Journal articles on the topic 'Glucocorticoids'
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1
Crowson, L., J. M. Davis, A. Hanson, E. Myasoedova, V. Kronzer, A. Makol, L. Peterson, D. Bekele, and C. S. Crowson. "POS0309 TIME TRENDS IN GLUCOCORTICOID USE IN RHEUMATOID ARTHRITIS DURING THE BIOLOGICS ERA: 1999-2018." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 398–99. http://dx.doi.org/10.1136/annrheumdis-2023-eular.2025.
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BackgroundClinical guidelines recommend minimizing glucocorticoid use among patients with rheumatoid arthritis (RA) and many new therapeutic options in recent decades offer alternatives to glucocorticoids, but it is unknown whether glucocorticoid use has declined in patients with RA.ObjectivesTo examine time trends in glucocorticoid use among patients diagnosed with rheumatoid arthritis (RA) during the biologic era.MethodsA population-based inception cohort of RA patients diagnosed during 1999 - 2018 was followed longitudinally through their medical records until death, migration or 12/31/2020. All patients fulfilled 1987 and/or 2010 American College of Rheumatology classification criteria for RA. Glucocorticoid start and stop dates were collected along with dosages in prednisone equivalents. The cumulative incidence of glucocorticoid initiation and discontinuation adjusted for the competing risk of death was estimated. Cox models adjusted for age and sex were used to compare trends between time periods.ResultsThe study population was comprised of 399 patients (71% females) diagnosed in 1999 – 2008 and 430 patients (67% females) diagnosed in 2009 – 2018. Glucocorticoid use was initiated within 6 months of meeting RA criteria in 66.7% of patients in 1999-2008 and 70.9% of patients in 2009-2018, corresponding to a 29% increase in hazard for initiation of glucocorticoids in 2009-2018 (adjusted hazard ratio [HR]: 1.29; 95% confidence interval[CI]: 1.09-1.53). Among glucocorticoid users, similar rates of glucocorticoid discontinuation within 6 months after glucocorticoid initiation were observed in patients with RA incidence in 1999 – 2008 and 2009 – 2018 (39.1% versus 42.9%, respectively), with no significant association in adjusted Cox models (HR: 1.11; 95% CI: 0.93-1.31). Even in the 2009-2018 cohort, a large proportion of patients with RA (52%) remained on glucocorticoids beyond 3 months, and 30% were still on glucocorticoids after 2 years.Older patients with RA were more likely to initiate glucocorticoids (HR 1.06 per 10 year increase in age, 95% CI 1.00-1.13) and less likely to discontinue glucocorticoids (HR 0.91 per 10 year increase in age, 95% CI 0.86-0.96). There was no difference in the initiation of glucocorticoids by sex. Although females had a higher discontinuation rate within the first 12 months, afterwards discontinuation rates of glucocorticoids were similar in females and males. Smokers were less likely to discontinue glucocorticoids compared to non-smokers (HR 0.65; 95% CI: 0.51-0.82).ConclusionMore patients are initiating glucocorticoids early in their disease course now compared to previously despite the availability of biologics and other disease modifying antirheumatic drugs. The rates of glucocorticoid discontinuation are similar. A substantial proportion of patients remain on glucocorticoids for more than 3 months with a large proportion continuing use of glucocorticoidss even beyond 2 years. Real world use of glucocorticoids in patients with RA is not optimal or improving despite advances in RA therapy.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsLisa Crowson: None declared, John M Davis III Grant/research support from: Pfizer, Andrew Hanson: None declared, Elena Myasoedova: None declared, Vanessa Kronzer: None declared, Ashima Makol Consultant of: Boehringer Ingelheim, Lynne Peterson: None declared, Delamo Bekele: None declared, Cynthia S. Crowson: None declared.
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Washburn, Brian E., Joshua J. Millspaugh, John H. Schulz, Susan B. Jones, and Tony Mong. "Using Fecal Glucocorticoids for Stress Assessment in Mourning Doves." Condor 105, no. 4 (November 1, 2003): 696–706. http://dx.doi.org/10.1093/condor/105.4.696.
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Abstract Fecal glucocorticoid assays provide a potentially useful, noninvasive means to study physiological responses of wildlife to various stressors. The objective of our study was to validate a method for measuring glucocorticoid metabolites in Mourning Dove (Zenaida macroura) feces. We validated the assay using standard procedures (e.g., parallelism, recovery of exogenous corticosterone) to demonstrate that the assay accurately and precisely measured glucocorticoid metabolites in Mourning Dove fecal extracts. We conducted adrenocorticotropin (ACTH) challenge experiments to validate the assay's ability to determine biologically important changes in fecal glucocorticoids. Fecal glucocorticoid levels increased significantly approximately 2–3 hr after administration of ACTH at 50 IU per kg body mass to wild Mourning Doves held in captivity. In contrast, fecal glucocorticoid metabolites did not increase in control birds, birds that received saline injections, or a lower dose of ACTH (1 IU per kg body mass). Variation in overall fecal glucocorticoid metabolite levels may have been influenced by season and the length of time birds were held in captivity. Noninvasive fecal glucocorticoid metabolite analyses, in combination with demographic information, may have considerable utility for monitoring the effects of natural and anthropogenic disturbances on Mourning Dove populations. Uso de Glucocorticoides Fecales Para Evaluar el Estrés en Zenaida macroura Resumen. Las evaluaciones de glucocorticoides fecales representan un medio no invasor potencialmente útil para estudiar las respuestas fisiológicas de los animales silvestres ante agentes causantes de estrés. El objetivo de nuestro estudio fue validar un método para medir metabolitos glucocorticoides en heces de palomas Zenaida macroura. Validamos el método mediante procedimientos estándar (e.g., paralelismo, recuperación de corticosterona exógena) para demostrar que éste mide con exactitud y precisión los metabolitos glucocorticoides en extractos fecales de Z. macroura. Realizamos experimentos de desafío con adrenocorticotropina (ACTH) para validar la habilidad que tenía el método para determinar cambios biológicamente importantes en los glucocorticoides fecales. Los niveles de glucocorticoides fecales aumentaron de forma significativa aproximadamente 2–3 hr después de la administración de ACTH a 50 IU por kg de peso corporal a palomas silvestres mantenidas en cautiverio. En contraste, los metabolitos glucocorticoides fecales no aumentaron en aves control, ni en aves que recibieron inyecciones salinas o una menor dosis de ACTH (1 IU por kg de peso corporal). La variación en los niveles generales de metabolitos glucocorticoides fecales podría haber sido influenciada por la estación y la longitud del período de tiempo en que las aves fueron mantenidas en cautiverio. Los análisis no invasores de metabolitos glucocorticoides, en combinación con información demográfica, podrían ser de considerable utilidad para monitorear los efectos de los disturbios naturales y antropogénicos sobre las poblaciones de Z. macroura.
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Kajita, S., H. Iizuka, M. Hirokawa, M. Tsutsui, and T. Mizumoto. "Topical application of potent glucocorticoids augments epidermal beta-adrenergic adenylate cyclase response in vivo." Acta Dermato-Venereologica 66, no. 6 (November 1, 1986): 491–96. http://dx.doi.org/10.2340/0001555566491496.
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The effects of topical application of glucocorticoids on the epidermal beta-adrenergic adenylate cyclase response were investigated. A significant increase in this receptor response was observed 24 h following topical application of potent glucocorticoid ointments (0.12% betamethasone-17-valerate, 0.05% clobetasol-17-propionate). The application of a relatively weak glucocorticoid, hydrocortisone-17-butyrate, revealed no augmentation effect. There was no significant difference in other adenylate cyclase responses (adenosine-, and histamine-) between control and glucocorticoid-treated epidermis. UVB irradiation is known to augment the beta-adrenergic response of epidermis. Comparison of the effects revealed that topical glucocorticoid treatment had less effect than UVB irradiation, and when the UVB irradiation was combined with glucocorticoid treatment, the beta-adrenergic augmentation effect was not enhanced. Cyclic AMP phosphodiesterase activities were not significantly altered by the glucocorticoid-, UVB-, or combined treatments. Our data indicate that epidermal beta-adrenergic adenylate cyclase response is affected by topical application of ´potent´ glucocorticoids in vivo. Although the effect is weaker than that induced by UVB irradiation, we believe the system might be a useful tool for dissecting the glucocorticoidal potency of topical preparations using the epidermal keratinocyte response in vivo.
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Roberts, Jessica K., Chad D. Moore, Erin G. Romero, Robert M. Ward, Garold S. Yost, and Christopher A. Reilly. "Regulation of CYP3A genes by glucocorticoids in human lung cells." F1000Research 2 (August 13, 2013): 173. http://dx.doi.org/10.12688/f1000research.2-173.v1.
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Inhaled glucocorticoids are the first-line treatment for patients with persistent asthma. However, approximately thirty percent of patients exhibit glucocorticoid insensitivity, which may involve excess metabolic clearance of the glucocorticoids by CYP3A enzymes in the lung. CYP3A4, 3A5, and 3A7 enzymes metabolize glucocorticoids, which in turn induce CYP3A genes. However, the mechanism of CYP3A5 mRNA regulation by glucocorticoids in lung cells has not been determined. In hepatocytes, glucocorticoids bind to the glucocorticoid receptor (GR), which induces the expression of the constitutive androstane receptor or pregnane X receptor; both of which bind to the retinoid X receptor alpha, leading to the induction of CYP3A4, 3A5, and 3A7. There is also evidence to suggest a direct induction of CYP3A5 by GR activation in liver cells. In this study, these pathways were evaluated as the mechanism for CYP3A5 mRNA induction by glucocorticoids in freshly isolated primary tracheal epithelial, adenocarcinomic human alveolar basal epithelial (A549), immortalized bronchial epithelial (BEAS-2B), primary normal human bronchial/tracheal epithelial (NHBE), primary small airway epithelial (SAEC), and primary lobar epithelial lung cells. In A549 cells, beclomethasone 17-monopropionate ([M1]) induced CYP3A5 mRNA through the glucocorticoid receptor. CYP3A5 mRNA induction by five different glucocorticoids was attenuated by inhibiting the glucocorticoid receptor using ketoconazole, and for beclomethasone dipropionate, using siRNA-mediated knock-down of the glucocorticoid receptor. The constitutive androstane receptor was not expressed in lung cells. SAEC cells, a primary lung cell line, expressed CYP3A5, but CYP3A5 mRNA was not induced by glucocorticoid treatment despite evaluating a multitude of cell culture conditions. None of the other lung cells expressed CYP3A4, 3A5 or 3A7 mRNA. These studies demonstrate that CYP3A5 mRNA is induced by glucocorticoids in A549 cells via the glucocorticoid receptor, but that additional undefined regulatory processes exist in primary lung cells.
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Roberts, Jessica K., Chad D. Moore, Erin G. Romero, Robert M. Ward, Garold S. Yost, and Christopher A. Reilly. "Regulation of CYP3A genes by glucocorticoids in human lung cells." F1000Research 2 (October 8, 2013): 173. http://dx.doi.org/10.12688/f1000research.2-173.v2.
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Inhaled glucocorticoids are the first-line treatment for patients with persistent asthma. However, approximately thirty percent of patients exhibit glucocorticoid insensitivity, which may involve excess metabolic clearance of the glucocorticoids by CYP3A enzymes in the lung. CYP3A4, 3A5, and 3A7 enzymes metabolize glucocorticoids, which in turn induce CYP3A genes. However, the mechanism of CYP3A5 mRNA regulation by glucocorticoids in lung cells has not been determined. In hepatocytes, glucocorticoids bind to the glucocorticoid receptor (GR), which induces the expression of the constitutive androstane receptor or pregnane X receptor; both of which bind to the retinoid X receptor alpha, leading to the induction of CYP3A4, 3A5, and 3A7. There is also evidence to suggest a direct induction of CYP3A5 by GR activation in liver cells. In this study, these pathways were evaluated as the mechanism for CYP3A5 mRNA induction by glucocorticoids in freshly isolated primary tracheal epithelial, adenocarcinomic human alveolar basal epithelial (A549), immortalized bronchial epithelial (BEAS-2B), primary normal human bronchial/tracheal epithelial (NHBE), primary small airway epithelial (SAEC), and primary lobar epithelial lung cells. In A549 cells, beclomethasone 17-monopropionate ([M1]) induced CYP3A5 mRNA through the glucocorticoid receptor. CYP3A5 mRNA induction by five different glucocorticoids was attenuated by inhibiting the glucocorticoid receptor using ketoconazole, and for beclomethasone dipropionate, using siRNA-mediated knock-down of the glucocorticoid receptor. The constitutive androstane receptor was not expressed in lung cells. SAEC cells, a primary lung cell line, expressed CYP3A5, but CYP3A5 mRNA was not induced by glucocorticoid treatment despite evaluating a multitude of cell culture conditions. None of the other lung cells expressed CYP3A4, 3A5 or 3A7 mRNA. These studies demonstrate that CYP3A5 mRNA is induced by glucocorticoids in A549 cells via the glucocorticoid receptor, but that additional undefined regulatory processes exist in primary lung cells.
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Muhammad, Salam Abed. "Hydrocortisone as Antiallergic Drug." Journal for Research in Applied Sciences and Biotechnology 3, no. 1 (March 27, 2024): 305–14. http://dx.doi.org/10.55544/jrasb.3.1.50.
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Glucocorticoids are widely used for the suppression of inflammation in chronic inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases, all of which are associated with increased expression of inflammatory genes. The molecular mechanisms involved in this anti-inflammatory action of glucocorticoids is discussed, particularly in asthma, which accounts for the highest clinical use of these agents.
Glucocorticoids bind to glucocorticoid receptors in the cytoplasm which then dimerize and translocate to the nucleus, where they bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, resulting in increased transcription. Glucocorticoids may increase the transcription of genes coding for anti-inflammatory proteins, including lipocortin-1, interleukin-10, interleukin-1 receptor antagonist and neutral endopeptidase, but this is unlikely to account for all of the widespread anti-inflammatory actions of glucocorticoids.[3]
The most striking effect of glucocorticoids is to inhibit the expression of multiple inflammatory genes.[3]
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CROXTALL, Jamie D., Mark PAUL-CLARK, and Peter Th W. van HAL. "Differential modulation of glucocorticoid action by FK506 in A549 cells." Biochemical Journal 376, no. 1 (November 15, 2003): 285–90. http://dx.doi.org/10.1042/bj20030821.
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Glucocorticoids inhibit the release of eicosanoid pro-inflammatory mediators. The immunosuppressant FK506 is known to enhance many aspects of glucocorticoid action. In the present study we show that FK506 (1 μM or 10 μM) inhibits the release of arachidonic acid and prostaglandin E2 from A549 cells and also inhibits their proliferation. Simultaneous treatment of FK506 together with the glucocorticoids dexamethasone, methyl-prednisolone, fluticasone or mometasone (10 nM) enhances the growth inhibitory effect of these steroids. Furthermore, the simultaneous use of FK506 and these glucocorticoids similarly results in enhanced inhibition of arachidonic acid release. When pretreated for 2 h, FK506 enhances glucocorticoid inhibition of COX2 (cyclo-oxygenase 2) expression. However, when administered simultaneously, FK506 blocks glucocorticoid inhibition of COX2 expression. Nuclear uptake of glucocorticoid receptors mediated by glucocorticoids is also blocked by the simultaneous administration of FK506. These results suggest that the effect of simultaneous treatment of FK506 with glucocorticoids differs significantly from that where pre-treatment of the immunosuppressant is used. Recently, immunophilin interchange has been identified as a first step in glucocorticoid receptor activation following ligand activation. We show here that the FKB51 (FK506-binding protein 51)–FKB52 switch is differentially regulated by glucocorticoid and FK506 treatment strategy.
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Walker, Brian R. "Glucocorticoids and Cardiovascular Disease." European Journal of Endocrinology 157, no. 5 (November 2007): 545–59. http://dx.doi.org/10.1530/eje-07-0455.
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AbstractChronic excessive activation of glucocorticoid receptors induces obesity, insulin resistance, glucose intolerance, dyslipidaemia and hypertension. Subtle abnormalities of the hypothalamic–pituitary–adrenal axis and/or of tissue sensitivity to glucocorticoids are also associated with these cardiovascular risk factors in patients with the metabolic syndrome. Furthermore, glucocorticoids have direct effects on the heart and blood vessels, mediated by both glucocorticoid and mineralocorticoid receptors and modified by local metabolism of glucocorticoids by the 11β-hydroxysteroid dehydrogenase enzymes. These effects influence vascular function, atherogenesis and vascular remodelling following intra-vascular injury or ischaemia. This article reviews the systemic and cardiovascular effects of glucocorticoids, and the evidence that glucocorticoids not only promote the incidence and progression of atherogenesis but also modify the recovery from occlusive vascular events and intravascular injury. The conclusion is that manipulation of glucocorticoid action within metabolic and cardiovascular tissues may provide novel therapeutic avenues to combat cardiovascular disease.
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Macfarlane, David P., Shareen Forbes, and Brian R. Walker. "Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome." Journal of Endocrinology 197, no. 2 (February 28, 2008): 189–204. http://dx.doi.org/10.1677/joe-08-0054.
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Glucocorticoid hormones constitute an integral component of the response to stress, and many of the manifestations of glucocorticoid excess (Cushing's syndrome) are predictable on the basis of their acute effects to raise blood pressure, induce insulin resistance, increase protein catabolism and elevate plasma glucose. However, it appears to be a paradox that the acute lipolytic effect of glucocorticoids is not manifest in long-term weight loss in humans. The effects of glucocorticoids on glucose metabolism are well characterised, involving impaired peripheral glucose uptake and hepatic insulin resistance, and there is mounting evidence that subtle abnormalities in glucocorticoid concentrations in the plasma and/or in tissue sensitivity to glucocorticoids are important in metabolic syndrome. The effects of glucocorticoids on fatty acid metabolism are less well understood than their influence on glucose metabolism. In this article, we review the literature describing the effects of glucocorticoids on fatty acid metabolism, with particular reference to in vivo human studies. We consider the implications for contrasting acute versus chronic effects of glucocorticoids on fat accumulation, effects in different adipose depots and the potential role of glucocorticoid signalling in the pathogenesis and therapy of metabolic syndrome.
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Ponticelli, Claudio, and Francesco Locatelli. "Glucocorticoids in the Treatment of Glomerular Diseases." Clinical Journal of the American Society of Nephrology 13, no. 5 (February 23, 2018): 815–22. http://dx.doi.org/10.2215/cjn.12991117.
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Glucocorticoids exert anti-inflammatory and immunosuppressive activities by genomic and nongenomic effects. The classic genomic effects are mediated by cytosolic glucocorticoid receptors that can upregulate the expression of anti-inflammatory proteins in the nucleus (transactivation) or repress the translocation of proinflammatory transcription factors from the cytosol into the nucleus (transrepression). The nongenomic effects are probably mediated by membrane glucocorticoid receptors. Glucocorticoid receptors are expressed also in podocytes and experimental data suggest that glucocorticoids may protect from podocyte injury. Glucocorticoids have a low therapeutic index and may exert a number of time-dependent and dose-dependent side effects. Measures to prevent or attenuate side effects include single-morning administration of short-acting glucocorticoids, dietetic counseling, increasing physical activity, frequent monitoring, and adapting the doses to the clinical conditions of the patient. Synthetic glucocorticoids, either given alone or in combination with other immunosuppressive drugs, are still the cornerstone therapy in multiple glomerular disorders. However, glucocorticoids are of little benefit in C3 glomerulopathy and may be potentially deleterious in patients with maladaptive focal glomerulosclerosis. Their efficacy depends not only on the type and severity of glomerular disease, but also on the timeliness of administration, the dosage, and the duration of treatment. Whereas an excessive use of glucocorticoids can be responsible for severe toxicity, too low a dosage and too short duration of glucocorticoid treatment can result in false steroid resistance.
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Hughes, David, Nicole Vlahovich, Marijke Welvaert, Nicolin Tee, Peter Harcourt, Susan White, Alan Vernec, Ken Fitch, and Gordon Waddington. "Glucocorticoid prescribing habits of sports medicine physicians working in high-performance sport: a 30-nation survey." British Journal of Sports Medicine 54, no. 7 (February 5, 2020): 402–7. http://dx.doi.org/10.1136/bjsports-2019-101175.
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ObjectivesGlucocorticoids are commonly prescribed in medicine. When administered via certain routes, glucocorticoids are prohibited for incompetition use by WADA. The glucocorticoid prescribing habits of sports medicine doctors have not been reported.MethodsAn online survey was distributed internationally to physicians working in high-performance sports. The survey queried the doctors about their use of glucocorticoids with athletes and their understanding of WADA’s regulations regarding glucocorticoid use in competition.Results603 sports medicine doctors from 30 different countries participated. The majority (>85%) routinely injected glucocorticoids and/or prescribed glucocorticoids by other routes. There were substantial differences in the common routes of injection as well as types of glucocorticoid used among the physicians from various countries. A relatively small percentage of sports doctors (<25%) accurately identified which routes of glucocorticoid administration are prohibited in competition by WADA. There was a great variation in how long before competition the use of glucocorticoids would cause the doctor to consider applying for a therapeutic use exemption (TUE). A better understanding of the clearance rates of glucocorticoids from athletes’ bodies would greatly aid sports medicine doctors’ decisions on how and when to apply for a TUE. A small number of doctors had observed side effects of glucocorticoid administration, with the majority of side effects being minor in nature.ConclusionGlucocorticoids are widely prescribed by sports physicians. There is a need to better educate sports physicians on the current WADA regulations in relation to glucocorticoid administration.
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Carter, Bradley S., Fan Meng, and Robert C. Thompson. "Glucocorticoid treatment of astrocytes results in temporally dynamic transcriptome regulation and astrocyte-enriched mRNA changes in vitro." Physiological Genomics 44, no. 24 (December 15, 2012): 1188–200. http://dx.doi.org/10.1152/physiolgenomics.00097.2012.
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While general effects of glucocorticoids are well established, the specific cellular mechanisms by which these hormones exert tissue-dependent effects continue to be elaborated. Diseases that demonstrate altered glucocorticoid signaling have been associated with alterations in astrocytes, yet relatively little is known about the effects of glucocorticoids upon this cell type. We have analyzed mRNA expression patterns following glucocorticoid treatment of mouse primary astrocyte cultures. Microarray analysis of cortical astrocyte cultures treated with dexamethasone over an eight-point, 24 h time course identified 854 unique genes with ≥twofold change in mRNA expression at one or more time points. Clustering analysis associated subsets of these mRNA expression changes with gene ontology categories known to be impacted by glucocorticoids. Numerous mRNAs regulated by dexamethasone were also regulated by the natural ligand corticosterone; all of the mRNAs regulated ≥twofold by corticosterone were substantially attenuated by cotreatment with the glucocorticoid receptor antagonist RU486. Of the mRNAs demonstrating ≥twofold expression change in response to both glucocorticoids, 33 mRNAs were previously associated with glucocorticoid regulation, and 36 mRNAs were novel glucocorticoid targets. All genes tested by qPCR for glucocorticoid regulation in cortical astrocyte cultures were also regulated by glucocorticoids in hippocampal astrocyte cultures (18/18). Interestingly, a portion of glucocorticoid-regulated genes were astrocyte enriched; the percentage of astrocyte-enriched genes per total number of regulated genes was highest for the early time points and steadily decreased over the time course. These findings suggest that astrocytes in vitro may initially deploy cell type-specific patterns of mRNA regulatory responses to glucocorticoids and subsequently activate additional cell type-independent responses.
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Lapp, Hannah E., Andrew A. Bartlett, and Richard G. Hunter. "Stress and glucocorticoid receptor regulation of mitochondrial gene expression." Journal of Molecular Endocrinology 62, no. 2 (February 2019): R121—R128. http://dx.doi.org/10.1530/jme-18-0152.
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Glucocorticoids have long been recognized for their role in regulating the availability of energetic resources, particularly during stress. Furthermore, bidirectional connections between glucocorticoids and the physiology and function of mitochondria have been discovered over the years. However, the precise mechanisms by which glucocorticoids act on mitochondria have only recently been explored. Glucocorticoids appear to regulate mitochondrial transcription via activation of glucocorticoid receptors (GRs) with elevated circulating glucocorticoid levels following stress. While several mechanistic questions remain, GR and other nuclear transcription factors appear to have the capacity to substantially alter mitochondrial transcript abundance. The regulation of mitochondrial transcripts by stress and glucocorticoids will likely prove functionally relevant in many stress-sensitive tissues including the brain.
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Song, Rui, Xiang-Qun Hu, and Lubo Zhang. "Glucocorticoids and programming of the microenvironment in heart." Journal of Endocrinology 242, no. 1 (July 2019): T121—T133. http://dx.doi.org/10.1530/joe-18-0672.
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Glucocorticoids are primary stress hormones and can improve neonatal survival when given to pregnant women threatened by preterm birth or to preterm infants. It has become increasingly apparent that glucocorticoids, primarily by interacting with glucocorticoid receptors, play a critical role in late gestational cardiac maturation. Altered glucocorticoid actions contribute to the development and progression of heart disease. The knowledge gained from studies in the mature heart or cardiac damage is insufficient but a necessary starting point for understanding cardiac programming including programming of the cardiac microenvironment by glucocorticoids in the fetal heart. This review aims to highlight the potential roles of glucocorticoids in programming of the cardiac microenvironment, especially the supporting cells including endothelial cells, immune cells and fibroblasts. The molecular mechanisms by which glucocorticoids regulate the various cellular and extracellular components and the clinical relevance of glucocorticoid functions in the heart are also discussed.
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Jia, D., C. A. O’Brien, S. A. Stewart, S. C. Manolagas, and R. S. Weinstein. "Glucocorticoids Act Directly on Osteoclasts to Increase Their Life Span and Reduce Bone Density." Endocrinology 147, no. 12 (December 1, 2006): 5592–99. http://dx.doi.org/10.1210/en.2006-0459.
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Glucocorticoid administration to mice results in a rapid loss of bone mineral density due to an imbalance in osteoblast and osteoclast numbers. Whereas excess glucocorticoids reduce both osteoblast and osteoclast precursors, cancellous osteoclast number surprisingly does not decrease as does osteoblast number, presumably due to the ability of glucocorticoids to promote osteoclast life span. Whether glucocorticoids act directly on osteoclasts in vivo to promote their life span and whether this contributes to the rapid loss of bone with glucocorticoid excess remains unknown. To determine the direct effects of glucocorticoids on osteoclasts in vivo, we expressed 11β-hydroxysteroid dehydrogenase type 2, an enzyme that inactivates glucocorticoids, specifically in the osteoclasts of transgenic mice using the tartrate-resistant acid phosphatase promoter. Bone mass, geometry, and histomorphometry were similar in untreated wild-type and transgenic animals. Glucocorticoid administration for 7 d caused equivalent increases in cancellous osteoblast apoptosis, and equivalent decreases in osteoblasts, osteoid, and bone formation, in wild-type and transgenic mice. In contrast, glucocorticoids stimulated expression of the mRNA for calcitonin receptor, an osteoclast product, in wild-type but not transgenic mice. Consistent with the previous finding that glucocorticoids decrease osteoclast precursors and prolong osteoclast life span, glucocorticoids decreased cancellous osteoclast number in the transgenic mice but not wild-type mice. In accord with this decrease in osteoclast number, the loss of bone density observed in wild-type mice was strikingly prevented in transgenic mice. These results demonstrate for the first time that the early, rapid loss of bone caused by glucocorticoid excess results from direct actions on osteoclasts.
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Deroo, Bonnie J., and Trevor K. Archer. "Glucocorticoid Receptor Activation of the IκBα Promoter within Chromatin." Molecular Biology of the Cell 12, no. 11 (November 2001): 3365–74. http://dx.doi.org/10.1091/mbc.12.11.3365.
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The glucocorticoid receptor (GR) is a ligand-activated transcription factor that induces expression of many genes. The GR has been useful for understanding how chromatin structure regulates steroid-induced transcription in model systems. However, the effect of glucocorticoids on chromatin structure has been examined on few endogenous mammalian promoters. We investigated the effect of glucocorticoids on the in vivo chromatin structure of the glucocorticoid-responsive IκBα gene promoter, the inhibitor of the ubiquitous transcription factor, nuclear factor kappa B (NFκB). Glucocorticoids inhibit NFκB activity in some tissues by elevating the levels of IκBα. We found that glucocorticoids activated the IκBα promoter in human T47D/A1-2 cells containing the GR. We then investigated the chromatin structure of the IκBα promoter in the absence and presence of glucocorticoids with the use of micrococcal nuclease, restriction enzyme, and deoxyribonuclease (DNaseI) analyses. In untreated cells, the promoter assembles into regularly positioned nucleosomes, and glucocorticoid treatment did not alter nucleosomal position. Restriction enzyme accessiblity studies indicated that the IκBα promoter is assembled as phased nucleosomes that adopt an “open” chromatin architecture in the absence of hormone. However, glucocorticoids may be required for transcription factor binding, because DNaseI footprinting studies suggested that regulatory factors bind to the promoter upon glucocorticoid treatment.
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Mann, Cynthia L., and John A. Cidlowski. "Glucocorticoids Regulate Plasma Membrane Potential During Rat Thymocyte Apoptosis in Vivo and in Vitro." Endocrinology 142, no. 1 (January 1, 2001): 421–29. http://dx.doi.org/10.1210/endo.142.1.7904.
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Abstract Glucocorticoids induce a series of profound biochemical changes in thymocytes that initiate apoptosis; however, the pathways beyond receptor transactivation that lead to this form of cell death are not fully understood. In this study, we report a novel site of action for glucocorticoids at the site of the plasma membrane. Specifically, we find that glucocorticoids induce the loss of plasma membrane potential both in vivo and in vitro. The glucocorticoid-induced loss of plasma membrane potential in cultured primary isolated rat thymocytes was both dose and time dependent. Other steroid hormones, including progesterone, estrogen, and testosterone, fail to alter the depolarization state of the thymocyte plasma membrane. Interestingly, other nonsteroid stimuli that also activate apoptosis in thymocytes also lead to cellular depolarization. In contrast, HeLa cells, which contain functional glucocorticoid receptors but do not die in response to hormone, do not alter their plasma membrane potential in response to glucocorticoids, indicating a strong association between depolarization and apoptosis. Furthermore, the ability of glucocorticoids to depolarize the plasma membrane of thymocytes required the interaction of glucocorticoids with their cognate receptor, because RU486 failed to depolarize thymocytes and antagonized the effect of glucocorticoids. Finally, experiments using inhibitors of transcription and translation indicated that the loss of plasma membrane potential in thymocytes following glucocorticoid treatment required de novo gene expression. The results of these studies establish that the loss of plasma membrane potential is an early important feature of glucocorticoid-induced apoptosis of thymocytes.
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Koenen, Paola, Katarzyna Barczyk, Marc Wolf, Johannes Roth, and Dorothee Viemann. "Endothelial cells present an innate resistance to glucocorticoid treatment: implications for therapy of primary vasculitis." Annals of the Rheumatic Diseases 71, no. 5 (December 27, 2011): 729–36. http://dx.doi.org/10.1136/annrheumdis-2011-200530.
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BackgroundIn contrast to other chronic inflammatory diseases glucocorticoids alone do not maintain sufficient remission in primary vasculitis. The reasons for this therapeutic failure remain unclear.ObjectivesTo investigate the molecular effects glucocorticoids exert on endothelial cells (EC) and to elucidate the molecular pathways responsible.MethodsA comparative approach was used to treat human micro and macrovascular EC as well as monocytes long and short term with glucocorticoids or glucocorticoids and tumour necrosis factor alpha (TNFα). Gene expression changes were analysed applying microarray technology, sophisticated bioinformatic work-up and quantitative reverse transcription PCR. Glucocorticoid receptor translocation processes were traced by cell fractionation assays and immunofluorescence microscopy.ResultsIn EC glucocorticoids completely failed to inhibit the expression of immune response genes both after sole glucocorticoid exposure and glucocorticoid treatment of a TNFα-induced proinflammatory response. In contrast, an impressive downregulation of proinflammatory genes was seen in monocytes. The study demonstrated that the glucocorticoid receptor is comparably expressed in EC and monocytes, and demonstrated good translocation of ligand-bound glucocorticoid receptor allowing genomic glucocorticoid actions. Refined gene expression analysis showed that in EC transactivation takes place and causes glucocorticoid side effects on growth and metabolism whereas transrepression-mediated anti-inflammatory effects as in monocytes are missing. Insufficient induction of SAP30, an important constituent of the Sin3A-histone deacetylase complex, in EC suggests impairment of transrepression due to co-repressor absence.ConclusionsThe impressive unresponsiveness of EC to anti-inflammatory glucocorticoid effects is associated with deficiencies downstream of glucocorticoid receptor translocation not affecting transactivation but transrepression. The findings provide the first molecular clues to the poor benefit of glucocorticoid treatment in patients with primary vasculitis.
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Molitoris, Jason K., Karen S. McColl, and Clark W. Distelhorst. "Glucocorticoid-Mediated Repression of the Oncogenic microRNA Cluster miR-17∼92 Contributes to the Induction of Bim and Initiation of Apoptosis." Molecular Endocrinology 25, no. 3 (March 1, 2011): 409–20. http://dx.doi.org/10.1210/me.2010-0402.
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Abstract Synthetic glucocorticoids were one of the first effective treatments for lymphoid malignancies because of their ability to induce apoptosis and are still used in combination with other chemotherapeutic agents. Up-regulation of Bim, a proapoptotic member of the B-cell lymphoma-2 family, is an important mediator of glucocorticoid-induced apoptosis. Although glucocorticoids are known to elevate Bim mRNA and protein, little is known about the mechanism. Here, we report that glucocorticoids repress the expression of the microRNA cluster miR-17∼92, which results in elevated Bim protein expression as a mechanism by which glucocorticoids induce Bim. Using a luciferase-Bim 3′ untranslated region construct, we demonstrate that glucocorticoids mediate Bim induction posttranscriptionally after miR-17∼92 repression, resulting in increased Bim protein expression. Overexpression of miR-17∼92 microRNAs decreases Bim induction and attenuates glucocorticoid-mediated apoptosis. Conversely, knockdown of miR-17∼92 increases Bim protein expression and glucocorticoid-mediated apoptosis. These findings indicate that endogenous levels of miR-17∼92 repress Bim expression in T-cell lymphoid malignancies and that glucocorticoids induce Bim expression via down-regulation of the miR-17∼92 microRNA cluster. Our findings present a novel mechanism that contributes to the up-regulation of Bim and induction of apoptosis in lymphocytes after glucocorticoid treatment. Furthermore, our work demonstrating that inhibition of miR-17∼92 increases glucocorticoid-induced apoptosis highlights the potential importance of miR-17∼92 as a therapeutic target in leukemias and lymphomas.
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Barnes, Peter J. "Anti-inflammatory Actions of Glucocorticoids: Molecular Mechanisms." Clinical Science 94, no. 6 (June 1, 1998): 557–72. http://dx.doi.org/10.1042/cs0940557.
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1. Glucocorticoids are widely used for the suppression of inflammation in chronic inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases, all of which are associated with increased expression of inflammatory genes. The molecular mechanisms involved in this antiinflammatory action of glucocorticoids is discussed, particularly in asthma, which accounts for the highest clinical use of these agents. 2. Glucocorticoids bind to glucocorticoid receptors in the cytoplasm which then dimerize and translocate to the nucleus, where they bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, resulting in increased transcription. Glucocorticoids may increase the transcription of genes coding for antiinflammatory proteins, including lipocortin-1, interleukin-10, interleukin-1 receptor antagonist and neutral endopeptidase, but this is unlikely to account for all of the widespread anti-inflammatory actions of glucocorticoids. 3. The most striking effect of glucocorticoids is to inhibit the expression of multiple inflammatory genes (cytokines, enzymes, receptors and adhesion molecules). This cannot be due to a direct interaction between glucocorticoid receptors and GRE, as these binding sites are absent from the promoter regions of most inflammatory genes. It is more likely to be due to a direct inhibitory interaction between activated glucocorticoid receptors and activated transcription factors, such as nuclear factor-κB and activator protein-1, which regulate the inflammatory gene expression. 4. It is increasingly recognized that glucocorticoids change the chromatin structure. Glucocorticoid receptors also interact with CREB-binding protein (CBP), which acts as a co-activator of transcription, binding several other transcription factors that compete for binding sites on this molecule. Increased transcription is associated with uncoiling of DNA wound around histone and this is secondary to acetylation of the histone residues by the enzymic action of CBP. Glucocorticoids may lead to deacetylation of histone, resulting in tighter coiling of DNA and reduced access of transcription factors to their binding sites, thereby suppressing gene expression. 5. Rarely patients with chronic inflammatory diseases fail to respond to glucocorticoids, although endocrine function of steroids is preserved. This may be due to excessive formation of activator protein-1 at the inflammatory site, which consumes activated glucocorticoid receptors so that they are not available for suppressing inflammatory genes. 6. This new understanding of glucocorticoid mechanisms may lead to the development of novel steroids with less risk of side effects (which are due to the endocrine and metabolic actions of steroids). ‘Dissociated’ steroids which are more active in transrepression (interaction with transcription factors) than transactivation (GRE binding) have now been developed. Some of the transcription factors that are inhibited by glucocorticoid, such as nuclear factor-κB, are also targets for novel anti-inflammatory therapies.
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BAKI, Lia, and Michael N. ALEXIS. "Regulation of tyrosine aminotransferase gene expression by glucocorticoids in quiescent and regenerating liver." Biochemical Journal 320, no. 3 (December 15, 1996): 745–53. http://dx.doi.org/10.1042/bj3200745.
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Following 70% hepatectomy, the induction of tyrosine aminotransferase mRNA by glucocorticoids was marginal at 1.5 h, significantly impaired between 3 and 8 h and, at 16 h post-hepatectomy, reached a value approx. 5-fold the basal level, similar to the level observed in quiescent liver. The fold induction of the mRNA was accounted for by a similar fold activation of transcription of the gene by glucocorticoids in regenerating but not in quiescent liver; in the latter, activation of transcription was marginal in spite of glucocorticoid-induced hypersensitivity to cleavage by DNase I at the glucocorticoid-dependent enhancer of the gene. The possibility that in quiescent liver glucocorticoids act at a transcriptional step beyond initiation, increasing the rate of elongation or overcoming a blockage in elongation, was excluded. However, a similar fold induction was determined for total and nuclear tyrosine aminotransferase mRNA in the presence of glucocorticoids, suggesting that in quiescent liver glucocorticoids promote efficient maturation of the tyrosine aminotransferase primary transcript. Thus a glucocorticoid-induced nuclear post-transcriptional up-regulation apparently compensates for impaired activation of transcription of the tyrosine aminotransferase gene by glucocorticoids in quiescent liver.
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Buttgereit, F. "OP25. NEW GLUCOCORTICOIDS: SELECTIVE GLUCOCORTICOID RECEPTOR AGONISTS, NO-GLUCOCORTICOIDS AND LONG-CIRCULATING LIPOSOMAL GLUCOCORTICOIDS." Rheumatology 44, suppl_3 (July 1, 2005): iii11. http://dx.doi.org/10.1093/rheumatology/keh750.
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Hong, So Gun, Noriko Sato, Fanny Legrand, Manasi Gadkari, Michelle Makiya, Kindra Stokes, Katherine N. Howe, et al. "Glucocorticoid-induced eosinopenia results from CXCR4-dependent bone marrow migration." Blood 136, no. 23 (December 3, 2020): 2667–78. http://dx.doi.org/10.1182/blood.2020005161.
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Abstract Glucocorticoids are considered first-line therapy in a variety of eosinophilic disorders. They lead to a transient, profound decrease in circulating human eosinophils within hours of administration. The phenomenon of glucocorticoid-induced eosinopenia has been the basis for the use of glucocorticoids in eosinophilic disorders, and it has intrigued clinicians for 7 decades, yet its mechanism remains unexplained. To investigate, we first studied the response of circulating eosinophils to in vivo glucocorticoid administration in 3 species and found that the response in rhesus macaques, but not in mice, closely resembled that in humans. We then developed an isolation technique to purify rhesus macaque eosinophils from peripheral blood and performed live tracking of zirconium-89-oxine–labeled eosinophils by serial positron emission tomography/computed tomography imaging, before and after administration of glucocorticoids. Glucocorticoids induced rapid bone marrow homing of eosinophils. The kinetics of glucocorticoid-induced eosinopenia and bone marrow migration were consistent with those of the induction of the glucocorticoid-responsive chemokine receptor CXCR4, and selective blockade of CXCR4 reduced or eliminated the early glucocorticoid-induced reduction in blood eosinophils. Our results indicate that glucocorticoid-induced eosinopenia results from CXCR4-dependent migration of eosinophils to the bone marrow. These findings provide insight into the mechanism of action of glucocorticoids in eosinophilic disorders, with implications for the study of glucocorticoid resistance and the development of more targeted therapies. The human study was registered at ClinicalTrials.gov as #NCT02798523.
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Gao, Yanchun, Hongyi Zhu, Fan Yang, Qiyang Wang, Yong Feng, and Changqing Zhang. "Glucocorticoid-activated IRE1α/XBP-1s signaling: an autophagy-associated protective pathway against endotheliocyte damage." American Journal of Physiology-Cell Physiology 315, no. 3 (September 1, 2018): C300—C309. http://dx.doi.org/10.1152/ajpcell.00009.2018.
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Glucocorticoid-induced endothelial injury has been reported in several diseases. Although there are several theories, the exact mechanism underlying the role of glucocorticoids in this process remains unclear. Autophagy has been reported to occur as a response to different stimuli and can affect cell survival and function. In this study, we found that glucocorticoids induced apoptosis and endoplasmic reticulum (ER) stress in endotheliocytes. Furthermore, we discovered that glucocorticoids induced autophagy in these cells and the inositol requiring protein 1 (IRE1α)/X-box binding protein 1s (XBP-1s) axis, one of the downstream signaling pathways of ER stress, was associated with the glucocorticoid-induced autophagy. The autophagy partly protected endotheliocytes from glucocorticoid-induced apoptosis and inhibition of proliferation. In conclusion, glucocorticoid-induced endoplasmic reticulum stress activated the IRE1α/XBP-1s signaling and induced autophagy, which, in turn, played a protective role in endotheliocyte survival and proliferation, avoiding further cellular damage caused by glucocorticoids.
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Otlewska, Anna, Grzegorz Szpotowicz, and Agnieszka Otlewska. "Effects of glucocorticoids on the skin." Pediatria i Medycyna Rodzinna 16, no. 3 (October 30, 2020): 257–60. http://dx.doi.org/10.15557/pimr.2020.0047.
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Glucocorticoids are widely used in the treatment of many diseases. They have multiple therapeutic applications mainly because of their anti-inflammatory, immunosuppressive and antiproliferative activity. Glucocorticoids are broadly used in the therapy of dermatological diseases. Various routes of glucocorticoids administration are known. In the treatment of skin disorders, glucocorticoids are often administered topically. It must be noted that glucocorticoid-induced complications may occur not only as a result of systemic treatment, but also topical application of glucocorticoids to the skin. Commonly reported cutaneous adverse effects resulting from glucocorticoid therapy include changes in facial appearance – rounded appearance of the face, redness, development of stretch marks, difficulty in wound healing, and easy bruising. It needs to be highlighted that glucocorticoids also affect metabolism, water and electrolyte balance, and bones. Therefore, in addition to dermatological disorders, they may also cause many other types of complications. As a result, a degree of caution is advised in the use of drugs of this class. In order to reduce the risk of adverse effects, glucocorticoids should be used at the smallest effective dose for the shortest possible time.
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Kalafatakis, Konstantinos. "The translational aspects of glucocorticoid biorhythmicity in modern therapeutics." Review of Clinical Pharmacology and Pharmacokinetics - International Edition 38, Sup2 (May 5, 2024): 19–21. http://dx.doi.org/10.61873/xeyd8146.
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Glucocorticoids are a class of steroid hormones, vital for mammalian life. They have a plethora of biological effects, mainly supporting metabolic, cognitive, and immunological functions. The pharmacological use of glucocorticoids makes them one of the most frequently prescribed drugs across all continents, and in all types of forms. Nevertheless, a number of serious adverse effects accompany the prolonged treatment with high doses of glucocorticoids. Research developments over the last 20 years have gradually reshaped the way we think about glucocorticoid-based therapeu¬tics. Aside their circadian rhythm and their delayed regulatory influence over an extensive number of sensitive genes, glucocorticoids also possess an underlying, ultradian rhythm, and also exert rapid, non-genomic effects. The notion that chronicity of glucocorticoid stimulation may differentially modulate the type of biological effects of the hormone brings various chronopharmacological concepts on the table of modern glucocorticoid-based therapeutics.
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Bhattacharyya, Sandip, Christine K. Ratajczak, Sherri K. Vogt, Crystal Kelley, Marco Colonna, Robert D. Schreiber, and Louis J. Muglia. "TAK1 targeting by glucocorticoids determines JNK and IκB regulation in Toll-like receptor–stimulated macrophages." Blood 115, no. 10 (March 11, 2010): 1921–31. http://dx.doi.org/10.1182/blood-2009-06-224782.
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Abstract Glucocorticoids potently attenuate the production of inflammatory mediators by macrophages, a primary effector of innate immunity. Activation of different macrophage Toll-like receptors (TLRs) by their respective ligands presents a powerful system by which to evaluate stimulus-dependent glucocorticoid effects in the same cell type. Here, we test the hypothesis that glucocorticoids, acting through the glucocorticoid receptor, modulate macrophage activation preferentially depending upon the TLR-selective ligand and TLR adapters. We established that 2 adapters, Trif, MyD88, or both, determine the ability of glucocorticoids to suppress inhibitor of κB (IκB) degradation or Janus kinase (JNK) activation. Moreover, the sensitivity of transforming growth factor β–activated kinase 1 (TAK1) activation to glucocorticoids determines these effects. These findings identify TAK1 as a novel target for glucocorticoids that integrates their anti-inflammatory action in innate immunity signaling pathways.
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Zimmerman, Jessica A. O., Mimi Fang, and Miles A. Pufall. "PI3Kδ Inhibition Potentiates Glucocorticoids in B-lymphoblastic Leukemia by Decreasing Receptor Phosphorylation and Enhancing Gene Regulation." Cancers 16, no. 1 (December 27, 2023): 143. http://dx.doi.org/10.3390/cancers16010143.
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Glucocorticoids are the cornerstone of B-lymphoblastic leukemia (B-ALL) therapy. Because response to glucocorticoids alone predicts overall outcomes for B-ALL, enhancing glucocorticoid potency should improve treatment. We previously showed that inhibition of the lymphoid-restricted PI3Kδ with idelalisib enhances glucocorticoid activity in B-ALL cells. Here, we show that idelalisib enhances glucocorticoid potency in 90% of primary B-ALL specimens and is most pronounced at sub-saturating doses of glucocorticoids near the EC50. Potentiation is associated with enhanced regulation of all glucocorticoid-regulated genes, including genes that drive B-ALL cell death. Idelalisib reduces phosphorylation of the glucocorticoid receptor (GR) at PI3Kδ/MAPK1 (ERK2) targets S203 and S226. Ablation of these phospho-acceptor sites enhances sensitivity to glucocorticoids with ablation of S226 in particular reducing synergy. We also show that phosphorylation of S226 reduces the affinity of GR for DNA in vitro. We propose that PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing GR phosphorylation, increasing DNA binding affinity, and enhancing downstream gene regulation. This mechanism and the response of patient specimens suggest that idelalisib will benefit most patients with B-ALL, but particularly patients with less responsive, including high-risk, disease. This combination is also promising for the development of less toxic glucocorticoid-sparing therapies.
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Li, Jianneng, Michael Berk, Mohammad Alyamani, Navin Sabharwal, Christopher Goins, Joseph Alvarado, Mehdi Baratchian, et al. "Hexose-6-phosphate dehydrogenase blockade reverses prostate cancer drug resistance in xenograft models by glucocorticoid inactivation." Science Translational Medicine 13, no. 595 (May 26, 2021): eabe8226. http://dx.doi.org/10.1126/scitranslmed.abe8226.
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Prostate cancer resistance to next-generation hormonal treatment with enzalutamide is a major problem and eventuates into disease lethality. Biologically active glucocorticoids that stimulate glucocorticoid receptor (GR) have an 11β-OH moiety, and resistant tumors exhibit loss of 11β-HSD2, the oxidative (11β-OH → 11-keto) enzyme that normally inactivates glucocorticoids, allowing elevated tumor glucocorticoids to drive resistance by stimulating GR. Here, we show that up-regulation of hexose-6-phosphate dehydrogenase (H6PD) protein occurs in prostate cancer tissues of men treated with enzalutamide, human-derived cell lines, and patient-derived prostate tissues treated ex vivo with enzalutamide. Genetically silencing H6PD blocks NADPH generation, which inhibits the usual reductive directionality of 11β-HSD1, to effectively replace 11β-HSD2 function in human-derived cell line models, suppress the concentration of biologically active glucocorticoids in prostate cancer, and reverse enzalutamide resistance in mouse xenograft models. Similarly, pharmacologic blockade of H6PD with rucaparib normalizes tumor glucocorticoid metabolism in human cell lines and reinstates responsiveness to enzalutamide in mouse xenograft models. Our data show that blockade of H6PD, which is essential for glucocorticoid synthesis in humans, normalizes glucocorticoid metabolism and reverses enzalutamide resistance in mouse xenograft models. We credential H6PD as a pharmacologic vulnerability for treatment of next-generation androgen receptor antagonist–resistant prostate cancer by depleting tumor glucocorticoids.
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Fruchter, Oren, Tomoshige Kino, Emmanouil Zoumakis, Salvatore Alesci, Massimo De Martino, George Chrousos, and Ze’ev Hochberg. "The Human Glucocorticoid Receptor (GR) Isoform β Differentially Suppresses GRα-Induced Transactivation Stimulated by Synthetic Glucocorticoids." Journal of Clinical Endocrinology & Metabolism 90, no. 6 (June 1, 2005): 3505–9. http://dx.doi.org/10.1210/jc.2004-1646.
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The β-isoform of human glucocorticoid receptor β (hGRβ) acts as a natural dominant negative inhibitor of hGRα-induced transactivation of glucocorticoid-responsive genes. We determined hGRβ ability to suppress hGRα transactivation that was induced by commonly used synthetic glucocorticoids. HepG2/C3A cells were transiently cotransfected with GR cDNA and a glucocorticoid-responsive promoter, luciferase (MMTV-luc). Transfected cells were incubated for 16 h with glucocorticoid and luciferase. For each compound, a dose-response curve was constructed, and half-maximal effective concentrations and maximal transcriptional activities were compared. hGRβ, at a 1:1 ratio to hGRα, differentially suppressed hGRα-induced maximal transcriptional activity stimulated by triamcinolone, dexamethasone, hydrocortisone, and betamethasone (by 96, 68, 62, and 49%, respectively) but not by methylprednisolone. The suppressive effect of hGRβ on hGRα-induced transactivation was stronger at lower concentrations of all tested glucocorticoids, whereas it was blunted at higher concentrations. We conclude that the potency of the dominant negative effect of hGRβ on hGRα-induced transactivation depends on both the type and the dose of the synthetic glucocorticoids in use. These results may provide helpful information concerning the selection of synthetic glucocorticoids for treatment of pathological conditions in which hGRβ modulates the sensitivity of tissues to glucocorticoids.
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Diaz-Jimenez, David, Maria Grazia Petrillo, Jonathan T. Busada, Marcela A. Hermoso, and John A. Cidlowski. "Glucocorticoids mobilize macrophages by transcriptionally up-regulating the exopeptidase DPP4." Journal of Biological Chemistry 295, no. 10 (January 27, 2020): 3213–27. http://dx.doi.org/10.1074/jbc.ra119.010894.
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Glucocorticoids are potent endogenous anti-inflammatory molecules, and their cognate receptor, glucocorticoid receptor (GR), is expressed in nearly all immune cells. Macrophages are heterogeneous immune cells having a central role in both tissue homeostasis and inflammation and also play a role in the pathogenesis of some inflammatory diseases. Paradoxically, glucocorticoids have only a limited efficacy in controlling the resolution of these macrophage-related diseases. Here, we report that the transcriptomes of monocyte-like THP-1 cells and macrophage-like THP-1 cells (THP1-MΦ) have largely conserved gene expression patterns. In contrast, the differentiation to THP1-MΦ significantly altered the sensitivity of gene transcription to glucocorticoids. Among glucocorticoid-regulated genes, we identified the exopeptidase dipeptidyl peptidase-4 (DPP4) as a critical glucocorticoid-responsive gene in THP1-MΦ. We found that GR directly induces DPP4 gene expression by binding to two glucocorticoid-responsive elements (GREs) within the DPP4 promoter. Additionally, we show that glucocorticoid-induced DPP4 expression is blocked by the GR antagonist RU-486 and by GR siRNA transfection and that DPP4 enzyme activity is reduced by DPP4 inhibitors. Of note, glucocorticoids highly stimulated macrophage mobility; unexpectedly, DPP4 mediated the glucocorticoid-induced macrophage migration, and siRNA-mediated knockdowns of GR and DPP4 blocked dexamethasone-induced THP1-MΦ migration. Moreover, glucocorticoid-induced DPP4 activation was also observed in proinflammatory M1-polarized murine macrophages, as well as peritoneal macrophages, and was associated with increased macrophage migration. Our results indicate that glucocorticoids directly up-regulate DPP4 expression and thereby induce migration in macrophages, potentially explaining why glucocorticoid therapy is less effective in controlling macrophage-dominated inflammatory disorders.
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Qiao, Xiaojing, Yang Yang, Yan Zhao, Xiuju Wu, Li Zhang, Xinjiang Cai, Jaden Ji, Kristina I. Boström, and Yucheng Yao. "Aurora Kinase A Regulates Cell Transitions in Glucocorticoid-Induced Bone Loss." Cells 12, no. 20 (October 11, 2023): 2434. http://dx.doi.org/10.3390/cells12202434.
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Glucocorticoid-induced bone loss is a severe and toxic effect of long-term therapy with glucocorticoids, which are currently prescribed for millions of people worldwide. Previous studies have uncovered that glucocorticoids reciprocally converted osteoblast lineage cells into endothelial-like cells to cause bone loss and showed that the modulations of Foxc2 and Osterix were the causative factors that drove this harmful transition of osteoblast lineage cells. Here, we find that the inhibition of aurora kinase A halts this transition and prevents glucocorticoid-induced bone loss. We find that aurora A interacts with the glucocorticoid receptor and show that this interaction is required for glucocorticoids to modulate Foxc2 and Osterix. Together, we identify a new potential approach to counteracting unwanted transitions of osteoblast lineage cells in glucocorticoid treatment and may provide a novel strategy for ameliorating glucocorticoid-induced bone loss.
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Sato, A., K. E. Sheppard, M. J. Fullerton, and J. W. Funder. "cAMP modulates glucocorticoid-induced protein accumulation and glucocorticoid receptor in cardiomyocytes." American Journal of Physiology-Endocrinology and Metabolism 271, no. 5 (November 1, 1996): E827—E833. http://dx.doi.org/10.1152/ajpendo.1996.271.5.e827.
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Glucocorticoids have complex effects on cardiac muscle growth in vivo, and one possible reason may the regulatory cross talk between glucocorticoids and second messengers. In this study we investigated the effect of adenosine 3',5'-cyclic monophosphate (cAMP), shown to affect cardiomyocyte growth and glucocorticoid action in several systems, on glucocorticoid-induced protein accumulation and glucocorticoid receptor (GR) in neonatal rat cardiomyocytes. Dexamethasone (DEX) decreased the protein-to-DNA ratio, and 8-bromoadenosine 3',5'-cyclic monophosphate (BrcAMP) or forskolin increased this ratio. The inhibitory effect of DEX was potentiated by an elevated cAMP, despite the stimulatory effect of cAMP alone. Nuclear GR binding was increased by BrcAMP, with no change in GR mRNA or protein levels, via increased affinity of nuclear GR. H-89 blocked the effects of BrcAMP. In conclusion, glucocorticoids have an inhibitory effect on protein accumulation in cardiomyocytes via GR, an effect potentiated by elevated cAMP via increased nuclear GR binding. These results suggest that glucocorticoid effects on cardiomyocytes may be modulated by cAMP-mediated mechanisms, which may produce the complex effects of glucocorticoids on cardiomyocyte growth in vivo.
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Pansters, N. A., R. C. Langen, E. F. Wouters, and A. M. Schols. "Synergistic stimulation of myogenesis by glucocorticoid and IGF-I signaling." Journal of Applied Physiology 114, no. 9 (May 1, 2013): 1329–39. http://dx.doi.org/10.1152/japplphysiol.00503.2012.
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Muscle wasting is associated with poor prognosis in chronic obstructive pulmonary disease (COPD). Exercise stimulates muscle recovery, but its efficacy is variable, depending on the clinical condition and medical treatment. Systemic glucocorticoids, commonly administered in high doses during acute disease exacerbations or as maintenance treatment in end-stage disease, are known to contribute to muscle wasting. As muscle mass recovery involves insulin-like growth factor (IGF)-I signaling, which can be stimulated by anabolic steroids, the impact of glucocorticoids and the effect of simultaneous IGF-I stimulation by anabolic steroids on muscle recovery and growth were investigated. The effects of, and interactions between, glucocorticoid and IGF-I signaling on skeletal muscle growth were assessed in differentiating C2C12 myocytes. As proof of principle, we performed a post hoc analysis stratifying patients by glucocorticoid use of a clinical trial investigating the efficacy of anabolic steroid supplementation on muscle recovery in muscle-wasted patients with COPD. Glucocorticoids strongly impaired protein synthesis signaling, myotube formation, and muscle-specific protein expression. In contrast, in the presence of glucocorticoids, IGF-I synergistically stimulated myotube fusion and myofibrillar protein expression, which corresponded with restored protein synthesis signaling by IGF-I and increased transcriptional activation of muscle-specific genes by glucocorticoids. In COPD patients on maintenance glucocorticoid treatment, the clinical trial also revealed an enhanced effect of anabolic steroids on muscle mass and respiratory muscle strength. In conclusion, synergistic effects of anabolic steroids and glucocorticoids on muscle recovery may be caused by relief of the glucocorticoid-imposed blockade on protein synthesis signaling, allowing effective translation of glucocorticoid-induced accumulation of muscle-specific gene transcripts.
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Castagliuolo, Ignazio, Katia Karalis, Leyla Valenick, Asiya Pasha, Sigfus Nikulasson, Michael Wlk, and Charalabos Pothoulakis. "Endogenous corticosteroids modulateClostridium difficiletoxin A-induced enteritis in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 4 (April 1, 2001): G539—G545. http://dx.doi.org/10.1152/ajpgi.2001.280.4.g539.
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We examined the role of glucocorticoids in acute inflammatory diarrhea mediated by Clostridium difficile toxin A. Toxin A (5 μg) or buffer was injected in rat ileal loops, and intestinal responses were measured after 30 min to 4 h. Ileal toxin A administration increased plasma glucocorticoids after 1 h, at which time the toxin-stimulated secretion was not significant. Administration of the glucocorticoid analog dexamethasone inhibited toxin A-induced intestinal secretion and inflammation and downregulated toxin A-mediated increase of macrophage inflammatory protein-2. Adrenalectomy followed by replacement with glucocorticoids at various doses suggested that intestinal responses to toxin A were related to circulating levels of glucocorticoids. Administration of the glucocorticoid receptor antagonist RU-486 enhanced toxin A-mediated intestinal secretion and inflammation. We conclude that C. difficile toxin A causes increased secretion of endogenous glucocorticoids, which diminish the intestinal secretory and inflammatory effects of toxin A.
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Lewis, Trevor, Eva Zeisig, and Jamie E. Gaida. "Does glucocorticoid exposure explain the association between metabolic dysfunction and tendinopathy?" Endocrine Connections 9, no. 3 (March 2020): R36—R46. http://dx.doi.org/10.1530/ec-19-0555.
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Background While metabolic health is acknowledged to affect connective tissue structure and function, the mechanisms are unclear. Glucocorticoids are present in almost every cell type throughout the body and control key physiological processes such as energy homeostasis, stress response, inflammatory and immune processes, and cardiovascular function. Glucocorticoid excess manifests as visceral adiposity, dyslipidemia, insulin resistance, and type 2 diabetes. As these metabolic states are also associated with tendinopathy and tendon rupture, it may be that glucocorticoids excess is the link between metabolic health and tendinopathy. Objective To synthesise current knowledge linking glucocorticoid exposure to tendon structure and function. Methods Narrative literature review. Results We provide an overview of endogenous glucocorticoid production, regulation, and signalling. Next we review the impact that oral glucocorticoid has on risk of tendon rupture and the effect that injected glucocorticoid has on resolution of symptoms. Then we highlight the clinical and mechanistic overlap between tendinopathy and glucocorticoid excess in the areas of visceral adiposity, dyslipidemia, insulin resistance and type 2 diabetes. In these areas, we highlight the role of glucocorticoids and how these hormones might underpin the connection between metabolic health and tendon dysfunction. Conclusions There are several plausible pathways through which glucocorticoids might mediate the connection between metabolic health and tendinopathy.
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MacLeod, Clare, Patrick W. F. Hadoke, and Mark Nixon. "Glucocorticoids: Fuelling the Fire of Atherosclerosis or Therapeutic Extinguishers?" International Journal of Molecular Sciences 22, no. 14 (July 16, 2021): 7622. http://dx.doi.org/10.3390/ijms22147622.
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Glucocorticoids are steroid hormones with key roles in the regulation of many physiological systems including energy homeostasis and immunity. However, chronic glucocorticoid excess, highlighted in Cushing’s syndrome, is established as being associated with increased cardiovascular disease (CVD) risk. Atherosclerosis is the major cause of CVD, leading to complications including coronary artery disease, myocardial infarction and heart failure. While the associations between glucocorticoid excess and increased prevalence of these complications are well established, the mechanisms underlying the role of glucocorticoids in development of atheroma are unclear. This review aims to better understand the importance of glucocorticoids in atherosclerosis and to dissect their cell-specific effects on key processes (e.g., contractility, remodelling and lesion development). Clinical and pre-clinical studies have shown both athero-protective and pro-atherogenic responses to glucocorticoids, effects dependent upon their multifactorial actions. Evidence indicates regulation of glucocorticoid bioavailability at the vasculature is complex, with local delivery, pre-receptor metabolism, and receptor expression contributing to responses linked to vascular remodelling and inflammation. Further investigations are required to clarify the mechanisms through which endogenous, local glucocorticoid action and systemic glucocorticoid treatment promote/inhibit atherosclerosis. This will provide greater insights into the potential benefit of glucocorticoid targeted approaches in the treatment of cardiovascular disease.
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Qiao, Xiaojing, Xiuju Wu, Yan Zhao, Yang Yang, Li Zhang, Xinjiang Cai, Jocelyn A. Ma, et al. "Cell Transitions Contribute to Glucocorticoid-Induced Bone Loss." Cells 12, no. 14 (July 8, 2023): 1810. http://dx.doi.org/10.3390/cells12141810.
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Glucocorticoid-induced bone loss is a toxic effect of long-term therapy with glucocorticoids resulting in a significant increase in the risk of fracture. Here, we find that glucocorticoids reciprocally convert osteoblast-lineage cells into endothelial-like cells. This is confirmed by lineage tracing showing the induction of endothelial markers in osteoblast-lineage cells following glucocorticoid treatment. Functional studies show that osteoblast-lineage cells isolated from glucocorticoid-treated mice lose their capacity for bone formation but simultaneously improve vascular repair. We find that the glucocorticoid receptor directly targets Foxc2 and Osterix, and the modulations of Foxc2 and Osterix drive the transition of osteoblast-lineage cells to endothelial-like cells. Together, the results suggest that glucocorticoids suppress osteogenic capacity and cause bone loss at least in part through previously unrecognized osteoblast–endothelial transitions.
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Rog-Zielinska, Eva A., Rachel V. Richardson, Martin A. Denvir, and Karen E. Chapman. "Glucocorticoids and foetal heart maturation; implications for prematurity and foetal programming." Journal of Molecular Endocrinology 52, no. 2 (December 3, 2013): R125—R135. http://dx.doi.org/10.1530/jme-13-0204.
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Glucocorticoids are steroid hormones, essential in mammals to prepare for life after birth. Blood levels of glucocorticoids (cortisol in most mammals including humans; corticosterone in rats and mice) rise dramatically shortly before birth. This is mimicked clinically in the routine administration of synthetic glucocorticoids to pregnant women threatened by a preterm birth or to preterm infants to improve neonatal survival. Whilst effects on lung are well documented and essential for postnatal survival, those on heart are less well known. In this study, we review recent evidence for a crucial role of glucocorticoids in late gestational heart maturation. Either insufficient or excessive glucocorticoid exposure before birth may alter the normal glucocorticoid-regulated trajectory of heart maturation with potential life-long consequences.
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Scheff, Jeremy D., Steve E. Calvano, Stephen F. Lowry, and Ioannis P. Androulakis. "Transcriptional implications of ultradian glucocorticoid secretion in homeostasis and in the acute stress response." Physiological Genomics 44, no. 2 (January 2012): 121–29. http://dx.doi.org/10.1152/physiolgenomics.00128.2011.
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Endogenous glucocorticoids are secreted by the hypothalamic-pituitary-adrenal (HPA) axis in response to a wide range of stressors. Glucocorticoids exert significant downstream effects, including the regulation of many inflammatory genes. The HPA axis functions such that glucocorticoids are released in a pulsatile manner, producing ultradian rhythms in plasma glucocorticoid levels. It is becoming increasingly evident that this ultradian pulsatility is important in maintaining proper homeostatic regulation and responsiveness to stress. This is particularly interesting from a clinical perspective given that pathological dysfunctions of the HPA axis produce altered ultradian patterns. Modeling this system facilitates the understanding of how glucocorticoid pulsatility arises, how it can be lost, and the transcriptional implications of ultradian rhythms. To approach these questions, we developed a mathematical model that integrates the cyclic production of glucocorticoids by the HPA axis and their downstream effects by integrating existing models of the HPA axis and glucocorticoid pharmacodynamics. This combined model allowed us to evaluate the implications of pulsatility in homeostasis as well as in response to acute stress. The presence of ultradian rhythms allows the system to maintain a lower response to homeostatic levels of glucocorticoids, but diminished feedback within the HPA axis leads to a loss of glucocorticoid rhythmicity. Furthermore, the loss of HPA pulsatility in homeostasis correlates with a decrease in the peak output in response to an acute stressor. These results are important in understanding how cyclic glucocorticoid secretion helps maintain the responsiveness of the HPA axis.
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Nurullina, G. I. "Glucocorticoid pulse therapy аnd carbohydrate metabolism in rheumatic diseases." Kazan medical journal 94, no. 6 (December 15, 2013): 920–23. http://dx.doi.org/10.17816/kmj1820.
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Glucocorticoids are used in clinical practice for more than 50 years and are a great advance in the treatment of systemic inflammatory diseases. High doses of intravenous glucocorticoids (pulse therapy) are effective in conditions requiring rapid immunosuppression and antiinflammatory effect, such as systemic lupus erythematosus, rheumatoid arthritis, glomerulonephritis and systemic vasculitides. The advantage of this method are increased efficacy and lower rate of complications associated with prolonged administration of glucocorticoids. At the same time, glucocorticoid pulse therapy is associated with increased risk of hyperglycemia or even can be a cause of steroid-induced diabetes in patients without known hyperglycemia, as well as worsen glycemia control in patients with diabetes. Increased hepatic gluconeogenesis, inhibition of glucose uptake and metabolism in peripheral tissues and altered both receptor and post-receptor insulin action can lead to an increased serum glucose levels. In patients with inadequate compensatory reserves of pancreas, a clinical picture of diabetus mellitus can develop while treated with glucocorticoids. Blood glucose levels begin to rise 6-12 hours after the infusion of high doses of glucocorticoids. Risk factors for developing glucose intolerance and diabetes include advanced age, obesity, family history of diabetes and high cumulative doses of glucocorticoids. Glucocorticoid-induced diabetes is a common complication of pulse therapy, but exact causes are still not elucidated yet, current literature data on glucocorticoid-induced hyperglycemia are scarce.
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Tatsuno, Ichiro, Takao Sugiyama, Sawako Suzuki, Tomohiko Yoshida, Tomoaki Tanaka, Makoto Sueishi, and Yasushi Saito. "Age Dependence of Early Symptomatic Vertebral Fracture with High-Dose Glucocorticoid Treatment for Collagen Vascular Diseases." Journal of Clinical Endocrinology & Metabolism 94, no. 5 (May 1, 2009): 1671–77. http://dx.doi.org/10.1210/jc.2008-1578.
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Abstract Objectives: Collagen vascular diseases requiring treatment with high-dose glucocorticoids are frequently complicated by vertebral fracture. We investigated the incidence of symptomatic vertebral fractures for 20 yr among patients who were treated with high-dose glucocorticoids in the Chiba-Shimoshizu Rheumatic Cohort. Methods: A total of 2631 patients with collagen vascular diseases (aged ≥18 yr) was registered between 1986 and 2006. The prevalence of symptomatic vertebral fracture was compared between the high-dose glucocorticoid group newly treated with high-dose glucocorticoids (≥20 mg/d prednisolone equivalent) (n = 700), and the non-glucocorticoid controls not treated with glucocorticoids (n = 194). Results: During the 20-yr study period, symptomatic vertebral fractures occurred more frequently in the high-dose glucocorticoid group (23.9%) than in the non-glucocorticoid controls (2.6%). According to a Kaplan-Meier analysis, the cumulative incidence of symptomatic vertebral fracture was significantly higher in the high-dose glucocorticoid group than in the non-glucocorticoid controls (P < 0.001). Stratified into age quartiles of the high-dose glucocorticoid group (age 18–31, 32–47, 48–59, and 60–88 yr), the patients had a markedly increased incidence of symptomatic vertebral fracture with aging. The hazard ratios were also significantly higher in the older age quartile of 60–68 than in the younger age quartile of 32–47 (P < 0.001 for trend). The hazard ratio was 26-fold higher in patients aged 60–88 than in patients aged 18–31 (P < 0.01). In the group with fractures, the treatment duration before fracture was negatively associated with the initial age (r = −0.6587; P < 0.001). Conclusions: The prevalence of symptomatic vertebral fractures was higher in the patients treated with high-dose glucocorticoids than the untreated controls. Vertebral fractures were age dependent in patients treated with high-dose glucocorticoids. Treatment duration before fracture incidence was significantly shorter in the older patients.
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Ricci, Erika, Elena Roselletti, Marco Gentili, Samuele Sabbatini, Stefano Perito, Carlo Riccardi, Graziella Migliorati, Claudia Monari, and Simona Ronchetti. "Glucocorticoid-Induced Leucine Zipper-Mediated TLR2 Downregulation Accounts for Reduced Neutrophil Activity Following Acute DEX Treatment." Cells 10, no. 9 (August 28, 2021): 2228. http://dx.doi.org/10.3390/cells10092228.
Full textAbstract:
Glucocorticoids are the most powerful anti-inflammatory and immunosuppressive pharmacological drugs available, despite their adverse effects. Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid-induced gene that shares several anti-inflammatory properties with glucocorticoids. Although immunosuppressive effects of glucocorticoids on neutrophils remain poorly understood, we previously demonstrated that GILZ suppresses neutrophil activation under glucocorticoid treatment. Here, we sought to explore the regulation of Toll-like receptor 2 (TLR2) by the synthetic glucocorticoid dexamethasone (DEX) on neutrophils and the associated GILZ involvement. Peripheral blood neutrophils were isolated from wild type and GILZ-knock-out (KO) mice. TLR2 was found to be downregulated by the in vivo administration of glucocorticoids in wild type but not in GILZ-KO neutrophils, suggesting the involvement of GILZ in TLR2 downregulation. Accordingly, the TLR2-associated anti-fungal activity of neutrophils was reduced by DEX treatment in wild type but not GILZ-KO neutrophils. Furthermore, GILZ did not interact with NF-κB but was found to bind with STAT5, a pivotal factor in the regulation of TLR2 expression. A similar modulation of TLR2 expression, impaired phagocytosis, and killing activity was observed in circulating human neutrophils treated in vitro with DEX. These results demonstrate that glucocorticoids reduce the ability of neutrophils to respond to infections by downregulating TLR2 via GILZ, thereby reducing critical functions.
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Osterlund, Chad D., Vanessa Thompson, Laura Hinds, and Robert L. Spencer. "Absence of glucocorticoids augments stress-induced Mkp1 mRNA expression within the hypothalamic–pituitary–adrenal axis." Journal of Endocrinology 220, no. 1 (January 2014): 1–11. http://dx.doi.org/10.1530/joe-13-0365.
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Stress-induced activation of hypothalamic paraventricular nucleus (PVN) corticotropin-releasing hormone (CRH) neurons trigger CRH release and synthesis. Recent findings have suggested that this process depends on the intracellular activation (phosphorylation) of ERK1/2 within CRH neurons. We have recently shown that the presence of glucocorticoids constrains stress-stimulated phosphorylation of PVN ERK1/2. In some peripheral cell types, dephosphorylation of ERK has been shown to be promoted by direct glucocorticoid upregulation of the MAP kinase phosphatase 1 (Mkp1) gene. In this study, we tested the hypothesis that glucocorticoids regulateMkp1mRNA expression in the neural forebrain (medial prefrontal cortex, mPFC, and PVN) and endocrine tissue (anterior pituitary) by subjecting young adult male Sprague–Dawley rats to various glucocorticoid manipulations with or without acute psychological stress (restraint). Restraint led to a rapid increase inMkp1mRNA within the mPFC, PVN, and anterior pituitary, and this increase did not require glucocorticoid activity. In contrast to glucocorticoid upregulation ofMkp1gene expression in the peripheral tissues, we found that the absence of glucocorticoids (as a result of adrenalectomy) augmented basal mPFC and stress-induced PVN and anterior pituitaryMkp1gene expression. Taken together, this study indicates that the presence of glucocorticoids may constrainMkp1gene expression in the neural forebrain and endocrine tissues. This possible constraint may be an indirect consequence of the inhibitory influence of glucocorticoids on stress-induced activation of ERK1/2, a known upstream positive regulator ofMkp1gene transcription.
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Cao, Qilin, Yamil Boo Irizarry, Svetlana Yazhuk, Thai Tran, Manasi Gadkari, and Luis Miguel Franco. "GCgx: transcriptome-wide exploration of the response to glucocorticoids." Journal of Molecular Endocrinology 68, no. 2 (February 1, 2022): B1—B4. http://dx.doi.org/10.1530/jme-21-0107.
Full textAbstract:
Glucocorticoids are the cornerstone of immunosuppressive and anti-inflammatory therapy in humans, yet the mechanisms of glucocorticoid immunoregulation and toxicity remain unclear. The response to glucocorticoids is highly cell type-dependent, so translating results from different experimental systems into a better understanding of glucocorticoid effects in humans would benefit from rapid access to high-quality data on the response to glucocorticoids by different cell types. We introduce GCgx, a web application that allows investigators to quickly visualize changes in transcript abundance in response to glucocorticoids in a variety of cells and species. The tool is designed to grow by the addition of datasets based on input from the user community. GCgx is implemented in R and HTML and packaged as a Docker image. The tool and its source code are publicly available.
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Cooper, M. S. "11β-Hydroxysteroid dehydrogenase type 1 and bone." Osteologie 25, no. 04 (2016): 256–61. http://dx.doi.org/10.1055/s-0037-1619027.
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SummaryIntracellular enzymatic metabolism of glucocorticoids is an important contributor to glucocorticoid action. The most extensively studied glucocorticoid metabolising enzymes are the 11β-hydroxysteroid dehydrogenases (11β-HSDs). These enzymes interconvert hormonally inactive glucocorticoids such as cortisone and dehydrocorticosterone with their active counterparts cortisol and corticosterone. 11β-HSDs have been reported to be expressed in bone and bone cells. This article reviews the literature relating to the expression, activity and functional consequences of 11β-HSD expression in bone. This activity appears to have clinical consequences in terms of predisposition towards osteoporosis and fracture and in the variation between individuals in the sensitivity of bone to therapeutic glucocorticoids. The existence of this enzyme system within bone opens up opportunities for new treatments to protect bone from the adverse effects of glucocorticoids.
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Ronchetti, Simona, Erika Ricci, Graziella Migliorati, Marco Gentili, and Carlo Riccardi. "How Glucocorticoids Affect the Neutrophil Life." International Journal of Molecular Sciences 19, no. 12 (December 17, 2018): 4090. http://dx.doi.org/10.3390/ijms19124090.
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Glucocorticoids are hormones that regulate several functions in living organisms and synthetic glucocorticoids are the most powerful anti-inflammatory pharmacological tool that is currently available. Although glucocorticoids have an immunosuppressive effect on immune cells, they exert multiple and sometimes contradictory effects on neutrophils. From being extremely sensitive to the anti-inflammatory effects of glucocorticoids to resisting glucocorticoid-induced apoptosis, neutrophils are proving to be more complex than they were earlier thought to be. The aim of this review is to explain these complex pathways by which neutrophils respond to endogenous or to exogenous glucocorticoids, both under physiological and pathological conditions.
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de Lange, Pieter, Christine M. Segeren, Jan W. Koper, Erik Wiemer, Pieter Sonneveld, Albert O. Brinkmann, Anne White, Iain J. Brogan, Frank H. de Jong, and Steven W. J. Lamberts. "Expression in Hematological Malignancies of a Glucocorticoid Receptor Splice Variant That Augments Glucocorticoid Receptor-mediated Effects in Transfected Cells." Cancer Research 61, no. 10 (May 1, 2001): 3937–41. http://dx.doi.org/10.1158/0008-5472.3937.61.10.
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Abstract Glucocorticoids play an important role in the treatment of a number of hematological malignancies, such as multiple myeloma. The effects of glucocorticoids are mediated through the glucocorticoid receptor α, the abundance of which can be modulated by alternative splicing of the glucocorticoid receptor mRNA. Two splice variants of the glucocorticoid receptor mRNA have been described: glucocorticoid receptor β, which reportedly has a dominant negative effect on the actions of the glucocorticoid receptor α, and glucocorticoid receptor P, of which the effects are unknown. In this study, we have investigated the expression levels of these two splice variants at the mRNA level in multiple myeloma cells and in a number of other hematological tumors. Although the glucocorticoid receptor β mRNA was, if at all, expressed at very low levels, considerable amounts (up to 50% of the total glucocorticoid receptor mRNA) glucocorticoid receptor P mRNA was present in most hematological malignancies. In transient transfection studies in several cell types and in multiple myeloma cell lines, the glucocorticoid receptor P increased the activity of the glucocorticoid receptor α. These results suggest that the relative levels of the glucocorticoid receptor α and the glucocorticoid receptor P may play a role in the occurrence of glucocorticoid resistance in tumor cells during the treatment of hematological malignancies with glucocorticoids.
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van der Lugt, Timme, Antje R. Weseler, Misha F. Vrolijk, Antoon Opperhuizen, and Aalt Bast. "Dietary Advanced Glycation Endproducts Decrease Glucocorticoid Sensitivity In Vitro." Nutrients 12, no. 2 (February 10, 2020): 441. http://dx.doi.org/10.3390/nu12020441.
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Glucocorticoids are very effective anti-inflammatory drugs and widely used for inflammatory bowel disease (IBD) patients. However, approximately 20% of IBD patients do not respond to glucocorticoids and the reason for this is largely unknown. Dietary advanced glycation endproducts (AGEs) are formed via the Maillard reaction during the thermal processing of food products and can induce a pro-inflammatory reaction in human cells. To investigate whether this pro-inflammatory response could be mitigated by glucocorticoids, human macrophage-like cells were exposed to both LPS and AGEs to induce interleukin-8 (IL8) secretion. This pro-inflammatory response was then modulated by adding pharmacological compounds interfering in different steps of the anti-inflammatory mechanism of glucocorticoids: rapamycin, quercetin, and theophylline. Additionally, intracellular reactive oxygen species (ROS) were measured and the glucocorticoid receptor phosphorylation state was assessed. The results show that AGEs induced glucocorticoid resistance, which could be mitigated by quercetin and rapamycin. No change in the phosphorylation state of the glucocorticoid receptor was observed. Additionally, intracellular ROS formation was induced by AGEs, which was mitigated by quercetin. This suggests that AGE-induced ROS is an underlying mechanism to AGE-induced glucocorticoid resistance. This study shows for the first time the phenomenon of dietary AGE-induced glucocorticoid resistance due to the formation of ROS. Our findings indicate that food products with a high inflammatory potential can induce glucocorticoid resistance; these results may be of great importance to IBD patients suffering from glucocorticoid resistance.
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Woldeamanuel, Yohannes W., Bharati M. Sanjanwala, and Robert P. Cowan. "Endogenous glucocorticoids may serve as biomarkers for migraine chronification." Therapeutic Advances in Chronic Disease 11 (January 2020): 204062232093979. http://dx.doi.org/10.1177/2040622320939793.
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Aims: The aims of this study were to: (a) identify differences in serum and cerebrospinal fluid (CSF) glucocorticoids among episodic migraine (EM) and chronic migraine (CM) patients compared with controls; (b) determine longitudinal changes in serum glucocorticoids in CM patients; and (c) determine migraine-related clinical features contributing to glucocorticoid levels. Methods: Serum and CSF levels of cortisol and corticosterone were measured using liquid chromatography-mass spectrometry among adult patients with EM, CM, and controls. Serum and CSF samples were collected from 26 and four participants in each group, respectively. Serum glucocorticoids were measured at a second timepoint after 2 years among 10 of the CM patients, six of whom reverted to EM while four persisted as CM. Receiver operating characteristic (ROC) analysis was made to assess the migraine diagnostic performance of glucocorticoids. Regression analysis was conducted to determine the link between glucocorticoid levels and migraine-related clinical variables. Results: CM patients exhibited significantly elevated serum and CSF levels of cortisol and corticosterone compared with controls and EM patients (age, sex, body mass index adjusted; Kruskal–Wallis p < 0.05). ROC showed area-under-curve of 0.89 to differentiate CM from EM. CM patients with remission had their serum glucocorticoids return to control or near EM levels ( p < 0.05). Persistent CM showed unremitting serum glucocorticoids. Migraine frequency and disability contributed to increased cortisol, while pain self-efficacy predicted lower cortisol levels ( p < 0.005). Conclusion: Endogenous glucocorticoids may be biomarkers for migraine progression and for monitoring treatment response. Improving pain self-efficacy skills may help optimize endogenous glucocorticoid levels, which in turn may prevent migraine attacks.