The rapid emergence of new synthetic opioids (NSOs), especially potent 2-benzylbenzimidazole derivatives known as nitazenes, poses challenges to public health and toxicologists. Among these substances, 5-methyl etodesnitazene has recently appeared on the illicit market. This compound was shown to be approximately twice as potent as fentanyl at the µ-opioid receptor, and overdose may lead to potentially fatal respiratory depression. Detecting the drug and its metabolites is therefore critical for clinical and forensic investigations. This study aimed to characterize the metabolic profile of 5-methyl etodesnitazene in humans. Metabolic transformations were investigated through incubations with ten-donor pooled human hepatocytes and analysis of blood and urine samples from a postmortem case positive for 5-methyl etodesnitazene. Samples were analyzed using liquid chromatography-electrospray ionization-high-resolution tandem mass spectrometry (LC-ESI-HRMS/MS) in positive- and negative-ionization modes, and software-aided data mining. In positive mode, 5-methyl etodesnitazene produced an intense signal in its di-protonated form, which generated informative spectra, facilitating structural elucidation. Biotransformations included N- and O-deethylation, consistent with structural analogs, as well as ω-carboxylation specific to the methylated benzimidazole core; phase II metabolites were not detected. We suggest N-deethyl-5-methyl etodesnitazene, N-deethyl-5-carboxy etodesnitazene, and 5-carboxy etodesnitazene in blood, and N-deethyl-5-carboxy-4′-hydroxy etodesnitazene, 5-carboxy-4′-hydroxy etodesnitazene, and N-deethyl-5-carboxy etodesnitazene in urine, as metabolite biomarkers of consumption in clinical and forensic settings. Overall, metabolite profiles were consistent across in vitro and in vivo data, with minor matrix-specific differences. Considering that nitazene metabolites are often active and their metabolism is susceptible to genetic polymorphism, further research on the pharmacokinetics and pharmacodynamics of 5-methyl etodesnitazene is warranted.
BACKGROUND:Drug-eluting stents (DESs) are recommended treatment for coronary in-stent restenosis (ISR) but are not used in >20% of cases. OBJECTIVES:The aim of the SELUTION4ISR (SELUTION SLR 014 In-stent Restenosis) trial was to assess the safety and effectiveness of a novel sirolimus drug-eluting balloon (DEB). METHODS:After successful lesion predilation, patients with ISR were randomly assigned to the SELUTION Sustained Limus Release (MedAlliance) DEB or a control strategy of usual care, including any approved DES or balloon angioplasty (BA) on the basis of operator selection prerandomization. Randomization to selected BA control treatment was limited to 20% of patients. The primary outcome was target lesion failure (TLF) (cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization) assessed at 1 year in the per protocol group (all treated eligible patients with complete primary endpoint follow-up). Noninferiority was established if the upper limit of the 2-sided 95% credible interval was smaller than 10%. A sequential secondary hypothesis test was performed comparing DEB with DES in patients with single-layer ISR. RESULTS:From July 2020 to July 2024, 418 patients were randomly assigned to the DEB group (n = 210) or the control group (n = 208), with 390 patients per protocol (DEB, 197; control, 193 [154 DES; 39 BA]). TLF occurred in 32 (16.2%) of 197 patients in the DEB group and in 28 (14.5%) of 193 patients in the control group (difference: 1.7%; 95% credible interval: -5.5% to 8.9%; posterior probability of noninferiority: 98.80%). In the secondary hypothesis test, TLF occurred in 22 (14.2%) of 155 patients in the DEB group and in 9 (6.5%) of 138 patients in the DES control group (difference: 7.7%; 95% credible interval: 0.6%-14.6%, posterior probability for noninferiority: 76.07%). TLF according to operator selected control was higher for DEB compared with DES (15.3% vs 7.1%; difference: 8.1%; 95% credible interval: 1.4%-15.0%) and lower for DEB compared with BA (23.6% vs 43.6%; difference: 23.7%; 95% credible interval: -41.4% to -1.5%; Pforinteraction = 0.0026). CONCLUSIONS:The sirolimus DEB was noninferior to a usual care control strategy including 80% repeat DES but not noninferior to DES for single-layer ISR for TLF at 12 months. There was significant interaction on the basis of operator selection of DES vs BA. (SELUTION SLR 014 In-stent Restenosis [SELUTION4ISR]; NCT04280029).
Mitochondria are central regulators of cardiac homeostasis, integrating energy production, redox balance, calcium handling, and innate immune signaling. In cardiovascular disease (CVD), mitochondrial dysfunction acts as a unifying mechanism connecting oxidative stress, metabolic inflexibility, inflammation, and structural remodeling. Disturbances in mitochondrial quality control—encompassing fusion–fission dynamics, PINK1/Parkin- and receptor-mediated mitophagy, biogenesis, and proteostasis—compromise mitochondrial integrity and amplify cardiomyocyte injury. Excess reactive oxygen species, mitochondrial DNA release, and calcium overload further activate cGAS–STING, NLRP3 inflammasomes, and mPTP-driven cell death pathways, perpetuating maladaptive remodeling. Therapeutic strategies targeting mitochondrial dysfunction have rapidly expanded, ranging from mitochondria-targeted antioxidants (such as MitoQ and SS-31), nutraceuticals, metabolic modulators (SGLT2 inhibitors, metformin), and mitophagy or biogenesis activators to innovative approaches including mtDNA editing, nanocarrier-based delivery, and mitochondrial transplantation. These interventions aim to restore organelle structure, improve bioenergetics, and reestablish balanced quality control networks. This review integrates recent mechanistic insights with emerging translational evidence, outlining how mitochondria function as bioenergetic and inflammatory hubs in CVD. By synthesizing established and next-generation therapeutic strategies, it highlights the potential of precision mitochondrial medicine to reshape the future management of cardiovascular disease.
AIMS:We aimed to develop the European Society of Cardiology (ESC) quality indicators (QIs) for myocardial infarction (MI), from 1 year after hospital discharge, corresponding to transition to the chronic coronary syndrome phases. METHODS AND RESULTS:We collaborated with the European Association of Preventive Cardiology (EAPC) and developed QIs for the long-term management of patients following MI. We applied the ESC methodology for QI development by (i) determining key domains of post-MI care; (ii) developing candidate QIs by performing a systematic review of the literature, and (iii) selecting the final set of QIs using a modified Delphi approach. In total, 18 QIs were identified across seven domains of care including (i) structural framework, (ii) risk assessment and follow-up, (iii) pharmacological management, (iv) rehabilitation, behavioural, and preventive interventions, (v) coronary revascularization, (vi) clinical outcomes, and (vii) patient-reported outcomes. CONCLUSION:We present the ESC QIs from 1 year after hospitalization for MI, to standardize and address gaps in care for this high-risk group. These QIs are supported by evidence from contemporary literature, endorsed by expert consensus, and aligned with the 2024 ESC guidelines on the management of chronic coronary syndromes. LAY SUMMARY:Measures to evaluate and improve the long-term management of patients following a heart attack are needed. In this paper, we identified key aspects of care that can help clinicians, decision-makers and patients improve the quality of care, from one year after a heart attack onwards, and help address inequalities and variations in clinical practice.
Plant-derived extracellular vesicles (PDEVs) are emerging as bioactive dietary particles with the capacity to modulate mammalian physiology. Here, we characterize the structure and functional properties of apple-derived extracellular vesicles (ADEVs) and evaluate their relevance to neuroimmune and gut-brain communication. ADEVs exhibit canonical PDEV features and elicit rapid IP₃-dependent Calcium (Ca²⁺) signaling in fibroblasts while preserving blood-brain barrier integrity. Neural assays reveal marked cell-type specificity: ADEVs are efficiently internalized by glial cells and activate glial Ca²⁺ signaling yet display minimal neuronal uptake and no detectable Ca²⁺ response in differentiated SH-SY5Y neurons. Consistent with this selectivity, ADEVs attenuate TNF-α-induced cytokine secretion in activated glia but remain inert in resting neural cells. Although capable of encapsulating L-DOPA efficiently, ADEVs fail to deliver functional neuroprotection against rotenone toxicity, indicating limited neuronal compatibility for dopaminergic cargo. In parallel, using advanced in vitro colon simulation platforms, ADEVs modulate the colonic microbiome in a dose-dependent manner, promoting carbohydrate fermentation and short-chain fatty acid production while reducing proteolytic metabolism under physiologically relevant conditions, with sustained, region-specific effects during prolonged exposure. In vivo, ADEV administration in dogs with chronic intestinal inflammation is associated with altered circulating serotonin levels, suggesting engagement of gut-brain neurochemical pathways with potential implications for mood regulation. Collectively, these findings identify ADEVs as biocompatible, glia-responsive plant vesicles with potential neuromodulatory activity, while delineating intrinsic constraints in their use as neuronal drug-delivery systems.
