Search Results (1,830)

Glucagon-like peptide (GLP)-1 receptor (GLP1R) agonists exert a multitude of beneficial cardiovascular effects beyond control of blood glucose levels and obesity reduction. GLP-1R is a G protein-coupled receptor (GPCR), coupling to adenylyl cyclase (AC)-stimulatory Gs proteins to raise cyclic 3′-5′-adenosine monophosphate (cAMP) levels in cells. cAMP exerts various effects mainly via protein kinase A (PKA) and Exchange protein directly activated by cAMP (Epac). Cardiac GLP-1R has been reported to induce atrial natriuretic peptide (ANP) secretion via Epac2, while ANP is known to inhibit aldosterone secretion from adrenocortical zona glomerulosa (AZG) cells. Herein, we tested the effects of the GLP-1R agonist liraglutide on ANP secretion in H9c2 cardiomyocytes and on angiotensin II (AngII)-induced aldosterone secretion. We also examined whether phosphodiesterase (PDE)-4 inhibition with roflumilast could potentiate liraglutide’s effects. We found that liraglutide stimulated ANP secretion from H9c2 cardiomyocytes, an effect potentiated by roflumilast but blocked by AC inhibition. Epac inhibition with ESI-09 also significantly reduced liraglutide-dependent ANP secretion in H9c2 cardiomyocytes. Moreover, application of medium from liraglutide-treated H9c2 cardiomyocytes, but not from control cardiomyocytes, led to suppression of AngII-dependent aldosterone secretion from H295R cells. This effect was blocked by cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibition (an effector of ANP) in H295R cells, while direct application of liraglutide to these cells failed to suppress AngII-induced aldosterone secretion. Again, aldosterone suppression was more potent when medium from liraglutide plus roflumilast-treated cardiomyocytes was applied to H295R cells. Taken together, these results suggest that roflumilast enhances the adrenocortical aldosterone suppression induced by GLP-1R agonists via cardiac GLP-1R/cAMP/Epac-dependent ANP secretion. Given the cardio-toxic effects of elevated aldosterone levels in the context of various heart diseases, such as post-myocardial infarction heart failure, combination of a GLP-1R agonist drug with a PDE4 inhibitor drug may be more advantageous than either agent alone in treatment of certain cardiovascular diseases. Full article

Class B scavenger receptor BI splice variants (SR-BI) and BII (SR-BII) internalize lipoproteins but also bind and internalize bacteria. Their individual roles in sepsis are unknown. We overexpressed human SR-BI or BII in transgenic mice, primarily in the liver, but also in the kidney and in bone marrow-derived macrophages, and then performed cecal ligation and puncture (CLP) surgery. SR-BI and BII transgenic mice had significantly worse survival compared to WT mice. Twenty-four hours after CLP, liver injury markers and histological damage were elevated in both SR-BI and BII transgenic mice, whereas kidney damage was similar. Systemic inflammatory cytokines were markedly increased in SR-BI and BII transgenic mice; parallel increases were seen in liver mRNA expression, but not in the kidney. The highest degree of neutrophil infiltration was observed in the liver of SR-BI. Human SR-BI and BII dramatically decreased bacterial accumulation in the liver. Green fluorescent protein-labeled E. coli were efficiently phagocytosed in hepatic macrophages of SR-BI and BII transgenic mice; phagocytosis was more prominent in SR-BII transgenic mice. Finally, human SR-BI overexpression reduced systemic HDL-C levels, eliminated adrenal cortex lipid droplets, and dampened the systemic increase of corticosterone after CLP. Supplementation with glucocorticoid and mineralocorticoid improved survival in SR-BI but not in SR-BII transgenic mice after CLP. In summary, our findings suggest human SR-BI and BII overexpression contributes to higher mortality after CLP by different mechanisms: excessive inflammatory response due to adrenal insufficiency (SR-BI) or hyperactive phagocytosis (SR-BII) in the liver. Full article

Newborn screening for congenital adrenal hyperplasia (CAH) is effective in identifying patients with severe forms before a potentially lethal crisis, but has a relatively high false-positive rate. The aim of this study was to improve the national neonatal screening program in Sweden and the positive predictive value by implementing LC-MS/MS second-tier testing. A combination of two independent parameters, the steroid hormone ratio (androstenedione+17-hydroxyprogesterone)/cortisol and the concentration of 21-deoxycortisol and adjustment of cut-off levels resulted in an increase in the positive predictive value (PPV) from 14% to 84% for full-term infants. In total, the false-positive screening cases decreased by 88%. CYP21A2 genotyping was used to determine the severity of CAH in identified cases. We report on the stepwise approach that was used to optimize the cut-off levels for full-term and preterm infants in order not to miss any true cases in the process. Full article

Introduction: Depression and anxiety are highly prevalent disorders with a substantial impact on quality of life. Limitations related to the efficacy and tolerability of conventional pharmacological treatments have stimulated increasing interest in complementary therapeutic approaches, including phytotherapy. This review aims to provide an integrative analysis of some plant species present in the spontaneous flora of Romania, correlating their traditional use with the phytochemical, pharmacological, preclinical, and clinical data available globally. The approach aims to highlight the therapeutic relevance of these species in both regional and international contexts. Relevant sections: This narrative review integrates available data on seven species commonly used in traditional medicine: Matricaria chamomilla L., Galium odoratum L., Melissa officinalis L., Leonurus cardiaca L., Hypericum perforatum L., Tilia spp., and Crataegus monogyna Jacq. This review examines their geographical distribution, taxonomic classification, phytochemical composition, proposed mechanisms of action, and available preclinical and clinical evidence, as well as safety considerations and products currently available on the Romanian pharmaceutical sales. Discussion: Current evidence suggests that Hypericum perforatum L. and Melissa officinalis L. are supported by relatively robust clinical data regarding their efficacy in reducing anxiety and depressive symptoms. For the remaining species, evidence is derived mainly from preclinical studies or traditional use. The proposed mechanisms of action include modulation of neurotransmitter activity, antioxidant and anti-inflammatory effects, and regulation of the hypothalamic–pituitary–adrenal (HPA) axis. Conclusions: Phytotherapy represents a promising approach in the management of anxiety and depressive disorders, particularly as a complementary therapeutic option. However, the strength of evidence varies considerably among the analyzed species, and clinical data remain limited for several of them. Future directions: From a future perspective, advancing the clinical relevance of the analyzed plant species requires a more coherent integration of existing pharmacological, preclinical, and emerging clinical data. Particular attention should be given to species for which the current evidence remains predominantly experimental, by promoting research strategies that facilitate the translation of mechanistic findings into clinically meaningful outcomes. Full article

Stress has been prevalent and has become an epidemic health burden, loaded with chronic disorders. The stress response is an adaptive mechanism that prepares an individual to respond to threats or other stressors in a fight-or-flight situation. The stress response involves the induction of neurological and hormonal networks and is usually resolved when stress subsides; however, persistent stress leads to permanent and detrimental impacts on health. With the rise of advanced single-cell analysis technologies, a wave of basic and translational research aimed at elucidating stress has shed light on the underlying mechanisms. Among 80 studies in this review, stressors are classified into acute/chronic physical, physiological, and psychological groups, whereas some studies have more than one stress source. Single-cell RNA-seq was the dominant technology utilized in these studies. This advanced technique systematically reveals cellular heterogeneity in gene expression patterns and the differential transcriptomic landscape of stress response in a wide array of tissues and organ systems, e.g., the nervous system, the endocrine system, the immune system, and others. Bioinformatics identified a single-cell atlas of stress-specific cell subtypes, cell-to-cell interactions, and enriched pathways, showing promise for stress syndrome biomarkers, attenuation, and targeted therapy. The limits of these stress studies were mainly focused on transcriptomics, so future studies using multi-omics approaches across multiple organ systems will yield insights into stress disorders and novel therapeutic strategies. Full article

Objectives: Small-cell lung cancer (SCLC) is an aggressive malignancy often diagnosed at the extensive stage (ES-SCLC). While chemoimmunotherapy (CIT) has emerged as a first-line option, SCLC’s “cold” immune profile limits broad efficacy. This study evaluates the real-world clinical efficacy of CIT versus chemotherapy (CT) alone and analyzes the association between gene mutation characteristics and clinical indicators. Methods: We retrospectively analyzed 170 patients with ES-SCLC treated at a single center between January 2020 and January 2024. Patients were categorized by first-line treatment (CIT vs. CT). Subgroup analyses were conducted to evaluate treatment response. Genomic profiling was integrated for a subset of patients to identify associations between mutation signatures and clinicopathological factors. Results: Of the 115 patients (67.6%) who received CIT and 55 (32.4%) who received CT, the CIT group achieved a significantly higher objective response rate (76.5% vs. 56.4%). Median progression-free survival was numerically but not significantly longer in the CIT group (6.0 vs. 5.8 months). Adrenal metastasis was identified as an independent adverse prognostic factor. Genomic analysis revealed site-specific correlations: MYC mutations with pleural metastasis, NTRK3 with brain metastasis, ALK with adrenal metastasis, and NTRK1 with intrapulmonary metastasis. Additionally, smokers showed higher mutation frequencies in SMAD4 and PIK3CA. Conclusions: CIT significantly improves initial response rates in ES-SCLC compared to CT alone. Baseline adrenal metastasis serves as a poor prognostic indicator. Distinct genomic mutation signatures are associated with clinical characteristics, suggesting potential pathways for personalized treatment strategies. Full article

21-deoxycortisol is a sensitive and specific blood marker for congenital adrenal hyperplasia (CAH). We postulated that 21-deoxycortisone, the 11β-hydroxysteroid dehydrogenase metabolite of 21-deoxycortisol, may also be an accurate bloodspot marker of CAH. Measurement of 21-deoxycortisone was performed on 42 residual NBS specimens with a true positive result for CAH, 11 with a false negative result, and 439 specimens with a false positive result. For this study, the test was considered positive if 21-deoxycortisone was detected. The sensitivity and specificity of 21-deoxycortisone as a marker for classical CAH was calculated and compared to 21-deoxycortisol data from a previous New Zealand study. The method for 21-deoxycortisone measurement was linear to 1000 nmol/L and precision was 7.3–10.3%. The lower limit of quantification was 2 nmol/L, and recovery was 99%. 21-deoxycortisone was ≥2 nmol/L in all 42 true positive samples and in 10 false negative samples, and was not detected in the false positive group of specimens. The sensitivity of 21-deoxycortisone was 98.1%, and specificity was 100%. In a previous study, the sensitivity of 21-deoxycortisol was 88.7% and specificity was 99.8% in 1910 newborn screening tests carried out between 2018 and 2021. Incorporating 21-deoxycortisone into a second-tier test and adjustment of primary screening protocols could improve the accuracy of newborn screening for CAH. Longer term prospective studies on the performance of 21-deoxycortisone are warranted. Full article

Background: Immune-mediated hypophysitis comprises a heterogeneous group of inflammatory pituitary disorders, including primary lymphocytic hypophysitis, immune checkpoint inhibitor (ICI)-induced hypophysitis, IgG4-related hypophysitis, and paraneoplastic autoimmune hypophysitis. Although these entities share immune-mediated mechanisms, they differ substantially in clinical presentation, imaging features, and therapeutic implications. Methods: This narrative review synthesizes current evidence on the pathophysiology, clinical manifestations, radiological characteristics, diagnostic approach, and management of immune-mediated hypophysitis, with particular emphasis on etiological heterogeneity. Results: Hypopituitarism—particularly ACTH deficiency—is the most frequent and clinically relevant manifestation, as secondary adrenal insufficiency may be life-threatening if not promptly recognized and treated. It is often accompanied by headache, arginine vasopressin deficiency, or mass effect depending on the subtype. Magnetic resonance imaging typically shows symmetrical pituitary enlargement and stalk thickening in inflammatory forms, although findings vary according to etiology and may be minimal in certain subtypes such as PD-1/PD-L1 inhibitor-associated hypophysitis. Distinct clinical phenotypes are observed across subtypes, particularly in ICI-induced hypophysitis and IgG4-related disease. Diagnosis relies on the integration of endocrine, radiological, and clinical features, supported by clinicoradiological scoring systems in selected cases. Management is primarily based on prompt hormone replacement, with selective use of glucocorticoids or immunosuppressive therapies depending on disease severity and underlying etiology. Conclusions: Immune-mediated hypophysitis represents a clinically relevant and increasingly recognized spectrum of disorders requiring a multidisciplinary and etiology-specific approach. Early recognition is essential to prevent life-threatening endocrine complications. Advances in the understanding of immunopathogenic mechanisms and the identification of reliable biomarkers may enable earlier diagnosis and more personalized therapeutic strategies. Full article

Keloids and hypertrophic scars are fibroproliferative disorders of wound healing characterized by excessive extracellular matrix deposition, constant inflammation, and high recurrence rates despite appropriate management. Conventional therapies, including surgical excision, corticosteroid injections, laser therapy, and radiation, can provide temporary relief. However, treatment failure remains common, specifically in refractory keloids. Recent findings suggest these outcomes cannot be fully explained by technical or mechanical factors alone, and pathological scarring may reflect underlying immune and neuroimmune dysfunction. Current evidence shows prolonged activation of pro-inflammatory and pro-fibrotic cytokine pathways like IL-6, TNF-α, TGF-β, and IL-17 drives sustain fibroblast activation and disrupts normal wound healing and remodeling. Additionally, the skin functions as an integrated neuro-endocrine-immune organ, allowing bidirectional communication between cutaneous nerves, immune cells, and stromal tissue. Neurogenic inflammation is mediated by neuropeptides, mast cell activation, and stress-induced hypothalamic–pituitary–adrenal axis dysregulation, which further amplifies inflammation within scar tissue. Psychiatric comorbidities like depression, anxiety, and chronic psychological stress serve as a positive feedback mechanism and are increasingly recognized as biologically active contributors to immune dysregulation. This review highlights critical gaps in current management strategies and emphasizes the need for biologically informed, multidisciplinary approaches to improve long-term outcomes for keloid and hypertrophic scar management. Full article

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

Radiopharmaceutical Theranostics defines the combination of molecularly targeted imaging and therapy in two consecutive phases. Targeted theranostic approaches are most established for the management of advanced prostate, thyroid and hepatocellular cancer, as well as neuroendocrine tumors (NETs). Adrenal malignancies present a complex challenge, requiring highly specialized management. The two primary entities addressed by targeted radiotheranostics—pheochromocytoma/paraganglioma (PPGL) and adrenocortical cancer (ACC)—consist of fundamentally distinct molecular targets and, consequently, different radiopharmaceutical agents. While most existing literature focuses on nuclear medicine–driven perspectives, the implications of theranostic advances for surgical decision-making remain underexplored. This narrative review aims to integrate available clinical evidence with multidisciplinary practice considerations, in reshaping the role of surgery in adrenal malignancies. Full article

The skin–brain axis constitutes a complex, bidirectional network integrating cutaneous sensory, immune, and neuroendocrine systems with central neural circuits involved in emotion regulation, stress responsivity, and social cognition. Advances in psychodermatology and cosmetic science have progressively extended this framework to the emerging field of neurocosmetics, which explores how topical formulations, sensorial properties, and cutaneous neuromodulators may influence psychological well-being, affective states, and perceived stress. The aim of this narrative review is to synthesize current evidence on the biological foundations of the skin–brain axis and to critically examine the implications of these mechanisms for neurocosmetic interventions from a psychological and psychiatric perspective. It describes the biological substrates underlying skin–brain communication, including the cutaneous hypothalamic–pituitary–adrenal axis, neuropeptides, neurotrophins, transient receptor potential channels, and endocannabinoid signaling, and examines how these pathways are targeted by neurocosmetic interventions. Particular attention is devoted to neuroactive compounds, such as peptides, cannabinoids, botanicals, and aromatherapeutic molecules, as well as to sensorial strategies involving texture, temperature, and olfactory cues, which may modulate mood, anxiety, and self-perception through peripheral mechanisms. From a psychological and psychiatric perspective, the review discusses the intersection between stress-related skin conditions, body image disturbances, and emotional dysregulation, highlighting how cosmetic practices may influence subjective well-being beyond purely aesthetic outcomes. Methodological limitations of the existing literature, including the heterogeneity of study designs and outcome measures, as well as ethical considerations related to mood- and stress-related claims in cosmetic products, are critically examined. Finally, future research directions are outlined, and a translational framework is proposed to integrate dermatology, neuroscience, and mental health within next-generation cosmetic science. 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

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition with high morbidity among survivors. Emerging evidence suggests that acute biochemical hypothalamic–pituitary axis disturbances, resulting from disruption of neuroendocrine regulation, are an underrecognized complication in the acute phase of aSAH. However, its correlation with clinical severity remains insufficiently explored. To investigate whether clinical severity of aSAH predicts acute biochemical pituitary-axis abnormalities and identify which hormonal axes are most affected in the acute phase. A prospective observational study was conducted at The National Institute of Neurology and Neurovascular Diseases, Bucharest (October 2024–March 2025) on 38 patients confirmed aSAH admitted within 48 h of symptom onset, of which 20 patients were included. Hormonal panels assessing adrenocorticotropic hormone (ACTH), growth hormone (GH), thyroid-stimulating hormone (TSH), and antidiuretic hormone (ADH) were obtained prior to surgical intervention. Clinical severity was evaluated using the Glasgow Coma Scale (GCS), the Hunt and Hess (HH) scale, and the Modified Fisher Scale. Correlations between hormonal deficiencies and severity scores were analyzed using the Spearman correlation. Biochemical abnormality of the ACTH axis was most prevalent (75%), followed by ADH (50%) and TSH (40%), while GH deficiency was rare (5%). ACTH-axis biochemical abnormality correlated significantly with lower GCS (ρ = −0.61, p = 0.004) and higher HH scores (ρ = 0.59, p = 0.006). Multiple-axis abnormalities demonstrated the strongest correlations with all severity metrics (GCS: ρ = −0.68, p = 0.001; HH: ρ = 0.72, p < 0.001; Fisher: ρ = 0.57, p = 0.009). Greater clinical severity in aSAH is associated with a higher prevalence of acute biochemical endocrine abnormalities, particularly involving the ACTH axis and multiple hormonal pathways. These findings are exploratory and hypothesis-generating. Early hormonal assessment in patients with severe aSAH may help identify individuals at risk for acute endocrine abnormality, but validation in larger prospective studies is required before influencing clinical practice. Full article

Chronic diseases increasingly reflect a shared biological origin: persistent cellular stress. This review summarizes the biochemical mechanisms that normally preserve cellular homeostasis, namely redox regulation, endoplasmic reticulum proteostasis, mitochondrial quality control, autophagy, and DNA damage response, and explains how they fail under sustained lifestyle-related overload. Repeated exposure to psychological stress, sleep disruption, hypercaloric intake, and physical inactivity shifts adaptive signaling toward maladaptation, promoting oxidative damage, protein misfolding, mitochondrial dysfunction, low-grade inflammation, and genomic instability. These interconnected processes contribute to the development and progression of major chronic non-communicable diseases, including obesity, type 2 diabetes, cardiovascular disease, neurodegeneration, and cancer. Particular emphasis is placed on circadian and neuroendocrine regulation, especially overactivation of the hypothalamic–pituitary–adrenal axis and impaired nocturnal regenerative pathways such as glymphatic clearance and DNA repair. Together, the evidence supports a unifying model in which chronic pathology emerges from cumulative failure of cellular resilience systems rather than isolated organ-specific defects. This perspective highlights sleep optimization, stress reduction, and metabolic regulation as mechanistically grounded strategies for prevention and supportive interventions for chronic disease. Full article