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Glucocorticoid receptor

Charlotte L George, Matthew T Birnie, Benjamin Flynn, Yvonne Kershaw, Stafford L Lightman, Becky L Conway-Campbell
In this paper we report differential decoding of the ultradian corticosterone signal by glucocorticoid target tissues. Pulsatile corticosterone replacement in adrenalectomised rats resulted in different dynamics of Sgk1 mRNA production, with a distinct pulsatile mRNA induction profile observed in the pituitary in contrast to a non-pulsatile induction in the prefrontal cortex. We further report the first evidence for pulsatile transcriptional repression of a glucocorticoid-target gene in vivo, with pulsatile regulation of Pomc transcription in pituitary...
October 18, 2016: Molecular and Cellular Endocrinology
Greg Hodge, Eugene Roscioli, Hubertus Jersmann, Hai B Tran, Mark Holmes, Paul N Reynolds, Sandra Hodge
BACKGROUND: Corticosteroid resistance is a major barrier to effective treatment of COPD. We have shown that the resistance is associated with decreased expression of glucocorticoid receptor (GCR) by senescent CD28nullCD8+ pro-inflammatory lymphocytes in peripheral blood of COPD patients. GCR must be bound to molecular chaperones heat shock proteins (Hsp) 70 and Hsp90 to acquire a high-affinity steroid binding conformation, and traffic to the nucleus. We hypothesized a loss of Hsp70/90 from these lymphocytes may further contribute to steroid resistance in COPD...
October 21, 2016: Respiratory Research
Hiroaki Matsuno
BACKGROUND AND OBJECTIVES: Recently, the osteoporosis treatment has attracted attention, and several drugs have been developed. Among these, bisphosphonates (BPs), parathyroid hormone (PTH) and anti-receptor activator of nuclear factor kappa B ligand (RANKL) monoclonal (MAb) denosumab (DMAb) are the major osteoporosis agents. Several studies demonstrated that the effect of osteoporosis agents is evaluated by lumar or hip dual energy X-ray absorptiometry (DXA). However, private clinic commonly use the radial DXA...
October 20, 2016: Drugs in R&D
Gerwyn Morris, George Anderson, Michael Maes
There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels. This paper aims to review the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS, considering two possibilities: (a) Activation of immune-inflammatory pathways is secondary to HPA axis hypofunction via attenuated negative feedback mechanisms, or (b) chronic activated immune-inflammatory and O&NS pathways play a causative role in HPA axis hypoactivity...
October 20, 2016: Molecular Neurobiology
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
James Sm Cuffe, Eleanor L Turton, Lisa K Akison, Helle Bielefeldt-Ohmann, Karen M Moritz
Maternal stress can impair fetal development and program sex-specific disease outcomes in offspring through the actions of maternally produced glucocorticoids, predominantly corticosterone (Cort) in rodents. We have demonstrated in mice that male but not female offspring prenatally exposed to Cort (33µg/kg/h for 60h beginning at E12.5) develop cardiovascular/renal dysfunction at 12 months. At 6 months of age, renal function was normal but male offspring had increased plasma aldosterone concentrations, suggesting altered adrenal function may precede disease...
October 17, 2016: Journal of Endocrinology
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
InKyeom Kim
Histone deacetylases (HDACs) act as co-repressors in gene transcription by erasing the acetylation of histones, resulting in epigenetic gene silencing. Recent studies revealed that HDAC inhibitors attenuated blood pressure of several hypertensive animal models such as spontaneously hypertensive rats, hyperaldosteronism rats, angiotensin II-induced hypertensive rats and pulmonary hypertensive rats. Unexpectedly, microarray studies uncovered that administration of HDAC inhibitors decreased expression of some genes for example extracellular matrix proteins, oxidative stress-related proteins, cytokines, chemokines and ion transporters, mostly targets of corticoid receptors...
September 2016: Journal of Hypertension
Che Wei Liao, Chi Sheng Hung, Chia Hung Chou, Yen Tin Lin, Xue Ming Wu, Yi Yao Chang, Ying Hsien Chen, Vin Cent Wu, Yi Lwun Ho, Kwan Dun Wu, Yen Hung Lin
OBJECTIVE: Aldosterone induces myocardial fibrosis. The tissue inhibitor of metalloproteinases-1 (TIMP-1) is a key factor of myocardial fibrosis and diastolic dysfunction, but the effect of aldosterone on TIMP-1 expression remains unclear. We tested the hypothesis that aldosterone induces TIMP-1 expression and contributes to the fibrotic process. DESIGN AND METHOD: In the human study, we prospectively enrolled 54 patients with primary aldosteronism. Plasma TIMP-1 and echocardiographic parameters were measured...
September 2016: Journal of Hypertension
Naftali Stern
As both the rate of hypertension and cancer rise with age, concomitant hypertension in patients receiving treatment for cancer is very common. Increase in blood pressure during cancer treatment requires careful clinical assessment. Distinction between discontinuation or malabsorption of antihypertensive treatment due to factors such as nausea/vomiting/diarrhea and anti-cancer drug specific effects must be first made. De-novo hypertension during cancer treatment is likely related to anticancer drugs per se. Classical chemotherapeutic agents such as cyclophosphamide, cisplatin and busulfan have been previously linked to rising blood pressure...
September 2016: Journal of Hypertension
Gabriela M Balarini, Eliana Zandonade, Leandro Tanure, Gilda A Ferreira, Wildner M Sardenberg, Érica V Serrano, Cleia C Dias, Túlio P Navarro, Hilde H Nordal, Piotr M Mydel, Johan G Brun, Karl A Brokstad, Eva Gerdts, Roland Jonsson, Valéria Valim
OBJECTIVES: We aimed to identify the association of carotid atherosclerosis with the traditional risk factors, disease features, cytokine profile, and calprotectin in patients with primary Sjögren's syndrome (pSS). METHODS: 63 primary pSS patients and 63 age- and sex-matched healthy controls underwent carotid ultrasound, clinical and laboratory examination. The presence of carotid plaques was taken as carotid atherosclerosis. The covariates of carotid atherosclerosis were identified in univariate and multivariate regressions...
September 8, 2016: Clinical and Experimental Rheumatology
János Varga, Szilamér Ferenczi, Krisztina J Kovács, Ágnes Csáno, Barbora Prokopova, Daniela Jezova, Dóra Zelena
AIMS: In vasopressin-deficient rat pups stressor-induced adrenocorticotropin (ACTH) and corticosterone elevations markedly dissociate. We have shown recently that during the postnatal period mineralocorticoid secretion is more sensitive to stressor exposure than that of glucocorticoids. We have therefore hypothesized that in vasopressin-deficient pups during hypoglycemia, a stressor triggering aldosterone release mainly via ACTH, aldosterone release will change in parallel with ACTH. An additional aim was to reveal at which stage of the development occurs the shift from aldosterone to corticosterone as primarily stressor-induced adrenocortical hormone...
October 12, 2016: Life Sciences
Konrad Pazdrak, Christof Straub, Rosario Maroto, Susan Stafford, Wendy I White, William J Calhoun, Alexander Kurosky
The mechanisms contributing to persistent eosinophil activation and poor eosinopenic response to glucocorticoids in severe asthma are poorly defined. We examined the effect of cytokines typically overexpressed in the asthmatic airways on glucocorticoid signaling in in vitro activated eosinophils. An annexin V assay used to measure eosinophil apoptosis showed that cytokine combinations of IL-2 plus IL-4 as well as TNF-α plus IFN-γ, or IL-3, GM-CSF, and IL-5 alone significantly diminished the proapoptotic response to dexamethasone...
October 14, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
A E Hoban, R D Moloney, A V Golubeva, K A McVey Neufeld, O O'Sullivan, E Patterson, C Stanton, T G Dinan, G Clarke, J F Cryan
Gut microbiota colonization is a key event for host physiology that occurs early in life. Disruption of this process leads to altered brain development which ultimately manifests as changes in brain function and behaviour in adulthood. Studies using germ-free mice highlight the extreme impact on brain health that results from life without commensal microbes, however the impact of microbiota disturbances occurring in adulthood is less studied. To this end, we depleted the gut microbiota of 10-week-old male Sprague Dawley rats via chronic antibiotic treatment...
October 11, 2016: Neuroscience
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
Yasuharu Shinoda, Hideaki Tagashira, Md Shenuarin Bhuiyan, Hideyuki Hasegawa, Hiroshi Kanai, Chen Zhang, Feng Han, Kohji Fukunaga
Cardiovascular diseases are risk factors for depression in humans. We recently proposed that σ1 receptor (σ1R) stimulation rescued cardiac hypertrophy and heart failure induced by transverse aortic constriction (TAC) in mice. Importantly, σ1R stimulation reportedly ameliorates depression-like behaviors in rodents. Thus, we hypothesized that impaired σ1R activity in brain triggers depression-like behaviors in animals with cardiovascular disease. Indeed, here we found that cardiac hypertrophy and heart failure induced by TAC were associated with depression-like behaviors concomitant with downregulation of σ1R expression in brain 6 weeks after surgery...
2016: PloS One
Michele Miraglia Del Giudice, Annalisa Allegorico
The role of vitamin D in calcium and phosphate homeostasis is well known; however, in addition to traditional functions, vitamin D modulates a variety of processes, and evidence shows that it has an important role in different allergic diseases such as asthma, atopic dermatitis, and food allergy. Vitamin D acts by binding to the vitamin D receptor, which is present in a variety of tissues; for this reason it is considered a hormone. One of the most important functions is to modulate the immune system response, both innate and adaptive, by suppressing Th2-type response and increasing natural killer cells...
November 2016: Journal of Clinical Gastroenterology
Per Bäckman, Ulrika Tehler, Bo Olsson
BACKGROUND: Exposure following oral inhalation depends on the deposition pattern of the inhaled aerosol, the extent and rate of oral and pulmonary absorption, as well as systemic distribution and clearance. For lipophilic inhaled compounds with low water solubility and high permeability, the extent and rate of pulmonary absorption can be assumed dependent on deposition pattern as well as dissolution rate. MATERIALS AND METHODS: A mechanistic model of airway deposition, mucociliary clearance, dissolution, absorption, and dissipation was applied to simulate systemic exposure of the novel selective glucocorticoid receptor modulator, AZD5423, when dosed to healthy volunteers using two different nebulizers and two different dry powder inhalers in combination with two different primary particle size distributions...
October 14, 2016: Journal of Aerosol Medicine and Pulmonary Drug Delivery
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
Satoru Koyanagi, Naoki Kusunose, Marie Taniguchi, Takahiro Akamine, Yuki Kanado, Yui Ozono, Takahiro Masuda, Yuta Kohro, Naoya Matsunaga, Makoto Tsuda, Michael W Salter, Kazuhide Inoue, Shigehiro Ohdo
Diurnal variations in pain hypersensitivity are common in chronic pain disorders, but the underlying mechanisms are enigmatic. Here, we report that mechanical pain hypersensitivity in sciatic nerve-injured mice shows pronounced diurnal alterations, which critically depend on diurnal variations in glucocorticoids from the adrenal glands. Diurnal enhancement of pain hypersensitivity is mediated by glucocorticoid-induced enhancement of the extracellular release of ATP in the spinal cord, which stimulates purinergic receptors on microglia in the dorsal horn...
October 14, 2016: Nature Communications
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