BACKGROUND:Levothyroxine is widely prescribed, yet its real-world safety profile remain unclear. Although disproportionality analysis (DA) can detect potential safety signals, reporting raw findings without systematic prioritization may overemphasize statistical artifacts rather than clinically meaningful hypotheses. RESEARCH DESIGN AND METHODS:We analyzed FAERS Individual Case Safety Reports (2004-2023), identifying levothyroxine as the primary suspect drug. Signal detection used four DA measures: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Information Component (IC), and Empirical Bayes Geometric Mean (EBGM) with standard thresholds, including a dose-stratified comparison (≥100 µg vs <100 µg). Detected drug-event pairs were evaluated using a structured Signal Prioritization Framework integrating statistical strength, clinical seriousness, biological plausibility, and novelty to assign high, moderate, or low priority. Inter-rater reliability was assessed using weighted Cohen's κ. RESULTS:We identified 291 signals (22 labeled; 269 unexpected) and 21 dose-dependent signals. Fifteen signals were classified as high priority , while high-dose therapy identified additional moderate-priority signals, including acute kidney injury.Inter-rater agreement was substantial (κ = 0.63; SE = 0.092; 95% CI 0.45-0.81). CONCLUSION:A structured approach combining FAERS-based signal detection with systematic prioritization distinguished clinically plausible levothyroxine safety signals from statistical noise, supporting targeted pharmacoepidemiologic evaluation and improved clinical interpretation.
Heart failure (HF) remains a leading cause of morbidity and mortality with significant residual risk despite major advances in medical therapies. Development of cardiotropic vectors have allowed gene therapy to be revisited to target the molecular roots of (HF) to potentially improve structural cardiac remodeling and cardiac contractility on top of functional improvement offered by current standard of care therapies. In a first-in-human phase 1 trial, a cardiotropic vector gene AB-1002 targets a phosphorylation pathway responsible for calcium handling in cardiomyocytes. AB-1002 stimulates inhibitor 1 (I -1c), which functions to inhibit protein phosphatase 1 (PP1). PP1 overactivity contributes to maladaptive calcium dynamics. AB-1002 has favorable safety and efficacy profiles, potentially representing a promising new frontier in HF treatment.
BACKGROUND:Cardiovascular diseases (CVDs) represent a leading cause of global mortality. Myocardial fibrosis (MF), a common pathological hallmark in CVDs, signifies disease progression to severe stages. Its pathogenesis is highly complex, with autophagy playing a pivotal regulatory role. METHODS:This narrative review synthesizes and critically evaluates the current literature to elucidate the interplay between MF and autophagy. The focus lies on systematically examining the molecular mechanisms and key signaling pathways involved in autophagy-mediated regulation of MF. Review Content: We systematically examine key molecular pathways and components through which autophagy regulates MF, including mitophagy, the NLRP3 inflammasome, FOXO signaling, the ULK1 complex, the mTOR pathway, and TGF-β signaling. These pathways collectively influence fibroblast activation, collagen metabolism, and overall cardiac extracellular matrix remodeling. CONCLUSIONS:Autophagy serves as a crucial modulator of myocardial fibrosis through multiple interconnected molecular pathways. Targeting specific nodes within the autophagic process holds significant therapeutic promise for mitigating MF and slowing CVD progression. This review consolidates current understanding and highlights novel insights, underscoring the need for further research to translate these mechanisms into effective clinical interventions.
This study integrated network pharmacology and metabolomics to investigate the mechanism of allopurinol in treating hyperuricemia. Therapeutic targets were identified by screening drug and disease databases. A drug-target-disease network was constructed and validated by molecular docking using Cytoscape. A mouse model of hyperuricemia was established with yeast extract and potassium oxonate. Allopurinol efficacy was evaluated via body weight, renal histopathology, and serum biochemical indices. Enrichment analyses of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways were performed using DAVID platform. Serum metabolite profiles were analyzed by UPLC-Q-TOF/MS-based metabolomics, and metabolic pathways were explored using MetaboAnalyst 6.0. Network pharmacology and molecular docking identified 23 key targets and 43 signaling pathways related to allopurinol treatment. Animal experiments confirmed allopurinol significantly reduced serum levels of uric acid, creatinine, blood urea nitrogen, and xanthine oxidase activity. Metabolomic analysis revealed 5 differentially regulated metabolites and 13 key metabolic pathways associated with allopurinol intervention. The integrated results indicated that allopurinol treats hyperuricemia not only by modulating purine metabolism but also potentially through influencing oxidative stress and apoptosis-related pathways. This study provided preliminary experimental insights into the potential mechanistic basis of allopurinol in the treatment of hyperuricemia.
The purpose of the study was to identify the incidence and type of arrhythmias and their relationship to the vascular abnormalities in a cross sectional study of 110 patients with peripheral artery disease (PAD). Cardiac arrhythmias were found in 37% of the PAD subjects. Frequent premature ventricular and supraventricular contractions were the most common arrhythmias (78%) and most (65%) were observed at rest. PR segment duration, QRS complex duration and QTc interval were significantly longer in patients with arrhythmias. QTc differences were significant only for males. Both initial and absolute claudication distances were greater in patients with arrhythmias but ankle/brachial index values were not. For comparison, arrhythmias were monitored in a patients (n=111) with coronary artery disease (CAD) but without PAD. Cardiac arrhythmias were observed in 29% of this population. Age (>60 years), pre-existing CAD and greater arterial stiffness (as determined by significantly higher augmentation index values during pulse wave analysis (PWA)) were identified as predictors of arrhythmias in PAD patients. In conclusion, patients with PAD have a high incidence of cardiac arrhythmias at rest. Older age, concomitant CAD and greater arterial stiffness may pre-dispose PAD patients to arrhythmias. A simple, non-invasive technique like PWA may allow for risk stratification.
Patients with heart failure and reduced ejection fraction are often iron deficient in part due to the inflammatory nature of heart failure that limits iron absorption. Not surprisingly, these patients are often also anemic. The role of iron replacement in heart failure has been the subject of multiple investigations, in part triggered by the availability of newer, safer, parenteral iron preparations. Specifically, ferric carboxymaltose and ferric derisomaltose have been utilized in multiple heart failure trials. Additionally, there have been several smaller trials using oral iron salts in heart failure. This review investigates the role of iron supplementation in patients with heart failure and reduced ejection fraction including the provision of recommendations based on review of available evidence and consensus statements.
Royal Canadian Mounted Police (RCMP) frequently encounter potentially psychologically traumatic events (PPTEs) which include direct (e.g., happened to me) or indirect (e.g., part of my job) exposure to actual or threatened death, serious injury, or sexual violence, and subsequently demonstrate an increased risk of developing posttraumatic stress injuries (PTSIs). Although PTSIs include mental health disorders, physical impairments such as the development of chronic pain and cardiovascular conditions are also implicated. The current study was designed to assess for changes in cardiac function among RCMP within their first three years of field service. Participants (n=96) were mostly male (71.6%), men (71.6%), White (85.6%), with a mean age of 30.22±6.22 years. The current results evidenced deteriorations in cardiac function; diastolic cardiac function began to deteriorate as early as the second year of field service, with changes in systolic function occurring concurrently, or within the following year, suggesting that deteriorating cardiac function may constitute a PTSI. Incorporating bestpractice cardiac rehabilitation exercise prescription guidelines tailored to the maintenance or improvement of diastolic function into existing occupational health and wellness programs may support a mechanistic role in reducing the risk of major adverse cardiac events among RCMP officers and other high-risk occupational populations.
Beyond its antidepressant effects, esketamine (ESK) has the potential to enhance neuroplasticity, facilitating the reconnection with emotional and cognitive processes, improving social cognition, and promoting resilience. However, not much is known about its role in Alzheimer's disease (AD). This study aims to explore the potential mechanism of ESK in AD treatment. The potential targets of ESK were predicted by bioinformatics analysis, and 3xTg-AD male mice were subjected to adeno-associated virus and ESK treatment. Cognitive ability, neuronal damage, and proinflammatory factors in 3xTg-AD mice were evaluated. An inflammatory model was established by inducing mouse cortical neurons with mouse IL-17A protein. Neuronal viability was assessed after treatment with different concentrations of ESK. TAOK1 knockdown or IL-17RA knockdown was performed on 3xTg-AD mice and neurons. TAOK1 was highly expressed in the cerebral cortex of ESK-treated 3xTg-AD mice. ESK improved IL-17-induced neuronal inflammation and DNA damage in a TAOK1-dependent manner. TAOK1 interacted with IL-17RA. IL-17RA knockdown improved DNA damage and inflammatory responses in cells and alleviated cognitive impairment and neuroinflammation in AD mice. Overall, ESK protects against DNA damage-mediated neuroinflammation by promoting TAOK1 and inhibiting IL-17 signaling, thereby improving cognitive dysfunction in 3xTg-AD mice.
Despite extensive characterisation of immune responses across peripheral organs, the immunological landscape of the central nervous system (CNS) remains incompletely defined. Among the resident immune cell populations in the brain, mast cells and microglia have emerged as key modulators not only of neuroinflammatory processes but also of fundamental homeostatic functions, including regulation of sleep, affective states, and energy balance. These cells engage in complex bidirectional communication, mediated in part by the biogenic amine histamine. Although histamine was first identified over a century ago, its multifaceted roles in CNS homeostasis, immune surveillance, and neuropathophysiology remain poorly delineated. This review examines the biosynthesis, receptor-mediated signalling, and functional consequences of histaminergic activity within the brain, with a particular focus on microglial dynamics. We discuss crosstalk between mast cells and microglia via histamine signalling pathways, and the potential implications of this interaction in the etiology of neurodevelopmental disorders. Furthermore, we evaluate the emerging evidence on the capacity of centrally acting antihistamines, especially those capable of penetrating the blood-brain barrier, to modulate microglial phenotypes. Collectively, these insights underscore the urgent need for deeper mechanistic studies to elucidate histamine's role in CNS immunophysiology.
Heart transplantation remains the definitive treatment for end-stage heart failure. Preservation of donor hearts is a critical determinant of graft function and post-transplant outcomes. Traditional static cold storage (SCS) has limitations in ischemia tolerance and functional assessment, particularly for marginal and donation after circulatory death (DCD) hearts. Emerging strategies, including normothermic ex vivo perfusion (NEHP) and hypothermic oxygenated perfusion (HOPE), enable extended preservation, functional evaluation, and improved utilization of high-risk donor organs. This review summarizes current preservation techniques, discusses mechanistic strategies to mitigate ischemia-reperfusion injury, highlights emerging trends and controversies, and identifies future research directions to optimize outcomes in heart transplantation.
Alzheimer's disease (AD) is the most common form of dementia, primarily affecting the elderly population. It is a progressive neurodegenerative disease with key pathogenesis hallmarks being amyloid-beta plaque accumulation, and neurofibrillary tangles of tau protein. With an increasingly aging population and rising numbers of surgical procedures, growing interest has been directed toward the potential impact of inhalational anesthetics, particularly isoflurane, sevoflurane, and desflurane, in contributing to the neurodegenerative process. Evidence supporting anesthetic-related modulation of AD pathways is derived predominantly from in vitro and animal models, with comparatively limited and heterogeneous human biomarker and clinical data. This review will explore the various mechanisms by which these volatile anesthetics may contribute to the pathogenesis of neurodegeneration in the context of AD. This includes upregulation of beta-secretase 1 resulting in the formation of amyloid-beta oligomers and inhibition of tau dephosphorylation. While certain studies point toward a neuroprotective effect of these anesthetics, the evidence remains inconsistent. Collectively, these findings support perioperative strategies focused on maintenance of normothermia, optimization of oxygenation, and judicious anesthetic exposure as practical measures to mitigate vulnerability in at-risk populations.
Endothelin-1 (ET-1) was discovered in 1988, followed by identification of ETA and ETB receptors in 1990, enabling rapid development of the first endothelin receptor antagonists (bosentan, ambrisentan, and macitentan) for pulmonary arterial hypertension, a condition marked by elevated ET-1. Nearly a decade later, a new therapeutic wave began with the ETB agonist sovateltide (2021) for cerebral ischemic stroke, demonstrating the benefits of ETB activation. More recent antagonist development has shifted toward ETA-selective agents to preserve ETB function. Clazosentan (ETA) for cerebral vasospasm and aprocitentan (ETA/ETB) for resistant hypertension extended endothelin-targeted therapy into more common diseases. In kidney disease, sparsentan (AT1/ETA) and atrasentan (ETA) have both been approved for IgA nephropathy, with atrasentan succeeding after earlier failed trials. Repurposing has become a major strategy in G protein-coupled receptor drug development. This review outlines approaches for identifying legacy endothelin compounds suitable for new indications, using zibotentan, now combined with dapagliflozin to reduce fluid retention as an example. Kidney disease remains a central focus of current trials, which include new ETA-selective diosuxentan and monoclonal antibody getagozumab, and the ETB peptide antagonist vodudeutentan. The review summarizes recent pharmacology and clinical data and highlights emerging strategies for next-generation endothelin-pathway therapeutics.
Acetylcholinesterase (AChE) inhibitors constitute a group of compounds that inhibit the enzyme AChE. Some of these that are used to treat Alzheimer's disease have been reported to have favourable cardiovascular effects, i.e. a 35% reduction of the risk for cardiovascular disease. Due to their ability to correct the autonomic imbalance, a key component in the development of heart failure (HF), they have been proposed as a potential therapeutic approach. In the present study, HF was induced in male Wistar albino rats using an isoprenaline model (85 mg/kg/day s.c. for 2 days, followed by 3 weeks of HF development). Afterwards, rats were treated with pyridostigmine (20 mg/kg/day for 14 days) or received no treatment. Administration of pyridostigmine resulted in preservation of cardiac contractile function (↑EF), coupled with a decrease in chamber wall thinning (↑ PWDd, ↑ PWDs) and dilatation progression (↓LVIDd, ↓LVIDs). Additionally, pathohistological findings showed significantly reduced tissue damage score and attenuation of cardiac fibrosis development, indicating the cardioprotective potential of pyridostigmine when used as treatment for the early stages of heart failure; however, further investigations are needed to fully investigate the interplay between the several proposed mechanisms through which AChE inhibitors express their protective effects.
