Mounting evidence reframes stroke not as a single cerebral event but as a dynamic brain-body network disorder. Extracellular vesicles (EVs)-lipid bilayer-enclosed particles released by virtually all cells-serve as intercellular messengers that couple vascular injury, neuroinflammation, and systemic responses. EVs carry nucleic acids, proteins, and lipids reflective of their cellular sources and may reach the circulation and interface with the CNS via context-dependent routes, including blood-brain barrier (BBB) disruption and active transport mechanisms. This review integrates clinical and experimental evidence across vascular etiologies, intra-CNS communication, and systemic complications to outline how EV programs may encode and propagate stroke pathology. We further discuss emerging analytical standards, current clinical EV signatures, and translational frameworks-including how to distinguish stroke-specific signals from injury-generic responses-and outline trial designs to test whether modulating EV pathways can influence recovery trajectories.

BackgroundAldosterone excess contributes to uncontrolled and resistant hypertension, making aldosterone synthase inhibition a promising therapeutic strategy. Recent randomized trials have evaluated the selective aldosterone synthase inhibitors Lorundrostat and Baxdrostat; however, their efficacy and safety have not been comprehensively synthesized.MethodsPubMed, Embase, and Cochrane CENTRAL were searched from inception through April 2026 for randomized controlled trials evaluating Lorundrostat or Baxdrostat in adults with uncontrolled or resistant hypertension. The primary efficacy outcome was placebo-adjusted change in systolic blood pressure (SBP). Safety outcomes included hyperkalemia, treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs). Drug-specific pooled analyses were performed using random-effects models.ResultsThree randomized trials of Lorundrostat (n=1,568) demonstrated a significant reduction in SBP compared with placebo (mean difference [MD], -7.51 mmHg; 95% CI, -10.30 to -4.71; I² = 0%). Lorundrostat increased the risks of hyperkalemia (RR, 8.06; 95% CI, 2.92-22.27) and TEAEs (RR, 1.45; 95% CI, 1.27-1.66), without a significant increase in SAEs. Three placebo-controlled Baxdrostat trials (n = 1,483) also demonstrated significant reductions in office SBP (MD, -8.63 mmHg; 95% CI, -11.30 to -5.96; I² = 0%). Baxdrostat increased the risk of hyperkalemia (RR, 3.81; 95% CI, 1.82-7.97) but was not associated with significant increases in TEAEs or SAEs.ConclusionsSelective aldosterone synthase inhibition with Lorundrostat and Baxdrostat produced clinically meaningful reductions in SBP in patients with uncontrolled or resistant hypertension. Hyperkalemia emerged as the principal safety concern, whereas serious adverse events were not significantly increased. Larger and longer-term studies are needed to define long-term safety and cardiovascular outcomes.

The small heat shock protein HSPB1 is a ubiquitously expressed mechanoresponsive chaperone essential for cytoskeletal remodeling under mechanical load. Mutations in HSPB1, including S135F, cause Charcot-Marie-Tooth (CMT) peripheral neuropathy, yet the mechanisms underlying the selective vulnerability of peripheral nerves remain enigmatic. Here we demonstrate that substrate stiffness is a critical determinant of HSPB1^S135F-mediated neurodegeneration. Using stiffness-tunable polydimethylsiloxane (PDMS) substrates (1 kPa, 10 kPa, 2 MPa) and uniaxial cyclic stretch, we show that primary dorsal root ganglia (DRG) neurons and SH-SY5Y cells expressing HSPB1^S135F exhibit profound deficits in mechanoadaptation. On compliant substrates (10 kPa), HSPB1^S135F causes stretch-induced axon fragmentation and neuronal death, whereas HSPB1^WT confers robust neuroprotection. HSPB1^S135F also disrupts stiffness-directed neuritogenesis in differentiated SH-SY5Y cells: HSPB1^WT-expressing cells show optimal axonal outgrowth and βIII-tubulin expression on 10 kPa substrates mimicking muscle tissue stiffness, while HSPB1^S135F mutants display disorganized focal adhesions and complete differentiation failure. Mechanistically, we uncover that HSPB1^S135F dysregulates stage-specific transglutaminase (TGase) expression-insufficient TGase during early neuritogenesis impairs filopodia stabilization, whereas aberrant TGase persistence at late stages constrains axon extension. Our findings establish HSPB1 as a biomechanical sensor that integrates ECM stiffness signals to coordinate peripheral nerve regeneration, and identify defective mechanoadaptation as a previously unrecognized pathomechanism in CMT. These results open new avenues for stiffness-targeted therapeutic strategies in peripheral neuropathy.

The mechanisms underlying doxorubicin (DOX) cardiotoxicity include activation of the renin-angiotensin-aldosterone system (RAAS), oxidative stress, mitochondrial dysfunction, calcium overload, and cardiomyocyte apoptosis. Cortisol plays a key role in regulating multiple metabolic, immunological, cardiovascular, and neuroendocrine processes and may additionally influence drug pharmacokinetics by modulating the activity of P-glycoprotein (P-gp). The peptide apelin, through its specific target, angiotensin II protein J receptor (APJ), exerts cardioprotective, antifibrotic, and anti-inflammatory effects. The available data demonstrate that apelin signaling protects against DOX-induced cardiotoxicity, impacts cortisol secretion, and inhibits RAAS. Short-term elevation in cortisol levels, caused by apelin, may reduce inflammation and thus have cardioprotective properties. However, through chronically elevated cortisol levels, apelin may indirectly contribute to peripheral resistance, cardiac remodeling, and myocardial damage, especially when cortisol metabolism by 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) is altered. This narrative review explores the potential molecular and cellular mechanisms shaping the outcome of apelin-cortisol interplay, offering a potential foundation for developing cardioprotective strategies during anticancer therapy. Future studies should be aimed at assessing the complex interactions between cortisol, apelin, and the RAAS regarding DOX-induced cardiotoxicity.

Myocardial ischemia-reperfusion injury (MIRI) represents a major contributor to morbidity and mortality in patients undergoing reperfusion therapy after acute myocardial infarction. Although timely restoration of coronary blood flow is essential for myocardial salvage, reperfusion paradoxically initiates a complex cascade of molecular and cellular events that may aggravate myocardial injury. Oxidative stress is considered one of the central mechanisms underlying MIRI, primarily through excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to mitochondrial dysfunction, calcium overload, endothelial injury, inflammatory activation, and cardiomyocyte death. This review summarizes the current understanding of the pathophysiological mechanisms involved in oxidative stress-mediated reperfusion injury, with emphasis on mitochondrial permeability transition pore opening, inflammasome activation, cytokine release, neutrophil extracellular trap formation, macrophage polarization, and interconnected cell death pathways including PANoptosis. Emerging evidence regarding immunometabolic regulation and epigenetic modulation in MIRI is also discussed. In addition, current pharmacological and non-pharmacological cardioprotective strategies targeting oxidative stress, mitochondrial dysfunction, and inflammatory signaling are reviewed, highlighting both promising experimental findings and the persistent challenges in clinical translation. A deeper understanding of the molecular interplay between oxidative stress and inflammatory pathways may facilitate the development of integrated therapeutic approaches aimed at improving myocardial recovery and long-term cardiovascular outcomes following reperfusion therapy.

Thrombospondin-2 (TSP-2) is an extracellular matrix glycoprotein involved in angiogenesis, vascular remodeling, cell adhesion, and tissue repair. Its expression is induced by pathological stimuli, including mechanotransduction, hypoxia, and TGF-β signaling, and has been associated with several cardiovascular diseases (CVDs), such as heart failure, coronary artery disease, abdominal aortic aneurysm, and hypertension. Elevated circulating TSP-2 levels, particularly in combination with NT-proBNP, as well as alterations in THBS2 and its regulatory non-coding RNAs, have been linked to disease severity and adverse cardiovascular outcomes. This review summarizes current evidence on the role of TSP-2 in cardiovascular pathophysiology and its involvement in cardiovascular homeostasis. Although accumulating data suggest that TSP-2 may have diagnostic, prognostic, and therapeutic relevance, its clinical utility as a biomarker or therapeutic target has not yet been established. Further large-scale studies and standardized assessment methods are required to validate its potential and support future clinical translation.

Coronary artery vasospasm (CAV) is a transient, reversible constriction of the epicardial coronary arteries that reduces coronary blood flow and may cause myocardial ischemia. Despite its clinical significance, CAV remains underdiagnosed and can present as chest pain, acute coronary syndrome, malignant arrhythmias or sudden cardiac death. Vasospasm may occur in both angiographically normal coronary arteries and at sites of pre-existing atherosclerotic stenosis. The pathophysiology of CAV is multifactorial and involves vascular smooth muscle cells (VSMCs) hyperreactivity, endothelial dysfunction, chronic inflammation and autonomic dysregulation. VSMCs contraction is mediated by phosphorylation of the myosin light chain (MLC) through calcium (Ca²⁺)/calmodulin-dependent myosin light chain kinase (MLCK), while relaxation is regulated by myosin light chain phosphatase (MLCP). Increased intracellular Ca²⁺ levels and enhanced Ca²⁺ sensitivity contribute to excessive vasoconstriction. Rho-kinase (ROCK) plays a pivotal role in sustained vasospasm by inhibiting MLCP, thereby promoting prolonged smooth muscle contraction. Endothelial dysfunction contributes to CAV by disrupting normal vascular tone regulation, largely as a result of decreased nitric oxide (NO) mediated vasodilation. Chronic low-grade inflammation and oxidative stress exacerbate both endothelial dysfunction and VSMCs contraction. Understanding these molecular mechanisms is essential for identifying novel therapeutic targets. Emerging treatment strategies, including ROCK inhibitors, endothelin receptor antagonists and anti-inflammatory agents, may improve outcomes in patients with refractory CAV.

Pulmonary vascular involvement represents one of the most severe manifestations of Behçet's disease. Pulmonary artery aneurysm (PAA) and pulmonary artery thrombosis (PAT) are rare but potentially life-threatening complications. However, data regarding their frequency, coexistence, and clinical course remain limited, particularly from a pulmonology-based long-term follow-up perspective.

To evaluate the frequency and clinical characteristics of PAA and PAT in a large single-center Behçet's disease cohort and to describe diagnostic and therapeutic challenges encountered during routine clinical practice.

Retrospective single-center observational cohort study.

Adult patients diagnosed with Behçet's disease and followed at a tertiary pulmonology center between January 2014 and January 2024 were retrospectively reviewed. Pulmonary vascular involvement was assessed using contrast-enhanced thoracic computed tomography and CT pulmonary angiography. The presence of deep vein thrombosis (DVT), treatment approaches, and clinical outcomes were recorded.

Among 279 patients, pulmonary vascular involvement was identified in 9 patients. Pulmonary artery aneurysm was detected in three patients (1.07%), and pulmonary artery thrombosis in six patients (2.1%). Concomitant DVT was observed in a minority of patients with pulmonary vascular involvement. Clinical follow-up revealed heterogeneous disease courses, including aneurysm development during anticoagulant therapy, hemoptysis-related treatment discontinuation, persistent pulmonary thrombosis, and rare interventional complications such as late coil migration. Mortality occurred in patients with severe pulmonary vascular disease.

Pulmonary vascular complications in Behçet's disease are rare but associated with significant morbidity and mortality. The coexistence of inflammatory and thrombotic processes creates substantial diagnostic and therapeutic challenges, particularly regarding anticoagulation strategies. Although the limited number of cases precludes definitive conclusions regarding pathogenetic mechanisms, our findings highlight the need for careful, individualized, and multidisciplinary management of pulmonary vascular involvement in Behçet's disease.

Background and PurposeCurrent AHA and ACC guidelines warrant studies comparing direct oral anticoagulant (DOAC) and warfarin for post-myocardial infarction (MI) left ventricular thrombus (LVT). DOAC is increasingly considered due to its minimal monitoring requirement. However, DOAC efficacy in LVT resolution remains uncertain. We aim to evaluate the efficacy and safety of DOAC versus warfarin in post-MI LVT.MethodsWe searched Medline/PubMed, Scopus, Web of Science, and Cochrane. Library databases from inception up to August 2025. The primary outcome was LVT resolution. Secondary outcomes included all-cause death, stroke, and major bleeding rates.ResultsFour RCTs encompassing 396 patients (240 DOAC, 156 warfarin) were included. LVT resolution occurred in 90.0% of DOAC patients versus 86.5% in warfarin patients, with no significant difference (RR 0.99, 95% CI 0.94-1.06, p=0.84). Subgroup analysis revealed comparable outcomes for both rivaroxaban and apixaban versus warfarin. Stroke rates were higher in DOAC compared to warfarin but not statically significant between groups (2.5% vs 1.2%, RR 1.37, 95% CI 0.15-12.95). Similarly, all-cause mortality (3.3% vs 1.9%) and major bleeding (1.6% vs 1.9%) showed no significant differences.ConclusionDOACs demonstrate comparable efficacy and safety to warfarin for post-MI LVT management, with similar rates of thrombus resolution and complications. However, TSA indicates that current evidence is underpowered, and further large-scale randomized trials are required to confirm these findings.

Myocardial ischemia-reperfusion injury (MIRI) is a severe and largely unavoidable complication of reperfusion therapy and remains a major determinant of poor outcomes after acute myocardial infarction. Here, we developed a mitochondria-targeted, ischemic microenvironment-responsive nanotherapeutic, termed Berberine/Isoliensinine-loaded Melanin Nanocomposite (BIM), by co-encapsulating the anti-inflammatory agent berberine (BBR) and the anti-apoptotic agent isoliensinine (ILS) within a melanin capsule with a controllable channel (MCC). Owing to its appropriate size, negative surface charge, and dual responsiveness to acidic pH and reactive oxygen species, BIM preferentially accumulates in injured myocardium and targets damaged mitochondria, enabling precise drug release at the pathological core. Through a structured pharmacological design, MCC scavenges mitochondrial reactive oxygen species, BBR suppresses inflammatory signaling, and ILS inhibits intrinsic apoptosis, together achieving vertical modulation of mitochondrial pathological networks. Consequently, BIM attenuates oxidative stress, limits inflammatory amplification, reduces cardiomyocyte apoptosis, and markedly decreases infarct size. These findings establish mitochondria-centered vertical network modulation as a precise therapeutic strategy for MIRI.