Glucocorticoid

Glucocorticoids have potent anti-inflammatory and immunomodulatory effects and are widely use in the management of rheumatoid arthritis in combination with other synthetic and with biological disease-modifying anti-rheumatic drugs. Concerns about the risk of adverse effects of glucocorticoids, especially if they are given at higher dosages and for a longer time, hamper their use despite the clear symptomatic and disease modifying benefits. However, the evidence base for these concerns for low dose glucocorticoid therapy is quite limited due to the scarcity of quality literature on its safety in rheumatoid arthritis. This review discusses the current understanding about their disease-modifying effects, toxicity data from recent trials and observational studies, recommendations for their management and the current efforts to improve the therapeutic ratio of glucocorticoid through the development of new formulations, such as modified-release prednisone.

New methods of noninvasive evaluation of the endocrine status of animals by the content of hormones in their feces were used to study the relationship between the stress level and social (population density) and ecological (habitat integrity) indices in natural populations of midday gerbil in the Southern Kalmykia in 2000. Stress level proved to increase with habitat disturbance but did not depend on population density of animals. The obtained data are discussed in the context of species-specific ecology and social behavior of midday gerbils.

ABSTRACT: Poultry meat production has been dramatically increased in the last few decades due to increased population rate. Glucocorticoids decrease the growth of poultry and increase fat accumulation in liver and meat. In the coming days, it is important to consider the quality of meat to fulfill the increasing demand of proteins. The morphological and biometric properties of meat are associated with the quality of meat. The present research aimed to study the adaptations of muscular biology in response to potential glucocorticoid treatment in broiler chicken. This experiment was conducted into three groups of broilers (i.e. control group: homemade ration, group A: commercial broiler ration, and group B: a high dose of glucocorticoid at 7 mg/kg) started from day 7 to 28. Meat and blood samples were collected at day 7, 14, 21, and 28. For gross morphology, color and weight of meat were measured. Histomorphology of meat was studied under light microscope by Hematoxylin & Eosin stain. The length and width of meat fibers were measured using calibrated stage micrometer. The blood cholesterol dynamics was measured by spectrophotometer. The color of breast meat was more yellowish and lighter than thigh meat. The weight of meat was negatively affected by glucocorticoid. Glucocorticoid treatment negatively influenced the number of myofibers in breast meat, while positively influenced the thigh meat. Excess dietary glucocorticoid increased the biometry of breast meat and decreased that of thigh meat in broiler. Glucocorticoid non-significantly increased the serum cholesterol level. These findings advance our knowledge about the action of glucocorticoid in the muscular system and provide basis for novel therapies to prevent glucocorticoid-induced muscular atrophy.

Low- to medium-dose glucocorticoids have been shown to have not only anti-inflammatory but also disease-modifying properties in rheumatoid arthritis. The evidence for the benefit of its early use in combination with disease-modifying antirheumatic drugs underlines the need for a close evaluation of their risk-benefit ratio. Over time, numerous myths and fears about glucocorticoid toxicity in rheumatoid arthritis have arisen from observational studies, and many concerns have been unduly extrapolated from observations with higher-dose treatment. Furthermore, we cannot exclude the possibility of a powerful effect of bias by indication in these studies. Low- to medium-dose glucocorticoid regimens continued to be evaluated in randomized clinical trials, particularly in early disease, but these studies also have relevant methodological limitations in assessing safety, particularly due to small size and/or short duration. At present, the evidence on which to support clear recommendations about glucocorticoid toxicity remains remarkably weak. A large prospective pragmatic trial dedicated to the toxicity of low-dose glucocorticoids is dearly needed. Meanwhile, adherence to recommendations on standardized methodologies for registration and report of glucocorticoid adverse events is essential for improving our knowledge and competence in the best management of these important medications.

A key regulator of glucocorticoid action is 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD1), which catalyzes the conversion of cortisone to cortisol, the biologically active glucocorticoid. 11β-HSD1 is a paralog of 11β-HSD3, whose physiological function remains unclear. As reported here, 11β-HSD3 has orthologs in sea urchin, amphioxus and Ciona, while 11β-HSD1 first appears in sharks. Thus, 11β-HSD3 arose before the evolution of glucocorticoid signaling, suggesting different ancestral function(s) for 11β-HSD3. Four perplexing findings arise from this evolutionary analysis: (1) 11β-HSD1 is not present in a ray-finned fish genome, (2) zebrafish and fathead minnow contain two isoforms of 11β-HSD3; (3) neither rat nor mouse contain 11β-HSD3 and (4) amphioxus contains 16 11β-HSD3 paralogs.

The nuclear proteins which act synergistically with the glucocorticoid receptor to induce transcription of the tyrosine aminotransferase gene include factors recognizing the CACCC element. We have purified and characterized the proteins from rat liver nuclei which bind to the CACCC motif in the glucocorticoid-inducible enhancer of the gene. Three protein-DNA complexes (C1, C2, and C3) were detected in band-shift assays. The protein component of complex C1 also binds a GC motif (a Sp1 binding site) and is recognized by anti-Sp1 antiserum. The proteins forming complexes C2 and C3 have been purified by DNA-affinity chromatography and their molecular masses (75-80 kDa and 35-40 kDa, respectively) have been determined by ultraviolet cross-linking to radio-labelled DNA and SDS/PAGE. The DNA-affinity-purified C2 and C3 activities do not bind significantly to the GC motif and are not recognized by anti-Sp1 antiserum. Methylation interference analysis indicates that the nucleotides of the CACCC element bound by the C2 and C3 proteins correspond to those of the glucocorticoid-responsive enhancer which are contacted in vivo following glucocorticoid administration. Our data suggest that these proteins contribute to glucocorticoid-induced transcription of the tyrosine aminotransferase gene.

Recruitment of O-GlcNAc transferase (OGT) to promoters plays an important role in gene repression. Glucocorticoid signaling represses the transcriptional activities of NF-_B and AP-1 through direct binding, yet the molecular mechanisms remain to be elucidated. Here we report that OGT is an important component of GR-mediated transrepression. OGT associates with ligand-bound GR in a multi-protein repression complex. Overexpression of OGT potentiates the GR transrepression pathway, whereas depletion of endogenous OGT by
RNA interference abolishes the repression. The recruitment of OGT by GR leads to increased O-GlcNAcylation and decreased phosphorylation of RNA polymerase II on target genes. Functionally, overexpression of OGT enhances glucocorticoid-induced apoptosis in resistant cell lines while knockdown of OGT prevents sensitive cell lines from apoptosis. These studies identify a molecular mechanism of GR transrepression, and highlight the function of O-GlcNAc in hormone signaling.

Earlier studies from our laboratory demonstrated that acute experimental Trypanosoma cruzi infection promotes an intense inflammation along with a sepsis-like dysregulated adrenal response characterized by normal levels of ACTH with raised glucocorticoid secretion. Inflammation was also known to result in adrenal cell apoptosis, which in turn may influence HPA axis uncoupling. To explore factors and pathways which may be involved in the apoptosis of adrenal cells, together with its impact on the functionality of the gland, we carried out a series of studies in mice lacking death receptors, such as TNF-R1 (C57BL/6-(Tnfrsf1a tm1Imx) or TNF-R1(-/-)) or Fas ligand (C57BL/6 Fas-deficient lpr mice), undergoing acute T. cruzi infection. Here we demonstrate that the late hypercorticosterolism seen in C57BL/6 mice during acute T. cruzi infection coexists with and hyperplasia and hypertrophy of zona fasciculata, paralleled by increased number of apoptotic cells. Apoptosis seems to be mediated...

Introduction. Adrenal insufficiency results from the inadequate adrenocortical conjunction. Adrenal insufficiency can be primary, secondary and tertiary one. The most common cause of adrenal suppression is the effect of exogenous therapy with glucocorticoids. Glucocorticoids. Corticosteroids are used in treatment of endocrine and non-endocrine diseases. They are applied as a substitution therapy in the patients with primary and secondary adrenal insufficiency. Due to their immunosuppressive and anti-inflammatory characteristics, they are used to treat a wide range of diseases. They are usually divided according to the length and size of the effect i.e. how they are applied. Adrenal Insufficiency. Glucocorticoid therapy may lead to a number of adverse effects such as a disorder in glucose metabolism, osteoporosis or frequent infections. Adrenal suppression is the most common complication resulting from corticosteroid application. The function of the hypothalamus-pituitary-adrenal axi...

ObjectivesAutophagy has recently been shown to regulate osteoclast activity and osteoclast differentiation. Here, we aim to investigate the impact of autophagy inhibition as a potential therapeutic approach for the treatment of osteoporosis in preclinical models.MethodsSystemic bone loss was induced in mice by glucocorticoids and by ovariectomy (OVX). Autophagy was targeted by conditional inactivation of autophagy-related gene 7 (Atg7) and by treatment with chloroquine (CQ). Bone density was evaluated by microCT. The role of autophagy on osteoclastogenesis was analysed by osteoclastogenesis and bone resorption assays. The quantification of receptor activator of nuclear factor κ B ligand and osteoprotegerin proteins in cocultures was performed using ELISA whereas that of osteoclast and osteoblast differentiation markers was by qPCR.ResultsSelective deletion of Atg7 in monocytes from Atg7fl/fl_x_LysM-Cre mice mitigated glucocorticoid-induced and OVX-induced osteoclast differentiation ...

TNF is a central actor during inflammation and a well-recognized drug target for inflammatory diseases. We found that the mouse strain SPRET/Ei, known for extreme and dominant resistance against TNF-induced shock, displays weak expression of TNF receptor 1 protein (TNFR1) but normal mRNA expression, a trait genetically linked to the major TNFR1 coding gene Tnfrsf1a and to a locus harbouring the predicted TNFR1-regulating miR-511. This miRNA is a genuine TNFR1 regulator in cells. In mice, overexpression of miR-511 down-regulates TNFR1 and protects against TNF, while anti-miR-511 up-regulates TNFR1 and sensitizes for TNF, breaking the resistance of SPRET/Ei. We found that miR-511 inhibits endotoxemia and experimental hepatitis and that this miR is strongly induced by glucocorticoids and is a true TNFR1 modulator and thus an anti-inflammatory miR. Since minimal reductions of TNFR1 have considerable effects on TNF sensitivity, we believe that at least part of the anti-inflammatory effec...