Early diagnosis of cardiovascular diseases requires precise detection of multiple biomarkers, yet simultaneous analysis of these biomarkers without cross-talk remains a major challenge. To overcome this limitation, we developed a novel dual-zone biosensing platform capable of generating independent multimode signals for the parallel detection of cardiac troponin I (cTnI, the gold-standard biomarker) and interleukin-6 (IL-6, a key inflammatory marker). This platform features two spatially resolved zones, Zone I integrates rhodamine B (RhB) with a cadmium sulfide@bismuth tungstate (CdS@Bi₂WO₆) composite, allowing dual-signal detection of cTnI via photoelectrochemical (PEC) and smartphone-based fluorescent (FL) methods. Zone II is functionalized with dsDNA/methylene blue (MB), enabling dual-signal detection of IL-6 through PEC and electrochemical (EC) techniques. The biosensor exhibits excellent analytical performance, including high specificity against interfering species, a broad dynamic range covering clinically relevant concentrations, and high detection sensitivity (cTnI: 1 ∼ 50,000 pg mL^-1 for PEC, 10 ∼ 50,000 pg mL^-1 for FL; IL-6:1 ∼ 20,000 pg mL^-1 for PEC, 1 ∼ 20,000 pg mL^-1 for EC.) with low limits of detection (cTnI: 0.27 pg mL^-1 for PEC, 0.86 pg mL^-1 for FL; IL-6:0.57 pg mL^-1 for PEC, 0.65 pg mL^-1 for EC.). Importantly, it maintains robust functionality in human serum and shows strong correlation with established clinical methods. This work provides a generalizable framework for developing multiplexed biosensors that combine orthogonal detection principles, effectively addressing key challenges in multicomponent bioanalysis, which is a significant advancement in the field of clinical diagnostics.

Proton pump inhibitors (PPIs) may potentially reduce clopidogrel's antiplatelet effect and increase cardiovascular risk. The degree of CYP (cytochrome P450) 2C19 inhibition varies among PPIs. Few studies have evaluated individual PPIs by CYP2C19 inhibition strength across countries. This study aimed to compare the incidence of cardiovascular events between strong CYP2C19-inhibiting potency and weak CYP2C19-inhibiting potency (weak or non-CYP2C19-inhibiting PPIs) in patients receiving clopidogrel.

We conducted an international observational cohort study using 14 databases from the United States, South Korea, and Taiwan. We included patients aged ≥18 years who received clopidogrel with PPIs from 1985 to 2023. PPIs were classified into strong CYP2C19-inhibiting PPIs and weak or non-CYP2C19-inhibiting PPIs based on CYP2C19 inhibition. We compared the hazard ratios and 95% CIs for major adverse cardiovascular events, including myocardial infarction, stroke, and cardiovascular mortality, using the Cox proportional hazards model after 1:1 propensity score matching. Secondary outcomes included cardiovascular mortality, myocardial infarction, stroke, and all-cause mortality. A random-effects model calculated pooled hazard ratios and 95% CIs. Only databases meeting all diagnostic criteria were included in the meta-analysis.

Large-scale propensity score matching identified 166 005 patient pairs. During the 365-day follow-up, the risk of major adverse cardiovascular events did not differ significantly between patients receiving clopidogrel plus strong CYP2C19-inhibiting PPIs and those receiving clopidogrel plus weak or non-CYP2C19-inhibiting PPIs (17.63 per 1000 person-years versus 16.82 per 1000 person-years; calibrated hazard ratio, 1.00 [95% CI, 0.79-1.26]). No significant difference was observed in the risk of secondary outcomes (calibrated hazard ratio, cardiovascular mortality 1.10 [95% CI, 0.87-1.39], myocardial infarction 0.98 [95% CI, 0.81-1.19], stroke 1.05 [95% CI, 0.87-1.27], and all-cause mortality 1.18 [95% CI, 0.93-1.50]).

Concomitant use of clopidogrel and strong CYP2C19-inhibiting PPIs was not associated with a higher cardiovascular risk compared with concomitant use of clopidogrel and weak or non-CYP2C19-inhibiting PPIs. This large-scale study does not support the clinical significance of potential interactions between PPIs and clopidogrel.

Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Disruption of vascular smooth muscle cell (VSMC) homeostasis plays a vital role in triggering TAD. ELA (ELABELA) is a novel endogenous ligand for APJ (angiotensin receptor AT1-related receptor protein). However, the effects of ELA on TAD formation and development remain elusive.

Four-week-old C57BL/6J male mice were treated with β-aminopropionitrile monofumarate or β-aminopropionitrile monofumarate combined with Ang II (angiotensin II) to induce TAD models, and the aortic rupture occurred mainly in the descending thoracic region. ELA or saline was infused via osmotic minipumps into mice for 4 weeks. Transcriptomic studies and VSMC-derived conditioned medium were used to investigate the downstream molecular mechanisms of ELA.

ELA infusion mitigated TAD development and prevented aortic media degradation in mice, which was reversed by APJ antagonist ML221. Exogenous ELA prevented the disruption of VSMC homeostasis under PDGF (platelet-derived growth factor) stimulation in VSMCs. Based on transcriptomic studies, we showed that ELA significantly inhibits NLRP3 (NLR family pyrin domain-containing 3)/IL (interleukin)-1β pathway activation and modulates NET (neutrophil extracellular trap) formation in vivo and in vitro. In human neutrophils, ELA significantly inhibited NETs' formation, which is prevented by reactive oxidative species supplementation. Using VSMC-derived conditioned medium, we showed that NLRP3/IL-1β-related NETs' formation connects cellular signaling from VSMCs to neutrophils, leading to disruption of VSMC homeostasis. Notably, ELA was downregulated in both plasma and aortic tissues of human TAD, and lower plasma ELA levels were associated with an increased risk of TAD.

We provide evidence that ELA prevents TAD progression and aortic medial degeneration, primarily by maintaining VSMC homeostasis, which may be linked to the inhibition of NETosis in neutrophils and NLRP3/IL-1β-related cellular signaling between VSMCs and neutrophils. ELA shows promise as a target for pharmacological therapy and diagnostic TAD management.

In recent years, the global prevalence of overweight and obesity has exhibited a sustained upward trajectory. As an independent entity within the spectrum of chronic diseases, obesity serves as a significant pathogenic factor for multiple chronic conditions and ranks as the sixth leading risk factor for mortality and disability nationwide. It poses a severe threat to public health while imposing a considerable socioeconomic burden. The etiology of obesity is multifactorial; however, primary diagnostic modalities and therapeutic approaches remain relatively undiversified, and long-term weight maintenance remains challenging. Similar to other chronic diseases, obesity management demands a long-term multimodal strategy. This strategy must incorporate individualized treatment goals and balance the benefits and risks of different interventions to formulate personalized management plans. These plans aim to reduce body weight through multifaceted interventions, alleviate obesity-related comorbidities, enhance quality of life, and optimize overall health outcomes.

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. Research indicates that inflammatory responses and oxidative stress mediated by reactive oxygen species (ROS) are hallmark pathological mechanisms of CVD. Traditional anti-inflammatory drugs, though widely used, have limitations such as lack of targeting, low systemic delivery efficiency, and significant side effects. Nanozymes are a class of nanomaterials with enzyme-like activity, and their breakthrough applications offer new directions for the prevention and treatment of CVD. In the treatment of cardiovascular diseases, nanozymes demonstrate unique advantages: they can achieve local targeted delivery and ROS scavenging, and can also regulate the inflammatory microenvironment through multi-mechanism interventions. However, despite their promising applications, nanozymes still face challenges such as optimizing catalytic selectivity, improving biological targeting efficiency, and verifying long-term safety. This article will review the mechanisms of action of nanozymes in inflammation regulation and summarize their applications in cardiovascular diseases.

Hepatic sinusoidal obstruction syndrome (HSOS) induced by pyrrolizidine alkaloids (PAs) is a life-threatening liver injury for which standardized chronic models are lacking. This study aimed to establish a clinically relevant chronic PA-HSOS murine model and to identify potential therapeutic targets.

A 28-day model was developed using key alkaloids from Gynura segetum (seneciphylline, senecionine, and N-oxide derivatives), mirroring human exposure. Disease characteristics were evaluated via hematological profiling, CT imaging, histopathology, and transcriptomics. A hepatocyte-liver sinusoidal endothelial cell (LSEC) co-culture system was used to validate molecular mechanisms. TM5441, a Serpine1 inhibitor, was evaluated for therapeutic efficacy.

The model faithfully recapitulated human HSOS, characterized by elevated liver enzymes (ALT, 1.6-fold, p <0.001; AST, 5.7-fold, p <0.0001, n = 6), coagulation dysfunction (prothrombin time, 1.5-fold, p <0.001; activated partial thromboplastin time, 1.1-fold, p <0.05; D-dimer, 8.4-fold, p <0.0001, n = 6), increased liver weight (1.2-fold, p <0.0001, n = 6), reduced VE-cadherin expression (0.28-fold, p <0.001, n = 6), and sinusoidal fibrosis. RNA sequencing identified Serpine1 as the most significantly upregulated gene (|log₂fold-change| ≥2, p <0.05) associated with p53 signaling. Serum Serpine1 was elevated in patients (5.0-fold, p <0.01, n = 16,) and mice (3.7-fold, p <0.001, n = 6) with PA-HSOS. Co-culture confirmed that Serpine1-driven p53 activation (1.8-fold, p <0.01, n = 3) promoted endothelial senescence. TM5441 reduced Serpine1-p53 activity (0.5-fold, p <0.001, n = 6), improved liver function (ALT and AST reduced 30-40%, p <0.001, n = 6), normalized coagulation, restored LSEC integrity (VE-cadherin, 3.2-fold, p <0.001, n = 6), and attenuated inflammation and fibrosis.

This first chronic PA-HSOS murine model closely mirrors human disease and identifies Serpine1 as a critical therapeutic target. Targeting the Serpine1-p53 axis with TM5441 represents a promising strategy to mitigate endothelial injury in PA-HSOS.

This study establishes a chronic PA-HSOS (pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome) model that more accurately replicates human disease progression, thereby overcoming the limitations of previous acute models for mechanistic and therapeutic research. The researchers identify Serpine1 as a key regulatory target that could lead to new therapies for PA-HSOS by reducing endothelial senescence and inflammation. These findings provide clinicians and researchers with improved tools for studying drug-induced liver injury and a pathway for translating discoveries into clinical trials. The therapeutic compound TM5441 shows promise for reversing liver dysfunction and vascular damage, while the model itself may aid in the development of better diagnostic criteria and prevention strategies.

Not applicable.

Vagus nerve stimulation (VNS) is currently approved for conditions such as drug-resistant epilepsy and stroke with promising results. In addition, it is also being investigated for many other conditions. The goal of this study is to review the scope of VNS clinical trials.

We conducted a retrospective review of active and completed clinical trials using ClinicalTrials.gov, with "Vagus Nerve Stimulation" as the search term. The number of studies taking place over time was assessed using Pearson correlation coefficient.

An examination of ClinicalTrials.gov revealed 440 clinical trials, with 346 meeting our inclusion criteria. The number of VNS clinical trials increased annually from 2000 to 2024, demonstrating exponential growth after 2015 (P < 0.001, R² = 0.924). Of these, 42.5% were completed, with published results being available for 9.8% of the completed trials. Completed trials were predominantly from the United States, spanning various conditions including a wide variety of disorders such as cardiovascular diseases (n = 38), chronic pain disorders (n = 31), gastrointestinal disorders (n = 24), autoimmune disorders (n = 23), neurodegenerative diseases (n = 19), COVID-19 (n = 13) and diabetes (n = 11). Among the included trials, 86% were non-invasive with 91% of trials with results reporting improvements in symptoms.

This increasing number of trials assessing a wide breadth of clinical disorders suggests the promising future of VNS as from the currently approved treatments. Physicians should familiarize themselves with these results and potentially upcoming indications for VNS.

Atherosclerotic cardiovascular and cerebrovascular diseases are still the main cause of global incidence rate and mortality. The LDL-C/HDL-C ratio (LHR) has been identified as a potential biomarker for cardiovascular risk. However, the relationship between it and the long-term risk of carotid plaques is not yet clear, especially in low-income populations in China.

This prospective cohort study included adults aged ≥45 years without carotid plaque at baseline from low-income rural areas of Tianjin, China. Baseline characteristics were collected in 2014, and follow-up data were obtained in 2019. The primary outcome was the development of new carotid plaques, assessed using carotid ultrasound. The relationship between the LDL-C/HDL-C ratio (LHR) and new carotid plaques was analyzed using multifactorial logistic regression, with the presence or absence of new-onset plaques as the dependent variable. Additionally, we utilized restricted cubic spline (RCS) regression to visually present the potential nonlinear relationship between LHR and the risk of carotid plaque.

Over the six-year follow-up period, 606 participants (38.3%) developed new carotid plaques. Higher LHR was significantly associated with an increased risk of new carotid plaques, with each unit increase in LHR corresponding to a 35.9% higher risk (OR = 1.359, 95% CI: 1.180-1.566, p < 0.001). The RCS curve indicated a non-linear positive association between LHR and the likelihood of carotid plaques (p for non-linearity = 0.019), with an optimal cut-off at 1.257. Logistic regression analysis confirmed that LHR > 1.257 was linked to increased odds of carotid plaques in both unadjusted (OR: 1.80, p < 0.001) and adjusted models (OR: 1.835, p < 0.001), with LHR ≤ 1.257 serving as the reference. In subgroup analysis, all subgroups consistently demonstrated a significant association between increased LHR (all OR > 1).

The research results indicate that there is a non-linear positive correlation between LHR and the long-term risk of carotid plaques in middle-aged and elderly populations, suggesting that LHR may be an effective indicator for screening carotid plaques in grassroots middle-aged and elderly populations.

Congenital heart disease (CHD) is the most common birth defect, and its pathogenesis is closely related to the abnormal establishment of the left-right (LR) body axis, which highly depends on the ciliary function of the left-right organizer (LRO). This review systematically expounds the molecular pathways by which ciliary structural and functional abnormalities cause cardiac malformations by integrating multi-species model evidence. We believe that defects in multiple conserved genes (including CFAP45, ZIC3, FOXJ1, NEK3, APLNR, and microRNAs) disrupt ciliary assembly, motility, or signaling capacity, leading to the disappearance of the leftward nodal flow or mechanical sensing failure within the LRO. This further interrupts the left-specific calcium ion flicker and the activation of the Nodal-Pitx2 signaling cascade, ultimately resulting in failed cardiac looping and structural defects (such as ventricular septal defect and transposition of the great arteries). This review integrates transcriptional regulation, protein stability, miRNA-mediated fine regulation, and the planar cell polarity (PCP) pathway into a unified "cilia-LRO-heart" network and explores the molecular mechanisms of cilia in valve diseases and cardiac fibrosis. This not only deepens the understanding of the fundamental biological processes of heart development but also provides new molecular targets and theoretical frameworks for the genetic diagnosis and counseling of related congenital heart diseases.