A regulated stress response is essential for healthy child growth and development trajectories. We conducted a cluster-randomized trial in rural Bangladesh (funded by the Bill & Melinda Gates Foundation, ClinicalTrials.gov NCT01590095) to assess the effects of an integrated nutritional, water, sanitation, and handwashing intervention on child health. We previously reported on the primary outcomes of the trial, linear growth and caregiver-reported diarrhea. Here, we assessed additional prespecified outcomes: physiological stress response, oxidative stress, and DNA methylation (N = 759, ages 1-2 years). Eight neighboring pregnant women were grouped into a study cluster. Eight geographically adjacent clusters were block-randomized into the control or the combined nutrition, water, sanitation, and handwashing (N + WSH) intervention group (receiving nutritional counseling and lipid-based nutrient supplements, chlorinated drinking water, upgraded sanitation, and handwashing with soap). Participants and data collectors were not masked, but analyses were masked. There were 358 children (68 clusters) in the control group and 401 children (63 clusters) in the intervention group. We measured four F2-isoprostanes isomers (iPF(2α)-III; 2,3-dinor-iPF(2α)-III; iPF(2α)-VI; 8,12-iso-iPF(2α)-VI), salivary alpha-amylase and cortisol, and methylation of the glucocorticoid receptor (NR3C1) exon 1F promoter including the NGFI-A binding site. Compared with control, the N + WSH group had lower concentrations of F2-isoprostanes isomers (differences ranging from -0.16 to -0.19 log ng/mg of creatinine, P < 0.01), elevated post-stressor cortisol (0.24 log µg/dl; P < 0.01), higher cortisol residualized gain scores (0.06 µg/dl; P = 0.023), and decreased methylation of the NGFI-A binding site (-0.04; P = 0.037). The N + WSH intervention enhanced adaptive responses of the physiological stress system in early childhood.

UNASSIGNED: The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC).
UNASSIGNED: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity.
UNASSIGNED: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response.
UNASSIGNED: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.

Fear extinction is a phenomenon that involves a gradual reduction in conditioned fear responses through repeated exposure to fear-inducing cues. Functional brain connectivity assessments, such as functional magnetic resonance imaging (fMRI), provide valuable insights into how brain regions communicate during these processes. Stress, a ubiquitous aspect of life, influences fear learning and extinction by changing the activity of the amygdala, prefrontal cortex, and hippocampus, leading to enhanced fear responses and/or impaired extinction. Glucocorticoid receptors (GRs) are key to the stress response and show a dual function in fear regulation: while they enhance the consolidation of fear memories, they also facilitate extinction. Accordingly, GR dysregulation is associated with anxiety and mood disorders. Recent advancements in cognitive neuroscience underscore the need for a comprehensive understanding that integrates perspectives from the molecular, cellular, and systems levels. In particular, neuropharmacology provides valuable insights into neurotransmitter and receptor systems, aiding the investigation of mechanisms underlying fear regulation and potential therapeutic targets. A notable player in this context is cortisol, a key stress hormone, which significantly influences both fear memory reconsolidation and extinction processes. Gaining a thorough understanding of these intricate interactions has implications in terms of addressing psychiatric disorders related to stress. This review sheds light on the complex interactions between cognitive processes, emotions, and their neural bases. In this endeavor, our aim is to reshape the comprehension of fear, stress, and their implications for emotional well-being, ultimately aiding in the development of therapeutic interventions.

UNASSIGNED: Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist.
UNASSIGNED: Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D).
UNASSIGNED: A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65-38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation.
UNASSIGNED: Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.

BACKGROUND: Maternal elevated glucocorticoid levels during pregnancy can affect the developing fetus, permanently altering the structure and function of its brain throughout life. Excessive action of these hormones is known to contribute to psychiatric disorders, including depression.
METHODS: The study was performed in a rat model of depression based on prenatal administration of dexamethasone (DEX) in late pregnancy (0.1 mg/kg, days 14-21). We evaluated the effects of prenatal DEX treatment on the cognition and bioenergetic signaling pathways in the brain of adult male rats, in the frontal cortex and hippocampus, and in response to stress in adulthood, using behavioral and biochemical test batteries.
RESULTS: We revealed cognitive deficits in rats prenatally treated with DEX. At the molecular level, a decrease in the orexin A and orexin B levels and downregulation of the AMPK-SIRT1-PGC1α transduction pathway in the frontal cortex of these animals were observed. In the hippocampus, a decreased expression of orexin B was found and changes in the MR/GR ratio were demonstrated. Furthermore, an increase in HDAC5 level triggered by the prenatal DEX treatment in both brain structures and a decrease in MeCP2 level in the hippocampus were reported.
CONCLUSIONS: Our study demonstrated that prenatal DEX treatment is associated with cognitive dysfunction and alterations in various proteins leading to metabolic changes in the frontal cortex, while in the hippocampus adaptation mechanisms were activated. The presented results imply that different pathophysiological metabolic processes may be involved in depression development, which may be useful in the search for novel therapies.

The action of environmental steroids on the human glucocorticoid receptor (hGR) has been pointed out with the risk to impair physiological immune and metabolic processes regulated by this nuclear receptor. However, there is still a lack of mechanistic information regarding their ability to interact with GR in aquatic species.
To investigate ligand activation differences between hGR and zebrafish GR (zfGR), we tested several natural and synthetic steroids using reporter cell lines expressing hGR or zfGR.
Almost all the glucocorticoids tested (dexamethasone, cortisol, bimedrazol, medrol, cortivazol and fluticasone) are agonists of the two receptors with similar potencies. The dissociated glucocorticoids, RU24782 and RU24858 are agonists of both zfGR and hGR but with a better potency for the latter. On the other hand, the synthetic glucocorticoid forbimenol and the mineralocorticoid aldosterone are agonist on hGR but antagonist on zfGR. The other steroids tested, androgens and progestins, are all antagonists of both GRs with equal or lower potency on zfGR than on hGR. Surprisingly, the lower efficacy and potency on zfGR of aldosterone, forbimenol and the dissociated glucocorticoids is not related to their affinity for the receptors which would suggest that it could be related to less efficacious recruitment of coactivators by zfGR compared to hGR.

The glucocorticoid receptor (GR) is a nuclear receptor that controls critical biological processes by regulating the transcription of specific genes. GR transcriptional activity is modulated by a series of ligands and coenzymes, where a ligand can act as an agonist or antagonist. GR agonists, such as the glucocorticoids dexamethasone (DEX) and prednisolone, are widely prescribed to patients with inflammatory and autoimmune diseases. DEX is also used to induce osteogenic differentiation in vitro. Recently, it has been highlighted that DEX induces changes in the osteogenic differentiation of human mesenchymal stromal cells by downregulating the transcription factor SRY-box transcription factor 9 (SOX9) and upregulating the peroxisome proliferator-activated receptor γ (PPARG). SOX9 is fundamental in the control of chondrogenesis, but also in osteogenesis by acting as a dominant-negative of RUNX2. Many processes remain to be clarified during cell fate determination, such as the interplay between the key transcription factors. The main objective pursued by this work is to shed light on the interaction between GR and SOX9 in the presence and absence of DEX at an atomic level of resolution using molecular dynamics simulations. The outcome of this research could help the understanding of possible molecular interactions between GR and SOX9 and their role in the determination of cell fate. The results highlight the key residues at the interface between GR and SOX9 involved in the complexation process and shed light on the mechanism through which DEX modulates GR-SOX9 binding and exerts its biological activity.

All living organisms have been programmed to maintain a complex inner equilibrium called homeostasis, despite numerous adversities during their lifespan. Any threatening or perceived as such stimuli for homeostasis is termed a stressor, and a highly conserved response system called the stress response system has been developed to cope with these stimuli and maintain or reinstate homeostasis. The glucocorticoid receptor, a transcription factor belonging to the nuclear receptors protein superfamily, has a major role in the stress response system, and research on its interactome may provide novel information regarding the mechanisms underlying homeostasis maintenance. A list of 149 autosomal genes that have an essential role in GR function or are prime examples of GRE-containing genes was composed in order to gain a comprehensive view of the GR interactome. A search for SNPs on those particular genes was conducted on a dataset of 3554 Japanese individuals, with mentioned polymorphisms being annotated with relevant information from the ClinVar, LitVar, and dbSNP databases. Forty-two SNPs of interest and their genomic locations were identified. These SNPs have been associated with drug metabolism and neuropsychiatric, metabolic, and immune system disorders, while most of them were located in intronic regions. The frequencies of those SNPs were later compared with a dataset consisting of 1465 Korean individuals in order to find population-specific characteristics based on some of the identified SNPs of interest. The results highlighted.that rs1043618 frequencies were different in the two populations, with mentioned polymorphism having a potential role in chronic obstructive pulmonary disease in response to environmental stressors. This SNP is located in the HSPA1A gene, which codes for an essential GR co-chaperone, and such information showcases that similar gene may be novel genomic targets for managing or combatting stress-related pathologies.

This three-wave longitudinal study examined whether methylation alterations in promoter exon 1F of a stress-related gene-NR3C1 (NR3C1-1F)-explained the longitudinal associations between childhood maltreatment and adolescent depressive symptoms. A total of 370 Han Chinese adolescents (Mage  = 16.31 ± 1.28 years; 51.4% girls) recruited from Shandong, China were tracked from 2018 to 2020. The results showed that the severity of childhood maltreatment, especially that of emotional abuse and physical neglect, conferred risk for adolescent depressive symptoms via reducing NR3C1-1F methylation levels. These mediation effects of NR3C1-1F methylation did not vary between adolescent sex or NR3C1 BclI and Tth111I polymorphisms. The findings highlight how childhood maltreatment contributes to psychopathology development at a biological level.

Academic pressure is a prevalent stressor among Chinese adolescents and is often linked to anxiety symptoms, although the underlying mechanism remains unclear. This study aimed to investigate the association between NR3C1 gene methylation, academic pressure, and anxiety symptoms among Chinese adolescents.
This nested-case control study included 150 adolescents (boys: 38.7%; baseline age: 12-17 years) from a school-based longitudinal study of Chinese adolescents. Cases (n = 50) were defined as those with anxiety symptoms at both baseline and follow-up, while controls (n = 100) were randomly selected from those without anxiety symptoms at both timepoints. The cases and controls were 1:2 matched by age. Academic pressure, anxiety symptoms, and potential covariates were measured using a self-report questionnaire. Peripheral whole blood samples were collected from each participant for the detection of cortisol level (i.e., morning serum cortisol level) and DNA methylation. The methylation analysis included a total of 27 CpG units at the NR3C1 promoter region.
The final adjusted models showed that students with heavy academic pressure at baseline were at a higher risk of anxiety symptoms at follow-up compared to those with mild academic pressure (β estimate: 6.24 [95% CI: 3.48 ~ 9.01]). After adjusting for covariates, the methylation level of one CpG unit (NR3C1-16 CpG10) in NR3C1 differed significantly between cases and controls (F = 6.188, P = 0.014), and the difference remained significant after correction for multiple testing (P < 0.025). The adjusted regression models showed that moderate (β estimate = 0.010 [95% CI: 0.000 ~ 0.020], P = 0.046) and heavy (β estimate = 0.011 [95% CI: 0.001 ~ 0.020], P = 0.030) academic pressure were significantly associated with the methylation level of NR3C1-16 CpG 10. Further mediation analysis demonstrated that the association of academic pressure and anxiety symptoms was significantly mediated by the methylation of NR3C1-16 CpG 10 (β estimate for indirect effect = 0.11 [95% CI: 0.005 ~ 0.32]; indirect/total effect = 8.3%).
The present study suggests that NR3C1-16 CpG 10 DNA methylation might be a potential mechanism that partially explains the lasting effects of academic pressure on subsequent anxiety symptoms among adolescents. Further studies with larger sample sizes are recommended to replicate this finding.