Mast cells (MCs) are versatile immune cells that play a key role in neuroimmune interactions due to their strategic localization in barrier tissues and perineuronal sites, including the meninges, choroid plexus, thalamus, hypothalamus, and hippocampus within the central nervous system (CNS), as well as peripheral sites such as the skin, gastrointestinal tract, and dorsal root ganglia. They rapidly release stored and newly synthesized mediators, including histamine, tryptase, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), substance P, and prostaglandins, which regulate nerve signaling, vascular function, and inflammation. This review presents a framework integrating MC differentiation with distinct CNS microenvironments to explain their neuroprotective and toxic roles. The anatomical and molecular basis of MC-neuron interaction is discussed, with emphasis on bidirectional signaling via neuropeptides, neurotransmitters, and cytokines. MC functions in the CNS are highlighted, including neuroprotection through synaptic plasticity and BBB integrity under homeostatic conditions, as well as neurotoxicity, where aberrant activation promotes BBB breakdown, microglial priming, and neuroinflammatory cascades. Furthermore, the roles in which mast cell dysfunction is implicated in neurodegenerative and psychiatric disorders are examined, including Alzheimer's disease (AD), where amyloid-β triggers MC degranulation, Parkinson's disease (PD), where α-synuclein induces MC activation, multiple sclerosis (MS), autism, anxiety, and depression, as well as peripheral neuroimmune conditions affecting the skin, gut-brain axis, and pain. Current and emerging mast cell-targeted therapies, including stabilizers, histamine receptor blockers, tryptase inhibitors, and anti-IgE biologics, are discussed, along with future challenges in mast cell-based neuroimmunological treatment.

Minimally invasive lumbar spinal surgery can precipitate rare perioperative Takotsubo syndrome (stress-induced cardiomyopathy, SIC), a condition frequently misdiagnosed as acute myocardial infarction. Cardiac magnetic resonance (CMR) serves as a valuable diagnostic tool for the multimodal evaluation of Takotsubo syndrome, helping exclude alternative etiologies such as myocarditis. Diagnosis of Takotsubo syndrome relies on comprehensive integration of clinical manifestations, ventricular imaging, coronary angiography, electrocardiography, and cardiac biomarkers, rather than depending on CMR alone. We herein report the case of a 66-year-old postmenopausal woman without conventional cardiovascular risk factors who developed Takotsubo syndrome shortly after elective lumbar discectomy. Obstructive coronary artery lesions were ruled out by coronary angiography. Owing to the patient's claustrophobia, we implemented a combined imaging protocol of two-dimensional speckle-tracking echocardiography (2D-STE) and dynamic single‑photon emission computed tomography (D-SPECT), which verified reversible myocardial dysfunction. The patient received guideline-directed medical therapy consisting of sacubitril/valsartan, beta-blockers, mineralocorticoid receptor antagonists, and a sodium‑glucose cotransporter 2 (SGLT2) inhibitor. Cardiac biomarkers returned to normal levels on postoperative day 11, and myocardial strain parameters showed substantial improvement at the eight-week outpatient follow-up. This case underscores the need for clinical vigilance for Takotsubo syndrome after spinal surgery. In this individual patient with CMR contraindications, combined 2D‑STE and D‑SPECT provided complementary supportive diagnostic information. Further studies are required to validate the general utility of this multimodal imaging approach.

Background Lower urinary tract symptoms (LUTS), highly prevalent among aging men, adversely affect the quality of life. Pharmacological management has evolved with multiple drug classes, but real-world prescribing patterns in India have not been adequately studied. Thus, we evaluated prescription trends among Indian urologists for the management of male LUTS, assessed symptom patterns, evaluated factors influencing choice of fixed-dose combination (FDC), with special focus on silodosin-mirabegron FDC, and identified adverse events (AEs) and adherence. Methods This cross-sectional, questionnaire-based survey was performed over three months (January 2, 2026, to April 5, 2026) and included 110 Indian urologists actively managing male patients with LUTS. A 27-item structured questionnaire captured demographic characteristics, clinical practice patterns, and prescribing preferences for LUTS pharmacotherapy, including monotherapies, combination therapies, and FDCs, along with AEs and adherence. Results Of 135 urologists invited, 110 (81.48%) completed the survey. LUTS mainly involved a combination of storage, voiding, and post-micturition symptoms (n = 59, 53.6%). As a class, α1-blockers were the most frequently prescribed monotherapy (n = 109, 99.1% frequent/very frequent use), with silodosin (n = 98, 89.1%) and tamsulosin (n = 84, 76.4%) being most preferred. Use of dutasteride (n = 108, 98.2%) exceeded finasteride (n = 13, 11.8%). In patients with benign prostatic hyperplasia (BPH) with overactive bladder, silodosin-mirabegron was the most favored FDC (n = 97, 88.2%). FDCs of α1-blockers with muscarinic receptor antagonists and β-3 adrenergic agonists were preferred due to their proven efficacies (n = 83, 75.5% and n = 87, 79.1%, respectively) and lower incidences of AEs (n = 69, 62.7% and n = 80, 72.7%). Common AEs included dry mouth (n = 73, 66.4%), anejaculation (n = 69, 62.7%), and headache (n = 67, 60.9%). Moderate adherence (25%-75%) was reported by 95 (86.4%) urologists. Conclusion Adherence to pharmacotherapy, as assessed by participating urologists, was moderate, with urologists preferring silodosin as first-line therapy and silodosin-mirabegron FDC for mixed LUTS.

Carotid-cavernous fistula (CCF) requires comprehensive postembolization management to address secondary complications, including glaucoma. A 70-year-old male presented with the inability to open his left eye, progressive eyelid swelling, and orbital congestion. Examination revealed severe conjunctival chemosis with dilated episcleral vessels, elevated intraocular pressure (IOP; 20 mmHg), and corneal Descemet's folds. Imaging confirmed an arteriovenous fistula at the left sphenoid bone draining into the superior ophthalmic vein. The patient underwent successful endovascular embolization of the left sphenoid arteriovenous fistula. Medical management included topical dorzolamide, beta-blockers, and oral acetazolamide for IOP control. Postembolization, there was a significant reduction in orbital congestion, improved eyelid function, and stabilization of IOP. Visual acuity improved from counting fingers to 6/12 with successful preservation of optic nerve function. This case highlights the importance of timely multispecialty collaboration between ophthalmology and interventional radiology in managing CCF-related secondary glaucoma.

Selective β1-blockers are fundamental in managing hypertension, coronary artery disease, and heart failure. Yet, despite their widespread use, practical guidance on safe and individualized prescribing remains limited. Existing evidence is largely derived from controlled clinical trials, which may not fully capture drug-specific adverse events, sex-related susceptibility, or early-onset risks observed in routine clinical practice. To generate real-world, evidence-based recommendations for the safe use of selective β1-blockers, we compared the adverse event profiles of metoprolol, bisoprolol, and atenolol using 2 large pharmacovigilance systems. Adverse drug events reported for the 3 agents between 2004 and Q2 2025 were retrieved from the US Food and Drug Administration Adverse Event Reporting System, a spontaneous-reporting system, and compared with reports from the Canadian Vigilance Adverse Reaction Online Database. Disproportionality analyses, preferred term mapping, exploratory sex-stratified comparisons, and time-to-onset modeling were conducted to characterize shared reporting patterns, drug-specific signals, and potential patient-level modifiers. Across all 3 agents, disproportionate reporting was observed for a common cardiovascular spectrum that included bradycardia, conduction abnormalities, heart failure, and blood pressure instability. Metoprolol showed prominent reporting signals for BRASH syndrome and neuropsychiatric and suicide-related events. Bisoprolol showed signals for bradyarrhythmia, hyperkalemia, and acute kidney injury. Atenolol showed reporting patterns involving blood pressure perturbations, electrolyte imbalance, and interaction-related events. Exploratory sex-stratified analyses identified differences in the reporting distributions of several PT = preferred terms for metoprolol and atenolol, whereas bisoprolol showed a more balanced distribution. All 3 agents displayed early-failure time-to-onset patterns, supporting closer monitoring after treatment initiation. This real-world pharmacovigilance assessment identifies drug-specific patterns of disproportionate reporting that may inform hypothesis generation and individualized monitoring. Because spontaneous-reporting data cannot establish incidence or causality, the findings should complement, rather than replace, clinical judgment and confirmation in controlled or longitudinal data sources.

Objectives: Adverse drug reactions (ADRs) to antihypertensive medications contribute to poor medication adherence and treatment discontinuation. Pharmacogenomic approaches offer a potential means of identifying genetic variants that predict ADR risks, thereby supporting more tailored antihypertensive therapy and improved tolerability. We systematically identify and synthesize available pharmacogenomic evidence for gene-drug-ADR interaction in hypertension across all major drug classes. Methods: This systematic review follows PRISMA guidelines. Five bibliographic databases were systematically searched for pharmacogenomic studies examining associations between genetic variants and adverse drug reactions in adults receiving antihypertensive therapy. Google Scholar was additionally used as a supplementary source during full-text retrieval and citation screening to identify potentially relevant peer-reviewed publications not captured by the primary database searches. Two reviewers independently screened studies, extracted data, and assessed methodological quality using the Newcastle-Ottawa Scale. The protocol was registered in PROSPERO (CRD420251247856). Results: Seven studies published between 2002 and 2024 fulfilled the inclusion criteria, encompassing populations from Pakistan, China, Russia, South Africa, Spain, South Korea, and Japan. Notably, no pharmacogenomic evidence was identified for beta-blockers, angiotensin receptor blockers, thiazide diuretics, alpha-blockers, or loop diuretics when used as antihypertensives. The studies focused on two antihypertensive medication classes: angiotensin-converting enzyme inhibitors (ACE-I) and calcium channel blockers (CCBs). Variants in BDKRB2 have significant links to ACE-I-induced cough in different populations, with individual investigations identifying other genes involved in bradykinin metabolism and signalling (MME, PTGER3) and hepatic drug transport (SLCO1B1). Associations between CCB-related peripheral edema and CYP3A5 polymorphisms were found in Chinese Han and Russian Caucasian groups. The quality of the studies varied, but two were rated as good. Conclusions: Preliminary pharmacogenomic evidence linking antihypertensive medications to ADRs is emerging but remains limited in scope and concentrated in two drug classes. These findings represent early-phase, hypothesis-generating contributions to the evidence base required for personalized medicine in hypertension pharmacotherapy. Realizing this potential will require prospective validation in diverse, multi-ethnic cohorts, standardization of ADR reporting and causality assessment, and sustained investment in pharmacogenomic implementation science.

Ziziphus lotus (L.) Lam (wild jujube) leaves are traditionally used in Moroccan medicine to treat hypertension. The present study evaluated the aqueous extract of Z. lotus leaves (ZLAqExt) for its vasorelaxant effects, mechanisms of action, acute toxicity, antioxidant potential, and phytochemical profile. In phenylephrine-precontracted rat aortic rings, the ZLAqExt induced concentration-dependent relaxation (Emax = 79.25 ± 2.77% at 10[-1] mg/mL). The mechanism of action was investigated using specific antagonists and blockers. Complete inhibition by endothelium denudation, and preincubation with L-NAME, hydroxocobalamin, ODQ, and thapsigargin confirmed endothelium-dependent nitric oxide (NO)/cyclic GMP (cGMP)/sarco/endoplasmic reticulum Ca[2+]-ATPase (SERCA) pathway involvement. A partial inhibition by BaCl2, indomethacin, calmidazolium, and KCl indicated cyclooxygenase (COX), endothelium-derived hyperpolarizing factor (EDHF), and inward-rectifier potassium (Kir) channel contributions. Acute oral toxicity did not show any mortality at 2 g/kg BW in mice. The extract displayed potent antioxidant activity (DPPH IC50: 18.12 ± 1.49 µg/mL; β-carotene bleaching IC50: 8.3 ± 0.014 µg/mL). UHPLC-ESI-MS identified rutin as the major compound, followed by 3',5'-di-C-β-glucopyranosyl phloretin with high docking affinity for guanylate cyclase and SERCA pump. The presence of flavonoids in the ZLAqExt might have mediated its vasorelaxant effects, supporting its traditional use as an antihypertensive. Our results highlight that Z. lotus is a potential natural therapeutic agent against vascular dysfunction-related cardiovascular disorders.

Background and Objectives: Drug repurposing provides an opportunity to identify anticancer activities among established pharmacological agents. Labetalol (LB), an α1- and non-selective β-adrenergic receptor antagonist, has been insufficiently investigated in melanoma. This study evaluated the potential anti-melanoma activity of LB in A375 human melanoma cells, compared its effects with those observed in HaCaT immortalized non-tumoral keratinocytes, and investigated the cellular mechanisms associated with LB-induced cytotoxicity. Materials and Methods: A375 and HaCaT cells were exposed to 75-500 μM LB for 24 h. Cell viability and lysosomal dye retention were assessed using MTT and NRU assays. A DMSO-only concentration series (0.075-0.50% v/v) was additionally evaluated by MTT in both cell lines. Mitochondrial membrane potential, mitochondrial staining patterns, nuclear morphology, cytoskeletal organization, caspase-3/7 and caspase-9 activities, and plasma membrane integrity were evaluated using JC-1, MitoTracker Red CMXRos, immunofluorescence, luminescence-based caspase assays, and AO/PI staining. The acute irritation potential of 500 μM LB was assessed using the HET-CAM assay. Results: DMSO alone did not significantly reduce viability over the investigated concentration range in either cell line. LB reduced A375 cell viability in a concentration-dependent manner, with a 24 h IC50 of 422.5 μM and a viability of 33.61% at 500 μM. Under the same experimental conditions, HaCaT viability remained at 89.01% at 500 μM, and an IC50 was not reached within the investigated concentration range. At the highest concentration, neutral red uptake and the JC-1 aggregate/monomer ratio decreased to approximately 33% and 24% of the corresponding control values, respectively. The apoptotic index increased from approximately 3% in control cells to 31%, while caspase-3/7 and caspase-9 activities increased to approximately 482% and 324% of the control. Qualitative imaging demonstrated mitochondrial staining redistribution, cytoskeletal disorganization, apoptosis-associated morphology, and loss of plasma membrane integrity at higher concentrations. In the HET-CAM assay, 500 μM LB produced a mean irritation score of 0.71 ± 0.27, within the non-irritant range. Conclusions: LB displayed concentration-dependent in vitro cytotoxicity in A375 melanoma cells, whereas HaCaT keratinocytes showed limited changes under the investigated conditions. LB treatment was also associated with mitochondria-associated apoptotic signaling in A375 cells. These findings provide preliminary evidence supporting further investigation of LB within a melanoma-directed drug-repurposing strategy. Additional studies are required to establish receptor dependence, achievable local exposure, safety, and translational relevance.

Background and Objectives: Conjunctival hyperemia is common with netarsudil, but redness may not reflect the overall patient experience when treatment burden is reduced. We evaluated ocular surface symptoms, objective redness, tear-film parameters, intraocular pressure (IOP), and treatment preference after a routine-care switch from twice-daily fixed dorzolamide/timolol to once-daily netarsudil 0.02%, while continuing latanoprost. Materials and Methods: This prospective, single-center observational cohort included 30 consecutive adults with primary open-angle glaucoma or ocular hypertension and controlled IOP. Outcomes were assessed at baseline and months 1 and 2. The primary outcome was the Ocular Surface Disease Index (OSDI). Continuous eye-level outcomes were analyzed using mixed-effects models accounting for fellow-eye and repeated-measures correlation; grade ≥ 2 hyperemia was analyzed using participant-clustered logistic regression. Results: Twenty-seven participants (54 eyes) completed evaluable 2-month follow-up. Median OSDI decreased from 7.50 at baseline to 6.25 at month 1 and 5.00 at month 2 (Friedman p = 0.0015). The mean baseline-to-month 2 change was -2.95 points (95% CI, -4.80 to -1.10), and 6/27 participants (22.2%) improved by at least 7 points. Serle grade ≥ 2 hyperemia increased from 7.4% of eyes at baseline to 51.9% at month 1 and 44.4% at month 2. Estimated mean bulbar redness index increased from 1.57 to 2.14 (p < 0.0001), tear meniscus height increased modestly, and non-invasive keratograph break-up time showed no significant longitudinal change. Estimated mean IOP changed from 14.50 to 13.65 mmHg (p = 0.0083), with no eye showing an increase of at least 4 mmHg. Burning improved after multiplicity adjustment, and 17/27 participants with available month-2 preference data (63.0%) preferred netarsudil. Conclusions: The switch was associated with modest OSDI improvement and maintained short-term IOP control despite increased objective redness. Patient preference appeared to reflect factors beyond redness alone.

Background and Objectives: Pseudoexfoliative glaucoma (PEXG) is a secondary glaucoma caused by the deposition of abnormal flaky protein-like material inside the eye, leading to blockage of the drainage system, increased intraocular pressure (IOP), and optic nerve damage. This study aimed to evaluate the effects of latanoprost and timolol-dorzolamide therapy on the concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70, and tumor necrosis factor-alpha (TNF-α) in the aqueous humor and serum samples of patients with PEXG. Materials and Methods: This prospective observational study included 60 patients allocated to three age-matched groups (n = 20 per group). Group 1 received latanoprost therapy, Group 2 received timolol-dorzolamide therapy, and Group 3 comprised patients with cataracts without PEXG who were not receiving antiglaucoma medication (control group). All participants underwent a comprehensive ophthalmological examination, including visual acuity assessment, specular microscopy, IOP measurement, and intraocular lens (IOL) measurement. Peripheral venous blood was taken from each patient before the surgical procedure and aqueous humor samples were collected during cataract surgery. Concentrations of IL-1β, IL-6, IL-8, IL-10, IL-12p70, and TNF-α were determined using a Cytometric Bead Array and flow cytometry. Results: No significant differences were observed in the aqueous humor and serum concentrations of IL-6 and IL-8 between the treatment groups, while IL-1β, IL-10, IL-12p70, and TNF-α did not reach detection. A significant positive correlation was found between IOL and aqueous humor IL-6 concentration in group 1 and between IL-6 and IL-8 serum concentration and IOP in controls. Conclusions: Latanoprost and timolol-dorzolamide therapy were not associated with significant differences in aqueous humor or serum IL-6 and IL-8 concentrations in patients with PEXG. IL-1β, IL-10, IL-12p70, and TNF-α were not detectable in the analyzed samples. These findings support the presence of low-grade inflammation in patients with PEXG that does not differ according to the therapy administered. Corneal endothelial alterations are disease-related rather than treatment-induced.

Heart failure (HF) is a complex clinical syndrome that represents an increasingly relevant health issue, associated with substantial morbidity and mortality in pediatric patients. While considerable therapeutic advances have transformed the prognosis of adult patients with heart failure over the past three decades, progress in pediatric heart failure has been considerably slower. In adult patients, large randomized controlled trials (RCTs) have established angiotensin-converting enzyme inhibitors (ACE inhibitors), beta-blockers, mineralocorticoid receptor antagonists (MRAs), angiotensin receptor-neprilysin inhibitors (ARNIs), and, more recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors as the cornerstone of guideline-directed medical therapy. Evidence supporting pharmacological therapy in pediatric heart failure remains scarce and frequently inconclusive, with most available studies being limited by small sample sizes and heterogeneous patient populations. Therefore, heart failure treatment in children is mostly extrapolated from adult studies and guidelines. However, developmental differences in myocardial structure and function, neurohormonal signaling, pharmacokinetics and pharmacodynamics may substantially influence therapeutic response. In addition, the rarity and the etiological heterogeneity of pediatric HF create major methodological challenges for adequately powered clinical trials. This review compares the pharmacological management of HF in adult and pediatric populations, examines the strength of evidence for contemporary therapies and discusses the biological and methodological limitations of translating adult evidence into pediatric practice. Multicenter collaborative studies and well-designed pediatric randomized controlled trials are essential for establishing truly evidence-based pharmacological strategies for children with HF.

Beta (β)-adrenergic receptors are Gs-protein-coupled receptors with many physiological actions but are also expressed in various types of cancers. Preclinical in vitro and in vivo research studies demonstrated that the antagonism of β-adrenergic receptor signalling by β-blockers inhibits multiple cellular processes involved in cancer progression, including tumour cell proliferation, extracellular matrix invasion, matrix metalloproteinase (MMP) activation, expression of inflammatory or chemotactic cytokines, and angiogenesis, thus regulating the growth of tumours and reducing the development of metastasis in a dose-dependent manner. Furthermore, several experimental studies reported that in patients treated with the combination of neoadjuvant chemotherapy, targeted therapies, and β-blockers, the risk of cancer recurrence and metastasis development was reduced and associated with a decreased rate of mortality. This review aims to compile and critically evaluate preclinical and clinical research of the association between β-blocker administration and tumour growth across various tumour types.

Background: Chronic coronary syndrome (CCS) has evolved from a stenosis-centered concept to a dynamic clinical entity in which obstructive and non-obstructive coronary disease, microvascular dysfunction, and vasomotor abnormalities coexist with complex neurohormonal and endocrine activation. However, CCS has rarely been examined through an integrated endocrine lens, and no unified hormonal-phenotype framework currently links neurohormonal, sex-hormone, thyroid, and cardiometabolic pathways across CCS presentations. Objective: To synthesize contemporary evidence on how neurohormonal and endocrine pathways shape CCS phenotypes and to outline potential endocrine targets for phenotype-guided therapy. Methods for Synthesis of Data: We performed a structured literature appraisal in PubMed, Embase, the Cochrane Library, and ScienceDirect from inception to May 2026, using CCS/stable coronary artery disease and hormone-related search terms, and included comparative clinical studies in adults that evaluated neurohormonal or endocrine interventions with clinically relevant cardiovascular outcomes. Results: From 851 records, 34 studies were retained for qualitative synthesis, encompassing randomized trials, observational cohort studies, systematic reviews, and consensus documents. These data support a central role for renin-angiotensin-aldosterone and sympathetic activation, counterregulatory natriuretic peptides, endothelin-1, sex and thyroid hormones, and adipose-derived mediators in modulating CCS phenotypes, symptoms, and residual risk. Hormone-targeting therapies-including RAAS blockade, beta-blockers, mineralocorticoid receptor antagonists, sex- and thyroid-hormone modulation, and cardiometabolic agents such as GLP-1 receptor agonists and SGLT2 inhibitors-show variable yet often significant impact on outcomes across specific CCS subsets. Conclusions: CCS is best conceptualized as a state of coordinated neurohormonal and endocrine disturbance rather than a purely anatomical disease. A hormonal phenotype framework may support more biologically rational, individualized management and define a research agenda for phenotype-stratified trials in CCS. This review proposes a hormonal-phenotype framework that is conceptually novel compared with anatomy- or comorbidity-based CCS classifications and is intended to be hypothesis-generating rather than prescriptive, by highlighting specific knowledge gaps and potential endocrine targets for future phenotype-guided trials.