Search Results (68)

Sports-associated traumatic brain injury is emerging as an under-recognized driver of acute and chronic cardiovascular diseases. Larger population-based studies show that individuals with moderate-to-severe traumatic brain injury experience up to a two-fold excess risk of incident hypertension, coronary artery disease, myocardial infarction, and stroke that persists for at least a decade. Among former professional American-style football players, a higher lifetime concussion burden is uniquely related to a more atherogenic cardiometabolic profile and greater long-term stroke risk. Mechanistically, an acute “sympathetic storm” triggered by cerebral injury provokes catecholamine surges, endothelial dysfunction, and myocardial stunning, manifesting as neurogenic stunned myocardium or Takotsubo-like cardiomyopathy and malignant arrhythmias. Sub-acute to chronic phases are characterized by persistent autonomic imbalance, reflected by reduced heart-rate variability and impaired baroreflex sensitivity weeks to months after concussion, coupled with neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and lifestyle changes that accelerate atherosclerosis. The interplay of these pathways accounts for the elevated burden of cardiovascular disease observed long after neurological function has been restored. Despite robust evidence linking TBI to adverse cardiac outcomes, contemporary sports–cardiology risk stratification prioritizes hemodynamic load, genetics, and performance-enhancing substances, largely overlooking brain injury history. This review integrates epidemiological, clinical, and mechanistic data to (i) delineate acute neurocardiac complications secondary of sports-related traumatic brain injury, (ii) synthesize evidence for chronic cardiovascular risk, (iii) highlight emerging autonomic and inflammatory biomarkers, and (iv) propose surveillance and therapeutic strategies, ranging from heart-rate-variability-guided return-to-play decisions to aggressive cardiometabolic risk modification aiming to mitigate long-term morbidity in this athletic population. By framing sports-related traumatic brain injury as a modifiable cardiovascular risk factor, we aim to foster interdisciplinary collaboration among neurologists, cardiologists, and sports medicine practitioners, ultimately improving both neurological and cardiovascular outcomes across the athlete’s lifespan. Full article

Background: Takotsubo Syndrome (TTS), or stress-induced cardiomyopathy, is an acute and typically reversible cardiac condition that mimics acute coronary syndrome without obstructive coronary artery disease. Predominantly affecting postmenopausal women, TTS has been increasingly recognized as a psychobiological disorder involving neuroendocrine dysregulation, autonomic imbalance, psychosocial stress, and gendered patterns of emotional regulation. This review aimed to synthesize multidisciplinary evidence to propose an integrative, gender-informed model of TTS. Methods: A narrative literature review was conducted using PubMed/MEDLINE, Scopus, and Web of Science (2000–2025) to identify clinical, neurobiological, psychosocial, and psychoanalytic studies addressing sex/gender differences, psychiatric comorbidities, and emotional regulation in TTS. Results: Evidence indicates that catecholamine surge, hypothalamic–pituitary–adrenal axis dysregulation, estrogen deficiency, and autonomic imbalance provide a biological substrate for stress-induced myocardial stunning. Psychosocial factors, such as caregiving burden, chronic stress, and alexithymia, further decrease resilience. Gendered coping scripts and unconscious symbolic processes may amplify vulnerability and influence clinical presentation. The integrative model combines biological, psychological, and social mechanisms, highlighting the predominance of emotional triggers in women and worse in-hospital outcomes in men. Conclusions: TTS should be approached as both a cardiac and affective disorder. Gender-sensitive, multidisciplinary management, including psychiatric screening, psychocardiology interventions, and psychoanalytically informed care, may improve prevention, diagnosis, and patient outcomes. Full article

The gas transmitters nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) play important roles in physiological regulation, including adrenal function. Among them, only NO has been directly implicated in controlling catecholamine biosynthesis. This study examined whether CO and H₂S exert similar effects by treating PC12 cells with a CO donor (CORM-2) or an H₂S donor (NaHS), with or without glucocorticoid stimulation. Gene expression of tyrosine hydroxylase (Th), dopamine β-hydroxylase (Dbh), and phenylethanolamine N-methyltransferase (Pnmt) was assessed by RT-qPCR, and catecholamine release was measured by ELISA. We found that exogenous CO decreased Th and Dbh expression, attenuated glucocorticoid-induced upregulation of catecholamine biosynthesis genes, and differentially modulated dopamine and norepinephrine release. In contrast, exogenous H₂S treatment had no significant effect. These findings identify CO as a novel regulator of catecholamine biosynthesis and highlight important differences among gas transmitters in stress-related signaling. Full article

Background: The catecholamine-induced hypertensive crisis is a rare, life-threatening condition caused by excessive catecholamine release, often resulting in cardiogenic shock and multiorgan failure. Management is challenging, especially when hemodynamic instability persists despite standard medical therapy. Methods: We conducted a narrative review of published articles between 2013 and 2025. The search was conducted in MEDLINE (PubMed, Scholar and Embase). We also presented a case managed at our reference center. Results: Overall, 42 studies including 69 patients were included. ECMO was the most commonly used modality, often serving as a bridge to surgery. The overall hospital mortality rate was 17.4%. Timing of adrenalectomy varied, with no clear consensus on the optimal approach. We report also a case of a 43-year-old woman with neurofibromatosis type 1 who developed acute cardiogenic shock due to an adrenal paraganglioma. She was supported with ECMO and underwent emergency bowel resection for intestinal ischemia, followed by adrenalectomy. Despite aggressive treatment, the patient died from progressive multiorgan failure. Conclusions: This case highlights the complexity of managing paraganglioma crisis, the potential role of ECMO as a bridge to surgery, and the importance of individualized, multidisciplinary care. Early recognition and referral to specialized centers are essential, though further studies are needed to guide optimal management strategies. Full article

The adrenal medulla and organs of Zuckerkandl consist of chromaffin cells that produce, store, and secrete catecholamines. In humans, the adrenal medulla is known to function throughout postnatal life, while the organs of Zuckerkandl degenerate by 2–3 years of postnatal life. Although the history of investigation of chromaffin cells goes back more than a century, little is known about the reciprocal organogenesis of the adrenal glands and organs of Zuckerkandl during human fetal development. In the current study, we compared these two organs using serial sectioning, routine histological staining, and immunohistochemical reactions in human embryos, prefetuses, and fetuses from 8 to 26 gestational weeks. In our study, we used antibodies for tyrosine hydroxylase, dopamine beta-hydroxylase, and phenylethanolamine N-methyltransferase, which are enzymes of catecholamine synthesis, β-III tubulin, and S100. We found two morphological cell types (large and small) in the developing ganglia, organs of Zuckerkandl, and adrenal medulla, and two migration patterns of large cells and small cells. The immunohistochemical characteristics of these cells were determined. We revealed that the number of small cells increased significantly at the ages from 16 to 21–22 gestational weeks, followed by a decrease at 22.5–26 gestational weeks. The presence of two large cell subpopulations was suggested—those that migrate primarily from organs of the Zuckerkandl region and those that differentiate later from the small cells. We also determined that 12 gestational weeks was the age of the first appearance of phenylethanolamine N-methyltransferase reactivity in developing chromaffin cells, temporally correlating with synaptogenesis events. This is important data in the light of the controversial glucocorticoid theory of phenylethanolamine N-methyltransferase induction in humans. Full article

Despite the known impacts of weaning on animal health, the underlying molecular mechanisms remain unclear, particularly how psychological and nutritional stress differentially affect gut health and immune function over time. This study hypothesized that early weaning exerts distinct short- and long-term effects on lamb stress physiology, immunity, and gut health, mediated by specific molecular pathways. Twelve pairs of full-sibling male Hu sheep lambs were assigned to control (CON) or early-weaned (EW) groups. Plasma stress/immune markers were dynamically monitored, and intestinal morphology, antioxidant capacity, apoptosis, and transcriptomic profiles were analyzed at 5 and 28 days post-weaning. Early weaning triggered transient psychological stress, elevating hypothalamic–pituitary–adrenal (HPA) axis hormones (cortisol, catecholamines) and inflammatory cytokines (TNF-α) within 1 day (p < 0.05); however, stress responses were transient and recovered by 7 days post-weaning. Sustained intestinal remodeling was observed in EW lambs, featuring reduced ileal villus height, increased crypt depth (p < 0.05), and oxidative damage (MDA levels doubled vs. CON; p < 0.01). Compensatory epithelial adaptation included increased crypt depth but paradoxically reduced villus tip apoptosis. The transcriptome analysis revealed significant changes in gene expression related to immune function, fat digestion, and metabolism. Key DEGs included APOA4, linked to lipid transport adaptation; NOS2, associated with nitric oxide-mediated immune–metabolic crosstalk; and mitochondrial gene COX1, reflecting energy metabolism dysregulation. Protein–protein interaction analysis revealed NOS2 as a hub gene interacting with IDO1 and CXCL11, connecting oxidative stress to immune cell recruitment. Early weaning exerts minimal lasting psychological stress but drives persistent gut dysfunction through transcriptome-mediated changes in metabolic and immune pathways, highlighting key genes such as APOA4, NOS2, and COX1 as potential regulators of these effects. Full article

Understanding the regulatory mechanisms of stress-induced immunosuppression and developing reliable diagnostic methods are important tasks in clinical medicine. This will allow for the development of effective strategies for the prevention and treatment of conditions associated with immune system dysfunction induced by chronic stress. The purpose of this review is to conduct a comprehensive analysis and synthesis of existing data on the regulatory mechanisms of stress-induced immunosuppression. The review is aimed at identifying key neuroendocrine, cytokine, and cellular processes underlying the suppression of the immune response under stress. This study involved a search of scientific literature covering the neuroendocrine, cellular, and molecular mechanisms of stress-induced immunosuppression regulation, as well as modern methods for its diagnosis. Major international bibliographic databases covering publications in biomedicine, psychophysiology, and immunology were selected for the search. The results of the analysis identified key mechanisms regulating stress-induced immunosuppression. The reviewed publications provided detailed descriptions of the neuroendocrine and cytokine processes underlying immune response suppression under stress. A significant portion of the data confirms that the activation of the hypothalamic–pituitary–adrenal (HPA) axis and subsequent elevation of cortisol levels exert substantial immunosuppressive effects on immune cells, particularly macrophages and lymphocytes, leading to the suppression of innate and adaptive immune responses. The data also highlight the crucial role of cortisol and catecholamines (adrenaline and noradrenaline) in initiating immunosuppressive mechanisms under chronic stress. Full article

Background: Quantifying urinary catecholamines and metanephrines is essential for the clinical screening and diagnosis of neuroendocrine tumours. HPLC with electrochemical detection (HPLC-ECD) is commonly used for this type of analysis but requires extensive sample cleanup. Simple and rapid dilute-and-shoot LC–multiple-reaction monitoring (MRM)-MS assays have been developed for quantitating these analytes in urine but have not yet been validated according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Methods: A simple dilute-and-shoot sample preparation without derivatization was used. C18 RP-UPLC-MRM-MS and positive-ion ESI were used, usually with two transitions per analyte being monitored. Certified deuterated internal standards were used for each analyte. Results: This assay was validated according to the CLSI C62-A guidelines, including accuracy/trueness, imprecision, sensitivity, specificity, carryover, stability, and linearity. The final MRM-MS method was compared to the established HPLC-ECD clinical chemistry reference method. The run time was reduced from 25 min to 5 min. Conclusions: A simple, robust, rapid, and cost-effective LC-MRM-MS assay for measuring urinary catecholamines and metanephrines was developed and validated according to the CLSI guidelines. This validated method requires minimal sample manipulation before analysis and provides sensitivity, specificity, and improved precision. The implementation of this assay in clinical laboratories will facilitate early and accurate diagnosis. Full article

Heat stress (HS) due to high temperatures has adverse effects on poultry, including decreased feed intake, lower feed efficiency, decreased body weight, and higher mortality. There are complex mechanisms behind heat stress in poultry involving the neuroendocrine system, organ damage, and other physiological systems. HS activates endocrine glands, such as the pituitary, adrenal, thyroid, and gonadal, by the action of the hypothalamus and sympathetic nerves, ultimately causing changes in hormone levels: HS leads to increased corticosterone levels, changes in triiodothyronine and thyroxine levels, decreased gonadotropin levels, reduced ovarian function, and the promotion of catecholamine release, which ultimately affects the normal productive performance of poultry. Meanwhile, heat stress also causes damage to the liver, lungs, intestines, and various immune organs, severely impairing organ function in poultry. Nutrient additives to feed are important measures of prevention and treatment, including natural plants and extracts, probiotics, amino acids, and other nutrients, which are effective in alleviating heat stress in poultry. Future studies need to explore the specific mechanisms through which heat stress impacts the neuroendocrine system in poultry and the interrelationships between the axes and organ damage so as to provide an effective theoretical basis for the development of preventive and treatment measures. Full article

Pheochromocytoma and paraganglioma (PPGL) are rare tumors derived from the adrenal medulla and extra-adrenal chromaffin cells. Diagnosis is often challenging due to the great variability in clinical presentation; the complexity of management due to the dangerous effects of catecholamine excess and the potentially malignant behavior require in-depth knowledge of the pathology and multidisciplinary management. Nowadays, diagnostic ability has certainly improved and guidelines and consensus documents for treatment and follow-up are available. A major impulse to the development of this knowledge has come from the new findings on the genetic and molecular characteristics of PPGLs. Germline mutation in susceptibility genes is detected in 40% of subjects, with a mutation frequency of 10–12% also in patients with sporadic presentation and genetic testing should be incorporated within clinical care. PPGL susceptibility genes include “old genes” associated with Neurofibromatosis type 1 (NF1 gene), Von Hippel Lindau syndrome (VHL gene) and Multiple Endocrine Neoplasia type 2 syndrome (RET gene), the family of SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), and genes less frequently involved such as TMEM, MAX, and FH. Each gene has a different risk of relapse, malignancy, and other organ involvement; for mutation carriers, affected or asymptomatic, it is possible to define a tailored long-life surveillance program according to the gene involved. In addition, molecular characterization of the tumor has allowed the identification of somatic mutations in other driver genes, bringing to 70% the PPGLs for which we know the mechanisms of tumorigenesis. This has expanded the catalog of tumor driver genes, which are identifiable in up to 70% of patients Integrated genomic and transcriptomic data over the last 10 years have revealed three distinct major molecular signatures, triggered by pathogenic variants in susceptibility genes and characterized by the activation of a specific oncogenic signaling: the pseudo hypoxic, the kinase, and the Wnt signaling pathways. These molecular clusters show a different biochemical phenotype and clinical behavior; they may also represent the prerequisite for implementing customized therapy and follow-up. Full article

The complement system is critically involved in the pathogenesis of sepsis. In particular, complement anaphylatoxin C5a is generated in excess during sepsis, leading to cellular dysfunction. Recent studies have shown that excessive C5a impairs adrenomedullary catecholamine production release and induces apoptosis in adrenomedullary cells. Currently, the mechanisms by which C5a impacts adrenal cell function are poorly understood. The PC12 cell model was used to examine the cellular effects following treatment with recombinant rat C5a. The levels of caspase activation and cell death, protein kinase signaling pathway activation, and changes in inflammatory protein expression were examined following treatment with C5a. There was an increase in apoptosis of PC12 cells following treatment with high-dose C5a. Ten inflammatory proteins, primarily involved in apoptosis, cell survival, and cell proliferation, were upregulated following treatment with high-dose C5a. Five inflammatory proteins, involved primarily in chemotaxis and anti-inflammatory functions, were downregulated. The ERK/MAPK, p38/MAPK, JNK/MAPK, and AKT protein kinase signaling pathways were upregulated in a C5aR-dependent manner. These results demonstrate an apoptotic effect and cellular signaling effect of high-dose C5a. Taken together, the overall data suggest that high levels of C5a may play a role in C5aR-dependent apoptosis of adrenal medullary cells in sepsis. Full article

Paragangliomas are rare extra-adrenal neuroendocrine tumors originating from chromaffin tissue that present a diagnostic and therapeutic challenge due to their diverse clinical manifestations and low incidence. While these tumors often manifest as catecholamine-secreting functional tumors, their clinical presentation can vary, leading to delayed diagnosis and challenging management. This study presents the case of a 22-year-old patient with cardiac paraganglioma who initially presented with angina-like symptoms, highlighting the importance of considering this rare condition in young individuals with nonspecific complaints. Diagnostic imaging, including transthoracic echocardiography, CT angiography, and MRI, played a crucial role in identifying the tumor’s location and vascularization. Surgical excision, including pulmonary artery graft and CABG, was the primary management approach, which was accompanied by intraoperative complications that later led to CCU admission, followed by postoperative complications, ultimately leading to the patient’s death. This case highlights the significance of early recognition and management of complications following a surgical approach to treat paragangliomas. Full article

Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE) release from peripheral sympathetic nerve terminals. Adrenal CA production from chromaffin cells is tightly regulated by sympatho-inhibitory α₂-adrenergic (auto)receptors (ARs), which inhibit both epinephrine (Epi) and NE secretion via coupling to Gi/o proteins. α₂-AR function is, in turn, regulated by G protein-coupled receptor (GPCR)-kinases (GRKs), especially GRK2, which phosphorylate and desensitize them, i.e., uncouple them from G proteins. On the other hand, the short-chain free fatty acid (SCFA) receptor (FFAR)-3, also known as GPR41, promotes NE release from sympathetic neurons via the Gi/o-derived free Gβγ-activated phospholipase C (PLC)-β/Ca²⁺ signaling pathway. However, whether it exerts a similar effect in adrenal chromaffin cells is not known at present. In the present study, we examined the interplay of the sympatho-inhibitory α_2A-AR and the sympatho-stimulatory FFAR3 in the regulation of CA secretion from rat adrenal chromaffin (pheochromocytoma) PC12 cells. We show that FFAR3 promotes CA secretion, similarly to what GRK2-dependent α_2A-AR desensitization does. In addition, FFAR3 activation enhances the effect of the physiologic stimulus (acetylcholine) on CA secretion. Importantly, GRK2 blockade to restore α_2A-AR function or the ketone body beta-hydroxybutyrate (BHB or 3-hydroxybutyrate), via FFAR3 antagonism, partially suppress CA production, when applied individually. When combined, however, CA secretion from PC12 cells is profoundly suppressed. Finally, propionate-activated FFAR3 induces leptin and adiponectin secretion from PC12 cells, two important adipokines known to be involved in tissue inflammation, and this effect of FFAR3 is fully blocked by the ketone BHB. In conclusion, SCFAs can promote CA and adipokine secretion from adrenal chromaffin cells via FFAR3 activation, but the metabolite/ketone body BHB can effectively inhibit this action. Full article

Hypoglycaemia-associated autonomic failure (HAAF) is characterised by an impairment in adrenal medullary and neurogenic symptom responses following episodes of recurrent hypoglycaemia. Here, we review the status quo of research related to the regulatory mechanisms of the adrenal medulla in its response to single and recurrent hypoglycaemia in both diabetic and non-diabetic subjects with particular focus given to catecholamine synthesis, enzymatic activity, and the impact of adrenal medullary peptides. Short-term post-transcriptional modifications, particularly phosphorylation at specific residues of tyrosine hydroxylase (TH), play a key role in the regulation of catecholamine synthesis. While the effects of recurrent hypoglycaemia on catecholamine synthetic enzymes remain inconsistent, long-term changes in TH protein expression suggest species-specific responses. Adrenomedullary peptides such as neuropeptide Y (NPY), galanin, and proenkephalin exhibit altered gene and protein expression in response to hypoglycaemia, suggesting a potential role in the modulation of catecholamine secretion. Of note is NPY, since its antagonism has been shown to prevent reductions in TH protein expression. This review highlights the need for further investigation into the molecular mechanisms involved in the adrenal medullary response to hypoglycaemia. Despite advancements in our understanding of HAAF in non-diabetic rodents, a reliable diabetic rodent model of HAAF remains a challenge. Full article

Orexins are neuronal peptides that play a prominent role in sleep behavior and feeding behavior in the central nervous system, though their receptors also exist in peripheral organs, including the adrenal gland. In this study, the effects of orexins on catecholamine synthesis in the rat adrenomedullary cell line PC12 were investigated by focusing on their interaction with the adrenomedullary bone morphogenetic protein (BMP)-4. Orexin A treatment reduced the mRNA levels of key enzymes for catecholamine synthesis, including tyrosine hydroxylase (Th), 3,4-dihydroxyphenylalanie decarboxylase (Ddc) and dopamine β-hydroxylase (Dbh), in a concentration-dependent manner. On the other hand, treatment with BMP-4 suppressed the expression of Th and Ddc but enhanced that of Dbh with or without co-treatment with orexin A. Of note, orexin A augmented BMP-receptor signaling detected by the phosphorylation of Smad1/5/9 through the suppression of inhibitory Smad6/7 and the upregulation of BMP type-II receptor (BMPRII). Furthermore, treatment with BMP-4 upregulated the mRNA levels of OX1R in PC12 cells. Collectively, the results indicate that orexin and BMP-4 suppress adrenomedullary catecholamine synthesis by mutually upregulating the pathway of each other in adrenomedullary cells. Full article