Search Results (596)

Background: Gestation is a period of significant biological plasticity where the intrauterine environment influences fetal development via “fetal programming”. This study systematically reviews and meta-analyzes the association between genetic determinants—specifically the NR3C1, FKBP5, and CRHR1 genes, chosen for their pivotal role in the functional regulation and feedback sensitivity of the hypothalamic–pituitary–adrenal (HPA) axis—and stress reactivity during pregnancy. Methods: Following PRISMA guidelines, a systematic search was conducted across PubMed, Scopus, and Web of Science, yielding an initial total of 1430 records. After removing duplicates and screening 669 studies, a total of 34 primary observational studies were included in the systematic review and qualitative synthesis. For the quantitative synthesis, 27 articles provided sufficient data, resulting in k = 39 independent effect sizes analyzed via a mixed-effects model to account for tissue-specific and cohort-specific outcomes. Results: Systematic analysis reveals that maternal psychosocial stress significantly correlates with NR3C1 hypermethylation, acting as a biological mediator for neonatal cortisol dysregulation and hippocampal volume reduction. The FKBP5 rs1360780 polymorphism emerged as a key moderator of structural vulnerability, showing a “double-hit” effect when combined with epigenetic alterations. Furthermore, the study identifies sex-specific susceptibility, with divergent placental trajectories for male and female fetuses. Meta-analytic estimates confirmed the robustness of these associations (Rosenthal Fail-Safe N = 431,000), despite a general trend toward statistical significance (p = 0.079) in heterogeneous cohorts. Conclusions: The findings underscore a stable link between genetic determinants and prenatal stress reactivity. The interaction between molecular predisposition and environmental factors defines the health of the mother–infant dyad. These results advocate for a transition toward Precision Prenatal Medicine, integrating polygenic risk scores and epigenetic monitoring to implement early, targeted preventive interventions. Full article

Environmental chemicals are rarely considered stressors in the way that psychological or physical stressors are. Yet many endocrine-disrupting chemicals (EDCs) interact with the body’s core stress response system. This review examines how EDCs alter hypothalamic–pituitary–adrenal (HPA) regulation and how biological sex influences those responses. Drawing on human epidemiological data and experimental models, we describe how EDC exposure affects cortisol dynamics, feedback sensitivity, and adrenal signaling, with a particular focus on sex-dependent outcomes. We propose the concept of endocrine noise to describe how low-dose, often mixed EDC exposures introduce persistent interference into hormone signaling without necessarily causing overt endocrine deficiency or excess. In this framework, EDCs act as chronic, low-grade stressors that reset the timing, feedback precision, and rhythmic organization of the HPA axis rather than as isolated reproductive toxicants. We argue that EDCs should be understood as chronic, context-dependent stress modifiers that reshape sex-specific “risk architectures” for affective, metabolic, and immune disorders. Recognizing sex-specific HPA architecture and endocrine noise has immediate implications for study design and regulation, including the need for sex-stratified analyses, circadian-sensitive sampling of cortisol, and risk assessments that consider how the same exposure can push female and male stress systems in divergent directions. Full article

Background: Dermatological conditions represent a leading cause of global nonfatal disease burden, accounting for approximately 42.9 million disability-adjusted life years annually. Their complex pathogenesis is increasingly understood through the skin–brain–exposome axis, a bidirectional neuroimmunological and environmental communication network. The study aims to synthesize the neurobiological mechanisms of the skin–brain–exposome axis with macroscopic sociodemographic modifiers, clinical manifestations, and evidence-based psychodermatological interventions. Methods: A narrative review was conducted, following a structured search of PubMed, Scopus, and Web of Science (from inception to February 2026), yielding 54 sources. Mechanistic and interventional data (including randomized controlled trials and meta-analyses) were integrated with large-scale population-based epidemiological findings, anchored by a recent cross-sectional Polish cohort of 27,000 adults. Results: Psychological distress is associated with hyperactivation of the hypothalamic–pituitary–adrenal (HPA) axis and peripheral neurogenic inflammation (e.g., Substance P, corticotropin-releasing hormone), exacerbating stress-sensitive conditions such as atopic dermatitis, psoriasis, acne, and chronic pruritus. External exposome factors (urbanization, pollution) and sociodemographic variables (education, gender) may modify biological risk and diagnostic capture rates, frequently generating an epidemiological diagnostic paradox. Randomized trials support that psychotherapeutic interventions, particularly Cognitive Behavioral Therapy (CBT) and Mindfulness-Based Stress Reduction (MBSR), effectively disrupt the physical itch–scratch–stress cycle and improve disease-specific quality of life, serving as evidence-based adjunctive strategies in comprehensive care. Conclusions: Effective dermatological management requires targeting both the cutaneous barrier and the psychological exposome. Integrating routine psychosocial screening and stratified behavioral interventions into standard clinical care is essential for addressing the neuroimmune chronicity of inflammatory skin diseases. Full article

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent urological disorder characterized by persistent pelvic pain, urinary symptoms, and significant impact on quality of life. In addition to its clinical symptoms, CP/CPPS is frequently associated with psychiatric comorbidities, such as anxiety and depression, indicating complex neurobiological mechanisms. This review explores the mechanisms linking CP/CPPS with affective disorders, emphasizing central nervous system alterations, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, and neuroimmune interactions. Evidence in-dicates that central sensitization, microglial and astrocytic activation, and elevated proinflammatory cytokines (IL-1β, IL-6, TNF-α) contribute to maladaptive painemotion network interactions. Additionally, dysregulation of hormones and neurotransmitters may exacerbate both pain perception and mood disorders. Psychosocial factors, including stress, coping strategies, and cognitive-emotional processes, further modulate symptom severity and treatment outcomes, highlighting the importance of a biopsychosocial approach. Gaining a deeper understanding of the neurobiological and psychosocial mechanisms behind anxiety and depression in CP/CPPS can lead to more effective, multidimensional management strategies and enhance patient-centered care. Full article

Objective: ZhiZhu Kuanzhong (ZZKZ) capsule, a Chinese herbal extract, is extensively employed for the clinical management of functional dyspepsia (FD) in China. This study aimed to elucidate the therapeutic efficacy and underlying mechanisms of ZZKZ on the co-morbidity of anxiety and depression of FD. Methods: The FD model was established in Sprague–Dawley rats via neonatal gastric irritation with 0.1% iodoacetamide. Subsequently, FD rats were gavaged with ZZKZ or fluoxetine. Depression-like behaviors were evaluated using the sucrose preference test (SPT) and forced swimming test (FST), while anxiety-like behaviors were assessed via light-dark box (LDB) and open field tests (OFTs). Network pharmacology and molecular docking were conducted to explore the mechanisms of ZZKZ’s action. Hippocampal levels of monoamine neurotransmitters and monoaminergic system components were evaluated by HPLC and RT-qPCR, respectively. Serum concentrations of HPA axis hormones were determined by ELISA. Results: ZZKZ administration reversed the deficits in body weight gain and food intake in FD rats. Behaviorally, ZZKZ increased sucrose consumption in SPT and prolonged swimming duration in FST, and it increased duration and entries into the central zone in OFT. According to the prediction of network pharmacology, ZZKZ treatment elevated hippocampal levels of 5-HT/NE/DA, increased expression of TPH2/TH, and decreased expression of MAO_A/SERT in FD rats. Molecular docking further confirmed high-affinity binding between core ingredients of ZZKZ and TPH2/TH/MAO_A/SERT. Moreover, ZZKZ administration attenuated the stress-induced elevation of serum CRH/ACTH/CORT. Conclusions: ZZKZ effectively ameliorates the disordered gut–brain interaction and mitigates anxiety-like and depression-like behaviors, which might be modulated by the hippocampal monoaminergic system and hypothalamic–pituitary–adrenal axis response. Full article

This study investigated whether tongue motor loss induced by bilateral transection of the hypoglossal nerves (Hx) alters anxiety- and/or depression-like behaviors in rats and examined the associated neuroendocrine changes. Male Sprague–Dawley rats underwent Hx or sham surgery and were evaluated in the ambulatory activity, elevated plus maze, forced swim, and sucrose preference tests at different postoperative time points. Neuroendocrine parameters were assessed by plasma corticosterone assay, quantitative real-time PCR, Western blot analysis, and adrenal histology. At two weeks after surgery, Hx rats exhibited anxiety-like behavioral changes in the elevated plus maze and increased immobility with reduced struggling in the forced swim test, consistent with a depression-like behavior. Reduced sucrose intake was observed at earlier postoperative stages, suggesting early anhedonia-like behavior. Hx rats also showed chronically increased plasma corticosterone levels, adrenocortical hypertrophy, and decreased hippocampal glucocorticoid receptor expression. These findings highlight a potential oral–systemic interaction in which loss of oral motor function alters neuroendocrine homeostasis and emotional regulation. Full article

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder with a high incidence of anxiety and depression. However, the underlying mechanisms of these symptoms remain to be fully elucidated. This study investigated the effects and mechanisms of a 20% ethanolic extract of Petasites japonicus leaves (EPJ) on dextran sulfate sodium (DSS)-induced colitis and depression-like behaviors. The physiological compounds identified in the EPJ were citric acid, chlorogenic acid, caffeic acid, fukinolic acid, 3,5-dicaffeoylquinic acid, quercetin 3-O-β-D-glucose-6″-acetate, 4,5-dicaffeoylquinic acid, kaempferol-3-O-(6″-acetyl)-β-glucopyranoside, and pedunculoside. EPJ significantly alleviated DSS-induced colitis, as evidenced by improvements in body weight loss (87.41% vs. 76.02% in the DSS group), colon length (5.75 vs. 4.34 cm), intestinal permeability (52.80 vs. 163.01 μg/mL), and myeloperoxidase (MPO) activity (0.24 vs. 0.67 U/mg) (p < 0.05). Histological analysis further confirmed recovery of goblet cells and attenuation of muscle layer thickening. EPJ also reversed DSS-induced gut microbiota dysbiosis and contributed to the restoration of microbial homeostasis. Behavioral assessments showed that EPJ effectively ameliorated depression-like behaviors. EPJ improved antioxidant systems in colon and brain tissues by modulating malondialdehyde (MDA) levels and reduced glutathione (GSH) and superoxide dismutase (SOD) activity. EPJ further upregulated tight junction protein expression and suppressed TLR4/NF-κB inflammatory pathway activation in both colon and brain tissues. Moreover, EPJ modulated serum stress-related hormones, normalized hypothalamic–pituitary–adrenal (HPA) axis dysregulation, regulated the BDNF/TrkB signaling pathway, and modulated tryptophan–kynurenine metabolism. Collectively, these findings suggest that EPJ exerts protective effects against DSS-induced colitis and depression-like behaviors. Full article

The adrenal glands are central regulators of endocrine function and stress physiology, yet detailed species-specific anatomical baselines remain limited in cetaceans. This study provides a comprehensive gross, histological, morphometric, and ultrastructural characterization of the adrenal glands in 55 short-beaked common dolphins (Delphinus delphis) examined postmortem in the Canary Islands. Adrenal glands were evaluated macroscopically and microscopically, and histological corticomedullary ratios were calculated from mid-transverse sections. Associations with body length, sexual maturity, and cause-of-death category were assessed statistically. Transmission electron microscopy was used to characterize cortical and medullary cellular ultrastructure. Adrenal weight showed a positive correlation with body length. The histological corticomedullary ratio showed no lateral asymmetry but differed significantly between sexually immature and mature individuals, indicating ontogenetic remodeling of adrenal architecture. In contrast, the corticomedullary ratio did not differ significantly between adult dolphins that died from acute events and those that died following more progressive pathological conditions. Ultrastructural analysis identified characteristic steroidogenic cortical cells and two distinct chromaffin cell populations in the medulla. These findings establish the first integrated anatomical baseline for the adrenal gland in Delphinus delphis, providing essential reference data for comparative anatomy, veterinary pathology, and the interpretation of endocrine-related findings in cetaceans. Full article

Chronic stress is defined as a prolonged state of emotional disturbance and psychological strain resulting from an inability to maintain internal homeostasis. It is recognized as a significant risk factor for breast cancer, primarily through the chronic activation of the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis. This neuroendocrine activation leads to elevated systemic levels of epinephrine, norepinephrine, and glucocorticoids. By binding to their respective adrenergic and glucocorticoid receptors, these hormones disrupt immune homeostasis and exacerbate oxidative stress within the tumor microenvironment. Such physiological shifts promote critical oncogenic processes, including angiogenesis and tumor cell proliferation, thereby driving the development, progression, and distant metastasis of breast cancer. Mastication, or the act of chewing, serves as a practical and effective behavioral strategy for modulating the deleterious effects of chronic psychological stress. Recent animal studies have provided compelling evidence that chewing can attenuate excessive stress responses. Specifically, it has been shown to mitigate stress-induced breast cancer progression and metastasis by modulating the expression of stress hormones, their corresponding receptors, and key downstream signaling pathways. These findings suggest that the rhythmic activity of chewing may exert a protective effect against stress-related tumor exacerbation. Consequently, further clinical research is warranted to determine whether chewing interventions can serve as a viable complementary strategy alongside conventional breast cancer prevention and treatment protocols. Full article

Background: The low-dose Synacthen stimulation test (LD-SST) is the reference dynamic test for diagnosing glucocorticoid-induced adrenal insufficiency (AI) in children, but it is resource-intensive and costly. This study aimed to establish morning cortisol thresholds predictive of hypothalamic–pituitary–adrenal (HPA) axis response to LD-SST in pediatric patients receiving chronic corticosteroid therapy. Methods: We conducted a prospective study including 71 children (mean age 6.23 ± 3.49 years; 57.7% male) receiving prolonged oral or inhaled corticosteroids. All patients underwent LD-SST with cortisol measurements at 0, 30, and 60 min. Patients were classified as having AI (peak cortisol < 18 μg/dL at T30 or T60, n = 39) or normal adrenal function (peak cortisol ≥ 18 μg/dL, n = 32). ROC curve analysis determined optimal cortisol thresholds for predicting AI. Results: Among the 71 patients, 44 received inhaled corticosteroids (62%) and 27 oral corticosteroids (38%). Asthma (61.9%) and autoimmune diseases (18.3%) were the main indications. The prevalence of AI was 54.9% (n = 39). Mean morning cortisol was significantly lower in the AI group compared to the normal group (6.69 ± 1.99 vs. 9.21 ± 2.49 μg/dL, p < 0.001). ROC analysis identified a morning cortisol <6 μg/dL as predictive of AI with 96.9% sensitivity and 46.2% specificity (AUC = 0.823), while a threshold >13 μg/dL predicted normal HPA function with 100% specificity. Using these thresholds would have avoided LD-SST in 29.6% of patients. The cortisol increment following stimulation also demonstrated diagnostic value (AUC = 0.822), with an increment <9 μg/dL suggesting AI and ≥9 μg/dL likely excluding the diagnosis. Conclusions: In this North African pilot study, morning cortisol measurement at 7 days after oral corticosteroid withdrawal predicted LD-SST response. A threshold of ≤6 μg/dL identified patients with persistent HPA suppression with high sensitivity (97.4%), while ≥13 μg/dL identified patients with preserved function with high specificity (100%). However, the 7-day washout period might be insufficient for complete HPA recovery; therefore, these thresholds reflect residual suppression rather than permanent adrenal insufficiency. Full article

Eating disorders (EDs), including anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorder (BED), are complex psychiatric conditions characterized by high morbidity and mortality. Increasing evidence suggests that beyond disorder-specific symptomatology, shared transdiagnostic mechanisms contribute to their onset and persistence. This narrative review synthesizes current data on neurobiological and nutritional factors implicated in EDs, with particular emphasis on trait–state interactions and starvation-induced neuroadaptations. Predisposing vulnerabilities such as heightened anxiety, cognitive rigidity, and perfectionism appear to interact with state-dependent biological alterations induced by malnutrition. Chronic dietary restriction is associated with measurable alterations in serotonergic and dopaminergic systems, altered reward processing, and persistent activation of the hypothalamic–pituitary–adrenal (HPA) axis. Experimental studies suggest that acute tryptophan depletion may transiently reduce anxiety in individuals with anorexia nervosa, suggesting that, in some individuals, food restriction may function as a biologically reinforced strategy of affect regulation. Furthermore, disturbances in leptin and ghrelin signaling, along with widespread micronutrient deficiencies—including zinc, iron, selenium, and B vitamins—may exacerbate cognitive inflexibility, mood instability, and impaired decision-making. These metabolic and endocrine adaptations may contribute to a self-perpetuating cycle in which starvation-induced neurochemical changes reinforce restrictive or dysregulated eating behaviors. Importantly, several of these mechanisms extend beyond anorexia nervosa and may represent common transdiagnostic processes across eating disorders and related mental health conditions, including anxiety, depression, and addictive behaviors. Recognition of these biological and nutritional factors has significant implications for treatment. Nutritional rehabilitation should be conceptualized not solely as weight restoration, but as a neurobiological recalibration of stress regulation, reward sensitivity, and affective processing systems. An integrative treatment approach that combines behavioral stabilization with attention to underlying neurobiological and relational mechanisms may offer a more comprehensive framework for long-term recovery. Full article

Background: Postnatal corticosteroids (CS) improve respiratory outcomes in preterm infants, but effects on growth and neurodevelopment remain incompletely understood. Methods: This third instalment of a narrative review series builds on physiologic principles to examine systemic CS consequences. Main Findings: We explore the interplay between growth restriction, hypoxia, and neurodevelopmental vulnerability, discussing brain imaging, metabolic disruptions, and HPA axis suppression. Conclusion: This review advocates for a holistic, physiology-informed approach to optimize outcomes by integrating nutritional vulnerability with cardiorespiratory status. Full article

Chronic stress is among the most pervasive health challenges of contemporary urban life, yet its persistence is not simply a matter of external pressure. When adult hippocampal neurogenesis is impaired, the brain loses its capacity to regulate the hypothalamic–pituitary–adrenal (HPA) axis and distinguish new threats from familiar ones through dentate gyrus pattern separation, rendering stress self-perpetuating. Physical activity is widely recognised as a promoter of neurogenesis through brain-derived neurotrophic factor (BDNF), yet the built environments in which most people spend approximately 90% of their time simultaneously suppress BDNF through chronic stress and deny sufficient physical activity intensity to restore it, a condition known as type 2 allostatic overload sustained by architectural impoverishment. This paper proposes architectural enrichment as a theoretical framework designed to resolve this problem at its root through two independent but synergistic mechanisms: architecturally mediated voluntary stair use to elevate peripheral BDNF via metabolic pathways, and neurobiophilic design based on the Neurobiophilia Index to attenuate cortisol and passively support BDNF and neurogenesis. Twelve hypothesised neurobiological profiles are derived in a framework that advances the concept of hippocampal neurosustainability, proposing that buildings can be designed not merely to avoid harming the brain but to actively sustain its capacity for resilience amid the stressors of modern urban living. Full article

The use of olive by-products in livestock farming is a valuable resource, given their high levels of bioactive compounds with antioxidant and health-promoting properties. This preliminary study adopted an integrated approach to evaluate the influence of dietary Olea europaea L. polyphenols on animal welfare, physiological stress response, intestinal morphofunctional traits, and meat quality in Neroametà finishing pigs, a novel Casertana × Large White genetic line (Neroametà). Thirty pigs reared under extensive farming conditions were randomly allocated to two groups (n = 15): a control group fed a standard diet (C) and a treatment group (OL) supplemented with 300 mg/head/day of olive polyphenolic extract for 90 days. The study focused on the systemic correlation between host health and product quality. Meat composition, rheological properties, meat antioxidant activity, stress parameters, and fatty acid profiles of the longissimus lumborum and psoas major muscles were analyzed. Results showed that the OL diet significantly modulated the HPA axis, as evidenced by a marked reduction in plasma ACTH and cortisol levels, alongside improved antioxidant status. These physiological changes were positively associated with a trophic effect on the intestinal mucosa, characterized by increased villus height and a more favorable villus/crypt ratio. Regarding meat quality, the OL group exhibited superior oxidative stability, optimized pH decline, and an improved intramuscular fatty acid profile (increased MUFA and n-3 PUFA, reduced SFA). Despite the pilot scale of 30 animals, these findings provide a solid foundation for characterizing the Neroametà breed. In conclusion, Olea europaea L. polyphenols act as a multi-level modulator, enhancing physiological resilience and meat quality, offering a sustainable strategy for high-quality pork production in line with circular economy and One Health principles. Full article

The hypothalamic–pituitary–adrenal (HPA) axis coordinates metabolic, immune, and behavioral responses to a changing environment. Its molecular effectors are the nuclear receptors for glucocorticoids and mineralocorticoids (the GRs/MRs), encoded by nr3c1/nr3c2. The MR serves as the high-affinity sensor of basal hormone concentrations, whereas the GR amplifies the stress response and mediates negative feedback. Despite their shared domain architecture, the receptors have diverged functionally: isoform composition, post-translational modifications, and the complement of co-regulators together determine which genes are activated or repressed in a given tissue at a given time. The regulation of the HPA axis activity is a major determinant of embryonic development. Pregnancy adds a placental control layer that meters maternal signals: 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in the syncytiotrophoblast inactivates cortisol, whereas 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) can regenerate it, and systemic buffering by transcortin (cortisol-binding globulin, CBG) limits the free hormone fraction. Under stress, inflammation, or hypoxia, this barrier weakens, exposing the fetus to stronger glucocorticoid pulses during windows of heightened vulnerability for brain and immune development. Such overexposure not only reshapes ongoing transcription but is also epigenetically inscribed: the methylation of alternative nr3c1 promoters, the remodeling of histones, and the shifts in ncRNA profiles recalibrate the axis sensitivity for the long term. At the phenotypic level, this manifests as variability in stress reactivity, cognitive and affective trajectories, and an immune and metabolic risk across later ontogeny. In this review, we integrate evidence on the structure and functions of the GR, the mechanisms of its post-translational and epigenetic regulation, and the role of the placenta, to provide a coherent framework for understanding the multifaceted consequences of prenatal stress and to identify potential targets for early prevention. Full article