoid activity.. Invest. Ophthalmol. Vis. Sci. 1983;24(2):147-152. Download citation file:. ...
There are no specific protocols for Human Glucocorticoid Receptor alpha peptide (ab39764). Please download our general protocols booklet
I STRUCTURE AND FUNCTION OF CYTOSOLIC GLUCOCORTICOID RECEPTORS IN RODENT LYMPHOID CELLS: STUDIES OF RECEPTOR STABILITY, SUBUNIT COMPOSITION, AND PHOSPHORYLATION A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Dirk B. Mendel DARTMOUTH COLLEGE Hanover, New Hampshire February 1986 ...
I STRUCTURE AND FUNCTION OF CYTOSOLIC GLUCOCORTICOID RECEPTORS IN RODENT LYMPHOID CELLS: STUDIES OF RECEPTOR STABILITY, SUBUNIT COMPOSITION, AND PHOSPHORYLATION A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Dirk B. Mendel DARTMOUTH COLLEGE Hanover, New Hampshire February 1986 ...
383. McDonald, M.D., Wood, C.M., Grosell, M., Walsh, P.J. (2004) Glucocorticoid receptors are involved in the regulation of pulsatile urea excretion in toadfish. J. Comp. Physiol. B. 174 pp: 649-658. (PDF). ...
The cell nucleus is highly organized. Many nuclear functions are localized in discrete domains, suggesting that compartmentalization is an important aspect of the regulation and coordination of nuclear functions. We investigated the subnuclear distribution of the glucocorticoid receptor, a hormone-dependent transcription factor. By immunofluorescent labeling and confocal microscopy we found that after stimulation with the agonist dexamethasone the glucocorticoid receptor is concentrated in 1,000-2,000 clusters in the nucleoplasm. This distribution was observed in several cell types and with three different antibodies against the glucocorticoid receptor. A similar subnuclear distribution of glucocorticoid receptors was found after treatment of cells with the antagonist RU486, suggesting that the association of the glucocorticoid receptor in clusters does not require transformation of the receptor to a state that is able to activate transcription. By dual labeling we found that most ...
TY - JOUR. T1 - Correlation of membrane glucocorticoid receptor levels with glucocorticoid-induced apoptotic competence using mutant leukemic and lymphoma cells lines. AU - Gametchu, Bahiru. AU - Watson, Cheryl S.. PY - 2002. Y1 - 2002. N2 - We have studied the presence and functional implications of membrane glucocorticoid receptor (mGR) in several wild type (WT) and mutant mouse lymphoid cell lines (nuclear transfer decrease, NT-; nuclear transfer increase, NTi; and receptorless, R-). Direct fluorescent antibody staining revealed large aggregates of mGR-specific fluorescing antigens in the plasma membrane of the WT and mGR-enriched (mGR++) S-49 cells. While R- cells totally lacked mGR, this receptor level was low in NT- and NTi groups. FACS analysis corroborated these results, showing a ∼4-10-fold difference between the highest mGR levels (mGR++) and the R- and NTi cells. Membrane extracts were analyzed for mGR by immunoblotting. Multiple receptor forms, ranging in Mr from 94,000 to , ...
TY - JOUR. T1 - L-Carnitine is a modulator of the glucocorticoid receptor alpha. AU - Alesci, Salvatore. AU - De Martino, Massimo U.. AU - Kino, Tomoshige. AU - Ilias, Ioannis. PY - 2004/1/1. Y1 - 2004/1/1. N2 - L-Carnitine (LC) is a nutrient with an essential role in cellular energy production. At high doses, LC can mimic some of the biological activities of glucocorticoids, particularly immunomodulation. To explore the molecular bases of this property, we tested the influence of LC on glucocorticoid receptor-α (GRα) functions. LC reduced the binding capacity of GRα, induced its nuclear translocation, and stimulated its transcriptional activity. Moreover, LC suppressed TNFα and IL-12 release from human monocytes in glucocorticoid-like fashion. We conclude that pharmacologic doses of LC can activate GRα and, via this mechanism, regulate glucocorticoid-responsive genes, potentially sharing some of the biological and therapeutic properties of glucocorticoids.. AB - L-Carnitine (LC) is a ...
The present invention provides compositions of an anti-inflammatory glucocorticosteroid and a glucocorticoid receptor (GR) modulator useful for inhibiting glucocorticoid receptor induced transactivation without substantially inhibiting glucocorticoid receptor induced transrepression. Also provided are methods of treating a disorder or condition and reducing the side effects of glucocorticosteroid treatment, using the compositions of the present invention.
Identification of complementary DNAs encoding the human glucocorticoid receptor predicts two protein forms, of 777 (alpha) and 742 (beta) amino acids, which differ at their carboxy termini. The proteins contain a cysteine/lysine/arginine-rich region which may define the DNA-binding domain. Pure radi …
The glucocorticoid receptor (GR) is a gene found in almost all cells, but its possible that the gene also plays a role in the suppression of cancer.
We describe for the first time novel data relating to analyses of glucocorticoid hormone signaling in human skeletal myoblasts. Importantly, these results reveal key molecular mechanisms underlying recent suggestions that altered levels of glucocorticoid hormone action may play an important role in the etiology of the metabolic syndrome (12). Our analyses indicate important associations between in vivo features of the metabolic syndrome and levels of basal and glucocorticoid-dependent GRα expression and glucocorticoid-dependent 11β-HSD1 expression in skeletal myoblasts in vitro.. Studies investigating mechanisms underlying GR expression and GR downregulation by its ligand, cortisol, indicate that this occurs predominantly at the level of mRNA transcription and stability and, to a much lesser degree, through post-translational increases in GR turnover (23). Thus, most GR regulation studies have focused on analyses of GR mRNA expression (23,40). The close agreement between levels of GRα mRNA ...
Glucocorticoid hormones (GCs) are used to treat a variety of diseases because of their potent anti-inflammatory effect and their ability to induce apoptosis in lymphoid malignancies through the glucocorticoid receptor (GR). Despite ongoing research, high glucocorticoid efficacy and widespread usage in medicine, resistance, disease relapse and toxicity remain factors that need addressing. Understanding the mechanisms of glucocorticoid signalling and how resistance may arise is highly important towards improving therapy. To gain insight into this we undertook a systems biology approach, aiming to generate a Boolean model of the glucocorticoid receptor protein interaction network that encapsulates functional relationships between the GR, its target genes or genes that target GR, and the interactions between the genes that interact with the GR. This model named GEB052 consists of 52 nodes representing genes or proteins, the model input (GC) and model outputs (cell death and inflammation), connected ...
Glucocorticoid hormones (GCs) are used to treat a variety of diseases because of their potent anti-inflammatory effect and their ability to induce apoptosis in lymphoid malignancies through the glucocorticoid receptor (GR). Despite ongoing research, high glucocorticoid efficacy and widespread usage in medicine, resistance, disease relapse and toxicity remain factors that need addressing. Understanding the mechanisms of glucocorticoid signalling and how resistance may arise is highly important towards improving therapy. To gain insight into this we undertook a systems biology approach, aiming to generate a Boolean model of the glucocorticoid receptor protein interaction network that encapsulates functional relationships between the GR, its target genes or genes that target GR, and the interactions between the genes that interact with the GR. This model named GEB052 consists of 52 nodes representing genes or proteins, the model input (GC) and model outputs (cell death and inflammation), connected ...
Read "HIV-1 Vpr enhances production of receptor of activated NF-κB ligand (RANKL) via potentiation of glucocorticoid receptor activity, Archives of Virology" on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.
Increased levels of glucocorticoid receptors and enhanced glucocorticoid receptor auto-regulation after hydrocortisone challenge in B-lymphoblastoids from patients with affective disorders ...
The hippocampus is the principal target site in the brain for adrenocortical steroids, as it has the highest concentration of receptor sites for glucocorticoids. The aged rat has a specific deficit in hippocampal glucocorticoid receptors, owing in large part to a loss of corticoid-sensitive neurons. This deficit may be the cause for the failure of aged rats to terminate corticosterone secretion at the end of stress, because extensive lesion and electrical stimulation studies have shown that the hippocampus exerts an inhibitory influence over adrenocortical activity and participates in glucocorticoid feedback. We have studied whether it is the loss of hippocampal neurons or of hippocampal glucocorticoid receptors in the aged rat that contributes most to this syndrome of corticosterone hypersecretion. To do this, we used two model systems for producing reversible glucocorticoid receptor depletion in the hippocampus, and we found that depletion of receptors without inducing cell loss results in ...
TY - JOUR. T1 - Transcriptional transactivation functions localized to the glucocorticoid receptor N terminus are necessary for steroid induction of lymphocyte apoptosis. AU - Dieken, E. S.. AU - Miesfeld, R. L.. PY - 1992/1/1. Y1 - 1992/1/1. N2 - Genetic studies have suggested that transcriptional regulation of specific target genes (by either induction or repression) is the molecular basis of glucocorticoid-mediated lymphocyte apoptosis. To examine the role of transcriptional regulation more directly, we developed a complementation assay utilizing stable transfection of wild-type (wt) and mutant (nt(i)) glucocorticoid receptor (GR) cDNA constructs into a GR-deficient S49 murine cell line (7r). Our data confirm that the level of functional GR is rate limiting for S49 apoptosis and moreover that the GR amino terminus (N terminus), which has been deleted from the nt(i) GR, is absolutely required for complementation in this system. Surprisingly, we found that at physiological levels of receptor, ...
TY - JOUR. T1 - Tissue- and context-dependent modulation of hormonal sensitivity of glucocorticoid-responsive genes by hexamethylene bisacetamide-inducible protein 1. AU - Shimizu, Noriaki. AU - Yoshikawa, Noritada. AU - Wada, Tadashi. AU - Handa, Hiroshi. AU - Sano, Motoaki. AU - Fukuda, Keiichi. AU - Suematsu, Makoto. AU - Sawai, Takashi. AU - Morimoto, Chikao. AU - Tanaka, Hirotoshi. PY - 2008/12/1. Y1 - 2008/12/1. N2 - Physiological and pharmacological processes mediated by glucocorticoids involve tissue- and context-specific regulation of glucocorticoid-responsive gene expression via glucocorticoid receptor (GR). However, the molecular mechanisms underlying such highly coordinated regulation of glucocorticoid actions remain to be studied. We here addressed this issue using atp1a1 and scnn1a, both of which are up-regulated in response to corticosteroids in human embryonic kidney-derived 293 cells, but resistant in liver-derived HepG2 cells. Hexamethylene bisacetamide-inducible protein 1 ...
Glucocorticoid receptor levels were quantitated in leukemic blasts from bone marrow aspirates of 174 children with acute lymphocytic leukemia. Using a whole-cell assay, we found that [3H]dexamethasone binding had the following characteristics: (a) reached a steady state in 30 min at 22° and was stable for at least 2 hr; (b) was linear with cell number between 1 and 6 × 106 cells/assay; (c) was higher in freshly prepared blasts compared to blasts stored for 18 hr at 4 or 22°; (d) was specific for glucocorticoids; (e) had a Kd of ≈1 × 10-8 m; and (f) required a postincubation washing step to maximize sensitivity and decrease nonspecific binding. Glucocorticoid receptor levels in patient samples exhibited a wide range from 2,248 to 79,364 sites/cell (median, 18,123). A lower level was correlated with the following biological and clinical characteristics at diagnosis: high leukocyte count; positive sheep erythrocyte rosette test; T-cell surface antigens; presence of mediastinal mass; age ,2 or ...
These data show that p38 MAPK inhibitors may have potential in reversing glucocorticoid insensitivity and reestablishing the beneficial effects of glucocorticoids in patients with severe asthma.
Glucocorticoids (GCs) are often prescribed for the treatment of inflammatory diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and psoriasis[1-3]. Despite their excellent efficacy, usage is limited because of side-effects such as insulin resistance, glucose intolerance, diabetes, central adiposity, dyslipidemia, skeletal muscle wasting and osteoporosis[4-8].. GCs bind to the glucocorticoid receptor (GR), which then dimerizes and translocates to the nucleus where it influences gene transcription. Positive regulation of genes (transactivation) is mainly mediated by direct binding of the GR-GC complex to glucocorticoid response elements located in the regulatory region of a target gene. The GR-GC complex may also bind to negative glucocorticoid response elements, which leads to a negative regulation of genes (transrepression). It is believed that transrepression, in which proinflammatory genes are downregulated, is mainly responsible for the efficacy of GCs as ...
Salt-sensitive hypertension is a major risk factor for cardiovascular morbidity. Humans and mice with glucocorticoid receptor haploinsufficiency (GR+/−) are hypertensive, which in mice reflects activation of the renin-angiotensin-aldosterone system. Furthermore, glucocorticoid receptor (GR) gene polymorphisms associate with increased cardiovascular disease risk. Here we investigated the effect of dietary salt intake on blood pressure, heart and kidney in GR+/− mice. Adult male GR+/− mice and wild-type (WT) littermates were fed a sodium-enriched (3%Na+) or standard chow diet (0.3%Na+) for one week, after which mice were anaesthetised for measurement of blood pressure and sodium excretion. Separate cohorts were killed by decapitation and kidneys and hearts taken for histology and mRNA quantification. Cardiac atrial natriuretic peptide (ANP) mRNA levels were elevated in GR+/− mice and were markedly augmented following sodium-enriched diet [Chow:WT 100±7%, GR+/−146±8%; Sodium:WT 157±7%, ...
Abstract: In presence of adenosine (10(-7)-10(-6) M) content of nuclear 3H-hydrocortisone-receptor complexes was increased in rat thymus lymphocytes, while amount of these complexes was decreased in cytosol of these cells. DEAE-cellulose chromatography of the 3H-hydrocortisone-receptor complexes demonstrated that adenosine 1.10(-6) M altered the ratio between active and non-active forms of the hormone-receptor complex. Adenosine appears to regulate transformation and translocation of the glucocorticoid-receptor complexes into the cell-target nuclei cAMP-dependent apparatus ...
In the current study, we investigated the importance of histone deacetylase (HDAC)6 for glucocorticoid receptor-mediated effects on glucose metabolism and its potential as a therapeutic target for the prevention of glucocorticoid-induced diabetes. Dexamethasone-induced hepatic glucose output and glucocorticoid receptor translocation were analyzed in wild-type (wt) and HDAC6-deficient (HDAC6KO) mice. The effect of the specific HDAC6 inhibitor tubacin was analyzed in vitro. wt and HDAC6KO mice were subjected to 3 weeks dexamethasone treatment before analysis of glucose and insulin tolerance. HDAC6KO mice showed impaired dexamethasone-induced hepatic glucocorticoid receptor translocation. Accordingly, dexamethasone-induced expression of a large number of hepatic genes was significantly attenuated in mice lacking HDAC6 and by tubacin in vitro. Glucose output of primary hepatocytes from HDAC6KO mice was diminished. A significant improvement of dexamethasone-induced whole-body glucose intolerance as ...
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
In vitro prednisolone resistance is a poor prognostic factor in the treatment of childhood acute lymphoblastic leukemia (ALL). In a cohort of 54 children with ALL, a lower expression of the glucocorticoid receptor (GR), but not the relative expression levels of the GR-alpha, GR-beta and GR-P isoforms, was associated with in vitro prednisolone resistance.. ...
TY - JOUR. T1 - Cell cycle regulation of membrane glucocorticoid receptor in ccrf-cem human all cells. T2 - Correlation to apoptosis. AU - Sackey, Faustina N A. AU - Watson, Cheryl S.. AU - Gametchu, Bahiru. PY - 1997/9. Y1 - 1997/9. N2 - The human leukemic cell line (CCRF-CEM) and a subline enriched for the plasma membrane-resident glucocorticoid receptor (mGR) were studied for the influence of the cell cycle on the expression and function of mGR. Three synchronization procedures (double thymidine, colcemid, and combined thymidine-colcemid blocks) were used. Fluorescent microscopy and flow cytometry simultaneously assessed antibody-tagged mGR and DNA. In addition, mGR was quantitated and characterized by immunoprecipitation and immunoblotting. Apoptosis was assayed by DNA fragmentation (TUNEL assay) and by cell survival (trypan blue exclusion). All synchronization procedures demonstrated that progression from DNA replication (S) to the second growth phase and mitosis (G2/M) leads to cells ...
Abstract. We determined the mol wt of glucocorticoid receptors in human leukemia cells in order to detect glucocorticoid receptor defects that might cause gluc
AgRP Neuron-Specific Deletion of Glucocorticoid Receptor Leads to Increased Energy Expenditure and Decreased Body Weight in Female Mice on a High-Fat DietAgRP Neuron-Specific Deletion of Glucocorticoid Receptor Leads to Increased Energy Expenditure and Decreased Body Weight in Female Mice on a High-Fat Diet ...
In this study, we compared the monocyte glucocorticoid sensitivity between middle aged men and women while controlling for known risk factors for cardiovascular disease. We used an in vitro assay to measure monocyte cytokine release in response to a standardised dose of lipopolysaccharide and to assess the extent to which this cytokine release was inhibited by increasing concentrations of two glucocorticoids.. The main finding of our study is that, even when controlling for well known cardiovascular risk factors, blood samples from men required larger quantities of either dexamethasone or hydrocortisone to inhibit lipopolysaccharide stimulated release of IL-6 and TNFα than did samples from women, while the cytokine release without glucocorticoid co-incubation was higher in samples from men than in those from women. The findings suggest higher proinflammatory activity in blood monocytes of men than in monocytes harvested from women. This notion becomes even stronger given that we controlled for ...
Synthetic glucocorticoids (GC) are the mainstay in the treatment of allergic and inflammatory diseases due to their potent anti-inflammatory effect. The anti-inflammatory action arises from a complex mechanism of action in which innate and adaptive immune functions are modulated through changes in gene expression for critical immune and proinflammatory genes such as TNF-α, GM-CSF, ILs, and chemokines (1). When used in the treatment of allergic airway diseases such as asthma and rhinitis, the effect of GC is deemed critical due to the efficacy in inhibiting the mucosal inflammation. This effect is chiefly driven by the inhibition of epithelial-derived cytokines and chemokines that support the recruitment and activation of eosinophils and other inflammatory cells (2).. The mechanism of GC-mediated gene regulation entails an integrated set of modifications spanning from early signaling events to posttranscriptional processes occurring in the cytoplasm, well after transcriptional changes have been ...
The availability of nutrients influences cellular growth and survival by affecting gene transcription. Glucocorticoids also influence gene transcription and have diverse activities on cell growth, energy expenditure, and survival. We found that the growth arrest-specific 5 (Gas5) noncoding RNA, which is abundant in cells whose growth has been arrested because of lack of nutrients or growth factors, sensitized cells to apoptosis by suppressing glucocorticoid-mediated induction of several responsive genes, including the one encoding cellular inhibitor of apoptosis 2. Gas5 bound to the DNA-binding domain of the glucocorticoid receptor (GR) by acting as a decoy glucocorticoid response element (GRE), thus competing with DNA GREs for binding to the GR. We conclude that Gas5 is a "riborepressor" of the GR, influencing cell survival and metabolic activities during starvation by modulating the transcriptional activity of the GR.. ...
Glucocorticoids have profound anti-inflammatory and immunosuppressive actions when used therapeutically. The therapeutic dose is very wide and depends on the indication for treatment, but can vary more than 200-fold. Clearly, different dosages and dosing regimens have distinct therapeutically relevant effects mediated by genomic and non-genomic actions. Genomic actions involve the binding to cytosolic glucocorticoid receptors, occur at any therapeutically relevant dosage, and are seen not earlier than 30 minutes after receptor binding. In contrast, non-genomic actions are mediated via biological membranes, and are seen at higher concentrations and within seconds or minutes (see below). However, the basis for the use of different dosages in different clinical conditions is essentially empirical as the evidence to support preferences in specific clinical settings is very scarce. This is aggravated by the discrepancy between the widespread use and the imprecise designation of glucocorticoid ...
FIG. 7. Ser404 phosphorylation decreases GR function. (A and B) GR-null U-2 OS cells or those expressing WT-, S404A-, or S404D-GR were transiently transfected with pRL-Renilla and the GRE-luc (A) or MHC-luc NF-κB (B) luciferase reporters. Cells were then treated with Dex (0 to 100 nM) as indicated. After 20 h, the cells were lysed and analyzed for luciferase activity, which was normalized to the Renilla activity. Plotted are the normalized percentages of GRE transactivation or NF-κB transrepression by Dex (*, P , 0.05). (C) WT-GR-expressing U-2 OS cells were treated with the GSK-3α/β inhibitor BIO (5 μM) and Dex (100 nM) for 20 h. Cells were then lysed, analyzed by Western blotting, and probed with antibodies directed to the NF-κB regulated prosurvival genes Bcl-xL, c-IAP, and survivin. The protein band intensities were quantitated from three independent experiments and normalized to actin. (D) WT-and S404D-GR-expressing U-2 OS cells were treated with Dex for 20 h (100 nM), lysed, analyzed ...
Studies on glucocorticoid receptor (GR) action typically assess gene responses by long-term stimulation with synthetic hormones. As corticosteroids are released from adrenal glands in a circadian and high-frequency (ultradian) mode, such treatments may not provide an accurate assessment of physiological hormone action. Here we demonstrate that ultradian hormone stimulation induces cyclic GR-mediated transcriptional regulation, or gene pulsing, both in cultured cells and in animal models. Equilibrium receptor-occupancy of regulatory elements precisely tracks the ligand pulses. Nascent RNA transcripts from GR-regulated genes are released in distinct quanta, demonstrating a profound difference between the transcriptional programs induced by ultradian and constant stimulation. Gene pulsing is driven by rapid GR exchange with response elements and by GR recycling through the chaperone machinery, which promotes GR activation and reactivation in response to the ultradian hormone release, thus coupling ...
5a-Reductase 1 (5aR1) metabolises steroids such as glucocorticoids and androgens and is highly expressed in the livers of mice. Genetic disruption of 5aR1 leads to adverse metabolic consequences in mice and pharmacological inhibition in humans induces peripheral insulin resistance. I hypothesised that these effects are due to increased hepatic glucocorticoid action and firstly set up an experimental paradigm using A-348441, a liver-selective glucocorticoid receptor antagonist, to assess the contribution of hepatic glucocorticoid action. A-348441 was then utilised to assess whether changes in hepatic glucocorticoid signalling underpinned metabolic changes in: 1) a genetic model where the gene for 5aR1 has been disrupted, and 2) a pharmacological model using dutasteride, a dual 5aR1, R2 inhibitor. Previous work with A-348441 has demonstrated it can lower blood glucose levels in ob/ob mice. However, monogenic models of obesity are not fully representative of idiopathic obesity, which is commonly ...
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A STEROID with GLUCOCORTICOID RECEPTOR activity that is used to manage the symptoms of ASTHMA; ALLERGIC RHINITIS, and ATOPIC DERMATITIS ...
Glucocorticoids, secreted by the adrenals in response to stress, profoundly affect structure and plasticity of neurons. Glucocorticoid action in neurons is mediated by glucocorticoid receptors (GR) that operate as transcription factors in the regulation of gene expression and either bind directly to genomic glucocorticoid response elements (GREs) or indirectly to the genome via interactions with bound transcription factors. These two modes of action, respectively called transactivation and transrepression, result in the regulation of a wide variety of genes important for neuronal function. The objective of the present study was to identify genome-wide glucocorticoid receptor binding sites in neuronal PC12 cells using Chromatin ImmunoPrecipitation combined with next generation sequencing (ChIP-Seq). In total we identified 1183 genomic binding sites of GR, the majority of which were novel and not identified in other ChIP-Seq studies on GR binding. More than half (58%) of the binding sites contained a GRE.
I dont have an answer, but do have a similar observation: when expressing two different genes that have obvious (positive) growth phenotypes, using heterologous promoters, the expression (i.e. phenotypes) is good on plates: poor growth without the inducer, good growth with the inducer. But the results are not the same when cells grown in liquid medium; the cells behave as though the expression is constitutively rather high. The promoters are CUP1 and the rat glucocorticoid receptor (constitutively expressed from the GPD promoter)/GRE/deoxycortisone system of Keith Yamamoto. Why the difference? Thanks, Arle ...
in liver extrahepatic : outside the liver Mobilize amino acids from extrahepatic tissues: These serve as substrates for gluconeogenesis. main adipose tissue Stimulation of fat breakdown how it signals with the targets: steroid hormone Primary function: stimulate tissues to raise blood glucose and break down protein the secreted glucocorticoids from the zona fasciculata, then travels through the circulatory system these glucocorticoids then attach themselves to the glucocorticoid receptors which are found on almost every cell a glucocorticoid receptor binds to glucocorticoids within the bloodstream, which allows the GCs to enter into the intercellular fluid of a cell the receptors are then transferred to the nucleus, where they perform specific functions depending on which glucocorticoid receptor was activated and which hormone was present superpowers surpress overactive immune system GCs travel through the blood until it reaches the inflammated area and then starts to break down the overactive ...
In an unbiased gene expression and chemical genomics screen, PDE4B was found as one of the highest expressed genes in glucocorticoid-resistant acute lymphoid leukemia (ALL).37 Furthermore, PDE4B variants were associated with a higher rate of relapse in childhood ALL.38 Corroborating these observations, genes associated with glucocorticoid resistance in ALL were enriched in DLBCLs that express high levels of PDE4B,8 whereas PDE4 inhibitors restored glucocorticoid sensitivity and reduced tumor burden in in vivo preclinical models of human lymphoma.8 In these studies, the effects of PDE4 on glucocorticoid sensitivity were associated with modulation of PI3K/AKT signals.8 These data informed the design of a first-in-cancer clinical trial of the PDE4 inhibitor roflumilast (FDA-approved for severe chronic obstructive pulmonary disease). In this single-arm, pharmacokinetics and pharmacodynamics phase Ib study (clinicaltrials.gov identifier NCT01888952), the combination of roflumilast with prednisone was ...
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.