Glucocorticoid Receptor Research Articles

Single Intranasal Administration of Ucn3 Affects the Development of PTSD Symptoms in an Animal Model

Post-traumatic stress disorder (PTSD) is a multifactorial psychological disorder that affects different neurotransmitter systems, including the central CRH system. CRH acts via the CRHR1 and CRHR2 receptors, which exert opposite effects, i.e., anxiogenic or anxiolytic. The aim of this work was to investigate how intranasal administration of the CRHR2-specific agonist urocortin 2 (Ucn2) or urocortin 3 (Ucn3) affects manifestations of PTSD in a single prolonged stress (SPS) animal model of PTSD. Elevated plus maze (EPM) and open field (OF) tests were used to assess anxiety-like behavior. Changes in the gene expressions of CRH, CRHR1, CRHR2, glucocorticoid receptor (GR), and FKBP5 were measured in brain regions (BNST, amygdala, and PVN) responsible for modulating the stress response. The SPS animals spent less time in the OF central zone and were less mobile than the controls; however, the Ucn3 treatment reversed this effect. SPS decreased the GR and FKPB5 mRNA levels in the PVN. Ucn3 suppressed the effect of SPS on FKBP5 mRNA expression in the PVN and increased FKBP5 mRNA in the BNST and PVN compared to the stressed animals. We demonstrate that Ucn3 has the potential to ameliorate anxiety-like behavior in SPS animals and also to affect the neuroendocrine system in the BNST and PVN. In addition, we confirm the important role of CRHR2 signaling in mediating the stress response.

Research status of anti-obesogenic functional foods: mechanism of endocrine-disrupting chemicals and glucocorticoid receptor pathway

Research status of anti-obesogenic functional foods: mechanism of endocrine-disrupting chemicals and glucocorticoid receptor pathway

Dexamethasone is a regulator of clock genes in testicular peritubular cells.

We recently found that peritubular cells of the human testis are a dominant site of expression of the glucocorticoid receptor (GR; encoded by NR3C1). Activation of GR by dexamethasone (Dex) strongly influences the phenotype of cultured human testicular peritubular cells (HTPCs), causing massive changes of their proteome and secretome. As glucocorticoids (GC) are also known to set the internal clock of peripheral organs by regulating clock genes, we tested such an influence of Dex in HTPCs. We performed cellular studies with HTPCs and immortalized nonhuman primate (Callithrix jacchus; Cj)-derived peritubular cells, organotypic incubations of testicular fragments of Cj, qPCR and proteomic, as well as immunohistochemical studies. Basal clock gene expression levels, when monitored by qPCR under standard culture conditions, showed alterations over 24 h, suggesting an endogenous circadian rhythm, especially for BMAL1. Dex (1 µM) when added to cells, caused a strong and significant increase of PER1, followed by elevations of BMAL1, and other clock genes. This action was observed as early as 4 h after the addition of Dex. Immunohistochemistry and data mining revealed GR in testicular peritubular cells and other somatic cells of Cj, in situ. We therefore performed organotypic incubations of testicular fragments of Cj (n = 3) and found that upon addition of Dex (1 µM), mRNA levels of BMAL1 and PER1 also increased in samples of two out of three animals after 6 h. Mass spectrometry did, however, not reveal significant alterations of the testicular proteome, possibly due to the short time point and/or the fact that the somatic GR-expressing cells represent only a small portion of the testis. In support for this assumption, Dex (1 µM; 6 h) significantly increased mRNA levels of BMAL1 and PER1 in Cj-derived immortalized testicular peritubular cells. The results indicate that an internal clock system likely exists in peritubular cells of the testis and that Dex, via testicular GR expressed by peritubular cells and other somatic cells, is a strong regulator of this system. In a physiological situation, GC thus may be important regulators of the testicular clock, while in a situation of prolonged stress or GC-medication, derangements in clock gene expression may result.

Dietary bile acids alleviate corticosterone-induced fatty liver and hepatic glucocorticoid receptor suppression in broiler chickens.

The aim of this study was to investigate the alleviating effects and mechanisms of bile acids (BA) on corticosterone-induced fatty liver in broiler chickens. Male Arbor Acres chickens were randomly divided into three groups: control group (CON), stress model group (CORT), and BA-treated group (CORT-BA). The CORT-BA group received a diet with 250mg/kg BA from 21 days of age. From day 36 to 43, both the CORT and CORT-BA groups received subcutaneous injections of corticosterone to simulate chronic stress. The results indicated that BA significantly mitigated the body weight loss, liver enlargement, and hepatic lipid deposition caused by corticosterone (P < 0.05). Liver RNA-seq analysis showed that BA alleviated corticosterone-induced fatty liver by inhibiting lipid metabolism pathways, including fatty acid biosynthesis, triglyceride biosynthesis, and fatty acid transport. Additionally, BA improved corticosterone-induced downregulation of glucocorticoid receptor (GR) expression (P < 0.05). Molecular docking and cellular thermal shift assays revealed that hyodeoxycholic acid (HDCA), a major component of compound bile acids, could bind to GR and enhance its stability. In conclusion, BA alleviated corticosterone-induced fatty liver in broilers by inhibiting lipid synthesis pathways and mitigating the suppression of hepatic GR expression.

Glucocorticoid Receptor Isoforms in Breast Cancer Raise Implications for Personalised Supportive Therapies

Glucocorticoid receptor (GR) activation may promote metastasis in oestrogen receptor-negative and triple-negative breast cancer (TNBC). However, the role of the GRβ isoform, which has opposing effects to the main isoform, has not been studied in clinical samples. We aimed to analyse the intracellular localisation of total GR and GRβ in vitro using plasmid constructs and fluorescent immunocytochemistry. Additionally, our goal was to perform immunostaining for total GR and GRβ on two cohorts: (i) on 194 clinical breast cancer samples to compare the expression in different molecular subtypes, and (ii) on 161 TNBC samples to analyse the association of GR with survival. We supplemented our analysis with RNA data from 1097 TNBC cases. We found that in the absence of the ligand, GR resided in the cytoplasm of breast cancer cells, while upon ligand activation, it translocated to the nucleus. A negative correlation was found between cytoplasmic GRtotal and Ki67 in luminal A tumours, while the opposite trend was observed in TNBC samples. Tumours with strong lymphoid infiltration showed higher cytoplasmic GRtotal staining compared to those with weaker infiltration. Patients with high nuclear GRtotal staining had shorter progression-free survival in univariate analysis. High cytoplasmic GRβ was a marker for better overall survival in multivariate analysis (10-year overall survival HR [95% CI]: 0.46 [0.22–0.95], p = 0.036). As a conclusions, this study is the first to investigate GRβ expression in breast tumours. Different expression and cellular localisation of GRtotal and GRβ were observed in the context of molecular subtypes, underscoring the complex role of GR in breast cancer. An inverse association between cytoplasmic GRtotal and the Ki67 proliferation index was observed in luminal A and TNBC. Regarding the impact of GR on outcomes in TNBC patients, while cytoplasmic GRβ was associated with a better prognosis, patients with nuclear GRtotal staining may be at a higher risk of disease progression, as it negatively affects survival. Caution should be exercised when using glucocorticoids in patients with nuclear GR staining, as it may negatively impact survival.

Glucocorticoids induce HMGB1 release in primary cultured rat cortical microglia

Stress, a risk factor for major depressive disorder and Alzheimer disease, leads to the release of high-mobility group box-1 (HMGB1) protein, which in turn causes neuroinflammation. The mechanism underlying stress-induced HMGB1 release is unknown, but stress-associated glucocorticoids could be involved. Primary cultured rat cortical microglia and neurons were treated with corticosterone, a stress-associated glucocorticoid, and HMGB1 release was measured by ELISA and western blotting to test this hypothesis. With corticosterone treatment, significant HMGB1 was released in microglia but not in neuronal cell cultures. HMGB1 mRNA expression and HMGB1 protein expression in microglia were not affected by corticosterone treatment. Thus, the source of extracellular HMGB1 released into the medium is likely to be existing nuclear HMGB1 rather than newly synthesized HMGB1. Corticosterone-induced HMGB1 release in microglia culture was significantly attenuated by blocking glucocorticoid receptors but not mineralocorticoid receptors. Dexamethasone, a selective glucocorticoid receptor agonist, and dexamethasone-bovine serum albumin (BSA), a membrane-impermeable glucocorticoid receptor agonist used to confirm the membrane receptor-mediated effects of glucocorticoids, increased the release of HMGB1. Immunocytochemistry showed that HMGB1 translocated from the nucleus to the cytoplasm following dexamethasone or dexamethasone-BSA treatment through glucocorticoid receptors. The present findings suggest that glucocorticoids stimulate microglial membrane glucocorticoid receptors and trigger cytoplasmic translocation and extracellular release of nuclear HMGB1. Thus, under stress conditions, glucocorticoids induce microglial HMGB1 release, leading to a neuroinflammatory state that could mediate neurological disorders.

A comprehensive evaluation of the endocrine-disrupting effects of emerging organophosphate esters

The ubiquitous presence of organophosphate esters (OPEs) in the environment has prompted growing concerns about their potential health risks, particularly their endocrine-disrupting effects. This study comprehensively evaluated the endocrine-disrupting properties of six emerging OPEs: five aryl-OPEs (2-ethylhexyl diphenyl phosphate (EHDPP), tris (2-biphenylyl) phosphate (TBPP), resorcinol bis (diphenyl phosphate) (RDP), 4-hydroxyphenyl diphenyl phosphate (para-OH-TPHP), and 3-hydroxyphenyl diphenyl phosphate (meta-OH-TPHP)) and one alkyl-OPE, triallyl phosphate (TAP). Our findings revealed that all tested aryl-OPEs exhibited antagonistic effects on one or more hormone receptors. Importantly, para-OH-TPHP demonstrated the most potent antagonistic activity, inhibiting estrogen receptor α (ERα), thyroid hormone receptor β (TRβ), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) with the concentration of test compounds showing 20 % relative inhibitory concentration (RIC20) value below 10−6 mol/L (M). RDP antagonized ERα and cortical receptors (GR and MR), TBPP affected TRβ and GR, while EHDPP and meta-OH-TPHP targeted MR. Regarding steroidogenesis, para-OH-TPHP significantly inhibited genes for estrogen (cyp19) and cortisol synthesis (cyp11b2), and along with meta-OH-TPHP, EHDPP, TAP, and RDP downregulated cyp11a1, a rate-limiting enzyme in hormone synthesis. All compounds caused malformations and swimming abnormalities in zebrafish embryos/larvae at concentrations of 10−7 M or higher, with para-OH-TPHP showing nearly 50 % peak induction. Furthermore, the six compounds tested influenced genes associated with the hypothalamic-pituitary–gonadal (HPG) axis in both zebrafish larvae and adult female zebrafish, in addition to affecting the reproductive behavior of zebrafish. A weighted scoring system was employed to rank the endocrine-disrupting potency of the OPEs, with para-OH-TPHP exhibiting the highest risk, followed by EHDPP, RDP, TBPP, meta-OH-TPHP, and TAP. Collectively, our results highlight the significant endocrine-disrupting effects of emerging OPEs, underscoring the urgent need for further research to assess their potential health implications.

Signature analysis of high-throughput transcriptomics screening data for mechanistic inference and chemical grouping.

High-throughput transcriptomics (HTTr) uses gene expression profiling to characterize the biological activity of chemicals in in vitro cell-based test systems. As an extension of a previous study testing 44 chemicals, HTTr was used to screen an additional 1,751 unique chemicals from the EPA's ToxCast collection in MCF7 cells using 8 concentrations and an exposure duration of 6 h. We hypothesized that concentration-response modeling of signature scores could be used to identify putative molecular targets and cluster chemicals with similar bioactivity. Clustering and enrichment analyses were conducted based on signature catalog annotations and ToxPrint chemotypes to facilitate molecular target prediction and grouping of chemicals with similar bioactivity profiles. Enrichment analysis based on signature catalog annotation identified known mechanisms of action (MeOAs) associated with well-studied chemicals and generated putative MeOAs for other active chemicals. Chemicals with predicted MeOAs included those targeting estrogen receptor (ER), glucocorticoid receptor (GR), retinoic acid receptor (RAR), the NRF2/KEAP/ARE pathway, AP-1 activation, and others. Using reference chemicals for ER modulation, the study demonstrated that HTTr in MCF7 cells was able to stratify chemicals in terms of agonist potency, distinguish ER agonists from antagonists, and cluster chemicals with similar activities as predicted by the ToxCast ER Pathway model. Uniform manifold approximation and projection (UMAP) embedding of signature-level results identified novel ER modulators with no ToxCast ER Pathway model predictions. Finally, UMAP combined with ToxPrint chemotype enrichment was used to explore the biological activity of structurally related chemicals. The study demonstrates that HTTr can be used to inform chemical risk assessment by determining in vitro points of departure, predicting chemicals' MeOA and grouping chemicals with similar bioactivity profiles.

Final overall survival data from a randomized, open-label, phase II study of relacorilant, a selective glucocorticoid receptor modulator, in combination with nab-paclitaxel among patients with recurrent platinum-resistant ovarian cancer

Final overall survival data from a randomized, open-label, phase II study of relacorilant, a selective glucocorticoid receptor modulator, in combination with nab-paclitaxel among patients with recurrent platinum-resistant ovarian cancer

High-Fructose Diet and Chronic Unpredictable Stress Modify Each Other’s Neurobehavioral Effects in Female Rats

A pervasive exposure to stressors and the consumption of fructose-containing beverages usually go hand-in-hand in everyday life. In contrast to their metabolic outcomes, their impact on the brain and behavior is still understudied. We examined the behavioral response to a novelty (open field test), the expression of biochemical indicators of neuronal activity (Egr1 and FosB/ΔFosB), the synaptic potentiation (CaMKIIα and pCaMKIIThr286), the synaptic plasticity (synaptophysin, PSD95, gephyrin, and drebrin), and the GABAergic system (parvalbumin and GAD67), along with the glucocorticoid receptor (GR) and AMPK, in the medial prefrontal cortex of female Wistar rats subjected to liquid fructose supplementation (F), chronic unpredictable stress (S), or both (SF) over 9 weeks. The only hallmark of the F group was an increased expression of pCaMKIIThr286, which was also observed in the S group, but not in the SF group. The SF group did not show hyperactivity, a decreased expression of FosB, or an increased expression of parvalbumin, as the S group did. The SF group, as with the S group, showed a decreased expression of the GR, although the basal level of corticosterone was unchanged. The SF group showed, as de novo marks, thigmotactic behavior, increased drebrin, and decreased gephyrin expression. These findings suggest that the long-term consumption of fructose, which itself has subtle neurobehavioral consequences, in combination with stress prevents some of its effects, but also contributes to novel outcomes not seen in single treatments.

Isolation, Characterization, and Anti-Inflammatory Effects of β-Sitosterol-β-D-Glucoside from Hygrophila auriculata: Experimental Validation, Molecular Docking, and Molecular Dynamics Simulations.

Hygrophila auriculata (K. Schum) Heine is known to treat various common aliment e.g. rheumatoid arthritis, kidney infections, jaundice, edema, and gout. This study aims to isolate bioactive components from the methanolic extract, assess their anti-inflammatory effects, and investigate their interactions with drug targets through docking and molecular dynamics simulations. Methanolic extract of H. auriculata furnished stigmast-5-en-3-ol-β-D-glucopyranoside (HA-06) which was characterized by using IR, NMR and mass spectral data. HA-06 alleviated carrageenan-induced inflammation in rats, while the methanolic extract of H. auriculata produced comparable results. The findings were similar to those of the positive control, indomethacin. The chemical structure of HA-06 was optimized using DFT at the B3LYP level and subsequently used for molecular docking against anti-inflammatory drug targets. HA-06 exhibited strong affinity towards phospholipase A2 and glucocorticoid receptor exhibiting binding energies of -11.25 kcal/mol and -11.07 kcal/mol, respectively.Molecular dynamics simulation was used to assess the dynamical stability of these two complexes and their native co-crystallized ligands. Principal component analysis, radius of gyration, free energy landscapes, solvent-accessible-surface-area, and root-mean square deviation/fluctuation all indicated stable interactions. Therefore, HA-06 could be a promising candidate for development into an effective therapy against inflammatory diseases targeting phospholipase A2 and glucocorticoid receptor.

Exploring the inhibitory activity and mechanism on lipid production in 3T3-L1 cells by hot water extract derived from Acacia confusa flowers.

Acacia confusa Merr. (Fabaceae) (A. confusa) is a native tree species of Taiwan, commonly found in the low-altitude mountains and hilly areas of the Hengchun Peninsula. This evergreen, perennial, and large-sized tree was the focus of a study that employed various chromatographic and spectroscopic methods to analyze the hot water extract of its flowers. The analysis revealed that the major components of the extract were myricitrin, quercitrin, europetin-3-O-rhamnoside, and chalconaringenin-2'-xyloside, with respective concentrations of approximately 0.22, 0.02, 0.26, and 0.10mg/g of the flowers. Subsequent cell assays were conducted to assess the inhibitory effect of the extract on lipid synthesis in fat cells. Oil Red O staining results indicated that the extract significantly suppressed fatty acid accumulation in 3T3-L1 cells, with the most pronounced effect observed at a concentration of 180μg/ml. Furthermore, the hot water extract of A. confusa flowers was found to increase the phosphorylation of AMP-activated protein kinase (AMPK), decrease the phosphorylation of cAMP response element-binding protein (CREB), and reduce the expression of glucocorticoid receptor (GR) protein. This, in turn, inhibited the expression of downstream transcription factors such as CCAT/ehancer binding proteins α (C/EBPα), CCAT/ehancer binding proteins β (C/EBPβ), CCAT/ehancer binding proteins δ (C/EBPδ), peroxisome proliferation-actived receptor γ (PPARγ), and sterol regulatory element binding proteins-1 (SREBP-1). Consequently, the expression of lipid synthesis-related proteins acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and fatty acid translocase (CD36) was reduced, ultimately inhibiting lipid generation. Therefore, the hot water extract of A. confusa flowers shows potential for development as a weight-loss tea.

Corticosterone-Mediated BDNF Changes and Their Effects on Adult Neurogenesis in Depression

Adult neurogenesis, the process of generating functional neurons from neural precursor cells in the adult brain, is essential for cognitive function and emotional regulation. Major Depressive Disorder (MDD), characterized by persistent sadness and decreased psychosocial function, is associated with impaired adult hippocampal neurogenesis (AHN). Elevated levels of corticosterone (CORT), a glucocorticoid released in response to stress, have been shown to downregulate brain-derived neurotrophic factor (BDNF), a crucial regulator of neurogenesis, thereby inhibiting AHN. Despite significant advances in understanding the impact of CORT and BDNF on neurogenesis, the precise molecular and cellular pathways involved remain unclear. This review highlights key gaps in the research, particularly the need for a deeper understanding of how glucocorticoid and mineralocorticoid receptors regulate BDNF transcription, the role of autophagic pathways in BDNF degradation, and the influence of glutamatergic signaling on these processes. Future research should focus on elucidating these mechanisms to develop targeted therapeutic strategies, including pharmacological interventions that modulate BDNF and CORT levels and lifestyle modifications like exercise and adequate sleep to enhance neurogenesis. Understanding these complex interactions will be crucial for advancing treatments for depression and improving mental health outcomes.

Serum proteomic profiling reveals potential inflammatory biomarkers in long-COVID patients: a comparative analysis with healthy controls

Abstract Background Long-COVID (also known as post-acute sequelae of SARS-CoV-2 infection, PASC), is defined as the persistence, or the new onset, of symptoms after recovery from the acute phase of COVID-19. It consists of a multiorgan syndrome expressing itself with a wide variety of cardiovascular and non-cardiovascular symptoms such us chest pain, fatigue, shortness of breath, autonomic dysfunction, cognitive impairment and sleep disorders even in the absence of a clear evidence of organ dysfunction. Some previous studies have suggested the potential role of an abnormal inflammatory response after SARS-CoV-2 infection, however the specific underlying mechanisms remain unclear. In this study we performed a proteomic analysis of the serum of 80 long-COVID patients to identify potential biomarkers that may act as indicators or therapeutic targets for long COVID. Methods and results We compared the levels of the proteins in both long-COVID group and a control group using multivariate and univariate analysis. Both PLS-DA and PCA analysis showed a clear distinction between the two groups; clustering analysis also clearly separated control from long-COVID patients. Proteins were then filtered based on (a) statistical analysis, considering proteins with a VIP&amp;gt;1 (PLSDA) and p&amp;lt;0.05 (t-test); (b) coefficient of variation (CV), where only proteins with CV&amp;lt;10 were considered; (c) and fold change (FC), for which proteins with FC&amp;lt;0.67 or FC&amp;gt;1.5 were selected for further analysis. The selected proteins were then subjected to a ROC curve analysis to identify antithrombin as a potential biomarker with an area under the curve (AUC) near 1. Other proteins, displaying an AUC &amp;gt; 0.98, were also identified as potential biomarkers (Sirtuin 1, NatriureticPeptide B, Hemopexin Arachidonate 5-Lipoxygenase). In addition, a multivariate ROC method, using linear SVM as classification method, identified that a combination of ten proteins would also result in an AUC near 1. Finally, a correlation analysis between the proteins of interest and the clinical manifestations was performed. A positive correlation (above 0.5) was found between dyspnea and Glucocorticoid Receptor and between memory deficit and Antithrombin. Arachidonate 5-Lipoxygenase was negatively correlated (below -0.5) with tremors and hair loss, MannoseBinding Lectin 2 was found to be positively linked to asthenia, Antithrombin with concentration deficit and Endothelin-2 with muscles aches. Conclusions The identified biomarkers are associated with inflammatory processes, corroborating literature evidence that long-COVID patients develop an inflammatory state that damages many tissues. Further studies are needed to validate this data in larger cohorts to identify specific biomarkers, and guide future preventive strategies or treatments to address long COVID and its cardiovascular and non-cardiovascular sequelae.

Stress Can Induce Bovine Alpha-Herpesvirus 1 (BoHV-1) Reactivation from Latency

Bovine alpha-herpesvirus 1 (BoHV-1) is a significant problem for the cattle industry, in part because the virus establishes latency, and stressful stimuli increase the incidence of reactivation from latency. Sensory neurons in trigeminal ganglia and unknown cells in pharyngeal tonsils are importantsites for latency. Reactivation from latency can lead to reproductive problems in pregnant cows, virus transmission to young calves, suppression of immune responses, and bacterial pneumonia. BoHV-1 is also a significant cofactor in bovine respiratory disease (BRD). Stress, as mimicked by the synthetic corticosteroid dexamethasone, reproducibly initiates reactivation from latency. Stress-mediated activation of the glucocorticoid receptor (GR) stimulates viral replication and transactivation of viral promoters that drive the expression of infected cell protein 0 (bICP0) and bICP4. Notably, GR and Krüppel-like factor 15 (KLF15) form a feed-forward transcription loop that cooperatively transactivates immediate early transcription unit 1 (IEtu1 promoter). Two pioneer transcription factors, GR and KLF4, cooperatively transactivate the bICP0 early promoter. Pioneer transcription factors bind silent viral heterochromatin, remodel chromatin, and activate gene expression. Thus, wepredict that these novel transcription factors mediate early stages of BoHV-1 reactivation from latency.

Effect of Short-Term Restraint Stress on the Expression of Genes Associated with the Response to Oxidative Stress in the Hypothalamus of Hypertensive ISIAH and Normotensive WAG Rats

Normotensive and hypertensive organisms respond differently to stress factors; however, the features of the central molecular genetic mechanisms underlying the reaction of the hypertensive organism to stress have not been fully established. In this study, we examined the transcriptome profiles of the hypothalamus of hypertensive ISIAH rats, modeling a stress-sensitive form of arterial hypertension, and normotensive WAG rats at rest and after exposure to a single short-term restraint stress. It was shown that oxidative phosphorylation is the most significantly enriched process among metabolic changes in the hypothalamus of rats of both strains when exposed to a single short-term restraint stress. The analysis revealed DEGs representing both a common response to oxidative stress for both rat strains and a strain-specific response to oxidative stress for hypertensive ISIAH rats. Among the genes of the common response to oxidative stress, the most significant changes in the transcription level were observed in Nos1, Ppargc1a, Abcc1, Srxn1, Cryab, Hspb1, and Fosl1, among which Abcc1 and Nos1 are associated with hypertension, and Fosl1 and Ppargc1a encode transcription factors. The response to oxidative stress specific to hypertensive rats is associated with the activation of the Fos gene. The DEG’s promoter region enrichment analysis allowed us to hypothesize that the response to oxidative stress may be mediated by the participation of the transcription factor CREB1 (Cyclic AMP-responsive element-binding protein 1) and the glucocorticoid receptor (NR3C1) under restraint stress in the hypothalamus of both rat strains. The results of the study revealed common and strain-specific features in the molecular mechanisms associated with oxidative phosphorylation and oxidative stress response in the hypothalamus of hypertensive ISIAH and normotensive WAG rats following a single short-term restraint stress. The obtained results expand the understanding of the most significant molecular targets for further research aimed at developing new therapeutic strategies for the prevention of the consequences of acute emotional stress, taking into account the hypertensive state of the patient.

Augmented cortisol and antiglucocorticoid therapy in mood disorders: the hippocampus as a potential drug target

The pathophysiology of many mood disorders is closely related to abnormal stress response associated with the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and cortisol overproduction. The hippocampus, a key structure of the limbic system responsible for both cognitive and emotional spheres, is selectively vulnerable to excess of glucocorticoids (GCs) inducing neuroinflammation and neurodegeneration. The antiGC therapy of psychiatric diseases, in particular depressive disorders, may be a useful additional treatment. Among other approaches, targeting glucocorticoid receptors, abounded in the hippocampus, is regarded as highly promising. However, though the preclinical data provide fairly firm evidence to the concept of antiGC therapy for stress-related diseases, clinical studies still are at the proof-of-concept stage. Noteworthy, chronic GC excess is associated not only with mood diseases, but also with cognitive decline, metabolic disorders, diabetes. Potentially, antiGC (HPA axis modifying) therapy may alleviate affective symptoms, cognitive disturbances, GC and insulin resistance and adverse side effects of conventional drugs through beneficial effects on the hippocampus mitigating its dysfunction and neurodegeneration, neuroinflammation, and impairment of neurogenesis. Since stress/GC-associated neuroinflammation-mediated pathology of the limbic system and, specifically, the hippocampus, is a general feature typical for many brain diseases, the concept of antiGC therapy may be extended, tested and validated in a wider spectrum of cerebral pathologies.

Chronic Corticosterone Administration-Induced Mood Disorders in Laboratory Rodents: Features, Mechanisms, and Research Perspectives

Mood disorders mainly affect the patient’s daily life, lead to suffering and disability, increase the incidence rate of many medical illnesses, and even cause a trend of suicide. The glucocorticoid (GC)-mediated hypothalamus–pituitary–adrenal (HPA) negative feedback regulation plays a key role in neuropsychiatric disorders. The balance of the mineralocorticoid receptor (MR)/glucocorticoid receptor (GR) level contributes to maintaining the homeostasis of the neuroendocrine system. Consistently, a chronic excess of GC can also lead to HPA axis dysfunction, triggering anxiety, depression, memory loss, and cognitive impairment. The animal model induced by chronic corticosterone (CORT) administration has been widely adopted because of its simple replication and strong stability. This review summarizes the behavioral changes and underlying mechanisms of chronic CORT administration-induced animal models, including neuroinflammatory response, pyroptosis, oxidative stress, neuroplasticity, and apoptosis. Notably, CORT administration at different doses and cycles can destroy the balance of the MR/GR ratio to make dose-dependent effects of CORT on the central nervous system (CNS). This work aims to offer an overview of the topic and recommendations for future cognitive function research.

Pharmacokinetics/pharmacodynamics of glucocorticoids: modeling the glucocorticoid receptor dynamics and dose/response of commonly prescribed glucocorticoids

Background and purpose: The main features of the dynamics of the glucocorticoid receptor (GR) have been known for 50 years: 1) in the absence of glucocorticoid (G), the receptor is localized entirely in the cytoplasm; 2) upon G binding, GR is converted into a tightly bound G form and is rapidly imported into the nucleus where it can bind DNA and modulate transcription; 3) nuclear export of GR is very slow; and 4) the nuclear form of GR can recycle through an unbound form, back to the bound transcription modulating form without leaving the nucleus. Experimental approach: A kinetic model that captures these features is presented, a set of model parameters for dexamethasone is derived, and the clinical implication for the commonly used glucocorticoids is discussed. Key results: At the high concentrations normally used to describe G pharmacodynamics, the model reduces to the standard Michaelis-Menten equation with a Km that is a function of 4 model parameters. At very low concentrations, it reduces to another Michaelis-Menten equation with about a 1000-fold greater affinity, eg. at the nadir human endogenous cortisol concentration, the full model GR activity is 2.6 times greater than that predicted by extrapolation of the high concentration results. Conclusion: The model is used to relate normal human 24-hour endogenous plasma cortisol levels to transcriptional activity and is applied to the commonly prescribed glucocorticoids (dexamethasone, methylprednisolone, prednisone) in an attempt to provide a pharmacological rationale for the very large therapeutic dosage range that has been traditionally used.

Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming

Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids (GC), widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2GC), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics that M2IL4 and M2GC transcriptomes share a striking overlap mirrored by a shift in chromatin landscape in both common and signal-specific gene subsets. This core homeostatic program is enacted by transcriptional effectors KLF4 and the glucocorticoid receptor, whose genome-wide occupancy and actions are integrated in a stimulus-specific manner by the nuclear receptor cofactor GRIP1. Indeed, many of the M2IL4:M2GC-shared transcriptomic changes were GRIP1-dependent. Consistently, GRIP1 loss attenuated phagocytic activity of both populations in vitro and macrophage tissue-repair properties in the murine colitis model in vivo. These findings provide a mechanistic framework for homeostatic macrophage programming by distinct signals, to better inform anti-inflammatory drug design.