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Glucocorticoid receptor ( GR )

Diego M Presman, Gordon L Hager
It is widely accepted that the glucocorticoid receptor (GR), a ligand-regulated transcription factor that triggers anti-inflammatory responses, binds specific response elements as a homodimer. Here, we will discuss the original primary data that established this model and contrast it with a recent report characterizing the GR-DNA complex as a tetramer.
October 20, 2016: Transcription
Sandip K Boss, Irina Hutson, Charles Harris
Exogenous glucocorticoid (GC) administration results in hyperglycemia, insulin resistance, hepatic dyslipidemia and hypertension, a constellation of findings known as Cushing's syndrome. These effects are mediated by the glucocorticoid receptor (GR). Since GR activation in liver and adipose has been implicated in metabolic syndrome we wanted to determine the role of GR in these tissues in the development of metabolic syndrome. Since GRKO mice (whole body KO) exhibit perinatal lethality due to respiratory failure, we generated tissue specific (liver or adipose) GRKO mice using cre-lox technology...
October 18, 2016: Endocrinology
Andrea B Schote, Martina Bonenberger, Haukur Pálmason, Christiane Seitz, Jobst Meyer, Christine M Freitag
Stress results in a variety of neuroendocrine, immune and behavioral responses and represents a risk factor for many disorders. Following exposure to stress, glucocorticoids are secreted from the adrenal cortex and act via the ligand-activated glucocorticoid receptor (GR). Several polymorphisms of the GR-encoding gene NR3C1 have been described and functionally investigated. However, the impact of these variants on complex diseases such as Attention-Deficit/Hyperactivity Disorder (ADHD) is still unclear. In this study, 251 children with ADHD, 19 affected and 35 unaffected siblings, and their parents were included in a family-based association study assessing seven common variants of NR3C1 (TthIIII_rs10052957; NR3C1-I_rs10482605; ER22/23EK_rs6189/rs6190; N363S_rs56149945; BclI_rs41423247; GR-9beta_rs6198)...
October 2, 2016: Psychiatry Research
Kazuki Okamoto, Shizu Hirata-Tsuchiya, Chiaki Kitamura, Kazuki Omoteyama, Toshiyuki Sato, Mitsumi Arito, Manae S Kurokawa, Naoya Suematsu, Tomohiro Kato
Nuclear factor-κB (NF-κB) is the most potent pro-inflammatory transactivator, and an inhibitor of NF-κB is a good anti-inflammatory drug. Glucocorticoids (GCs) are the strongest and the most frequently used anti-inflammatory drugs. GCs-bound glucocorticoid receptor (GR) inhibits the transcriptional activity of NF-κB, and thereby suppresses a broad range of inflammatory processes. Concurrently, in whole body out side of inflammation area, GR exerts a lot of hormone action, which results in severe side effects...
October 14, 2016: Endocrinology
Henry Reyer, Siriluck Ponsuksili, Ellen Kanitz, Ralf Pöhland, Klaus Wimmers, Eduard Murani
The glucocorticoid receptor (GR) is a central player in the neuroendocrine stress response; it mediates feedback regulation of the hypothalamus-pituitary-adrenal (HPA) axis and physiological actions of glucocorticoids in the periphery. Despite intensive investigations of GR in the context of receptor-ligand interaction, only recently the first naturally occurring gain-of-function substitution, Ala610Val, of the ligand binding domain was identified in mammals. We showed that this mutation underlies a major quantitative trait locus for HPA axis activity in pigs, reducing cortisol production by about 40-50 percent...
2016: PloS One
Q Lv
OBJECTIVE: In order to seek an effective strategy for clinical treatment of acute lung injury (ALI), we are committed to explore the effect of combination therapy of glucocorticoid and hyaluronic acid on acute lung injury caused by an endotoxin (LPS) and its mechanism. MATERIALS AND METHODS: Adult male Sprague-Dawley (SD) rats were divided randomly into 5 groups: normal group (n=8); LPS group (n=8); dexamethasone +LPS group (DXMS group, n=8); hyaluronic acid+ LPS group (HA group, n=8); dexamethasone +hyaluronic acid +LPS group (DXMS+HA group, n=8)...
September 2016: European Review for Medical and Pharmacological Sciences
Daniel García-Pérez, Szilamer Ferenczi, Krisztina J Kovács, M Luisa Laorden, M Victoria Milanés, Cristina Núñez
Drug-withdrawal aversive memories generate a motivational state leading to compulsive drug taking, with plasticity changes in the basolateral amygdala (BLA) being essential in aversive motivational learning. The conditioned-place aversion (CPA) paradigm allows for measuring the negative affective component of drug withdrawal. First, CPA triggers association between negative affective consequences of withdrawal with context (memory consolidation). Afterwards, when the animals are re-exposed to the paired environment, they avoid it due to the association between the context and aversive memories (memory retrieval)...
September 28, 2016: Psychoneuroendocrinology
Hang He, Ya-Li Nie, Jiang-Feng Li, Xiang-Guang Meng, Wei-Hong Yang, Yu-Long Chen, Shu-Jie Wang, Xiaochao Ma, Quan-Cheng Kan, Li-Rong Zhang
CYP3A4 and CYP3A7 are generally served as the major adult and fetal liver forms, respectively, and exhibited a developmental switch during liver maturation. The objective of this study was to explore the potential mechanisms associated with the developmental switch of CYP3A4 and CYP3A7 in the Chinese Han population. We analyzed CYP3A4/7, nuclear receptors, and epigenetic modifications in human liver samples. We found that the expression levels of CYP3A4 mRNA in adults were significantly higher than the levels in fetus...
September 9, 2016: Drug Metabolism and Pharmacokinetics
Dominique Piber, Katharina Schultebraucks, Sven C Mueller, Christian Deuter, Katja Wingenfeld, Christian Otte
OBJECTIVES: Stress hormones such as cortisol are known to influence a wide range of cognitive functions, including hippocampal based spatial memory. In the brain, cortisol acts via two different receptors: the glucocorticoid (GR) and the mineralocorticoid receptor (MR). As the MR has a high density in the hippocampus, we examined the effects of pharmacological MR stimulation on spatial memory. METHODS: Eighty healthy participants (40 women, 40 men, mean age=23.9years±SD=3...
October 7, 2016: Neurobiology of Learning and Memory
Rafael Carvalho Torres, Nathalia Santos Magalhães, Patrícia M R E Silva, Marco A Martins, Vinicius F Carvalho
Increased hypothalamus-pituitary-adrenal axis (HPA) activity in diabetes is strongly associated with several morbidities noted in patients with the disease. We previously demonstrated that hyperactivity of HPA axis under diabetic conditions is associated with up-regulation of adrenocorticotrophic hormone (ACTH) receptors (MC2R) in adrenal and down-regulation of glucocorticoid receptors (GR and MR) in pituitary. This study investigates the role of peroxisome proliferator-activated receptor (PPAR)-γ in HPA axis hyperactivity in diabetic rats...
October 8, 2016: Experimental and Molecular Pathology
Jeroen Melief, Jan W Koper, Erik Endert, Holger J Møller, Jörg Hamann, Bernard M Uitdehaag, Inge Huitinga
As high cortisol levels are implicated in suppressed disease activity of multiple sclerosis (MS), glucocorticoid receptor (GR) polymorphisms that affect glucocorticoid (GC) sensitivity may impact on this by changing local immunomodulation or regulation of the hypothalamus-pituitary-adrenal (HPA)-axis. In this post-mortem study, we investigated whether GR haplotypes affect MS disease course and production of cortisol and soluble CD163 (sCD163), a molecule induced by GC on microglia/macrophages. We found that GR haplotypes that confer high GC sensitivity are associated with more aggressive MS but do not affect levels of cortisol secreted by the HPA-axis or shedding of CD163...
October 15, 2016: Journal of Neuroimmunology
Zsolt Nagy, Alexa Marta, Henriett Butz, Istvan Liko, Karoly Racz, Attila Patocs
Peripheral clocks are set by different nervous, hormonal and metabolic stimuli, and regulate the circadian expression of several genes. We investigated whether a peripheral clock could be induced in the human adrenocortical cell line H295R and whether glucocorticoid receptor isoforms (GRα and GRß) are involved in this clock system. After synchronization of cells with serum shock, the rhythmic oscillation of clock genes PER1, PER2, REV-ERBα, and ARNTL was confirmed. In addition, H295R cells even without serum shock showed rhythmic expression of PER1, PER2, CRY1 and ARNTL...
October 7, 2016: Steroids
Tanwir Habib, Ameera Sadoun, Nancy Nader, Shigeru Suzuki, Wei Liu, Puthen V Jithesh, Tomoshige Kino
Glucocorticoids are important therapeutic compounds for acute lymphoblastic leukemia (ALL). AKT1 or the protein kinase B is frequently activated in ALL, and contributes to the development of glucocorticoid resistance. We examined impact of AKT1 on glucocorticoid receptor (GR)-induced transcriptional activity in cooperation with phospho-serine/threonine-binding protein 14-3-3. AKT1 has two distinct actions on GR transcriptional activity, one through segregation of GR in the cytoplasm by phosphorylating GR at Ser-134 and subsequent association of 14-3-3, and the other through direct modulation of GR transcriptional activity in the nucleus...
October 4, 2016: Molecular and Cellular Endocrinology
Olivier Malaise, Biserka Relic, Edith Charlier, Mustapha Zeddou, Sophie Neuville, Céline Deroyer, Philippe Gillet, Edouard Louis, Michel G Malaise, Dominique de Seny
BACKGROUND: Glucocorticoid-induced leucine zipper (GILZ) is a mediator of the anti-inflammatory activities of glucocorticoids. However, GILZ deletion does not impair the anti-inflammatory activities of exogenous glucocorticoids in mice arthritis models and GILZ could also mediate some glucocorticoid-related adverse events. Osteoarthritis (OA) is a metabolic disorder that is partly attributed to adipokines such as leptin, and we previously observed that glucocorticoids induced leptin secretion in OA synovial fibroblasts...
October 4, 2016: Arthritis Research & Therapy
Nora Sundahl, Dorien Clarisse, Marc Bracke, Fritz Offner, Wim Vanden Berghe, Ilse M Beck
Although adverse effects and glucocorticoid resistance cripple their chronic use, glucocorticoids form the mainstay therapy for acute and chronic inflammatory disorders, and play an important role in treatment protocols of both lymphoid malignancies and as adjuvant to stimulate therapy tolerability in various solid tumors. Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance...
2016: Oncoscience
Xavier Catteau, Philippe Simon, Frédéric Buxant, Jean-Christophe Noël
Cancer- associated fibroblasts (CAFs) are actively involved in breast carcinoma. Our previous study demonstrated that the majority of these CAFs were smooth muscle actin (SMA) positive and were therefore termed peritumoral myofibroblast (PMY). Glucocorticoid, linked or not with its receptor (GR), has been postulated to serve a major role in normal breast and breast carcinoma; however, their role in CAFs remains poorly understood. The aim of the present study was to assess the presence of GR in breast CAFs and particularly in PMY in 56 cases of invasive breast carcinoma in correlation with clinicopathological parameters, by immunohistochemistry...
October 2016: Molecular and Clinical Oncology
Katharina R Beck, Tanja J Sommer, Daniela Schuster, Alex Odermatt
The incidence of immune-related diseases increased over the last years in industrialized countries, suggesting a contribution of environmental factors. Impaired glucocorticoid action has been associated with immune disorders. Thus, there is an increasing interest to identify chemicals disrupting glucocorticoid action. The widely used flame retardant tetrabromobisphenol A (TBBPA) was reported earlier to potently inhibit glucocorticoid receptor (GR) and moderately androgen receptor (AR) activity in yeast-based reporter gene assays...
September 28, 2016: Toxicology
Takashi Okabe, Rohit Chavan, Sara S Fonseca Costa, Andrea Brenna, Jürgen A Ripperger, Urs Albrecht
REV-ERBα (Nr1d1) is a nuclear receptor that is part of the circadian clock mechanism and regulates metabolism and inflammatory processes. The glucocorticoid receptor (GR, Nr3c1) influences similar processes, but is not part of the circadian clock although glucocorticoid signaling affects resetting of the circadian clock in peripheral tissues. Because of their similar impact on physiological processes we studied the interplay between these two nuclear receptors. We found that REV-ERBα binds to the C-terminal part and GR to the N-terminal part of HSP90, a chaperone responsible for the activation of proteins to ensure survival of a cell...
September 29, 2016: Journal of Cell Science
Kristina M Mueller, Kerstin Hartmann, Doris Kaltenecker, Sabine Vettorazzi, Mandy Bauer, Lea Mauser, Sabine Amann, Sigrid Jall, Katrin Fischer, Harald Esterbauer, Timo D Müller, Matthias H Tschöp, Christoph Magnes, Johannes Haybaeck, Thomas Scherer, Natalie Bordag, Jan P Tuckermann, Richard Moriggl
Glucocorticoids (GCs) are important regulators of systemic energy metabolism, while aberrant GC action is linked to metabolic dysfunctions. Yet, the extent to which normal and pathophysiologic energy metabolism depend on the glucocorticoid receptor (GR) in adipocytes remains unclear. Here, we demonstrate that adipocyte GR-deficiency in mice significantly impacts systemic metabolism in different energetic states. Plasma metabolomics and biochemical analyses revealed a marked global effect of GR-deficiency on systemic metabolite abundance and thus, substrate partitioning in fed and fasted states...
September 20, 2016: Diabetes
Edward J Dougherty, Jason M Elinoff, Gabriela A Ferreyra, Angela Hou, Rongman Cai, Junfeng Sun, Kevin P Blaine, Shuibang Wang, Robert L Danner
Glucocorticoids are commonly used to treat inflammatory disorders. The glucocorticoid receptor (GR) can tether to inflammatory transcription factor complexes such as NFκB and AP-1 and trans-repress the transcription of cytokines, chemokines and adhesion molecules. In contrast, aldosterone and the mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by incompletely understood mechanisms. While MR has been shown to weakly repress NFκB, its role in modulating AP-1 has not been established...
September 20, 2016: Journal of Biological Chemistry
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