Endocrine Abstracts

Glucocorticoids (GCs) are used extensively in the treatment of inflammatory disease. Unfortunately, as GC act on virtually every organ system they also carry a broad range of serious side-effects which limits their clinical use.The structure of the bound GC strongly impacts the final conformation of the glucocorticoid receptor (GR) and thereby dictates downstream events. Designing drugs with different GR binding properties therefore offers a plausible ro...

Rheumatoid arthritis (RA) is a common chronic systemic inflammatory disease. Several new therapies exist for RA but long-term patient management remains problematic.We have discovered that hypoxia, a characteristic of inflamed tissues, potently inhibits glucocorticoid (Gc) sensitivity. This effect is mediated, in part by HIF1α, whose activity is induced in hypoxia. HIF1α gene expression is also induced in primary peripheral blood mononuclear ce...

Although glucocorticoids (Gc) are used to treat a range of pathologies, an individuals response to therapy varies considerably. There is a distinct correlation between certain cell types and steroid sensitivity. Aberrant glucocorticoid receptor (GR) function is well-characterised in lymphoid malignant cells but not small cell lung cancer (SCLC) (DMS79) or osteosarcoma (U2OS) cell lines, which are both Gc resistant.Previously we have shown reduced GR cont...

MIF is a potent pro-inflammatory mediator that opposes the anti-inflammatory actions of glucocorticoids (Gc) and is involved in the pathogenesis of multiple diseases. The MIF promoter is inhibited by Gc in lymphocytes (CEMC7A) but not in epithelial cells (A549), despite expression of functional glucocorticoid receptors (GR) in both. Deletion studies localized the cis element responsible for Gc inhibition to between MIF −71 and +85. This sequence contained no GR binding s...

Many glucocorticoid (Gc) actions are of rapid onset, and therefore require acute regulation of intracellular signalling cascades. We have previously identified rapid Gc-dependent activation of the caveolae specific integral membrane protein caveolin, and the cytosolic kinase PKB in the lung epithelial cells, A549.Immunofluorescence studies demonstrate the appearance of activated glucocorticoid receptor (P-ser211-GR) localised to focal points around the c...

Glucocorticoids (Gc) act on most cells and tissues, but their effects vary in a cell-type specific manner. A number of genes show divergent responses to glucocorticoid action, dependent on their tissue of origin. One such gene is MIF, a proinflammatory cytokine associated with Gc resistance in inflammation, and linked with susceptibility to chronic, human inflammatory disease. Importantly, MIF gene expression is inhibited by Gc in lymphoblasts, but not in epithelial cells; a f...

Introduction: The prevalence of obesity and metabolic disturbances is worryingly increasing worldwide, therefore the study of their pathophysiology is extremely important to find new strategies for their treatment. Obesity has an impact not only on the metabolism of the patients, but also profoundly influence their daily life, and potentially affect the quality of life and the quality of sleep. These latter are strictly related to the circadian rhythm of the individuals that, ...

Glucocorticoids (GCs) are steroid hormones used to treat inflammatory diseases such as rheumatoid arthritis, but their clinical efficacy is hampered by development of side effects such as impaired wound healing. GCs bind the glucocorticoid receptor (GR) to mediate cellular effects. The inactive GR is held in multi-protein complex in the cytoplasm and upon ligand binding undergoes a conformational change, interacts with cytoplasmic enzymes to mediate non-genomic effects (within...

Background: One percent of the adult population are, at any one time, prescribed oral glucocorticoids (GC). GCs are known to be associated with hypothalamic–pituitary–adrenal axis suppression. However, there remains uncertainty regarding: i) the prevalence of GC-induced adrenal insufficiency (AI); ii) the effects of GC dose and duration; and iii) the time course of adrenal recovery and how GCs should be withdrawn. We undertook a systematic literature review to addres...

Glucocorticoids act through the glucocorticoid receptor (GR) to regulate cell function. GR gamma (GRγ) is a constitutive exon3/4 splice variant, contributing 4–8% of the total GR transcripts and is highly conserved through mammalian evolution, but its biological function remains unknown. Using microarray analysis we identified the transcriptome response for GRγ in stable HEK-Flp cells. This revealed that although GRγ effectively modulated gene expression in...