ObjectiveCarotid artery stenosis (CAS) is a significant contributor to cerebral ischemic events (CIEs). This study investigated the expression pattern and clinical significance of lncRNA NEXN-AS1 in CAS and CIEs.Methods132 patients with CAS and 98 controls were enrolled. RT-qPCR was employed to quantify serum levels of NEXN-AS1 and miR-92a-1-5p. The diagnostic utility of NEXN-AS1 for CAS was assessed using ROC curves. Logistic regression pinpointed potential risk factors for severe CAS. Patients were followed for 2 years, and Kaplan-Meier and Cox methods evaluated the prognostic role of NEXN-AS1 and risk factors for CIEs in CAS cases. RIP and DLR assays were conducted to confirm the association between NEXN-AS1 and miR-92a-1-5p.ResultsSerum NEXN-AS1 was less expressed in CAS patients than in controls, which could effectively distinguish between the two groups with high sensitivity and specificity. CAS patients with severe stenosis had lower serum NEXN-AS1 levels than those with moderate stenosis. Patients with low NEXN-AS1 expression were more prone to developing CIEs compared to those with high expression (log-rank P = .0051). Cox regression analysis identified NEXN-AS1 as an independent risk factor for the development of CIEs. Molecularly, the target of NEXN-AS1 is miR-92a-1-5p.ConclusionPatients with low NEXN-AS1 expression could serve as diagnostic indicators for CAS and may predict the occurrence of CIEs. This study may offer new insights into the management of CAS and CIEs.

Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. Ferroptosis, an iron-dependent form of regulated cell death, plays a crucial role in AMI progression. However, the molecular mechanisms regulating ferroptosis in AMI remain poorly understood. This study aims to investigate the role and potential regulatory mechanism of TAF15 in AMI.

Bioinformatics analysis of gene expression datasets was conducted to identify differentially expressed genes in AMI samples. TAF15 expression was evaluated in clinical AMI patient blood samples, ischemia/reperfusion (I/R)-treated HL-1 cardiomyocytes, and myocardial tissues from the AMI mouse model using qRT-PCR and Western blot analyses. Gain- and loss-of-function experiments were performed to assess the effects of TAF15 and PRMT1 on myocardial injury, oxidative stress, and ferroptosis markers (Fe²⁺, MDA, GSH, GPX4, ROS) using electrocardiography, histopathology, CCK-8, EdU, TUNEL, ELISA, flow cytometry, qRT-PCR, and Western blot assays. Mechanistic studies, including luciferase reporter assays, chromatin immunoprecipitation (ChIP-qPCR), and bisulfite sequencing, were conducted to examine PRMT1-mediated TAF15 methylation and its regulatory effects.

TAF15 was significantly downregulated in AMI, as observed in patient samples and experimental models. Functionally, TAF15 overexpression significantly improved myocardial function by inhibiting ferroptosis. Notably, TAF15 overexpression restored GPX4 and NRF2 expression, reduced Fe²⁺ accumulation and lipid peroxidation (MDA levels), and increased GSH levels in both HL-1 cardiomyocytes and AMI mouse model. Mechanistic investigations revealed that TAF15 interacted with NRF2, enhancing TAF15 transcription and subsequently activating the GPX4/NRF2 axis, which protects against ferroptosis-induced cardiomyocyte death. Additionally, PRMT1 negatively regulated TAF15 via hypermethylation. PRMT1 knockdown significantly upregulated TAF15 expression, leading to reduced ferroptosis and improved cardiac function.

This study establishes TAF15 as a novel regulator of ferroptosis in AMI, activating the GPX4/NRF2 pathway to mitigate oxidative stress and myocardial injury. Furthermore, PRMT1-mediated TAF15 hypermethylation promotes ferroptosis, thereby exacerbating myocardial damage. These findings suggest that targeting the PRMT1/TAF15/GPX4-NRF2 axis represents a promising therapeutic strategy for AMI treatment by inhibiting ferroptotic cell death and improving cardiac function.

The restoration of cardiac function post-myocardial infarction (MI) remains a significant clinical challenge. Emerging evidence indicates that Goji berries ("Gouqi" in Chinese) and their extracts exhibit substantial cardioprotective properties. Here, we introduce fibrin gel-loaded Gouqi-derived nanovesicles (GqDNVs-gel) as a delivery system targeted at the infarcted myocardium. The application of GqDNVs-gel resulted in a marked improvement in survival rates over a 14-day period post-MI, enhanced cardiac function, reduced infarct size, myocardial apoptosis, and excessive fibrosis, and facilitated endogenous repair. Through a combination of transcriptomics and proteomics analyses, alongside in vitro and in vivo experiments, we identified that the cardioprotective effect of GqDNVs are mediated through the inhibition of the p38 MAPK-NF-κB p65 signaling pathway. Furthermore, GqDNVs contain abundant bioactive compounds, including proteins, genetic materials, lipids, polysaccharides, and flavonoids. GqDNVs-gel intervention can reshape the post-MI cardiac environment and modulate myocardial lipid metabolism, specifically impacting glycerophospholipid and α-linolenic acid metabolic pathways. The upregulation of the peptide Arg-Thr-Ile-Glu and the downregulation of phosphatidylethanolamine in the hearts of MI mice after GqDNVs-gel intervention may play crucial roles in modulating the associated metabolic pathways. This study is the first to highlight the multifaceted therapeutic effects of GqDNVs-gel, offering a promising strategy for enhancing cardiac function post-MI.

Alterations in kidney-associated adipose tissue depots, specifically renal sinus (RSAT) and perirenal adipose tissue (PRAT), may contribute to metabolic, cardiovascular, and chronic kidney diseases. We compared transcriptomic profiles and phenotypes, including adipocyte size, glucose uptake, and insulin action in RSAT and PRAT from healthy individuals.

Subcutaneous (SAT), omental (OAT) and renal adipose tissue biopsies were collected from healthy kidney donors (20 women, 20 men; BMI 20 to 36 kg/m²). Adipocyte size and basal and insulin-stimulated glucose uptake rate were measured in isolated adipocytes. Transcriptomic profiling and immune cell composition estimates (RNA seq, n = 30), were performed to evaluate differences between PRAT and RSAT, with OAT as a benchmark.

PRAT exhibited significantly larger adipocytes and higher insulin-stimulated glucose uptake than RSAT. Of 1113 significantly differentially expressed genes (DEGs) (PRAT: 571 down- and 542 upregulated), thermogenic and metabolic genes (UCP1, CIDEA, and CKMT1B) were enriched in PRAT, while inflammation-related genes (NFKBIA, BIRC3, and IRF1) in RSAT. Pathway analysis indicated activation of metabolic pathways (TCA cycle and oxidative phosphorylation), in PRAT, which contrasts with the immune and inflammatory pathways in RSAT and OAT. Immune cell gene signatures revealed an anti-inflammatory environment in PRAT (eosinophils and activated NK cells), and a pro-inflammatory profile in RSAT (M0 macrophages). Immunohistochemistry confirmed higher CD68- and IL1B-positive cells in RSAT than in PRAT. When overweight individuals were compared to lean, genes related to the VEGF signaling were upregulated in PRAT and Ras signaling in RSAT. Additionally, metabolic pathways linked to the TCA cycle as well as carbon and fatty acid metabolism were downregulated.

The different kidney-associated adipose tissue depots exhibit distinct gene expression and functional profiles. PRAT displays higher expression of thermogenic markers and less inflammatory profile compared to RSAT and also OAT. In contrast, RSAT exhibits an inflammatory and macrophage-enriched profile, more closely resembling OAT. This study highlights the heterogeneity of the kidney-associated adipose tissue depots and could suggest that an excessive amount of RSAT may impact development of metabolic, cardiovascular, and chronic kidney diseases.

The underlying pathological mechanism of ischemic stroke is complex, with oxidative stress and inflammation being two key factors that are intertwined and mutually influential. They also serve as important potential targets for the intervention of cerebral ischemia. Pyrroloquinoline quinone (PQQ) is known for its neuroprotective properties and the ability to modulate immune system function. Previous studies have demonstrated that PQQ mitigates brain infarction in rodent models of cerebral ischemia; however, the neuroprotective mechanisms underlying PQQ's effects against ischemic brain injury are not yet fully understood. This study used an MCAO rat model, an OGD model with SH-SY5Y cells, and an LPS-activated BV2 microglia model to investigate the neuroprotective functions of PQQ on brain ischemia. Using various experimental methods, including cell viability assays, oxidative stress damage assessments, inflammatory factor expression analysis, behavioral tests in animal models, and histological evaluations, we discovered that PQQ activates the nuclear translocation of Nrf2 in neurons, thereby enhancing downstream antioxidant responses. Additionally, PQQ inhibits NF-kB activation in microglia and suppresses their M1-type polarization, leading to decreased pro-inflammatory mediators' expression levels and reduced neural inflammatory damage. These results provide further insights into the neuroprotective mechanisms involved in PQQ's effects against cerebral ischemia and may offer evidence for its translational application in treating brain ischemia.

Hypertrophic cardiomyopathy (HCM) is frequently underdiagnosed. Although deep learning (DL) models using raw electrocardiographic (ECG) voltage data can enhance detection, their use at the point of care is limited. Here we report the development and validation of a DL model that detects HCM from images of 12-lead ECGs across layouts. The model was developed using 124,553 ECGs from 66,987 individuals at the Yale New Haven Hospital (YNHH), with HCM features determined by concurrent imaging (cardiac magnetic resonance (CMR) or echocardiography). External validation included ECG images from MIMIC-IV, the Amsterdam University Medical Center (AUMC) and the UK Biobank (UKB), where HCM was defined by CMR (YNHH, MIMIC-IV and AUMC) and diagnosis codes (UKB). The model demonstrated robust performance across image formats and sites (areas under the receiver operating characteristic curve (AUROCs): 0.95 internal testing; 0.94 MIMIC-IV; 0.92 AUMC; 0.91 UKB). Discriminative features localized to anterior/lateral leads (V4 and V5) regardless of layout. This approach enables scalable, image-based screening for HCM across clinical settings.

Marfan syndrome is a connective tissue disorder caused by FBN1 mutations, leading to aortic wall fragility and increased susceptibility to aneurysm and dissection. This study investigated microstructural and molecular alterations in the thoracic aorta of Fbn1mgΔ^lpn mice, with a focus on the tunica intima and media. Histological and ultrastructural analyses demonstrated elastic fiber fragmentation and reduced fibrillin-1 expression. In the intima, endothelial cells showed partial detachment and decreased levels of fibrillin-1, perlecan, collagen IV, and α5β1 integrins, suggesting compromised adhesion to the extracellular matrix. Serial block-face scanning electron microscopy revealed discontinuities in the internal elastic lamina. In the media, we observed reduced fibronectin, altered α5β1 integrin distribution, and increased α-smooth muscle actin, indicative of remodeling in elastin-contractile units. Second harmonic generation imaging revealed increased collagen deposition, and thickness in areas of elastic fiber disruption, along with reduced and disorganized type III collagen and increased type I collagen. Echocardiographic evaluation showed aortic root, and ascendant-aorta dilatation, altered blood flow, and diastolic dysfunction. Elastic fiber integrity correlated strongly with fibrillin-1 expression (r = 0.93, p = 0.0003) and aortic blood flow (r = 0.77, p = 0.0064). These results suggest that early alterations in matrix organization and endothelial-matrix interactions may contribute to aortic wall weakening in Fbn1mgΔ^lpn mice.

Myocardial infarction (MI) remains one of the leading causes of mortality worldwide, and cardiomyocyte death plays a critical role in cardiac remodeling after MI. Ferroptosis is a recently identified form of iron-dependent programmed cell death that has been shown to be involved in the progression of various cardiovascular diseases, including MI. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and a key regulator of cell survival. In this study, we screened an epigenetic target library containing 773 small-molecule compounds and found that (+)-JQ-1(hereafter abbreviated as JQ-1), a BRD4-specific inhibitor, markedly attenuated ferroptosis induced by erastin (a ferroptosis inducer) in cardiomyocytes. Both prophylactic and therapeutic JQ-1 administration significantly improved cardiac remodeling and reduced cardiomyocyte ferroptosis in mice with MI. Mechanistically, JQ-1 protected cardiomyocytes from erastin-induced ferroptosis by downregulating the expression of nicotinate phosphoribosyltransferase (NAPRT) and upregulating the expression of nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin1 (SIRT1). Inhibition of NAMPT or SIRT1 abrogated the protection conferred by JQ-1 in erastin-treated H9C2 cardiomyocytes. The combination of proteolysis-targeting chimeras (PROTACs) with JQ-1 (JQ-1-PROTAC) promoted BRD4 protein degradation and rescued erastin-induced ferroptosis in H9C2 cardiomyocytes, and prevented erastin-induced ferroptosis in human cardiomyocytes. Thus, JQ-1 can protect cardiomyocytes from ferroptosis through the NAMPT-SIRT1 pathway, and JQ-1-based therapy may serve as a novel promising strategy to improve cardiac remodeling after MI.

Stand-alone high-intensity focused ultrasound (HIFU) therapy is a promising non-invasive approach for treating thrombo-occlusive disease. The objective of this study was to investigate the ability of this approach to achieve safe thrombolysis in clinical treatment.

Two types of thrombo-occlusive models, utilizing plastic tubes (model-Ⅰ) and the abdominal aorta of rabbits (model-Ⅱ), were exposed to 1.1-MHz HIFU with a pulse repetition frequency (PRF) of 1-100 Hz and transducer power (P_elect) up to 180 W. A duty cycle of 0.6% was set to maintain tissue temperature below 43℃.

The experimental results from model-I demonstrated that extensive thrombolysis was seen at P_elect ≥ 120 W and PRF ≤ 10 Hz. In the experiments using model-Ⅱ (P_elect = 120-180 W, PRF = 1 Hz) a degree of thrombolysis of over 70% was found with treatment times between 12 and 33 minutes. Under these conditions the arteries appeared to have suffered only minor damage, with slight laceration of the intima/inner media and separation of medial lamellae. The mean damage score did not exceed the threshold for vascular rupture at any power level, with no significant differences observed (n = 3, p > 0.05), but slightly lower values were noted at lower power levels. The maximum diameter of the clot debris was < 8 μm, therefore comparable to that of a typical capillary, minimizing the danger of distal embolization.

The results confirm the potential of stand-alone HIFU as an effective treatment of thrombo-occlusive disease without causing significant vascular damage.

As a core risk factor for cardiovascular diseases, hypertension continues to be associated with a high global risk of major adverse cardiovascular events and mortality. Body roundness index (BRI), an emerging body morphology indicators reflecting central obesity and visceral fat accumulation through the ratio of waist circumference to height, is closely linked to cardiovascular risks such as hypertension. However, its value in assessing all-cause and cardiovascular mortality risks in hypertensive populations remains unclear. This study aimed to investigate the nonlinear association between BRI and all-cause mortality risk in hypertensive patients, evaluate its independent impact on cardiovascular mortality risk, and validate the robustness of results through subgroup analyses.

Using data from the National Health and Nutrition Examination Survey (NHANES), we included 8828 hypertensive patients with a median follow-up of 11.29 years, during which 2113 all-cause deaths (including 588 cardiovascular deaths) were recorded. By applying Cox proportional hazards models combined with restricted cubic splines (RCS), we found a nonlinear relationship between BRI and all-cause mortality risk in hypertensive patients, with a significant threshold effect. Competing risks model analysis showed that the impact of BRI on cardiovascular mortality risk was independent of other causes of death. Subgroup analyses further confirmed the robust association between BRI and mortality risk.

BRI may serve as an effective indicator for assessing all-cause and cardiovascular mortality risks in hypertensive patients. Its simplicity and cost-effectiveness suggest potential applications in clinical and public health practices.