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Abdominal aortic aneurysm (AAA) is a life-threatening condition with limited pharmacological therapies. The pathological progression of AAA is closely attributed to the phenotypic switching of vascular smooth muscle cells (VSMCs). NFS1 is the rate-limiting enzyme for the synthesis of iron-sulfur proteins, and the roles of NFS1 in AAA initiation and development have not been explored. Angiotensin II (Ang II) infusion-induced AAA animal model with Apoe Show less

Public responses to climate change are influenced by interpretations of scientific information and individual differences. Understanding these factors can improve targeted climate communication. We conducted a nationally representative survey of Lithuanian adults ( LPA using three climate-belief indicators supported a two-class solution among respondents with complete data ( The findings reveal heterogeneity in climate-change beliefs in Lithuania and suggest that audience segmentation and psychologically informed communication strategies may enhance climate-related science communication. Show less

To quantify the Number Needed to Test (NNT) to prevent one ARIA event as a function of A Bayesian simulation study using a Beta-Binomial model to analyze genotype-stratified contingency tables. Data were derived from two published, phase 3 clinical trials: Clarity-AD (lecanemab) and TRAILBLAZER-ALZ 2 (donanemab). Aggregate data from source trials. Simulation of varying treatment discontinuation probability NNT to prevent one ARIA event (any ARIA-E, any ARIA-H, and symptomatic ARIA-E) and the fractional reduction in total ARIA events as a function of NNTs increased (worsened) significantly as The direct safety impact of Show less

Cholinergic dysfunction is a key contributor to cognitive impairment observed in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Although acetylcholinesterase (AChE) inhibitors have been the mainstay of symptomatic treatment for over two decades, their limited efficacy and adverse effects underscore the need for alternative therapeutic approaches. Recent evidence indicates that mechanical stimulation can modulate neuronal and glial signaling through mechanotransduction, suggesting a potential strategy to enhance cognitive function via non-pharmacological means. Here, we developed a head-mounted vibrotactile stimulation system (HVSS) that delivers controlled vibration to the cranium and evaluated its effects in a pharmacological model of acute cholinergic dysfunction induced by scopolamine. To this end, male C57BL/6 mice received scopolamine (1 mg/kg, i.p.; on days 7, 14, and 28) and were exposed to daily vibrotactile stimulation at 20, 40, or 80 Hz for 28 days. Behavioral performance was assessed using passive avoidance and Morris water maze tests, followed by biochemical and histological analyses. HVSS at 40 Hz and 80 Hz significantly improved cognitive performance, enhanced hippocampal cholinergic function, reduced oxidative damage, and upregulated memory-related signaling genes, including BDNF, PI3K, AKt, ERK1/2, CREB, and CAMK4. These findings suggest that high-frequency HVSS improves memory hippocampal cholinergic function via activation of memory-related signaling pathways, highlighting its potential as a safe, non-pharmacological neuromodulatory strategy for cholinergic dysfunction-related cognitive decline. Show less

Endoplasmic reticulum (ER) stress during overnutrition causes leptin resistance in obese animals and humans. ER stress induces the activation of the unfolded protein response, which disrupts the leptin signaling pathway, accelerating atherosclerosis development and its complications. Indole-3-carbinol (I3C) improves metabolic dysfunction in diet-induced obesity; however, its role in protecting against ER stress-induced hyperleptinemia remains unclear. Herein, we explored whether dietary I3C alleviates ER stress in apolipoprotein E-deficient (apoE ApoE I3C supplementation (0.05%) resulted in reduced adipose tissue weight and plasma leptin levels compared with those in WD-fed apoE I3C may serve as a feasible compound for preventing atherosclerosis and its associated complications. Show less

Luteolin, a flavonoid naturally present in a variety of fruits, vegetables, and medicinal plants, has been recognized as a potentially effective neuroprotective nutraceutical because of its remarkable anti-inflammatory, antioxidant, and neurotrophic properties. Increasing evidence suggests that neuroinflammation and oxidative stress are major contributors to cognitive decline and neuronal degeneration in several prominent neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS). Luteolin significantly inhibits microglial activation, reduces pro-inflammatory cytokine production, modulates the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and enhances Nrf2-mediated antioxidant mechanisms. Furthermore, it promotes synaptic plasticity through brain-derived neurotrophic factor (BDNF)-associated pathways and mitigates the aggregation of pathological proteins, including Aβ, tau, α-synuclein, and mutant huntingtin. Preclinical studies consistently demonstrate substantial improvements in cognitive function, motor performance, demyelination, and neuronal viability in models of AD, PD, MS, and HD. Preliminary clinical observations also indicate prospective advantages for cognitive function, regulation of inflammatory responses, and alleviation of symptoms, particularly concerning AD and MS. Notwithstanding these encouraging outcomes, obstacles persist due to luteolin's restricted bioavailability, ideal dosing parameters, and the translational discrepancies between experimental models and human pathophysiological conditions. In summary, luteolin emerges as a noteworthy candidate for nutraceutical-oriented approaches designed to alleviate neuroinflammation and cognitive deterioration in the context of neurodegenerative diseases. Show less

Atherosclerotic macrophages predominantly exhibit a pro-inflammatory phenotype, driving chronic inflammatory and accelerating atherosclerotic progression. Interferon regulatory factor 5 (IRF5) is highly expressed in lesional macrophages within advanced atherosclerotic plaques, where it promotes the secretion of pro-inflammatory cytokines. However, current approaches lack an effective therapeutic strategy to specifically silence this gene in lesional macrophages for atherosclerosis treatment. This study aims to develop and evaluate a dual-targeted, siRNA-based nanotherapeutic platform that selectively acts on atherosclerosis-promoting genes in plaque macrophages, offering a potential strategy for treating atherosclerosis by reprogramming lesional macrophages. Here we designed and developed dual-targeted liposome-based nano-immunotherapeutics encapsulating small interfering RNA (siRNA) against IRF5 (siIRF5) to reprogram macrophage phenotypes within advanced plaques. In high-fat diet-fed Show less

Schematic presentation of possible mechanisms of hypertensive dementia, including amyloid beta metabolism (A), NVU dysfunction (B), vulnerability of the hippocampus (C), and activation of RAS (D), and possible new therapeutic approaches for discovering antihypertensive drugs with anti-dementia actions (E). See text for details. Aβ, amyloid β; APP, amyloid β precursor protein; BACE1, β-site amyloid precursor protein cleaving enzyme 1; BBB, blood-brain barrier; CBF, cerebral blood flow; eNOS, endothelial nitric oxide synthase; FDA, Food and Drug Administration; IL, interleukin; NOX, NADPH oxidase; NVU, neurovascular unit; RAS, renin-angiotensin system; ROS, reactive oxygen species. Show less

Functional decline may be an early indicator of dementia. This study examined the trajectories of frailty, grip strength, and gait speed over the 11 years prior to dementia, compared to matched individuals without dementia. A total of 1092 dementia cases were matched on age, sex and education to 4368 controls from a cohort of community-dwelling older adults recruited in Australia and the USA, aged 65 years or above at recruitment. Frailty was characterised by a deficit-accumulation index involving 67 items. Hand grip strength and gait speed were measured regularly by physical examination. Linear mixed-effects models estimated the backward trajectories of frailty, grip strength and gait speed before dementia, compared to controls. Secondary analyses were stratified by sex and ApoE ε4 carrier status. Higher frailty burden, with a steeper increase over time, was found in the years before dementia, compared to controls (P-interaction < .001). Hand grip strength and gait speed declined more rapidly in dementia cases than in controls (P-interaction < .001 for both). Differences between cases and controls became consistently significant four to six years prior to dementia (P-contrast < .001). An earlier divergence across all three measures was observed for females, and to a lesser extent in ApoE ε4 non-carriers. Functional decline occurs within the decade before dementia onset, with gait speed being the earliest indicator. These findings support the utility of functional measures as early markers of dementia risk, with potential implications for targeted monitoring and preventative strategies. Show less

This study aims to investigate the underlying pathophysiological relationship between obesity and osteoporosis (OP) in obese individuals, involving lipid metabolism, inflammation, and bone mineral density (BMD). Data from 318 patients diagnosed OP at our hospital between January 2023 to December 2025 were collected and analyzed. The basic information of the patient included gender, age, BMI, drinking and smoking history, diabetes, hypertension and bone mineral density (T-scores) were recorded. Baseline peripheral blood was employed to calculate lipid markers and inflammatory cytokines. Linear regression and mediation analyses were employed to assess the relevance and differences. Increased level of blood lipids and inflammatory cytokines were associated with increased risks of OP in obesity. Compared to normal-weight individuals, obese subjects exhibited significantly lower BMD. Dysregulated lipids (TC, TG, HDL-C, ApoB) negatively correlated with BMD in obesity. Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8) inversely associated with BMD, while anti-inflammatory IL-10 showed positive association. Hyperlipidemic obese individuals had elevated inflammatory cytokines (TNF-α, IL-1β) and exacerbated BMD loss. Mediation analysis revealed TNF-α mediated 41.91% and IL-6 mediated 33.20% of the TC-BMD association; TNF-α and IL-6 mediated 28.76% and 37.38% of HDL-C-BMD effects, respectively. Obesity-associated dyslipidemia drives BMD loss partly through inflammation-mediated pathways. Key inflammatory cytokines significantly mediate lipid metabolism’s impact on bone health. Targeting lipid-inflammatory crosstalk may optimize OP management in obese populations. Show less

Yiqi Huoxue Granule (YQHX), a traditional Chinese medicine (TCM) formulation, is extensively utilized for the treatment of atherosclerotic diseases. However, its active constituents and molecular mechanisms remain unclear. We utilized a systematic methodology to identify bioavailable compounds in vivo and predict and validate the principal targets and pathways responsible for their anti-atherosclerotic actions. Serum pharmacochemistry utilizing UPLC-Q-Exactive Orbitrap-MS was employed to identify the bioavailable compounds of YQHX. An integrated methodology combining network pharmacology and molecular docking was implemented to predict its potential targets and mechanisms against atherosclerosis, which were subsequently verified experimentally in apolipoprotein E-deficient (ApoE We identified 36 absorbable compounds in the serum of rats following YQHX administration, and 252 potential therapeutic targets were predicted. Protein-protein interaction analysis identified 10 hub targets, which are IL-6, TNF, EGFR, TP53, AKT, STAT3, SRC, CTNNB1, TLR4, and MMP-9. Enrichment analyses indicated that these targets are primarily involved in lipid metabolism and inflammatory responses, with significant enrichment in the PI3K-Akt and SRC signaling pathways. Molecular docking revealed strong binding affinities between the proteins EGFR, SRC, and AKT and their respective compounds. In ApoE This study systematically identified the bioactive compounds of YQHX and demonstrated its multi-target anti-atherosclerotic effect, which involved the enhancement of lipid metabolism and suppression of inflammation, mediated, at least in part, by the inhibition of the SRC/AKT signaling pathway. Show less

Preclinical atherosclerosis and prediabetes are key targets of preventive medicine as their prevalence rises. Therefore, it is crucial to identify early processes and limit confounders such as lipid-lowering or antidiabetic therapy and advanced atherosclerosis. Proteomics enables the identification of biomarkers and molecular pathways related to atherogenesis in prediabetes. To investigate the relationship between prediabetes and preclinical atherosclerosis in apparently healthy individuals using a comprehensive proteomic approach. This cross-sectional, population-based study included 389 participants (mean age 49 ± 10 years; 47% males) from the Białystok PLUS cohort in Poland. Individuals with known diabetes, major cardiovascular, inflammatory, or malignant diseases, or those receiving steroidal or lipid-lowering therapy were excluded. Carotid ultrasound was used to assess preclinical atherosclerosis, and prediabetes was defined as impaired fasting glucose, impaired glucose tolerance, or HbA1c 5.7–6.4%. Proteomic profiling was performed using the Olink® Reveal platform, enabling deep profiling of 1050 proteins with the Proximity Extension Assay and next-generation sequencing readout, yielding log2-scaled NPX (Normalized Protein eXpression) values. In preliminary analyses, we identified proteins associated with prediabetes and then linked them to early atherosclerotic lesions. A block-sPLS-DA model integrating clinical and proteomic data revealed clear separation between participants with and without prediabetes. The clinical block comprised eight variables reflecting cardiometabolic status, whereas the proteomic block retained 45 proteins across two components. The heatmap shows pairwise Pearson correlations between selected serum proteins and clinical variables (Fig. 1). Vascular and age measures cluster together and share correlation patterns distinct from those of BMI and glycaemic parameters. A protein module including the ectodysplasin A2 receptor (EDA2R) and leiomodin 1 (LMOD1) correlates positively with age and vascular parameters, and inversely with GFR and HDL-C. Multivariable linear regression analyses were performed with selected vascular parameters as dependent variables and clinical covariates, together with proteins identified in Component 2, which are weakly related to clinical parameters and thus may represent novel biomarkers associated with prediabetes (Fig. 2). Expression of EDA2R (B = 0.05; An integrative block-sPLS-DA approach separated individuals with prediabetes from those without and revealed a proteomic signature independent of clinical covariates. Within this signature, the expression of LMOD1, EDA2R, and C16orf89 showed robust associations with atherosclerosis-related vascular traits. Enrichment analyses highlighted proteins involved in neuronal processes as candidate pathways linking early glucose disturbances with preclinical atherosclerosis. The online version contains supplementary material available at 10.1186/s12933-026-03128-w. Show less

The APOE-ε4/ε4 genotype is the strongest genetic risk factor for sporadic Alzheimer's disease, though the relative risk is diminished in individuals with African ancestry. Through analysis of phased APOE alleles, we identify a 19 bp deletion approximately 1.1 kb distal to the APOE 3'UTR in a SPI1 microglial transcription factor binding site. The deletion is present in 60% of African American APOE-ε4 homozygotes and reduces Alzheimer's disease odds ratio relative to individuals without the deletion. The deletion also delays Alzheimer's disease onset in APOE-ε4/ε4 cases with local African ancestry at APOE. The All of Us dataset confirms reduced Alzheimer´s disease risk associated with the deletion and identifies additional variants between APOE and APOC1 that disentangle APOE-ε4 neurological and lipid-related phenotypes. Functional assays reveal that the 19 bp deletion abolishes SPI1 repression at this region. Collectively, these findings describe a protective allele at APOE in African Americans that mediates APOC1 expression, reducing relative Alzheimer´s disease risk. Show less

Smooth muscle cells (SMCs) exhibit remarkable plasticity, undergoing extensive phenotypic switching to generate a highly heterogeneous population within atherosclerotic plaques. While recent studies have highlighted the contribution of SMC-derived macrophage-like cells to plaque inflammation, the specific molecular drivers governing the transition to these pathogenic states remain poorly understood. Here, we re-analyzed single-cell RNA sequencing data from lineage-traced mice to dissect SMC heterogeneity during atherogenesis. Trajectory analysis revealed that SMCs transdifferentiate into a distinct pro-inflammatory macrophage-like subpopulation (macrophage 4) via an intermediate "stem-endothelial-monocyte" cell state. Integrated gene regulatory network inference and Clinically, IRF7 expression was significantly upregulated in unstable and advanced human atherosclerotic plaques, correlating strongly with inflammatory macrophage burden. These findings identify IRF7 as a critical checkpoint in maladaptive SMC phenotype switching. We demonstrate that IRF7 drives the transdifferentiation of SMCs into a pro-inflammatory macrophage-like state, thereby fueling plaque instability. Consequently, therapeutic strategies capable of inhibiting IRF7-mediated SMC plasticity may prove effective in stabilizing vulnerable atherosclerotic plaques. Show less

Anti-amyloid antibody treatment for Alzheimer's disease is linked to Amyloid-Related Imaging Abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), especially in ApoE ε4/4 carriers. To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models. Acutely, 3D6 bound to cerebral amyloid angiopathy (CAA), resulting in C1q binding and classical complement activation. Weekly short-term immunization over 7 weeks resulted in elevated CAA- and plaque-associated complement deposition, red blood cell extravasation and microhemorrhages, and was accompanied by significant transcriptomic changes in genes related to complement, inflammation, vascular dysfunction, and endothelial lipid responses. Longer-term dosing over 13-15 weeks further increased complement deposition and was associated with blood-brain barrier disruption, MMP-9 upregulation, and microhemorrhages, accompanied by reduced amyloid burden and modest CAA clearance. C3 levels correlated with microhemorrhage severity. Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk. Show less

Mitochondrial dysfunction is a hallmark of neurodegenerative diseases, where respiratory defects and downstream bioenergetic failures arise from impaired mitophagy or the accumulation of damaged mitochondria. Mitophagy is a mitochondrial quality-control pathway in which mitochondria tagged with ubiquitin phosphorylated at Serine 65 (pS65-Ub) are targeted for degradation via the autophagy-lysosome system. We previously identified a significant genome-wide association between apolipoprotein E ε4 [APOE ε4] with pS65-Ub levels in the hippocampus of Lewy body disease (LBD). However, the relationship between genetic background in the mitochondrial genome and the PINK1-PRKN pathway biomarker pS65-Ub remains to be elucidated. In this study, we examined whether mitochondrial DNA (mtDNA) variation contributes to changes in pS65-Ub level in 514 neuropathologically confirmed LBD brains, with replication in an independent cohort of 384 LBD brains. No individual mtDNA haplogroup was significantly associated with pS65-Ub levels after correction for multiple testing (P < 0.005 considered significant); mtDNA haplogroup V exhibited a nominally significant (P < 0.05) association, but this association was not observed in an independent replication series. Our data reveal an overall lack of direct evidence linking mtDNA variations to mitophagy marker pS65-Ub levels in LBD, suggesting that mitochondrial damage is unlikely to be explained by major mtDNA determinants alone and may instead reflect cumulative and multilayered perturbations of mitochondrial function. Single cell analyses combined with larger replication cohorts integrating multi-omics datasets will be essential to validate these findings and to advance the discovery of biomarkers for mitochondrial dysfunction in neurodegeneration. Show less

In anticipation of updates to cholesterol guidelines globally, evidence since the most recent iteration of recommendations across US and Europe for risk assessment and lipid management are reviewed. ASCVD risk estimation is at the core of determining lipid lowering goals and consideration for therapies. In primary prevention, incorporation of the PREVENT equations will be featured in updated guidelines, which will likely demarcate new, lower risk thresholds compared to the prior Pooled Cohort Equations. Additionally, the use of coronary artery calcium (CAC) improves risk estimation to inform medication allocation and LDL-C goals beyond traditional risk factor risk estimation. To achieve lower LDL-C, many adults will need multiple lipid-lowering medications. For high-risk individuals, combination therapy with low/moderate intensity statin and ezetimibe or bempedoic acid should be considered. Additionally, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) therapies can be used to attain lower LDL-C in high-risk individuals, including those with clinical ASCVD or a high CAC burden. In very-high risk patients, treatment to LDL-C values as low as <30 mg/dL further reduces ASCVD risk without significant adverse events. Among individuals treated with PSCK9i therapy, those with elevated Lp(a) may have greater ASCVD risk reduction and may be a patient population that is prioritized for PCSK9i until therapies directly targeting Lp(a) are available. An ASCVD risk-based approach should be the foundation for determining LDL-C goals with consideration that multiple lipid-lowering therapies are often necessary for high and very-high risk patients who were treated to very low LDL-C in more recent randomized controlled trials. Show less

Cervical cancer (CC) is the most common gynecological malignancy and is strongly linked to human papillomavirus (HPV) infection. Currently, immune checkpoint blockade therapy has shown limited clinical benefits for CC, highlighting the need to find more effective therapeutic targets. LILRB4, a member of the leukocyte immunoglobulin-like receptor superfamily, is considered a key mediator of cancer immunosuppression. However, its role in the CC immune microenvironment remains unclear. Here, LILRB4 expression was upregulated in CC tissues, and high expression levels were positively associated with advanced disease and immunosuppressive genes in tumors. In an immunocompetent mouse model, LILRB4 expression in CC tumors increased with tumor growth, whereas blocking LILRB4 reduced tumor growth. Flow cytometry analysis revealed that blockade of LILRB4 reduced CD8 Show less

Atherosclerosis (AS), a chronic inflammatory process driven largely by macrophage-mediated plaque formation, remains poorly understood in mitochondrial-macrophage crosstalk. While CYBA polymorphisms correlate with cardiovascular risk, the functional role of CYBA in connecting mitochondrial dysfunction to macrophage phenotypic alteration and functional modulation remains largely unknown. In this study, we integrated multi-omics profiling of AS immune microenvironments with mitochondrial-associated gene sets. Machine learning and single-cell RNA sequencing identified CYBA as a key oxidative stress regulator. CYBA expression was significantly upregulated both in oxidized low-density lipoprotein (ox-LDL)-stimulated THP-1 macrophages and in atherosclerotic lesions, with immunofluorescence confirming macrophage enrichment. Show less

Extracorporeal cardiac shock wave (ECSW) therapy enhances the function of endothelial colony-forming cells (ECFCs), but whether it can serve as a preconditioning strategy to enhance myocardial infarction (MI) therapy remains unclear. This study investigated the efficacy and mechanism of intravenously delivered ECSW-preconditioned ECFCs (SW-ECFCs) in a rat MI model. ECFCs were isolated from the bone marrow of ApoE Transcriptomic analysis revealed significant enrichment of the PI3K/AKT pathway in SW-ECFCs. Functionally, ECSW enhanced ECFCs migration, tube formation, proliferation, and VEGF-A secretion, while reducing apoptosis; these effects were largely abolished by PI3K inhibition. In vivo, serum levels of CK, CK-MB, and LDH were significantly elevated in all MI groups compared to the Sham group (P < 0.01), indicating comparable initial injury. However, no significant differences were observed among treatment groups (P > 0.05). SW-ECFCs transplantation significantly improved cardiac function, reduced infarct size, fibrosis, and apoptosis, and enhanced angiogenesis (P < 0.05). These benefits were associated with increased levels of p-AKT, p-eNOS, and BCL-2 protein as well as nitric oxide content, while suppressing the expression of cleaved caspase-3 (P < 0.05). Crucially, all these therapeutic benefits were largely abolished by PI3K inhibition. In conclusion, this study demonstrates that preconditioning ECFCs with ECSW significantly enhances their therapeutic efficacy for myocardial infarction, improving both cardiac function and structural repair. These benefits are mediated primarily through activation of the PI3K/AKT signaling pathway, which augments cell homing, paracrine activity, and survival, thereby providing a novel and promising strategy for cardiac regeneration. Show less

Dyslipidemia is a heterogeneous group of disorders that typically presents asymptomatically during childhood but increases the risk of atherosclerotic cardiovascular disease later in life. Understanding the genetic basis can provide valuable insights for early diagnosis and may support more tailored therapeutic approaches. This study aimed to investigate the genetic etiology of childhood-onset dyslipidemia and explore genotype-phenotype correlations. We retrospectively analyzed genetic data from 133 pediatric patients evaluated for suspected dyslipidemia between 2018 and 2023. Targeted next-generation sequencing (NGS) was performed using a panel covering 20 genes associated with lipid metabolism. Only pathogenic or likely pathogenic variants were included in the analysis. Pathogenic or likely pathogenic variants were identified in 17% of patients (n = 23). The most frequently affected gene was LDLR (74%), followed by significant variants in APOB, APOA5, LDLRAP1, and ALMS1. Three novel pathogenic variants were identified in this cohort: a splice-site variant in LDLRAP1 (c.231+2T>C) and two truncating variants in APOB (p.Tyr992Ter and p.Lys576Ter). Genotype-phenotype analysis revealed distinct impacts of variant types on lipid profiles. Notably, APOB variants were associated with both hypercholesterolemia and hypocholesterolemia. Our findings highlight the substantial contribution of genetic factors to childhood dyslipidemia and underscore the clinical utility of genetic testing in guiding diagnostic and therapeutic decisions. Show less

The neural precursor cell expressed developmentally down-regulated protein 1 (NEDD1) is implicated in tumorigenesis, but its role in hepatocellular carcinoma (HCC) remains unclear. This study aims to explore the oncogenic role, regulatory mechanisms, and tumor microenvironment interactions of NEDD1 in HCC. Multi-omics analyses were performed using public datasets (TCGA, GEO) and in-house clinical samples. These included expression and survival analysis, epigenetic (DNA methylation) and post-translational (phosphorylation) profiling, functional pathway enrichment, and drug sensitivity prediction. Functional validation was conducted via NEDD1 knockdown in HCC cells and a subcutaneous xenograft model. The co-expression and spatial distribution of NEDD1 and its predicted partner MZT2B were investigated using single-cell (GSE140228) and spatial transcriptomic (HRA000437) datasets. NEDD1 was significantly overexpressed in HCC tissues and correlated with poor prognosis. Its overexpression was potentially linked to promoter hypomethylation and aberrant phosphorylation. NEDD1 knockdown suppressed HCC cell proliferation, migration, and tumor growth in vivo. Notably, NEDD1 expression positively correlated with immune checkpoint molecules (PD-1, CTLA-4), and low NEDD1 expression was associated with better predicted response to immunotherapy. Single-cell and spatial transcriptomics revealed that NEDD1 and MZT2B co-expression was highly enriched in specific macrophage subsets (e.g., APOE+) and exhibited cell context-dependent heterogeneity, suggesting they may constitute a dynamic functional module within the HCC microenvironment. This multi-omics study suggests NEDD1 as a potential prognostic biomarker and therapeutic target in HCC. We propose a novel model wherein the NEDD1-MZT2B module may operate in both tumor cells and immunosuppressive macrophages, potentially influencing disease progression and immunotherapy response. Show less

Atherosclerosis is a common vascular disease that poses a serious threat to global health. However, the mechanism underlying the pathogenesis and progression of atherosclerosis remains elusive. We analysed the expression of deubiquitinating enzymes in human atherosclerotic lesions and found that USP25 was significantly downregulated. The role of USP25 in atherosclerosis was validated in mouse models with an ApoE USP25 was predominantly expressed in macrophages in atherosclerotic lesions, and ablation of macrophagic USP25 significantly exacerbated atherosclerosis in ApoE This study elucidated the function and molecular mechanism of USP25 in atherosclerosis, identifying USP25 as a beneficial regulator for this disease. This work was supported by the Natural Science Foundation of Zhejiang Province (LZ24H090003 to X.W. and LTGY23H090001 to W.W.), the National Natural Science Foundation of China (82150710557 and 82293642 to W.S.; 81971143 to X.W., and 82271347 to G.W.), and Wenzhou Municipal Science and Technology Bureau (Y2021094 to J.H.). Show less

Atherosclerosis (AS) serves as the pathological foundation for numerous cardiovascular and cerebrovascular diseases and is highly comorbid with depression. The mechanisms underlying this co-morbidity are exceptionally complex, posing significant challenges to effective clinical treatment. Consequently, our study aims to explore the potential biomarkers and mechanisms involved in developing atherosclerosis co-depression disease. We performed differential expression analysis, protein-protein interaction analysis, Gene Ontology (GO) function enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on co-differentiated genes using AS and depression-related datasets from the GEO database. Potential biomarkers were identified through ROC curve analysis. To evaluate the effectiveness of the model, we established an animal model of AS comorbid with depressive disorder and performed a series of assessments, including the sugar-water preference test, open field test, tail suspension test, lipid profile analysis, and pathological examination of aortic sections. Additionally, RNA sequencing analysis of brain tissue, Golgi staining, and detection of synaptic function-related proteins were performed in AS comorbid depressed mice. Finally, in vitro cellular experiments were conducted to further validate the molecular targets and underlying mechanisms. We identified 968 differentially expressed genes associated with AS and 472 differentially expressed genes associated with depression, with 30 genes co-differentially expressed. Protein-protein interaction (PPI) analysis revealed that CCR5, CCR2, NPY, and OPRM1 were strongly associated with AS co-depression, while ROC analysis indicated that Shank2, MDGA2, and S100B were diagnostic markers for AS with depression. Differentially expressed genes were closely associated with the chemokine signaling pathway, neuroactive ligand-receptor interaction, cytokine-cytokine receptor interaction, and taste transduction. Animal studies demonstrated that ApoE Our study identified seven candidate AS co-depression biomarkers and verified that inflammation-induced damage to synaptic plastic rows is an important mechanism of AS co-depression, providing new insights into the diagnosis and treatment of AS co-depression disorders. Show less

Exercise training improves endothelial function and reduces vascular inflammation. However, whether aerobic exercise training-induced secretion of irisin, a myokine cleaved from fibronectin type III domain-containing protein 5 ( Show less

Published data suggest that compared to APOE3, APOE4 could increase the risk of neurodegeneration via higher cerebrovascular permeability. We recently proposed the concept that brain endothelial cell APOE is protective for cerebrovascular function in a genotype specific manner, APOE3 > APOE4, and therefore APOE4 brain endothelial cells may be predisposed to dysfunction during aging and disease. In addition to mechanistic implications, our concepts and methods may have therapeutic applications; identifying compounds that protect APOE4 brain endothelial cells. The goal of this proof-of-concept study was to determine whether APOE4 brain endothelial cells can be used as a phenotypic compound screen. Previously we found that APOE4 brain endothelial cells are particularly sensitive to lipopolysaccharide- (LPS) induced permeability disruption when measured by trans endothelial cell electrical resistance (TEER) in vitro. Here, we followed the NIH Assay guidance manual to convert our in vitro assay to a phenotypic screen. We scaled the isolation protocol, selected conditions for the min, mid and max signals, statistically validated the phenotypic assay, screened compounds, validated hits and tested the top hits in vivo. We scaled the isolation protocol and selected conditions for min (0.8 µg/ml LPS), mid (10 µM sildenafil/LPS) and max conditions (vehicle). Our final protocol met the reproducibility acceptance criteria for a statistically validated assay. We then screened a subset of ~ 900 molecules from the TargetMol Bioactive Library and identified two main groups compounds. The first group disrupted APOE4 brain endothelial cells as they were toxic or lowered TEER and many inhibited mTOR. The second group protected against LPS-induced TEER reduction. With relatively stringent criteria we identified 33 protective compounds that are grouped into those that inhibit growth factor receptor signaling and a range of intracellular signaling pathways. We compared the most active compounds and selected four to test in vivo. Tadalafil (PDE5 inhibitor), vorinostat (HDAC inhibitor), CCT196969 (raf inhibitor) and SGI-7079 (AXL inhibitor) mitigated acute LPS-induced cerebrovascular dysfunction in mice that express APOE4. Overall, our data supports the potential of our in vitro screen to identify compounds that prevent LPS-induced dysfunction in APOE4 brain endothelial cells. Show less

Accumulating evidence suggested that bile acids play a significant role in modulating metabolic and inflammatory diseases. In this study, we investigated the roles of the farnesoid X receptor (FXR) and its endogenous antagonist hyodeoxycholic acid (HDCA) in the development of atherosclerosis (AS). We found that serum HDCA was significantly reduced in patients with AS, and systemic HDCA therapy attenuated plaque burden in vivo. Adoptive transfer of HDCA-treated Foxp3+ Tregs into ApoE-deficient recipients reduced lesion growth, whereas FXR-deficient Tregs failed to confer benefit. HDCA enhanced Treg migration and accumulation within plaques and reprogrammed Treg metabolism by antagonizing FXR and modulating PD-1/mTORC1 signaling. This shift relieved CPT1a-driven fatty acid oxidation bias, increased glycolysis and ATP production, and improved migratory capacity and effector function. We further identify ZNF671 as a transcriptional inhibitor of Treg migration that is mitigated by HDCA-dependent metabolic switching. Collectively, HDCA reduced FXR-mediated metabolic constraints while activating glycolytic and migratory programs in Tregs, thereby improving lipid handling and immune regulation within the plaque microenvironment. These findings position the HDCA-FXR-PD-1/mTORC1 axis as a novel immunometabolic target for AS. Show less

Vascular damage, including cerebral amyloid angiopathy (CAA) and non-amyloid cerebral small vessel disease (CSVD), has been linked to glymphatic dysfunction, which may contribute to Alzheimer's disease (AD) pathology and cognitive decline. We investigated the associations among vascular damage, glymphatic function measured by the DTI-ALPS (Diffusion Tensor Imaging-Analysis Along the Perivascular Space) index, AD plasma biomarkers, and cognitive decline. This study includes 1,249 participants recruited from Samsung Medical Center. We performed linear regression analysis to identify factors associated with the DTI-ALPS index. Further, linear regression analysis with vascular imaging markers, including CAA and CSVD summary scores, as predictors and DTI-ALPS index as an outcome was performed to investigate the effect of vascular pathology on glymphatic function. We conducted mediation analyses to investigate whether the DTI-ALPS index mediates the effect of vascular imaging markers on plasma biomarkers (phosphorylated tau 217 [p-tau 217], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NFL]). Additionally, mediation analyses with the DTI-ALPS index as a predictor, each plasma biomarker as a mediator, and annual MMSE or CDR-SOB change as an outcome to investigate whether plasma biomarkers mediate the effect of the DTI-ALPS index on longitudinal cognitive decline. First, the DTI-ALPS index was negatively associated with both CAA (β [95% CI] = -0.163 [-0.214, -0.112], p < 0.0001) and CSVD (β [95% CI] = -0.195 [-0.247, -0.143], p < 0.0001) summary scores after controlling for age, sex, BMI status, and APOE genotype. Second, the DTI-ALPS index fully mediated the relationship between these vascular markers and p-tau 217 (CSVD summary score, indirect effect β [95% CI] = 0.016 [0.010, 0.023], p < 0.001; CAA summary score, indirect effect β [95% CI] = 0.013 [0.008, 0.020], p < 0.001) and GFAP (CSVD summary score, indirect effect β [95% CI] = 0.015 [0.008, 0.022], p < 0.001; CAA summary score, indirect effect β [95% CI] = 0.012 [0.007, 0.019], p < 0.001), while partially mediating the relationship for NFL, regardless of Aβ uptake on PET. Finally, the DTI-ALPS index was significantly associated with cognitive decline and this association was partially mediated by plasma biomarkers. These findings highlight glymphatic dysfunction as a key mechanism linking vascular pathology with tau, inflammation and neurodegeneration, independent of Aβ uptakes. Show less

ApoB (apolipoprotein B)-containing lipoproteins are causal risk factors for atherosclerotic coronary artery disease (CAD). Since human cathelicidin LL-37 binds to ApoB-100 in this pathological context, we investigated whether the circulating LL-37-ApoB-100 complex could serve as a biomarker for CAD. We performed surface plasmon resonance and protein-protein docking to demonstrate the direct LL-37-ApoB-100 interaction. We developed a specific polyclonal antibody against the complex and measured its levels in human atherosclerotic plaques and plasma, as well as in We identified that LL-37 directly interacted with multiple distinct binding sites on ApoB-100. Plasma levels of LL-37-ApoB-100 complex were significantly elevated in human patients with atherosclerosis. Consistently, levels of this complex were positively correlated with atherosclerotic plaque area in Circulating LL-37-ApoB-100 levels are strongly associated with angiographically documented CAD, highlighting LL-37-ApoB-100 as an independent predictor for CAD. Show less