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Among hospitalized patients with Covid-19, treatment with dexamethasone resulted in lower 28-day mortality than usual care, according to the level of respiratory support the patients were receiving, indicating a possible correlation between efficacy and the stage of infection.

Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms mediating these effects are poorly understood. Here we identify the glucocorticoid receptor (GR) target gene, serum- and glucocorticoid-inducible kinase 1 (SGK1), as one such mechanism. Using a human hippocampal progenitor cell line, we found that a small molecule inhibitor for SGK1, GSK650394, counteracted the cortisol-induced reduction in neurogenesis. Moreover, gene expression and pathway analysis showed that inhibition of the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation. Experiments combining the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, demonstrated that SGK1 was involved in the cortisol-induced reduction in progenitor proliferation both downstream of GR, by regulating relevant target genes, and upstream of GR, by increasing GR function. Corroborating the relevance of these findings in clinical and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Our findings identify SGK1 as a mediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression.

In a trial that compared a 2-week course of dexamethasone with placebo in patients with a chronic subdural hematoma, a favorable outcome on the modified Rankin scale at 6 months was more common in the placebo group than in the dexamethasone group, but repeat surgery to evacuate a hematoma was performed more frequently in the placebo group.

The glucocorticoid receptor (GR) plays a significant role in breast cancer cell behaviour, although data on its effects are conflicting. The impact of GR agonist dexamethasone (dex) and antagonist mifepristone (mif) on oestrogen-positive (ER+) and triple-negative (TN) breast cancer cell lines in both 2D and 3D cultures was studied using multiple in vitro functional assays and transcriptome sequencing. GR activation increased cell motility in TN but not in ER + tumour cells, as observed in both collective and single-cell migration tests. Time-lapse analysis showed enhanced motility after 4–6 h in wound healing, despite dex inhibiting migration initially. This inhibition was observed at 2 h in single-cell tracking migration assays. Cell proliferation increased in TN and decreased in ER + cells upon GR activation, reversed by GR antagonist. RNA sequencing revealed dex’s impact on cell adhesion and extracellular matrix signalling in TN cells and on DNA replication in ER + cells. Based on data from 1085 human breast cancer specimens, GR pathway expression correlated with migratory, extracellular matrix, and angiogenesis gene signatures. Additionally, higher expression of GR and increased GR signature were observed in fast-migrating cells compared to slow-migrating ones. Positive correlation between the GR signature and migration signature at the single-cell level indicated an association between GR activity and cell migration. For the first time, we assessed altered time-lapse migration dynamics in TN breast cancer cells, potentially contributing to cancer progression and prognosis, highlighting that the effects of dexamethasone on breast cancer cell migration are influenced by ER status and treatment duration.

Among patients with moderate-to-severe asthma who were receiving a range of inhaled glucocorticoid maintenance therapies, the risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide than with albuterol alone.

Breast cancer (BC) patients experience increased stress with elevated cortisol levels, increasing risk of cancer recurrence. Cortisol binds to a cytoplasmic receptor, glucocorticoid receptor (GR) encoded by GR gene (NR3C1). We hypothesized that not only cancer cells, but even immune cells in the tumor microenvironment (TME) may contribute to GR expression in bulk tumor and influence prognosis. To test this, mRNA expression data was accessed from METABRIC and TCGA. “High” and “low” expression was based on highest and lowest quartiles of NR3C1 gene expression, respectively. Single-cell sequencing data were obtained from GSE75688 and GSE114725 cohorts. Computer algorithms CIBERSORT, Gene Set Enrichment Analysis and TIMER were used. GR-high BC has better median disease-free and disease-specific survival. Single cell sequencing data showed higher GR expression on immune cells compared to cancer and stromal cells. Positive correlation between GR-high BC and CD8+ T-cells was noted. In GR-high tumors, higher cytolytic activity (CYT) with decreased T-regulatory and T-follicular helper cells was observed. High GR expression was associated with lower proliferation index Ki67, enriched in IL-2_STAT5, apoptosis, KRAS, TGF-β signaling, and epithelial-to-mesenchymal transition. Immune cells significantly contribute to GR expression of bulk BC. GR-high BC has a favorable TME with higher CYT with favorable outcomes.

Glucocorticoids (GCs), mostly dexamethasone (dex), are routinely administered as adjuvant therapy to manage side effects in breast cancer. However, recently, it has been revealed that dex triggers different effects and correlates with opposite outcomes depending on the breast cancer molecular subtype. This has raised new concerns regarding the generalized use of GC and suggested that the context-dependent effects of GCs can be taken into potential consideration during treatment design. Based on this, attention has recently been drawn to the role of the glucocorticoid receptor (GR) in development and progression of breast cancer. Therefore, in this comprehensive review, we aimed to summarize the different mechanisms behind different context-dependent GC actions in breast cancer by applying a multilevel examination, starting from the association of variants of the GR-encoding gene to expression at the mRNA and protein level of the receptor, and its interactions with other factors influencing GC action in breast cancer. The role of GCs in chemosensitivity and chemoresistance observed during breast cancer therapy is discussed. In addition, experiences using GC targeting therapeutic options (already used and investigated in preclinical and clinical trials), such as classic GC dexamethasone, selective glucocorticoid receptor agonists and modulators, the GC antagonist mifepristone, and GR coregulators, are also summarized. Evidence presented can aid a better understanding of the biology of context-dependent GC action that can lead to further advances in the personalized therapy of breast cancer by the evaluation of GR along with the conventional estrogen receptor (ER) and progesterone receptor (PR) in the routine diagnostic procedure.

Stress responses play a key role in allowing animals to cope with change and challenge in the face of both environmental certainty and uncertainty. Measurement of glucocorticoid levels, key elements in the neuroendocrine stress axis, can give insight into an animal's well-being and can aid understanding ecological and evolutionary processes as well as conservation and management issues. We give an overview of the four main biological samples that have been utilized [blood, saliva, excreta (feces and urine), and integumentary structures (hair and feathers)], their advantages and disadvantages for use with wildlife, and some of the background and pitfalls that users must consider in interpreting their results. The matrix of choice will depend on the nature of the study and of the species, on whether one is examining the impact of acute versus chronic stressors, and on the degree of invasiveness that is possible or desirable. In some cases, more than one matrix can be measured to achieve the same ends. All require a significant degree of expertise, sometimes in obtaining the sample and always in extracting and analyzing the glucocorticoid or its metabolites. Glucocorticoid measurement is proving to be a powerful integrator of environmental stressors and of an animal's condition.

Sepsis, an exaggerated systemic inflammatory response, remains a major medical challenge. Both hyperinflammation and immunosuppression are implicated as causes of morbidity and mortality. Dendritic cell (DC) loss has been observed in septic patients and in experimental sepsis models, but the role of DCs in sepsis, and the mechanisms and significance of DC loss, are poorly understood. Here, we report that mice with selective deletion of the glucocorticoid receptor (GR) in DCs (GR(CD11c-cre)) were highly susceptible to LPS-induced septic shock, evidenced by elevated inflammatory cytokine production, hypothermia, and mortality. Neutralizing anti-IL-12 antibodies prevented hypothermia and death, demonstrating that endogenous GC-mediated suppression of IL-12 is protective. In LPS-challenged GR(CD11c-cre) mice, CD8(+) DCs were identified as the major source of prolonged IL-12 production, which correlated with elevations of NK cell-derived IFN-γ. In addition, the loss of GR in CD11c(+) cells rescued LPS-induced loss of CD8(+) DCs but not other DC subsets. Unlike wild-type animals, exposure of GR(CD11c-cre) mice to low-dose LPS did not induce CD8(+) DC loss or tolerance to subsequent challenge with high dose, but neutralization of IL-12 restored the ability of low-dose LPS to tolerize. Therefore, endogenous glucocorticoids blunt LPS-induced inflammation and promote tolerance by suppressing DC IL-12 production.

A widely regarded model for glucocorticoid receptor (GR) action postulates that dimeric binding to DNA regulates unfavorable metabolic pathways while monomeric receptor binding promotes repressive gene responses related to its anti-inflammatory effects. This model has been built upon the characterization of the GRdim mutant, reported to be incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric, genomic studies based on recovery of enriched half-site response elements suggest monomeric engagement on DNA. Here, we perform genome-wide studies on GRdim and a constitutively monomeric mutant. Our results show that impairing dimerization affects binding even to open chromatin. We also find that GRdim does not exclusively bind half-response elements. Our results do not support a physiological role for monomeric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repressive actions of glucocorticoids. Glucocorticoid receptors (GR) are thought to bind DNA as dimers or monomers, to regulate different transcription pathways. Here, the authors perform genome-wide studies on GRs with mutations that impair dimerization and provide evidence that monomeric GRs do not play a significant physiologic role.