CPD47, a novel GSK-3β inhibitor, demonstrates antidepressant-like effects via the GSK-3β/β-catenin signaling pathway: Involvement of neurogenesis promotion and neuroinflammation inhibition.

Thioredoxin interacting protein mediates corticosterone-induced depressive-like behavior in male mice.

Corticosterone regulates the balance between freezing and rearing in defensive responses to predator threat.

Comprehensive adrenal steroid profiling during frog metamorphosis.

Chlorogenic acid ameliorates chronic stress-induced depression-like behaviors in rats by inhibiting oxidative stress and neuroinflammation via the PI3K/Akt/Nrf2 pathway.

Untargeted metabolomics elucidates the enhanced protective effects of blackberry juice fermented with Lacticaseibacillus paracasei on hypothalamic-pituitary-adrenal (HPA) axis neuronal dysfunction.

Rationale: High-intensity psychological and physiological stress contributed greatly to development of cardiac disorders in contemporary society. However, the underlying molecular mechanisms remain largely unknown. Synaptotagmin-7 (Syt7), a Ca²⁺ sensor with high affinity, has been associated with synaptic transmission and tumor progression, but its role in cardiac stress responses remains poorly defined. Methods: Corticosterone (CORT) was used to induce stress injury in vivo and in vitro. The expression of Syt7 was modulated by genetic knockout, injection of adenoviral siRNA or injection of adeno-associated virus serotype 9 (AAV9) shRNA. Cardiac function and remodeling were evaluated by echocardiography, electrocardiography, and histological staining. Necroptosis was analyzed by propidium iodide (PI) staining, lactate dehydrogenase (LDH) release detection, and necroptosis marker levels. Ca²⁺ overload, ROS production, mitochondrial permeability transition pore (mPTP) opening, and bioenergetic profiling were assessed to evaluate mitochondrial function. Co-IP assay was performed to detect protein interaction, and ChIP- qPCR was performed to assess transcriptional regulation. Results: Syt7 expression was significantly upregulated in both cardiomyocytes and heart tissues exposed to CORT. Both genetic knockout and cardiomyocyte-specific knockdown of Syt7 significantly preserved cardiac function and rhythm, and alleviated myocardial hypertrophy and fibrosis in CORT-treated mice. Mechanistically, Syt7 regulated necroptosis by promoting calcium overload, ROS production, mitochondrial ΔΨm dissipation, and mPTP prolonged opening. Notably, Syt7 interacted with transcription factor p53 and enhanced p53- mediated transcription of Bcl-2 homologous antagonist/killer (Bak). Syt7, p53 and Bak constitute a novel signaling axis to regulate mitochondrial dysfunction and necroptosis. Therapeutically, cardiac delivery of Syt7-targeting siRNA via adenoviral vectors significantly alleviated structural remodeling, electrophysiological instability, and myocardial necrosis in CORT-challenged mice. Conclusions: The study identified Syt7 as a novel upstream regulator involved in cardiomyocyte necroptosis triggered by stress stimuli through a p53-Bak-mPTP pathway. Therapeutic targeting of Syt7 offers a promising strategy for protecting the heart against psychological or neuroendocrine stress-related injury.

Although the effects of social rank on behavior and physiology are well established, their relationship with gut microbiota is not yet fully understood. We investigated how social rank affects physiological responses, gut microbiota, and metabolites in the greater long-tailed hamster (Tscherskia triton), a naturally solitary rodent. Dominant male hamsters displayed a "high-vigilance, metabolically activated" phenotype, characterized by increased aggression, elevated serum corticosterone (CORT) and serotonin (5-HT) levels, and activation of the paraventricular nucleus, a key regulator of the hypothalamic-pituitary-adrenal axis. In contrast, subordinates exhibited lower CORT and 5-HT levels, with increased activation of the arcuate nucleus (ARC), suggesting a more energy-conserving and stress-resilient phenotype. Social rank strongly shaped gut microbiota and metabolic output: dominants were enriched in energy-harvesting taxa (e.g., Limosilactobacillus and Alistipes) and had higher fecal queuine levels, a metabolite derived from gut microbiota. Conversely, subordinates were enriched in immunomodulatory taxa (e.g., Faecalibacterium and Butyrivibrio). These findings suggest that dominance in solitary species may be supported by coordinated host-microbiome interactions, which meet high energetic demands while maintaining stress resilience. This provides a novel framework for understanding the gut-brain-microbiome axis in social dominance.

Cadmium (Cd), a widespread environmental contaminant, induces cardiotoxicity even at low doses through endocrine disruption and oxidative stress. This investigation assessed age-related susceptibility in female albino rats by comparing pre-pubertal (30-day-old) and post-pubertal (60-day-old) animals that were administered CdCl₂ at a dosage of 5.12mg/kg body weight per day via oral gavage for 15 days. Despite greater Cd accumulation in pre-pubertal rats, post-pubertal animals exhibited heightened cardiac injury. This paradox correlated with impaired induction of metallothionein (MT), enhanced glutathione and vitamin C depletion, and reduced enzymic antioxidants (SOD, CAT, GPx). Concomitantly, altered adrenal function with increased corticosterone (CORT) and reduced estradiol (E2) reflected differential hypothalamic-pituitary-adrenal (HPA) axis responsiveness, further compromising antioxidant defenses. Biomarkers of cardiac function confirmed this vulnerability: increased serum CK-MB and troponin I, electrocardiographic (ECG) abnormalities (ST elevation, QT prolongation, tachycardia), and larger infarct volume. Collectively, these findings demonstrate that post-pubertal susceptibility is driven by reduced MT inducibility and HPA axis-mediated endocrine dysregulation, which amplify oxidative injury and structural remodeling of ventricular myocardium. From a translational standpoint, our findings identify adolescence and early adulthood as critical windows during which females exhibit heightened vulnerability to environmental CdCl2 exposure. Variations in metallothionein (MT) expression capacity and estradiol levels may serve as informative biomarkers for predicting individual susceptibility. These results also suggest the potential value of targeted interventions such as MT induction, antioxidant therapy, or modulation of hormonal pathways, that merit further investigation. Collectively, the study emphasizes the urgent need for stricter regulation of cadmium exposure, particularly among peripubertal populations, to reduce lifelong cardiovascular risk.

BackgroundOvarian cancer (OC) is a leading cause of cancer-related death among women, with elevated levels of stress hormones linked to OC progression and immune evasion in the tumor microenvironment (TME). Chronic psychosocial stress has been associated with the expansion of immunosuppressive myeloid-derived suppressor cells (MDSCs), which promote tumor growth and negatively impact patient outcomes. This study tested how chronic daily restraint stress affected ovarian cancer progression, Notch signaling, and MDSCs in the OC TME. We hypothesized that chronic stress increases MDSCs infiltration in the TME, enhances Notch signaling in OC cells, and promotes cancer progression. MethodsFemale C57BL/6 mice were injected with ID8Luc or IG10Luc OC cells and subjected to daily restraint stress. We also isolated bone marrow from naïve C57BL/6 mice to differentiate myeloid cell precursors into MDSCs. These cells were then exposed to norepinephrine (NE), epinephrine (EPI), or corticosterone (CC). To further evaluate the effects of stress hormones on the dysregulation of the Notch signaling pathway, we treated OC cells with NE, EPI, or CC.ResultsChronic daily restraint stress increased MDSCs infiltration and enriched polymorphonuclear (PMN)-MDSCs in the TME and bone marrow in both models. Ex vivo studies demonstrated an increased enrichment of PMN-MDSCs along with a reduction of mononuclear (M)-MDSCs in the groups treated with stress hormones, particularly CC. Our results showed that stress hormones significantly increased the expression of notch intracellular domain (NICD) in OC cells. Additionally, we observed increased mRNA levels of Notch1, Jagged2, and Hes1, along with elevated NICD and HES1 protein levels, mediated by CC-induced GSK3β phosphorylation. Pharmacological inhibition of NICD and gLucocorticoid receptors blocked the CC-induced Notch pathway activation via GSK3β phosphorylation. Moreover, tumors from mice subjected to restraint stress had elevated expression of Notch1, Jagged 2, NICD, HES1, GR, ADRB2, and pS9-GSK3β. ConclusionThese data indicate that chronic stress leads to MDSCs infiltration and suppressive activity, which contributes to an immunosuppressive TME and OC progression.

Depression is a debilitating psychiatric disorder with high prevalence and suicide risk, imposing significant burdens on global health. Against this global health burden, the active ingredients of Gekko gecko Linnaeus (AIGG), a traditional Chinese medicine (TCM), have shown empirical antidepressant effects. However, their specific pharmacological mechanisms remain unclear. This study systematically elucidated the antidepressant mechanisms of AIGG by integrating GC-MS-based component analysis, network pharmacology, molecular docking, and a corticosterone (CORT)-induced depressive mouse model. GC-MS identified 10 bioactive compounds (including fatty acids) in AIGG. Network pharmacology screening of 51 potential targets revealed significant enrichment in synaptic transmission and cAMP pathways. Molecular docking confirmed strong binding affinities between AIGG-derived compounds and key targets. In vivo experiments demonstrated that AIGG significantly reversed depression-like behaviors in both forced swim and tail suspension tests, suppressed Interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and elevated β-nerve growth factor (β-NGF) levels, attenuated neuroinflammatory infiltration and neuronal apoptosis in brain tissue, and upregulated protein expression of protein kinase cAMP-activated catalytic subunit alpha (PRKACA), brain-derived neurotrophic factor (BDNF), and postsynaptic density protein 95 (PSD95). The study confirmed that AIGG alleviates depression by activating the cAMP-PRKACA-BDNF axis to restore synaptic plasticity, providing a novel natural product-based strategy for treatment of the resistant depression.

It has indicated that arsenic exhibits toxicity to skeletal muscle; however, the specific characteristics of arsenic-induced skeletal muscle damage and associated risk indicators remain unclear. Our previous research has demonstrated that arsenite-induced skeletal muscle atrophy exhibits a susceptibility in middle-aged rats, and other studies have shown that glucocorticoids play a significant role in maintaining skeletal muscle mass. This study was aimed at investigating the relationship between alterations in serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels and indicators of arsenic-induced skeletal muscle aging in mice. In this study, 24 male C57BL/6J mice were randomly assigned to a control group and three arsenite exposure groups with low dose (0.01 mg/L), medium dose (0.1 mg/L), and high dose (1 mg/L). The results showed that in the 0.1 and 1 mg/L arsenite exposure groups compared to the control group, a shortening in relative telomere length and a decreased ratio of type II/I myofibers were observed in the gastrocnemius muscle. Additionally, serum levels of ACTH and CORT were elevated, alongside increased indicators of oxidative stress (SOD, GSH, and MDA) as well as inflammatory factors (TNF-α, IL-1β, and IL-6) within the gastrocnemius muscle. In addition, mice exposed to 1 mg/L arsenite exhibited a significant decline in limb grip strength and skeletal muscle atrophy. The serum levels of ACTH and CORT in arsenite exposure groups exhibited a significant negative correlation with limb grip strength, gastrocnemius muscle index, and the relative length of telomeres in the gastrocnemius muscle. This study demonstrated that long-term exposure to arsenite could accelerate skeletal muscle aging in middle-aged mice, potentially linked to the dysregulation of the HPA axis.

Behavioral flexibility allows organisms to modify actions based on new information, such as shifts in reward value or availability, and is promoted by the dorsomedial striatum (DMS). In contrast, behavioral inflexibility provides efficiency and automaticity in familiar contexts, and is promoted by the dorsolateral striatum (DLS). Importantly, chronic elevation of the primary stress hormone, corticosterone (CORT) in rodents or cortisol in humans, impairs behavioral flexibility through dendritic atrophy in the DMS, and promotes inflexible behavioral response strategies through dendritic outgrowth in the DLS. However, understanding of changes in gene expression underlying behavioral inflexibility is lacking. We used a food-motivated operant task in male and female mice to define gene changes that accompany the shift to inflexible behavior with CORT. We discovered that CORT-accelerated loss of behavioral flexibility is accompanied by decreased DMS- and increased DLS-specific synaptic plasticity gene expression, and that distinct genes are either differentially expressed or spliced in the transition to inflexible behavior. Splicing analysis suggests that repressed activity in the DMS during the transition to inflexible behavior may reflect both reduced expression and increased degradation of plasticity-related mRNA transcripts. Finally, given the ability of CORT to influence histone acetylation, we defined CORT-mediated H3K9ac enrichment profiles associated with synaptic plasticity gene regulation stratified by sex and striatal subregion. This study is the first to define CORT-driven epigenetic regulation in the DMS and DLS during the CORT-accelerated transition from flexible to inflexible behavior in male and female mice.

SynopsisUnderstanding a species’ physiological state is important for advancing animal ecology and conservation. Endocrine responses to reproduction, stress, and nutritional status are commonly assessed through gonadal, adrenal, and thyroid hormones, respectively. Using nonconventional samples for endocrinological evaluation is an increasingly utilized method but remains uncommon for snakes. In this study, we assessed whether feces, urine, or shed skin from two Neotropical pit vipers (Bothrops jararaca and B. jararacussu) contain detectable testosterone (T), progesterone (P4), 17β-estradiol (E2), corticosterone (CORT), and triiodothyronine (T3) using enzyme immunoassay (EIA). We collected samples from 23 individuals, 10 B. jararaca and 13 B. jararacussu, and assessed detectability of hormones and/or immunoreactive hormone metabolites (IHM). We used tests of parallelism and accuracy to validate assays. Triiodothyronine was not detected in urine of either species; all other hormones were detected in all matrices. Testosterone and T3 showed good parallelism for all matrices tested. Parallelism tests for E2 (urine, both species), CORT (urine, B. jararaca, and shed skin, B. jararacussu), and P4 (urine, B. jararaca) showed marginally acceptable results. All accuracy validations were successful, except for T3 in shed skin extract (B. jararacussu) and P4 in urine extract (B. jararaca). This study demonstrates the applicability of nonconventional samples for hormone and IHM detection and quantification, offering valuable tools to monitor the endocrinological status of both free-ranging and confined snakes.

Gene expression profiles and the heterogeneity among hormone-producing pituitary cells remain poorly characterized in most vertebrates, especially in chicken embryos. Using single-cell RNA sequencing, the transcriptomes of 4346 basal and 10 835 corticosterone (CORT)-treated embryonic day 11 chicken pituitary cells were sequenced. Classical endocrine cell clusters were identified, and some were shown to express previously unreported marker genes. A cluster of uncommitted cells was identified that expressed markers for multiple endocrine cell types, with ∼30% coexpressing Gh and Pomc mRNA. We named this population of cells the cortico-somatotrophs. The existence of cortico-somatotrophs were confirmed at both the mRNA and protein level. We further characterized the corticosomatotrophs by utilizing the known effect of CORT to increase somatotroph abundance. Identification of cortico-somatotrophs challenges the prevailing view that corticotrophs and somatotrophs develop from distinct cell lineages.

Disturbance of endogenous glucocorticoid levels by phenicol antibiotics in living fish.

Individual differences in stress coping are linked to working memory performance in male and female F344 rats.

Gestational morin administration attenuates prenatal stress-induced apoptotic and associated neurobehavioral alterations in F1 generation Wistar rats.

Formononetin alleviates corticosterone-induced myelin damage through activating ERα and promoting the differentiation of oligodendrocyte precursor cells in the prefrontal cortex.

Chlorogenic acid reverses growth inhibition by suppressing the hypothalamic COX-2 signaling pathway in broilers under LPS-induced immune stress.