Vascular dementia (VaD), caused by reduced cerebral blood flow, is a common form of dementia lacking effective treatments. This study used genome-wide association study (GWAS) summary data, Mendelian randomization (MR), and colocalization analyzes to prioritize blood metabolites and candidate therapeutic targets associated with VaD. Key analyzes included metabolic pathway enrichment, a descriptive Phenome-Wide Association Study (PheWAS) of the broader curated association profiles of prioritized genes, mediation analysis, and in-silico compound prioritization with molecular docking. Twenty-four metabolites were associated with VaD, with taurocholate and glutaroyl carnitine prioritized as tier 1 metabolite-gene pairs. Pathway analysis implicated aminoacyl-tRNA and branched-chain amino acid biosynthesis pathways. Apolipoprotein E (APOE) and glutaryl-CoA dehydrogenase (GCDH) were prioritized candidate genes. The PheWAS recapitulated APOE's curated associations with Alzheimer's disease and lipid traits, whereas GCDH had a more restricted curated association profile dominated by glutaric acidemia type I; these patterns provide pleiotropic context but do not establish safety. Single-cell RNA-sequencing analysis localized APOE predominantly to microglia and astrocytes and GCDH predominantly to oligodendrocytes, providing cell-type-specific context. Mediation analysis identified a statistically supported indirect pathway involving alpha-2-macroglobulin receptor-associated protein for taurocholate. Aflatoxin B1 was highly ranked in an in-silico query but, because of its established toxicity, is not a therapeutic candidate. This study prioritizes metabolic and genetic candidates for experimental and clinical follow-up rather than establishing therapeutic targets.

Point-of-care compatible therapeutic drug monitoring requires platforms to rapidly quantify low-abundance small-molecule drugs in complex biofluids while resolving spectral interference from coexisting compounds. Surface-enhanced Raman spectroscopy offers molecular fingerprint specificity, yet its quantitative reliability is often compromised by heterogeneous hotspots, matrix interference, and overlapping drug spectra. Here, we develop an integrated microfluidic SERS platform based on charge-directed 3D Au@Ag plasmonic assemblies and machine learning-assisted spectral decoding. Oppositely charged gold nanopolytopes and silver nanospheres spontaneously assemble into ordered 3D structures with dense interparticle nanogaps. Optimized 1:1 Au@Ag assembly delivers enhanced electromagnetic coupling and stable, reproducible SERS signals. Combined with deuterated methanol as a ratiometric internal standard in microfluidic chips, this system achieves low-volume, fluctuation-corrected standardized drug analysis. Six therapeutic molecules are identified via SERS fingerprints, and binary or ternary mixtures are accurately decoded by 3D-LDA and CNN-RF with AUC > 0.98. Reliable discrimination in rat plasma, artificial sweat, and urine demonstrates excellent matrix tolerance. This work establishes a material microfluidic algorithm-integrated SERS strategy for rapid therapeutic drug analysis, paving the way toward portable intelligent drug monitoring systems.

This study evaluated the in vivo effects of hirudotherapy (medicinal leech therapy) on microcirculation and inflammation following global ischemia‑induced cerebral ischemia/reperfusion (I/R) in rats. Rats were divided into three groups of eight (control, I/R, and hirudotherapy) for this study. Global ischemia was created in the I/R and treatment groups by occluding both common carotid arteries. According to the I/R procedure, two Hirudo verbana leeches were applied bilaterally to the mastoid regions. Serum and tissue samples were analyzed for biochemical parameters including superoxide dismutase (SOD), interleukin 6 (IL‑6), nitric oxide (NO), calcitonin gene‑related peptide (CGRP), glutathione peroxidase (GPx), catalase (CAT), endothelin‑1, tumor necrosis factor alpha (TNF‑α), ischemia modified albumin (IMA), and hypoxia‑inducible factor‑1 alpha (HIF‑1α). Histopathological methods were used to examine edema, degeneration, necrosis, and hemorrhagic changes in brain tissue samples. The I/R group showed significantly increased tissue TNF‑α levels compared to controls. Tissue IMA and HIF‑1α levels were significantly higher in the treatment group. Treatment significantly reduced degeneration, necrosis, edema, and hemorrhage in brain tissues, as shown by histopathology. Histopathological analysis shows significantly less tissue damage in the hirudotherapy group compared to the I/R group, suggesting that hirudotherapy reduces brain damage after cerebral ischemia and reperfusion.

The aim of the present study was to elucidate the cellular and molecular mechanisms underlying refractory recurrent in-stent restenosis (RISR), thereby facilitating the identification of potential therapeutic targets. Coronary blood samples were obtained from culprit lesions of patients with RISR and non-ISR controls and subjected to single-cell RNA sequencing to comprehensively characterize immune cell heterogeneity and identify pathogenic signaling pathways. Key molecular mechanisms were validated in independent clinical samples using flow cytometry, monocyte-vascular smooth muscle cell (VSMC) coculture systems, and in vitro functional assays. Causality was further assessed using a monocyte-specific Fos knockdown mouse model of carotid wire injury to evaluate its role in vascular remodeling. Results revealed a pronounced inflammatory immune signature in RISR, with marked upregulation of activator protein-1 (AP-1) gene expression and transcriptional activity in monocytes as a central feature. Upstream mechanistic analyses identified the CCL5-CCR1/p38 MAPK axis as a key driver of AP-1 activation, promoting proinflammatory cytokine release and inducing a proliferative phenotypic switch in VSMCs. In vivo, monocyte-specific Fos knockdown significantly attenuated neointimal hyperplasia and luminal stenosis following vascular injury. Targeting monocyte AP-1 signaling may represent a novel therapeutic strategy for refractory restenosis driven by localized coronary inflammation.

Atrial fibrillation (AF) is a prevalent arrhythmia in endurance athletes, and many athletes report exercise as a trigger for AF episodes. We aimed to investigate the association between exercise sessions and arrhythmia episodes in endurance athletes with paroxysmal AF.

In endurance athletes diagnosed with paroxysmal AF, we continuously monitored arrhythmia episodes using insertable cardiac monitors and report event rates per 24 hours and temporal relation of arrhythmias with exercise sessions. Sports watches and chest straps were used for exercise monitoring. Exercise with a heart rate of 76% to 84% and ≥ 85% of the individual maximum heart rate was classified as high and very high intensity, respectively.

Forty-seven athletes (age 57±10, range 33-75 years, 3 women) were monitored with insertable cardiac monitors for a total of 55 994 hours (median 1008 [840-1344] equaling 42 days [35-56]) and performed a total of 1722 hours of exercise, of which 592 hours at high or very high intensity. Thirty-one athletes (66%) had a total of 1445 (median 17 [3-33]) AF episodes during monitoring. Thirteen athletes (27%) had AF during exercise of whom 2 had AF during high-intensity sessions. The event rate of AF was not higher during (0.34 per 24 hours [95% CI, 0.13-0.65]) or subsequently following an exercise session (0.37 [95% CI, 0.10-0.71]), compared with unrelated to exercise (>3 hours after, 0.61 [95% CI, 0.26-1.13]). There were no episodes of exercise-related ventricular tachycardia.

In this study on endurance athletes with paroxysmal AF, the rate of AF episodes was not increased during or subsequently following exercise sessions.

URL: Study Details: NCT04991337. Effects of Detraining in Endurance Athletes With Atrial Fibrillation. ClinicalTrials.gov (NEXAF Detraining).

Although carotid atherosclerosis is a recognized risk factor, the relationship between plaque characteristics and clinical outcomes after cardiac surgery remains unclear.

We retrospectively studied 1087 patients undergoing coronary artery bypass graft-containing cardiac surgery between January 2023 and January 2024. Preoperative carotid ultrasound was used to assign Carotid Plaque-Reporting and Data System (Plaque-RADS) grades 1 to 4. The primary outcome was in-hospital ischemic stroke. Given the low number of events, associations were evaluated using Firth penalized logistic regression with limited covariate adjustment.

In-hospital ischemic stroke occurred in 14 patients (1.3%). Stroke incidence increased across Plaque-RADS grades from 0% in grade 1 to 0.6%, 2.0%, and 6.3% in grades 2, 3, and 4, respectively (P=0.011). Higher Plaque-RADS grade was associated with greater odds of in-hospital ischemic stroke after adjustment for age, sex, surgical procedure, operative time, and aortic atherosclerotic burden (odds ratio per 1-grade increase, 4.31 [95% CI, 1.72-11.43]; P=0.002). The association was directionally similar among patients with carotid stenosis <50%. In exploratory discrimination analyses, the model including both stenosis and Plaque-RADS had the highest numerical area under the receiver operating characteristic curve, although the incremental gain over either individual parameter was modest.

Higher ultrasound-based Plaque-RADS grade was associated with in-hospital ischemic stroke after coronary artery bypass graft-containing cardiac surgery. Plaque-RADS may provide complementary risk information. These findings should be considered hypothesis generating and require validation in larger prospective cohorts.

Diabetic wounds are persistently exposed to pathological microenvironments, such as hyperglycemia and excessive ROS accumulation, which result in insufficient angiogenesis and restricted cell migration, representing a prominent challenge in clinical wound repair. Traditional wound dressings primarily focus on passive coverage and exudate absorption, making it difficult to actively regulate the microenvironment of diabetic wounds. Therefore, in this study, platinum nanozyme (PtNP)-loaded methacrylated gelatin (GelMA) microneedles (Pt-GelMA microneedles) were constructed, aiming to synergistically accelerate diabetic wound healing by leveraging the local penetration and delivery capacity of microneedles and the hydrogen peroxide decomposition capacity of PtNPs. In vitro assays demonstrated that the Pt-GelMA microneedles have favorable cytocompatibility and can alleviate oxidative stress, promote the migration of wound repair related cells and enhance the tube formation of endothelial cells. Furthermore, in a streptozotocin-induced diabetic full-thickness skin wound model, the Pt-GelMA microneedles significantly accelerated wound closure, and promoted collagen deposition and angiogenesis, without inducing evident hepatorenal toxicity. This study provides new insights into the treatment of diabetic wounds.

Cardiac rupture is a catastrophic complication of acute myocardial infarction (AMI), with poorly understood molecular mechanisms and no available therapeutic interventions.

Plasma samples were obtained from patients with AMI and animal models, while left ventricular tissue was collected from AMI mice. An unbiased proteomics analysis identified proteins significantly altered in patients with AMI with cardiac rupture. To explore causal relationships and underlying mechanisms, we used loss- and gain-of-function animal models.

Proteomics analysis revealed that 9 proteins were significantly upregulated and 24 proteins were significantly downregulated in patients with AMI with cardiac rupture compared with those without. Among these, SMOC-1 (secreted modular calcium-binding protein 1) was the most significantly upregulated protein. Validation in extended patient cohorts and animal models confirmed these findings. A time-course study revealed that SMOC-1 expression was transiently elevated, peaking 1 day after AMI and returning to baseline within a week. Immunological and cell-specific analyses identified cardiomyocytes as the predominant source of SMOC-1 in response to AMI. Surprisingly, cardiomyocyte-specific SMOC-1 knockout doubled the incidence of post-AMI cardiac rupture and reduced survival, while adeno-associated virus serotype 9-mediated SMOC-1 overexpression significantly decreased cardiac rupture rates. Mechanistic studies revealed that cardiomyocyte-derived SMOC-1 supports fibrosis by activating fibroblasts, enhancing collagen synthesis, and promoting collagen maturation, all of which are critical for the formation of reparative scars. SMOC-1 was shown to bind TGF-βR1 (transforming growth factor β receptor 1) in fibroblasts, recruiting EPRS (glutamyl-prolyl-tRNA synthetase) to form a signaling complex that activates the Smad pathway. Inhibiting EPRS abolished the profibrotic effects of SMOC-1.

Our study provides the first evidence that the transient upregulation and secretion of cardiomyocyte-derived SMOC-1 constitute an intrinsic profibrotic and antirupture response to severe ischemic injury. However, this natural protective mechanism is insufficient to fully prevent cardiac rupture, highlighting the potential of enhancing the SMOC-1 pathway as a promising therapeutic strategy to mitigate cardiac rupture and reduce AMI-associated mortality.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce cardiovascular disease (CVD) in type 2 diabetes (T2D) and have anti-inflammatory effects in experimental studies, but their mechanism of action in humans remains unclear. This study characterized the cardiovascular-haematopoietic axis in individuals with T2D receiving semaglutide, as a potential mediator of GLP-1RA cardioprotective properties.

In 16 individuals with T2D [63.2 ± 6.1 years, 37.5% female, weight 82.3 ± 15.3 kg, body mass index (BMI) 28.33 ± 3.5 kg/m2, LDL cholesterol 2.2 ± 0.9 mmol/L, glycated haemoglobin (HbA1c) 78.1 ± 13.1 mmol/mol, high-sensitivity C-reactive protein (hsCRP) 1.9 (1.2, 5.8) mg/L], blood and sternal bone marrow aspirates (subset, n = 14) were collected at baseline and after 6 months of semaglutide ≤2.0 mg weekly. Circulating monocytes and haematopoietic precursors were quantified by flow cytometry, plasma cytokines using an nELISA™ assay (Nomic Bio) and inflammatory macrophages in coronary arteries, bone marrow, and spleen by gallium-68-labelled DOTA-(Tyr3)-octreotate (68Ga-DOTATATE) positron emission tomography-computed tomography scans.

After 6 months of semaglutide, significant reductions in HbA1c (-21.1 mmol/mol, P < .0001), weight (-6.7 kg, P < .001), BMI (-2.5 kg/m2, P < .001), and hsCRP (-1.0 mg/L, P = .005) were observed. Circulating CD16+ monocytes were markedly lower (-18.8%, P = .034), with increased bone marrow retention correlating with weight loss, alongside reductions in interleukin-1 receptor antagonist, leptin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), C-C motif chemokine ligand 2, C-C motif chemokine ligand 11, and C-X-C motif chemokine ligand 13. Gallium-68-labelled DOTA-(Tyr3)-octreotate PET-CT showed lower bone marrow uptake (-17.5%, P = .037), but not in spleen or coronary arteries.

Semaglutide in T2D potentially reduces circulating inflammatory monocytes, increases bone marrow retention, and lowers markers of endothelial inflammation, with no reduction in coronary artery inflammatory macrophages. Semaglutide is associated with lower bone marrow 68Ga-DOTATATE uptake, which may relate to anti-inflammatory effects relevant to CVD risk.

The haemodynamic effects of vena cava occlusion are related to the patient's preserved cardiac function. Investigating the haemodynamic effects is critical for the clinical translation of vena cava occlusion devices.

A mock circulatory loop (MCL) system was developed for the in vitro haemodynamic simulation of the systemic venous system. Haemodynamic effects of vena cava occlusion were assessed under different heart failure states, different occlusion ratios and distinct occlusion sites.

Superior vena cava (SVC) occlusion significantly reduced both central venous pressure (CVP) and renal venous pressure (RVnP) while causing only a limited decrease in cardiac output (CO), however, jugular venous pressure (JVP) increased significantly. Inferior vena cava (IVC) occlusion below the right atrium caused negative CVP, a significant reduction in CO and increased RVnP. In contrast, IVC occlusion below the renal veins preserved CO while reducing RVnP and improving renal perfusion. Moreover, effective pressure gradients were observed at occlusion ratios of 82.3%-87.1% for SVC occlusion and IVC occlusion below the right atrium, compared with 94.5%-96.1% for IVC occlusion below the renal veins.

SVC occlusion and IVC occlusion below the renal veins reduce cardiac preload and increase renal venous (RVn) flow, without significantly reducing CO. However, compared with SVC occlusion, IVC occlusion below the renal veins requires a higher occlusion ratio and provides limited ventricular unloading. IVC occlusion below the right atrium is not recommended, as this would lead to a significant reduction in CO and have adverse effects on the circulatory system.