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

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

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

  • pioneer factors foxa1 and foxa2 assist selective glucocorticoid receptor signaling in human endometrial cells
    Endocrinology, 2017
    Co-Authors: Shannon Whirledge, Edwina P. Kisanga, Robert N Taylor, John A. Cidlowski
    Abstract:

    Successful pregnancy relies on dynamic control of cell signaling to achieve uterine receptivity and the necessary biological changes required for endometrial decidualization, embryo implantation, and fetal development. Glucocorticoids are master regulators of intracellular signaling and can directly regulate embryo implantation and endometrial remodeling during murine pregnancy. In immortalized human uterine cells, we have shown that Glucocorticoids and estradiol (E2) coregulate thousands of genes. Recently, Glucocorticoids and E2 were shown to coregulate the expression of Left-right determination factor 1 (LEFTY1), previously implicated in the regulation of decidualization. To elucidate the molecular mechanism by which Glucocorticoids and E2 regulate the expression of LEFTY1, immortalized and primary human endometrial cells were evaluated for gene expression and receptor recruitment to regulatory regions of the LEFTY1 gene. Glucocorticoid administration induced expression of LEFTY1 messenger RNA and protein and recruitment of the glucocorticoid receptor (GR) and activated polymerase 2 to the promoter of LEFTY1. Glucocorticoid-mediated recruitment of GR was dependent on pioneer factors FOXA1 and FOXA2. E2 was found to antagonize glucocorticoid-mediated induction of LEFTY1 by reducing recruitment of GR, FOXA1, FOXA2, and activated polymerase 2 to the LEFTY1 promoter. Gene expression analysis identified several genes whose glucocorticoid-dependent induction required FOXA1 and FOXA2 in endometrial cells. These results suggest a molecular mechanism by which E2 antagonizes GR-dependent induction of specific genes by preventing the recruitment of the pioneer factors FOXA1 and FOXA2 in a physiologically relevant model.

  • glucocorticoid action in human corneal epithelial cells establishes roles for corticosteroids in wound healing and barrier function of the eye
    Experimental Eye Research, 2016
    Co-Authors: Mahita Kadmiel, Agnes K Janoshazi, John A. Cidlowski
    Abstract:

    Glucocorticoids play diverse roles in almost all physiological systems of the body, including both anti-inflammatory and immunosuppressive roles. Synthetic Glucocorticoids are one of the most widely prescribed drugs and are used in the treatment of conditions such as autoimmune diseases, allergies, ocular disorders and certain types of cancers. In the interest of investigating glucocorticoid actions in the cornea of the eye, we established that multiple cell types in mouse corneas express functional glucocorticoid receptor (GR) with corneal epithelial cells having robust expression. To define glucocorticoid actions in a cell type-specific manner, we employed immortalized human corneal epithelial (HCE) cell line to define the glucocorticoid transcriptome and elucidated its functions in corneal epithelial cells. Over 4000 genes were significantly regulated within 6 h of dexamethasone treatment, and genes associated with cell movement, cytoskeletal remodeling and permeability were highly regulated. Real-time in vitro wound healing assays revealed that Glucocorticoids delay wound healing by attenuating cell migration. These functional alterations were associated with cytoskeletal remodeling at the wounded edge of a scratch-wounded monolayer. However, glucocorticoid treatment improved the organization of tight-junction proteins and enhanced the epithelial barrier function. Our results demonstrate that Glucocorticoids profoundly alter corneal epithelial gene expression and many of these changes likely impact both wound healing and epithelial cell barrier function.

  • corticosteroids mechanisms of action in health and disease
    Rheumatic Diseases Clinics of North America, 2016
    Co-Authors: Sivapriya Ramamoorthy, John A. Cidlowski
    Abstract:

    Glucocorticoids are primary stress hormones that regulate a variety of physiologic processes and are essential for life. The actions of Glucocorticoids are predominantly mediated through the classic glucocorticoid receptor (GR). GRs are expressed throughout the body, but there is considerable heterogeneity in glucocorticoid sensitivity and biologic responses across tissues. The conventional belief that Glucocorticoids act through a single GR protein has changed dramatically with the discovery of a diverse collection of receptor isoforms. This article provides an overview of the molecular mechanisms that regulate glucocorticoid actions, highlights the dynamic nature of hormone signaling, and discusses the molecular properties of the GR isoforms.

  • one hormone two actions anti and pro inflammatory effects of Glucocorticoids
    Neuroimmunomodulation, 2015
    Co-Authors: Diana Cruztopete, John A. Cidlowski
    Abstract:

    Glucocorticoids are essential steroid hormones secreted from the adrenal gland in response to stress. Since their discovery in the 1940s, Glucocorticoids have been widely prescribed to treat inflammatory disorders and hematological cancers. In the traditional view, Glucocorticoids are regarded as anti-inflammatory molecules; however, emerging evidence suggests that glucocorticoid actions are more complex than previously anticipated. The anti-inflammatory activity of Glucocorticoids is attributed to the repression of pro-inflammatory genes through signal transduction by their steroid receptor, the glucocorticoid receptor (GR). The mechanisms modulating the pro-inflammatory effects of Glucocorticoids are not well understood. In this review, we discuss recent findings that provide insights into the mechanism by which GR signaling can play a dual role in the regulation of the immune response. We hypothesize that these apparently opposite processes are working together to prepare the immune system to respond to a stressor (pro-inflammatory effects) and subsequently restore homeostasis (anti-inflammatory effects). Finally, we propose that determining the mechanisms which underlie the tissue-specific effects of Glucocorticoids will provide an excellent tool to develop more efficient and selective glucocorticoid therapies.

Benno Roozendaal - One of the best experts on this subject based on the ideXlab platform.

  • systems mediating acute glucocorticoid effects on memory consolidation and retrieval
    Progress in Neuro-psychopharmacology & Biological Psychiatry, 2003
    Co-Authors: Benno Roozendaal
    Abstract:

    It is well established that glucocorticoid hormones, secreted by the adrenal cortex after a stressful event, influence cognitive performance. This article reviews recent findings from this laboratory on the acute effects of Glucocorticoids in rats on specific memory phases, i.e., memory consolidation and memory retrieval. Posttraining activation of glucocorticoid-sensitive pathways involving glucocorticoid receptors (GRs) enhances memory consolidation in a dose-dependent manner. Glucocorticoid influences on memory consolidation depend on noradrenergic activation of the basolateral complex of the amygdala (BLA) and interactions of the BLA with other brain regions. By contrast, memory retrieval processes are usually impaired with high circulating levels of Glucocorticoids or following infusions of GR agonists into the hippocampus. Although the BLA does not appear to be a site of glucocorticoid action in influencing memory retrieval, an intact BLA is required for enabling glucocorticoid effects on memory retrieval. The BLA appears to be a key structure in a memory-modulatory system that regulates, in concert with other brain regions, stress and glucocorticoid effects on both memory consolidation and memory retrieval.

  • Stress and memory: opposing effects of Glucocorticoids on memory consolidation and memory retrieval.
    Neurobiology of learning and memory, 2002
    Co-Authors: Benno Roozendaal
    Abstract:

    It is well established that glucocorticoid hormones, secreted by the adrenal cortex after a stressful event, influence cognitive performance. Some studies have found glucocorticoid-induced memory enhancement. However, many studies have reported impairing effects of Glucocorticoids on memory function. This paper reviews recent findings from this laboratory on the acute effects of Glucocorticoids in rats on specific memory phases, i.e., memory consolidation and memory retrieval. The evidence suggests that the consequences of glucocorticoid activation on cognition depend largely on the different memory phases investigated. Posttraining activation of glucocorticoid-sensitive pathways involving glucocorticoid receptors enhances memory consolidation in a pattern highly similar to that previously described for adrenal catecholamines. Also, similar to catecholamine effects on memory consolidation, glucocorticoid influences on memory consolidation depend on noradrenergic activation of the basolateral complex of the amygdala and interactions with other brain regions. By contrast, memory retrieval processes are usually impaired with high circulating levels of Glucocorticoids or following infusions of glucocorticoid receptor agonists into the hippocampus. The hypothesis is proposed that these apparently dual effects of Glucocorticoids on memory consolidation and memory retrieval might be related and that the basolateral complex of the amygdala is a key structure in a memory-modulatory system that regulates, in concert with other brain regions, stress and glucocorticoid effects on both memory consolidation and memory retrieval.

Jen-chywan Wang - One of the best experts on this subject based on the ideXlab platform.

  • Pik3r1 Is Required for Glucocorticoid-Induced Perilipin 1 Phosphorylation in Lipid Droplet for Adipocyte Lipolysis.
    Diabetes, 2017
    Co-Authors: Taiyi Kuo, Tzu-chieh Chen, Rebecca A. Lee, Nguyen Huynh Thao Nguyen, Augusta E. Broughton, Danyun Zhang, Jen-chywan Wang
    Abstract:

    Glucocorticoids promote lipolysis in white adipose tissue (WAT) to adapt to energy demands under stress, whereas superfluous lipolysis causes metabolic disorders, including dyslipidemia and hepatic steatosis. Glucocorticoid-induced lipolysis requires the phosphorylation of cytosolic hormone-sensitive lipase (HSL) and perilipin 1 (Plin1) in the lipid droplet by protein kinase A (PKA). We previously identified Pik3r1 (also called p85α) as a glucocorticoid receptor target gene. Here, we found that Glucocorticoids increased HSL phosphorylation, but not Plin1 phosphorylation, in adipose tissue-specific Pik3r1-null (AKO) mice. Furthermore, in lipid droplets, the phosphorylation of HSL and Plin1 and the levels of catalytic and regulatory subunits of PKA were increased by Glucocorticoids in wild-type mice. However, these effects were attenuated in AKO mice. In agreement with reduced WAT lipolysis, glucocorticoid- initiated hepatic steatosis and hypertriglyceridemia were improved in AKO mice. Our data demonstrated a novel role of Pik3r1 that was independent of the regulatory function of phosphoinositide 3-kinase in mediating the metabolic action of Glucocorticoids. Thus, the inhibition of Pik3r1 in adipocytes could alleviate lipid disorders caused by excess glucocorticoid exposure.

  • Regulation of Glucose Homeostasis by Glucocorticoids.
    Advances in experimental medicine and biology, 2015
    Co-Authors: Taiyi Kuo, Allison E. Mcqueen, Tzu-chieh Chen, Jen-chywan Wang
    Abstract:

    Glucocorticoids are steroid hormones that regulate multiple aspects of glucose homeostasis. Glucocorticoids promote gluconeogenesis in liver, whereas in skeletal muscle and white adipose tissue they decrease glucose uptake and utilization by antagonizing insulin response. Therefore, excess glucocorticoid exposure causes hyperglycemia and insulin resistance. Glucocorticoids also regulate glycogen metabolism. In liver, Glucocorticoids increase glycogen storage, whereas in skeletal muscle they play a permissive role for catecholamine-induced glycogenolysis and/or inhibit insulin-stimulated glycogen synthesis. Moreover, Glucocorticoids modulate the function of pancreatic α and β cells to regulate the secretion of glucagon and insulin, two hormones that play a pivotal role in the regulation of blood glucose levels. Overall, the major glucocorticoid effect on glucose homeostasis is to preserve plasma glucose for brain during stress, as transiently raising blood glucose is important to promote maximal brain function. In this chapter we will discuss the current understanding of the mechanisms underlying different aspects of glucocorticoid-regulated mammalian glucose homeostasis.

  • genome wide analysis of glucocorticoid receptor binding sites in myotubes identifies gene networks modulating insulin signaling
    Proceedings of the National Academy of Sciences of the United States of America, 2012
    Co-Authors: Taiyi Kuo, Michelle J Lew, Oleg Mayba, Charles A Harris, Terence P Speed, Jen-chywan Wang
    Abstract:

    Glucocorticoids elicit a variety of biological responses in skeletal muscle, including inhibiting protein synthesis and insulin-stimulated glucose uptake and promoting proteolysis. Thus, excess or chronic glucocorticoid exposure leads to muscle atrophy and insulin resistance. Glucocorticoids propagate their signal mainly through glucocorticoid receptors (GR), which, upon binding to ligands, translocate to the nucleus and bind to genomic glucocorticoid response elements to regulate the transcription of nearby genes. Using a combination of chromatin immunoprecipitation sequencing and microarray analysis, we identified 173 genes in mouse C2C12 myotubes. The mouse genome contains GR-binding regions in or near these genes, and gene expression is regulated by Glucocorticoids. Eight of these genes encode proteins known to regulate distinct signaling events in insulin/insulin-like growth factor 1 pathways. We found that overexpression of p85α, one of these eight genes, caused a decrease in C2C12 myotube diameters, mimicking the effect of Glucocorticoids. Moreover, reducing p85α expression by RNA interference in C2C12 myotubes significantly compromised the ability of Glucocorticoids to inhibit Akt and p70 S6 kinase activity and reduced glucocorticoid induction of insulin receptor substrate 1 phosphorylation at serine 307. This phosphorylation is associated with insulin resistance. Furthermore, decreasing p85α expression abolished glucocorticoid inhibition of protein synthesis and compromised glucocorticoid-induced reduction of cell diameters in C2C12 myotubes. Finally, a glucocorticoid response element was identified in the p85α GR-binding regions. In summary, our studies identified GR-regulated transcriptional networks in myotubes and showed that p85α plays a critical role in glucocorticoid-induced insulin resistance and muscle atrophy in C2C12 myotubes.

  • transcriptional regulation of human dual specificity protein phosphatase 1 dusp1 gene by Glucocorticoids
    PLOS ONE, 2010
    Co-Authors: Lauren E Shipp, Chiyi Yu, Miles A Pufall, Pili Zhang, Donald K Scott, Jen-chywan Wang
    Abstract:

    Background: Glucocorticoids are potent anti-inflammatory agents commonly used to treat inflammatory diseases. They convey signals through the intracellular glucocorticoid receptor (GR), which upon binding to ligands, associates with genomic glucocorticoid response elements (GREs) to regulate transcription of associated genes. One mechanism by which Glucocorticoids inhibit inflammation is through induction of the dual specificity phosphatase-1 (DUSP1, a.k.a. mitogenactivated protein kinase phosphatase-1, MKP-1) gene. Methodology/Principal Findings: We found that Glucocorticoids rapidly increased transcription of DUSP1 within 10 minutes in A549 human lung adenocarcinoma cells. Using chromatin immunoprecipitation (ChIP) scanning, we located a GR binding region between 21421 and 21118 upstream of the DUSP1 transcription start site. This region is active in a reporter system, and mutagenesis analyses identified a functional GRE located between 21337 and 21323. We found that Glucocorticoids increased DNase I hypersensitivity, reduced nucleosome density, and increased histone H3 and H4 acetylation within genomic regions surrounding the GRE. ChIP experiments showed that p300 was recruited to the DUSP1 GRE, and RNA interference experiments demonstrated that reduction of p300 decreased glucocorticoid-stimulated DUSP1 gene expression and histone H3 hyperacetylation. Furthermore, overexpression of p300 potentiated Glucocorticoidstimulated activity of a reporter gene containing the DUSP1 GRE, and this coactivation effect was compromised when the histone acetyltransferase domain was mutated. ChIP-reChIP experiments using GR followed by p300 antibodies showed significant enrichment of the DUSP1 GRE upon glucocorticoid treatment, suggesting that GR and p300 are in the same protein complex recruited to the DUSP1 GRE. Conclusions/Significance: Our studies identified a functional GRE for the DUSP1 gene. Moreover, the transcriptional activation of DUSP1 by Glucocorticoids requires p300 and a rapid modification of the chromatin structure surrounding the GRE. Overall, understanding the mechanism of glucocorticoid-induced DUSP1 gene transcription could provide insights into therapeutic approaches against inflammatory diseases.

Jiménez-canizales, Carlos Eduardo - One of the best experts on this subject based on the ideXlab platform.

  • Baja frecuencia de prescripción de profilaxis para osteoporosis en pacientes en tratamiento crónico con corticoides en Colombia
    Instituto Nacional de Salud, 2014
    Co-Authors: Machado-alba Jorge, Alzate-carvajal Verónica, Mondragón-cardona Álvaro, Jiménez-canizales, Carlos Eduardo
    Abstract:

    Objective. To identify the frequency of drug use for the prevention of corticosteroid induced osteoporosis (CIO) among patients using corticosteroids for more than three months affiliated to the General Social Health Security System of Colombia. Materials and methods. Cross-sectional study. Information about people affiliated to the General Social Health Security System of Colombia (3.7 million) was used. This study included men and women of all ages having been prescribed any glucocorticoid from August 1 to November 30, 2011. Sociodemographic variables and the characteristics of of the glucocorticoid prescription and CIO prophylaxis drugs in a defined daily dose (DDD) were identified. Results. A database of 255,568 prescriptions of Glucocorticoids was obtained, with a total of 1,837 patients receiving some glucocorticoid chronically. The majority of participants were females (60.2%), with an average age of 55.2±16.9 years distributed in 65 cities of the country. Prednisolone was the most commonly used glucocorticoid (1,546 patients, 84.1%), whereas the most prescribed prophylaxis drug used was calcitriol (67.1%). Despite the need to receive prophylaxis, 994 cases (54.2%) were not receiving it. Conclusions. There is a poor utilization of CIO prophylaxis. The implementation of drug surveillance actions that allow the identification of problems related to these drugs in order to prevent adverse events and optimize resources is recommended, thus anticipating the emergence of complications in the patients.Objetivos. Identificar la frecuencia de uso de medicamentos para prevención de osteoporosis inducida por corticoides (OIC) en pacientes que reciben corticoides por un periodo mayor a tres meses y que son afiliados al Sistema General de Seguridad Social en Salud de Colombia. Materiales y métodos. Estudio de tipo transversal. Se utilizó información sobre, las personas afiliadas al Sistema General de Seguridad Social en Salud de Colombia (3,7 millones). Se incluyeron en el trabajo los usuarios de todas las edades y sexos a los cuales se les indicó algún glucocorticoide entre el 1 de agosto y 30 de noviembre de 2011.Se identificaron variables sociodemográficas y las características de prescripción de glucocorticoides y medicamentos para profilaxis de OIC con dosis expresadas en dosis diarias definidas (DDD). Resultados. Se obtuvo una base de datos de 255 568 prescripciones de glucocorticoides, de los cuales 1837 pacientes recibían algún glucocorticoide de manera crónica. Predominaron pacientes de sexo femenino (60,2%), edad promedio de 55,2±16,9 años distribuidos en 65 ciudades del país. El glucocorticoide más utilizado fue prednisolona en 1546 (84,1%), mientras que el medicamento para profilaxis más prescrito fue calcitriol (67,1%). Se encontraron 994 casos (54,2%) que no estaban recibiendo profilaxis para osteoporosis a pesar de requerirlo. Conclusiones. Existe un bajo empleo de profilaxis para OIC. Se recomienda implementar acciones de farmacovigilancia que permitan identificar problemas relacionados con medicamentos para prevenir eventos adversos y optimizar recursos, anticipándose a la aparición de complicaciones para el paciente

Carlos Eduardo Jiménez-canizales - One of the best experts on this subject based on the ideXlab platform.

  • Baja frecuencia de prescripción de profilaxis para osteoporosis en pacientes en tratamiento crónico con corticoides en Colombia Low frequency of prophylaxis prescription for osteoporosis in patients receiving chronic treatment with corticosteroids in Colombia
    Instituto Nacional de Salud, 2013
    Co-Authors: Jorge Machado-alba, Verónica Alzate-carvajal, Álvaro Mondragón-cardona, Carlos Eduardo Jiménez-canizales
    Abstract:

    Objetivos. Identificar la frecuencia de uso de medicamentos para prevención de osteoporosis inducida por corticoides (OIC) en pacientes que reciben corticoides por un periodo mayor a tres meses y que son afiliados al Sistema General de Seguridad Social en Salud de Colombia. Materiales y métodos. Estudio de tipo transversal. Se utilizó información sobre, las personas afiliadas al Sistema General de Seguridad Social en Salud de Colombia (3,7 millones). Se incluyeron en el trabajo los usuarios de todas las edades y sexos a los cuales se les indicó algún glucocorticoide entre el 1 de agosto y 30 de noviembre de 2011.Se identificaron variables sociodemográficas y las características de prescripción de glucocorticoides y medicamentos para profilaxis de OIC con dosis expresadas en dosis diarias definidas (DDD). Resultados. Se obtuvo una base de datos de 255 568 prescripciones de glucocorticoides, de los cuales 1837 pacientes recibían algún glucocorticoide de manera crónica. Predominaron pacientes de sexo femenino (60,2%), edad promedio de 55,2± 16,9 años distribuidos en 65 ciudades del país. El glucocorticoide más utilizado fue prednisolona en 1546 (84,1%), mientras que el medicamento para profilaxis más prescrito fue calcitriol (67,1%). Se encontraron 994 casos (54,2%) que no estaban recibiendo profilaxis para osteoporosis a pesar de requerirlo. Conclusiones. Existe un bajo empleo de profilaxis para OIC. Se recomienda implementar acciones de farmacovigilancia que permitan identificar problemas relacionados con medicamentos para prevenir eventos adversos y optimizar recursos, anticipándose a la aparición de complicaciones para el pacienteObjective. To identify the frequency of drug use for the prevention of corticosteroid induced osteoporosis (CIO) among patients using corticosteroids for more than three months affiliated to the General Social Health Security System of Colombia. Materials and methods. Cross-sectional study. Information about people affiliated to the General Social Health Security System of Colombia (3.7 million) was used. This study included men and women of all ages having been prescribed any glucocorticoid from August 1 to November 30, 2011. Sociodemographic variables and the characteristics of of the glucocorticoid prescription and CIO prophylaxis drugs in a defined daily dose (DDD) were identified. Results. A database of 255,568 prescriptions of Glucocorticoids was obtained, with a total of 1,837 patients receiving some glucocorticoid chronically. The majority of participants were females (60.2%), with an average age of 55.2± 16.9 years distributed in 65 cities of the country. Prednisolone was the most commonly used glucocorticoid (1,546 patients, 84.1%), whereas the most prescribed prophylaxis drug used was calcitriol (67.1%). Despite the need to receive prophylaxis, 994 cases (54.2%) were not receiving it. Conclusions. There is a poor utilization of CIO prophylaxis. The implementation of drug surveillance actions that allow the identification of problems related to these drugs in order to prevent adverse events and optimize resources is recommended, thus anticipating the emergence of complications in the patient