Search Results (684)

Background: Norepinephrine is commonly used during acute burn resuscitation to maintain adequate perfusion pressure. However, its effects, together with the burn-induced catecholamine surge, on arterial α₁-adrenergic receptors (α₁-AR) remain unclear. This study examined whether burn injury and continuous norepinephrine infusion alter arterial α₁-AR subtype expression at the transcriptional and protein levels. Methods: Sprague–Dawley rats were randomized to full-thickness scald burn involving 25% total body surface area with continuous intravenous norepinephrine or sodium chloride (NaCl) infusion, sham injury with norepinephrine infusion, or untreated controls. Mean arterial pressure (MAP) was measured at baseline and before euthanasia (six or 24 h). Aorta, carotid, and renal arteries were collected for analysis of α₁-AR subtypes (Adra1a, Adra1b, and Adra1d) using quantitative PCR (qPCR) and immunohistochemistry (IHC). Results: Norepinephrine efficiently increased MAP in sham animals. In burned animals with norepinephrine, MAP increased at six hours (+10.6 mmHg) but fell below baseline at 24 h (−6.4 mmHg). Burned animals given NaCl had persistently lower MAP than those given norepinephrine, at six hours (−19.1 mmHg) and 24 h (−21.1 mmHg). qPCR demonstrated significant downregulation of Adra1b in the renal artery across all groups compared to control (7.8–16.4-fold, p < 0.001). Overall, changes in protein expression across different vascular beds and receptor subtypes were inconsistent. Conclusions: Norepinephrine increased MAP in both sham and burned animals, confirming the drug’s efficacy. Burn injury and sustained norepinephrine exposure were associated with early, vessel-specific alterations in α₁-AR mRNA expression. The absence of consistent protein-level changes within 24 h suggests a delay in receptor expression on protein level. Full article

The electrochemical sensing of similar catecholamines remains challenging due to their overlapping redox behavior and similar reactivity, which often results in poorly selective reaction pathways. Herein, we report a bioinspired tyrosinase electro-catalytic system that enables the modulation of the catecholamine reactivity through the integration of enzymatic oxidation with electrochemical transformation. The biocatalytic platform consisted of electroactive lignin nanoparticles (LNPs) supporting tyrosinase drop cast on the graphene-based screen-printed electrode. The overall reaction included the oxidation of catecholamines to ortho-quinones, followed by nucleophile addition of cysteine under control of the redox environment. Overall, coupling enzymatic catalysis with electrochemical regulation enabled selectivity in the oxidative functionalization of catecholamines, providing a sustainable strategy for tuning reactivity in advanced bioinspired catalytic systems. Full article

Trauma with hemorrhagic shock causes about 2.3 million deaths yearly worldwide. Improved hemostatic management has shifted the relative distribution of mortality, leaving multiorgan failure (MOF) as a leading cause of death. Clinical observations suggest that the evolutionarily ancient and well-conserved sympathetic system and the microvascular endothelium are involved, and the experimental evidence is reviewed here. The analyzed clinical studies, human endothelial cell (EC) culture, and animal model-based experiments delineate how excess catecholamine levels increase endothelial cell reactive oxygen species production, causing glycocalyx damage and thrombomodulin cleavage. This leads to a prothrombotic EC surface, resulting in coagulation activation and thrombus formation that leaves tissues prone to hypoxia. Excess catecholamines also increase endothelial barrier permeability, leading to fluid extravasation, elevated tissue pressure, and hypoxia. The reviewed experimental data support, but do not yet prove, dysregulated sympathetic activation’s critical contribution to the development of shock-induced endotheliopathy prone to tissue hypoxia and, ultimately, death from coagulopathy, loss of immune competence, and MOF, as observed clinically in shocked trauma patients. Due to the physiological differences between humans and model organisms, and EC culture growth conditions, some molecular mechanisms require further investigation through clinical studies and targeted experiments. Full article

Vasoplegia remains one of the most challenging and incompletely understood complications across the spectrum of mechanical circulatory support (MCS). Initially described following cardiopulmonary bypass, it is increasingly recognized in patients supported with veno-arterial extracorporeal membrane oxygenation (V-A ECMO) and combined unloading strategies such as ECPELLA (ECMO and Impella support) as well as in patients bridged to heart transplantation with temporary or durable mechanical circulatory support (MCS). Despite occurring in different clinical settings, these syndromes share common pathophysiological features, including systemic inflammation, endothelial dysfunction, glycocalyx degradation, dysregulated nitric oxide signaling, neurohormonal imbalance, microcirculatory impairment and severe vasomotor dysregulation. Although vasoplegia is commonly considered a technology-specific complication, growing evidence suggests that CPB-associated vasoplegia, postcardiotomy vasoplegic syndrome, ECMO-related vasodilatory shock and distributive shock during ECPELLA may represent distinct manifestations of a common pathobiological process driven by blood–artificial surface interactions, ischemia–reperfusion injury, hemolysis and immune activation. This narrative review proposes a unified framework of vasoplegia across the continuum of MCS. Key mechanistic pathways and current therapeutic strategies, including catecholamines, vasopressin, angiotensin II, methylene blue and hydroxocobalamin, are discussed. By integrating evidence from cardiac surgery, critical care and mechanical circulatory support, vasoplegia is presented as a unifying syndrome of extracorporeal circulation. This perspective may support earlier recognition, phenotype-based management and the development of more targeted therapeutic strategies in a clinically significant yet underexplored area of cardiovascular critical care. Full article

The intricate relationship between the heart and the brain has transitioned from historical, cardio-centric theories to a modern, circuit-based, bi-directional framework known as neurocardiology. This review provides a comprehensive anatomical, physiological, and clinical synthesis of the bidirectional heart–brain axis, highlighting how disruptions in one organ systematically impact the other. Structurally, the heart–brain axis operates as a closed-loop feedback network. Vagal parasympathetic control dominates at rest, driven by an asymmetrical fiber distribution where sensory afferents actively supply interoceptive data to the brainstem. Hemodynamically, cerebral blood flow delivery is linked to cardiac output in an age-dependent fashion with the related vascular dysfunction. Clinically, brain-to-heart pathologies like acute brain injury trigger life-threatening catecholamine surges, neuroinflammation, and myocardial stunning, including Takotsubo cardiomyopathy. Conversely, heart-to-brain pathways reveal that atrial fibrillation and heart failure can independently trigger cardioembolic stroke, long-term neuroinflammation, and a profound, progressive burden of cognitive decline. The heart and brain are inexorably linked through complex structural, mechanical, and paracrine pathways. Ameliorating clinical outcomes demands integrated cross-specialty diagnostic screening, digital rhythm monitoring, and holistic neurocardioprotective therapeutic strategies. Full article

Psychological stress arises when individuals perceive demands as exceeding their capacity to cope. Social stress can be acute, such as giving a presentation, producing transient increases in heart rate, blood pressure, and neuroendocrine activation, or chronic, in which stressors persist over extended periods. Chronic psychosocial stress disrupts immune homeostasis and contributes to anxiety, depression, and post-traumatic stress, while also increasing risk for infections, inflammatory and autoimmune diseases, cardiovascular disease, metabolic dysfunction, and cancer. Persistent stress engages interconnected neuroendocrine–immune networks, including the hypothalamic–pituitary–adrenal axis, the sympathetic–adrenomedullary system, and the gut microbiota–brain–immune axis, leading to sustained glucocorticoid and catecholamine signaling, gut dysbiosis, impaired barrier integrity, and altered microbial metabolite profiles. In this review, we summarize the molecular and cellular mechanisms by which these axes remodel innate and adaptive immunity and shape disease susceptibility. Using social defeat and social isolation in mice as model systems, we highlight how chronic social stress reprograms immune responses in key tissues, including the lung, brain, and gut. Full article

Spontaneous coronary artery dissection (SCAD) and Takotsubo syndrome (TTS) are two conditions presenting as acute coronary syndromes that predominantly affect women and are frequently triggered by emotional or physical stress. While traditionally considered distinct entities, emerging evidence suggests that these conditions may coexist more frequently than previously recognized, sharing common pathophysiological mechanisms centered on catecholamine-mediated pathways, vascular vulnerability, and hormonal influences. Their overlapping presentations create significant diagnostic challenges that may lead to misdiagnosis and suboptimal management. This narrative review examines the pathophysiological convergence between SCAD and TTS, addresses the diagnostic complexity arising when these entities coexist, and proposes a novel stepwise diagnostic algorithm integrating clinical risk stratification, coronary angiography, intracoronary imaging, and cardiac magnetic resonance imaging. The review also provides scenario-dependent management guidance and outlines priorities for future research. Full article

Background/Objectives: Oral lichen planus (OLP) is a chronic immune-mediated disease of the oral mucosa in which T-cell infiltration, epithelial injury, and stress-related neuroendocrine signaling appear to intersect. Catestatin (CST), a peptide generated from chromogranin A (CgA), modulates catecholamine release and inflammatory cell responses; however, its association with localized mucosal inflammation in OLP has not been clarified. This study aimed to compare serum CST levels between OLP patients and healthy controls and to examine their association with clinical subtype, disease severity, and vitamin D status. Methods: In this cross-sectional study, 51 patients with clinically and histopathologically confirmed OLP and 60 healthy controls were enrolled at the University Hospital of Split. Serum CST was quantified using ELISA. OLP severity was assessed with the REU score by a single experienced oral medicine examiner who was blinded to laboratory results, and pain and burning were recorded separately using 0–10 VASs. Results: Serum CST levels were significantly higher in OLP patients compared to healthy controls (p < 0.001). CST levels showed a strong positive correlation with the REU total score (r = 0.781, p < 0.001), as well as with VAS pain (r = 0.708, p < 0.001) and VAS burning (r = 0.729, p < 0.001). Erosive OLP exhibited significantly higher CST levels compared to the non-erosive subtype (p < 0.001). Furthermore, serum vitamin D levels were significantly lower in OLP patients (p < 0.001), with no significant correlation observed between CST and vitamin D levels. Conclusions: Serum CST levels were higher in OLP patients and showed close associations with REU scores and symptoms, with the strongest signal observed in erosive disease. CST may therefore contribute to the neuroendocrine-immune profile of OLP and may be useful as an adjunctive marker of clinically active or erosive disease. Larger prospective studies including salivary and tissue-based CST measurements are needed before CST can be used for routine monitoring. Full article

European wild ungulates are captured for different purposes, requiring the assessment of animal welfare and health. Specific guidelines to assess stress and pathophysiological compromise in captured wild ungulates are lacking. This review aims to set the bases for establishing standardised protocols allowing the evaluation of capture and handling stress in wild European ungulates. Physical and chemical capture and handling elicit stress, a physiological response activating sympathetic–adrenal medulla and hypothalamic–pituitary–adrenal cortex axes, releasing catecholamines and corticosteroids, respectively. While being an adaptive response, if prolonged over time, the effects become harmful and life-threatening, increasing body temperature and heart rate, and provoking muscular and renal ischemia. This clinical outcome is known as capture myopathy, which encompasses four sequential syndromes: Hyper acute or capture shock, Acute or ataxic-myoglobinuric, Sub-acute or ruptured muscle, and Chronic debility or delayed per-acute. Monitoring temperature, heart rate, serum muscular enzyme (CK, AST, ALT, and LDH) activities and lactate, creatinine, urea, and potassium concentrations characterises pathophysiological compromise. Wild ungulate capture and handling protocols should include not only methodology but also monitoring, data recording, sample collection, and analyses. This information should serve to improve protocols and eventually develop specific guidelines for stress and welfare assessment when capturing and handling wild ungulates. Full article

Vasoplegic syndrome is a common and potentially life-threatening complication following cardiac surgery with cardiopulmonary bypass. It is characterized by profound hypotension due to persistently reduced systemic vascular resistance despite preserved or increased cardiac output. The reported incidence ranges from 8% to 44%, and severe, catecholamine-resistant forms are associated with markedly increased mortality. In this retrospective study, 3937 cardiac surgical patients treated at the University Hospital Frankfurt between 2017 and 2021 were analyzed. Postoperative vasoplegic syndrome occurred in 17.5% of the cases and was classified as mild to moderate or severe according to vasopressor requirements. Preoperative, intraoperative, and postoperative variables were assessed using descriptive statistics as well as univariate and multivariable regression analyses to identify independent risk factors. Advanced age, elevated body mass index, EuroSCORE II > 10%, arterial degenerative diseases, preoperative dialysis dependence, atrioventricular valve surgery, emergency procedures, prolonged cardiopulmonary bypass and operative times, blood loss or transfusion and elevated preoperative hematocrit were identified as independent risk factors. Postoperatively, impaired renal function, increased inflammatory markers, and low hemoglobin levels were associated with vasoplegic syndrome. Severe vasoplegic syndrome was associated with increased mortality, prolonged intensive care unit stay, and extended hospitalization. Further research is required to establish standardized definitions and optimize prevention and treatment strategies. Full article

The hormonal vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25D), produced primarily in the kidney, acts in numerous end-organs via the nuclear vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis, immune responsiveness, and aspects of behavior. Tyrosine hydroxylase (TH) encodes a neuronally expressed enzyme that catalyzes the initial, rate-limiting step in the production of several catecholamine neurotransmitters and hormones, including dopamine, norepinephrine, and epinephrine. Herein we report that TH mRNA is significantly induced (2.5-fold) and NURR1 mRNA is induced 9.3-fold by 10 nM 1,25D in differentiated human SH-SY5Y neuroblastoma cells. Similar results were observed in human U87 glioblastoma cells (TH, 2.6-fold; NURR1, 3.6-fold). Comparative analysis of TH gene promoter-proximal sequences from human, mouse, and rat identifies candidate NURR1-responsive elements (NBREs) at the following positions: −35, −855, −1470, and −2343 bp in the human gene; −34 and −961 bp in the mouse gene; and −34, −350, and −873 bp in the rat gene, consistent with NURR1 acting as a recurring regulatory factor at TH promoters across mammalian species. Furthermore, by interrogating VDR ChIP-seq/cistrome datasets, we identified candidate vitamin D-responsive elements (VDREs) at the human NURR1 locus that provide a plausible genomic framework for direct regulation of NURR1 by 1,25D/VDR. We propose that 1,25D-liganded VDR acts as a primary inducer of NURR1, which in turn secondarily activates expression of the TH gene, thereby defining a transcriptional route through which 1,25D/VDR signaling may influence TH-linked dopaminergic gene programs. Retinoid X receptor (RXR) may facilitate both NURR1-dependent and -independent potentiation of TH transcription because the rexinoid, bexarotene, significantly enhances TH mRNA in human U87 cells, either alone (2.0-fold) or in combination with 1,25D (4.1-fold). In addition, bexarotene and its novel analogs, A41 and A55, induce NURR1 mRNA expression in U87 cells by 2.8-, 3.1-, and 4.8-fold, respectively, with A55 outperforming the parent compound at matched concentration. Because Parkinson’s disease is characterized by the selective degeneration of dopaminergic neurons and impaired NURR1-dependent transcriptional programs, our findings identify a 1,25D/VDR–NURR1–RXR transcriptional axis as a previously underappreciated regulatory framework for studying TH gene expression and dopaminergic gene regulation in Parkinson’s disease-relevant neural contexts. Full article

Takotsubo syndrome (TTS) is an acute disorder characterized by transient left ventricular dysfunction with typical regional wall motion abnormalities, most commonly apical ballooning. It accounts for 1–3% of all suspected acute coronary syndromes and up to 5–6% in women presenting with ST-segment elevation myocardial infarction requiring coronary angiography to exclude obstructive coronary artery disease. The pathophysiology of TTS is complex and not fully elucidated, with sympathetic hyperactivation playing a central role through calcium dysregulation, oxidative stress, and metabolic alterations. Both clinical and experimental data demonstrate the importance of inflammation, with cell infiltration and persistent immune activation exceeding the acute phase. Increasing evidence highlights the impact of coronary microvascular disfunction (CMVD) as a secondary phenomenon, with some findings that support its role as a causative substrate. Beyond well-known predisposing conditions such as female sex, postmenopausal age, and neurological and psychiatric disorders with the trigger of a physical or psychological event, numerous case reports associate the syndrome with chronic autoimmune diseases, even if clear experimental evidence remains poor and worthy of further study. Echocardiography and advanced imaging techniques, including cardiac magnetic resonance and positron emission tomography, have provided insights into transient CMVD, reversible myocardial edema, and metabolic impairment, strengthening our knowledge of the syndrome as a dynamic process. It is also of growing interest to perform invasive hemodynamic assessment to explain the increase in microvascular resistance. This review offers a comprehensive and up-to-date overview of these techniques in the context of TTS. Since clinically, TTS may be associated with significant morbidity and mortality, with some unexplained cases of long-term myocardial disfunction or even recurrence, a deeper understanding of the interplay between catecholamines, inflammation, immune substrate, and CMVD may improve risk stratification and lead to the development of targeted therapeutic strategies. Full article

Transient myocardial thickening (TMT) is considered a reversible feline cardiac disease that initially mimics hypertrophic cardiomyopathy. The exact etiopathogenesis remains unknown and is likely multifactorial. General anesthesia and surgery may contribute to the development of TMT in predisposed patients due to systemic inflammation, perioperative stress, surgery itself, anesthetic management, and individual susceptibility. Additionally, inadequate analgesia could result in pain, which triggers a stress response. This stress response could stimulate endogenous catecholamine release and facilitate the development of TMT. In this retrospective study, anesthetic and analgesic protocols were compared between cats with and without TMT following gonadectomy. The study group consisted of 15 cats that presented with congestive heart failure after recent anesthesia and were later suspected of or diagnosed with TMT. The control group consisted of 300 cats without TMT after gonadectomy. All cats were considered healthy prior to gonadectomy based on physical examination; no echocardiography was performed prior to anesthesia. All cats in the TMT group were anesthetized with ketamine and an alpha-2 agonist, which was medetomidine in 14/15 (93.3%) and dexmedetomidine in 1/15 (6.7%) of the cats. In the control group, all cats were anesthetized with ketamine and dexmedetomidine. The ketamine dose was significantly higher (p < 0.001) in the TMT group compared to the control group, with a median dose of 6.78 mg/kg (4.52–10.34) and 4.29 mg/kg (2.08–6.45), respectively. The doses of the alpha-2 agonist and atipamezole were not significantly different. The most commonly administered non-steroidal anti-inflammatory drug was meloxicam in 83.3% of the study group cats and 98.7% of the control group cats. The dose of meloxicam was significantly lower (p < 0.001) in the study group compared to the control group, with median doses of 0.2 mg/kg (0–0.3) and 0.29 mg/kg (0–0.38), respectively. In the control group, 93.0% of the cats received buprenorphine, and 75.0% of males received intratesticular lidocaine. None of the cats in the study group received buprenorphine or intratesticular lidocaine during the procedure. Additionally, oxygen supplementation was significantly different (p < 0.017), and lack of oxygen was associated with the development of TMT. Anesthetic protocols between the two groups were significantly different. However, it is important to note that not all observed complications can solely be attributed to anesthetic or analgesic differences; effects might also be due to different perioperative circumstances. Full article

Metanephrine (MN) and normetanephrine (NMN) are critical biomarkers for neuroendocrine tumors (pheochromocytoma and paraganglioma). Following our previous development of a molecularly imprinted solid-phase extraction (MISPE) sorbent for urine analysis, this study evaluated MISPE coupled with HILIC-MS/MS for determining metanephrines in human plasma. Unlike conventional phases, the novel polymer selectively binds analytes as in situ-generated anions via quaternary alkylammonium groups in hydroxide form, ensuring accurate extraction from just 25 µL of plasma. Validated per U.S. FDA guidelines, the assay showed good intra- and interday precision (CV < 10.8%), accuracy (bias < −10.6%) and excellent linearity (R² > 0.99) across pathological ranges (184.3–877.8 ng/L for MN; 174.8–923.0 ng/L for NMN), with low relative standard errors (<6.9%). Excellent selectivity was demonstrated in the presence of structurally close analogs (catecholamines, DOPA and its derivatives). Compared with commercial WCX, the sorbent yielded cleaner extracts, significantly reducing the phospholipid interference. Although lower limits of quantification (92.2 ng/L MN; 87.4 ng/L NMN) slightly exceeded healthy upper thresholds, the method has potential for use in specific clinical scenarios with pronounced biomarker elevations: diagnosis of pheochromocytoma/paraganglioma, monitoring post-treatment metanephrine decline, and tracking tumor-induced hypertensive crises in emergencies. This accessible protocol forms a solid foundation for advanced diagnostics. Full article

Excessive administration of epinephrine and norepinephrine in critically ill patients may trigger a catecholamine storm and contribute to acute kidney injury (AKI) through activation of β-adrenoceptor signaling. Although clinical observations link high-dose catecholamine exposure to increased AKI risk, experimental models and mechanistic studies remain limited. We established a rodent model of combined epinephrine and norepinephrine infusion to investigate the renoprotective effects of subtype-selective β-adrenoceptor blockers. Animals received the β1-selective blockers metoprolol or atenolol, or the β2-selective blocker ICI 118,551. β1-adrenoceptor blockade, particularly with metoprolol, significantly attenuated renal histopathological injury and improved biochemical markers of kidney dysfunction. These protective effects were associated with suppression of ferroptosis-related pathways in the renal cortex. Atenolol partially improved biochemical parameters but did not significantly reduce tubulointerstitial damage, whereas β2-adrenoceptor blockade conferred limited functional benefit despite modest morphological improvement. Collectively, our findings indicate that β1-adrenoceptor activation plays a critical role in catecholamine-induced AKI by promoting ferroptosis. Targeting β1-adrenoceptors, especially with metoprolol, may represent a potential therapeutic strategy for preventing renal injury during catecholamine storms. Full article