👤 Meng Xu

The rising demand for high-quality pork among consumers has driven interest in genetic improvement strategies. Crossbreeding is well known to influence carcass performance and meat quality; however, the molecular mechanisms underlying these effects are still poorly understood. In this study, the F1 generation of the Songlei Crossbred Pig (SL) was developed through crossing the Songliao Black Pig (male) (SS) and the Leixiang Pig (female) (LL). We integrated the transcriptomes and metabolomes of the longissimus dorsi (LD) muscle of SS and SL under identical conditions to identify key mechanisms regulating the quality of crossbred meat. Compared with those of SS, the slaughter weight, carcass weight, and dressing percentage of SL were significantly lower, but the backfat thickness was greater; however, meat quality traits, including intramuscular fat (IMF), colour, and pH The meat quality of SL was better than that of their male parents, but not the carcass traits were not. Additionally, several critical genes and pathways related to lipid metabolism were identified. These findings provide new insights into how meat quality can be improved by hybridization. Show less

Xinjiang Brown cattle are an important beef breed in Northwest China. Although multigenerational selective breeding has improved their growth performance, the accompanying molecular adaptations and potential physiological trade- ofs remain insufficiently elucidated at the systemic level. This study aimed to decipher the dynamic serum proteomic profiles shaped by both ontogeny and generational selection in Xinjiang Brown cattle, and to identify the associated key proteins and pathways. Serum samples from 18 bulls across three genera- tions (A, B, C) at 3 and 9 months of age were analyzed using Tandem Mass Tag (TMT)-based quantitative proteomics. Under stringent quality control (FDR < 1%), 583 high-confidence proteins were identified. Diferentially expressed proteins (DEPs) were screened using thresholds of |fold change| ≥ 1.2 and This study reveals that the breeding strategy for Xinjiang Brown cattle prioritizes shaping a proteomic landscape that promotes growth and metabolism, potentially at the cost of atten- uated immune-vascular reactivity. The identified panel of candidate proteins pro- vides a molecular framework for evaluating breeding outcomes and designing balanced selection strategies. Follow-up research should further investigate the functions of these candidate proteins and validate their predictive value for health and production performance in independent herds. Show less

Depression is a heterogeneous psychiatric disorder with limited treatment efficacy, as 30-50% of patients exhibit inadequate responses to conventional monoaminergic antidepressants. Rhein, a bioactive anthraquinone derived from Rheum palmatum, exhibits rapid and sustained antidepressant effects in both acute and chronic social defeat stress (CSDS) mouse models. Using quantitative proteomics on prefrontal cortex (PFC) samples from control, CSDS, Rhein-treated, and imipramine-treated cohorts, we identified differentially expressed proteins that revealed Rhein's multi-target regulatory profile. Functional enrichment and clustering analyses indicated that Rhein predominantly restores dysregulated pathways related to lipid metabolism, ribosomal translation, mitochondrial and endoplasmic reticulum (ER) function, and synaptic plasticity, forming a coherent mechanistic axis underlying its therapeutic effects. Comparative analysis with imipramine-treated mice further highlighted Rhein's distinct capacity to modulate organelle homeostasis and synaptic remodeling with greater breadth. Parallel reaction monitoring (PRM) and Western Blotting validated key proteins involved in mitochondrial functions (BNIP1, PISD, MRPL42, MRPS30, LRBA, IGHM), ER homeostasis (ACBD5, APOA4, RPL14), and synaptic plasticity (HDAC1, FAM3C, SSU72). These molecular findings suggest that Rhein exerts its antidepressant effects by restoring the functional integrity of mitochondria and the ER, thereby reprogramming synaptic plasticity. We inferred that this organelle-centered regulation further reinforces its potent modulation through multiple mechanisms and signaling pathways of synaptic plasticity, enabling Rhein to exert antidepressant effects through a coordinated, multi-layered mechanism. Collectively, our findings provide a systems-level mechanistic framework for Rhein's antidepressant efficacy and support its potential as a multi-pathway natural therapeutic, particularly for metabolic subtypes of depression. Show less

To investigate changes in serum lipid profile parameters combined with tumor markers in gastric cancer (GC) patients and their value in GC screening. A total of 100 patients diagnosed with GC at Renji Hospital (West) between May and September 2025 were consecutively enrolled as the GC group (54 cases in stage Ⅰ/Ⅱ and 46 cases in stage Ⅲ/Ⅳ). Additionally, 100 age- and sex-matched healthy individuals undergoing routine physical examinations were included as the healthy control (HC) group. The serum levels of nine lipid indicators (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC], triglycerides [TG], small and dense low-density lipoprotein cholesterol [sdLDL-C], apolipoprotein [Apo] A1, ApoB, ApoC2, and ApoC3) and five tumor markers (carcinoembryonic antigen [CEA], carbohydrate antigen [CA] 19-9, CA50, CA242, and CA72-4) were measured using an automatic biochemical analyzer and an electrochemiluminescence instrument. Intergroup differences were analyzed using the Mann-Whitney Compared with the HC group, the GC group showed significantly lower levels of ApoA1, ApoC3, TC, HDL-C, LDL-C, and sdLDL-C ( The combined panel of ApoA1, ApoC3, HDL-C, LDL-C, TC, sdLDL-C, CEA, CA50 and age offers a potential auxiliary tool for detecting gastric cancer. Show less

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disorder. Notably, the differences in lipid metabolism between bulbar- and limb-onset subtypes of ALS remain unclear, particularly in non-Western populations. The present study investigated serum lipid profiles in a Chinese cohort of patients with ALS to explore their associations with disease severity and clinical subtypes. A retrospective, cross-sectional study was conducted, involving 158 patients with ALS and 62 matched healthy controls. Serum lipid parameters, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), small dense LDL cholesterol (sdLDL-c), apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB) and the TG/HDL ratio, were compared between the groups. Correlation analyses and multivariable linear regression models incorporating phenotype x lipid interaction terms were conducted after adjusting for age, sex, body mass index and disease duration. Patients with ALS exhibited significantly higher TC, TG, LDL, sdLDL-c, ApoA1, ApoB and TG/HDL ratios than controls. Subtype-specific analyses revealed different associations; in bulbar-onset ALS, higher sdLDL-c and TG/HDL ratios were associated with better functional status, whereas higher HDL and ApoA1 levels were negatively correlated with functional status. By contrast, in limb-onset ALS, higher sdLDL-c and ApoB levels were associated with worse function. Interaction analyses confirmed significant phenotype modification for sdLDL-c, TG/HDL ratio, HDL and ApoA1. These results suggest that lipid-severity relationships in ALS vary by subtype, indicating metabolic heterogeneity across phenotypes and supporting the potential of specific lipid parameters as exploratory markers for disease monitoring. Show less

AllergoOncology has emerged as an interdisciplinary field exploring the interaction between allergic diseases and cancer; however, the lack of stable in vivo models has limited mechanistic investigations. This study aimed to establish an experimental animal model to explore the impact of systemic allergic responses on tumor progression and to provide preliminary insights into the regulatory role of allergy in cancer development. An ovalbumin (OVA)-induced systemic allergy tumor-bearing mouse model (OVA-TM) was established by OVA sensitization followed by subcutaneous implantation of CT26 colon cancer cells. Tumor growth, immune responses, and behavioral changes were systematically evaluated. Tumor immune microenvironment alterations were assessed using immunological and histological analyses. Transcriptomic profiling and mass spectrometry imaging (MSI) were integrated to investigate immune-related metabolic alterations. Human tumor survival datasets were used to validate the prognostic relevance of differentially expressed genes (DEGs), and enrichment analyses of allergy- and cancer-associated genes were performed using humanized databases. OVA-induced systemic allergy significantly suppressed tumor growth and promoted immune cell infiltration, particularly CD3 This study establishes a practical in vivo model for AllergoOncology and demonstrates that systemic allergic responses can modulate tumor progression through immune activation, apoptosis, and inflammation-metabolism axis reprogramming, providing a foundation for future mechanistic and therapeutic studies. Show less

Elevated lipoprotein(a) [Lp(a)] is a genetically determined and independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that is largely resistant to conventional lipid-lowering therapies. Novel Lp(a)-targeted agents, including small interfering RNA (siRNA), antisense oligonucleotides (ASO), and the oral small-molecule inhibitor muvalaplin, have shown potent efficacy in early trials. We conducted a systematic review and network meta-analysis to comprehensively compare their efficacy and safety. A total of 25 randomized controlled trials (RCTs) involving 7715 participants were included, evaluating six siRNA agents, four ASO agents, and one small-molecule inhibitor. The primary outcome was percentage change from baseline in Lp(a). Secondary outcomes included absolute change in Lp(a), percentage changes in apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C), and adverse events. SiRNA therapies achieved the greatest Lp(a) reductions (olpasiran: mean difference [MD] -92.1%, 95% CI -100.1 to -84.0%; zerlasiran: -80.6%, 95% CI -87.7 to -73.5%), followed by muvalaplin (-76.8%, 95% CI -90.3 to -63.2%) and ASO therapy (pelacarsen: -54.2%, 95% CI -72.2 to -36.2%; all P < 0.001). Most agents achieved absolute Lp(a) reductions exceeding 105 nmol/L, suggesting clinically meaningful benefit. Baseline Lp(a) levels significantly modified treatment response (P < 0.001), and concomitant proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor use further enhanced LDL-C reduction (P = 0.024). All therapies were well tolerated, with injection-site reactions most frequent for injectables, while muvalaplin was well tolerated. These findings indicate that targeted Lp(a)-lowering therapies substantially reduce circulating Lp(a), with siRNA showing the greatest potency and muvalaplin offering a convenient oral alternative for personalized ASCVD risk reduction. Show less

Adolescent Idiopathic Scoliosis (AIS) is the most common form of spinal deformity among adolescents. To explore its etiology of progression and scoliosis-modifying drugs, chondrocytic senescence was confirmed in AIS facet joint cartilage by analyzing clinical specimen. Furthermore, through 4D/480 label-free proteomics analysis, we identified an exosome-mediated positive feedback loop during scoliosis progression, which driving the elevation of cholesterol flow between spinal cartilage and vertebra. To further investigate the pathological significance of the loop in vivo, high-cholesterol flow was reconstructed in C57BL/6 J mice by injecting with recombinant adeno-associated virus rAAV9-Runx2-HMGCR. Our results confirmed the important role of the positive feedback loop in the development of scoliosis. Meanwhile, Avasimibe or/and Corylin were used to delay the scoliosis progression by targeting the key exosomal proteins APOB (Apolipoprotein B-100) or/and HSP90β (Heat Shock Protein 90-beta). This research extends the etiology of scoliosis progression and provides an alternative perspective for scoliosis non-surgical treatment. Show less

To investigate the connection betweenischemic stroke (IS) patients' risk of dying after being discharged and their residual cholesterol (RC) levels uponadmission. 2021 IS patients between the ages of 35 and 80were chosen as the study's subjects, and data on deathendpoints following discharge were gathered. The doseresponse association between the risk of death and the RCat admission was examined using restricted cubic spline(RCS) regression. The hazard ratio (HR) and 95% CI werecalculated via Cox regression to analyse the associationbetween the RC level at admission and the risk of deathafter discharge in patients with IS. According to the RCS model, RC levels were nonlinearly associated with deaths from IS and other causes(P<0.001). With the median RC level as the cutoff value,the subjects were divided into two groups: a low RC group(RC<0.72 mmol/L) and a high RC group (RC≥0.72mmol/L). Compared with those in the high RC group, theage and male ratio in the low RC group were significantlygreater. The fasting blood glucose (GLU), total cholesterol(TC), triglyceride (TG), low-density lipoprotein cholesterol(LDL-C), non-high-density lipoprotein cholesterol (nonHDL-C), apolipoprotein A-1 (ApoA-1), and apolipoproteinB (ApoB) levels, as well as diabetes rates, were lower (P=0.01). Cox regression analysis revealed that withoutadjusting for covariates, the high-level RC group presenteda lower risk of all-cause death than the low-level RC group(HR=0.765, 95% CI: 0.619~0.946, P=0.013) and alower risk of death from IS (HR = 0.638, 95% CI:0.435~0.936, P=0.022). After adjusting for sex, age,smoking status, drinking status, hypertension status, anddiabetes status, the high-level group still had a lower risk ofall-cause death (HR = 760, 95% CI: 0.614~0.941,P=0.012) and a lower risk of death from IS (HR=0.653,95% CI: 0.444-0.961, P=0.031). Male sex (HR=0.753,95% CI: 0.572~0.990, P=0.042). Age ≥65 years (HR=0.598, 95% CI: 0.391~0.916, P=0.018), nonsmokingstatus (HR=0.628, 95% CI: 0.408~0.967, P=0.035),nonalcoholic status (HR=0.656, 95% CI: 0.439~0.979,P=0.039), not complicated with hypertension (HR=0.321, 95% CI: 0.108~0.957, P=0.041), no diabetesmellitus (HR=0.607, 95% CI: 0.389~0.947, P=0.028).Compared with those in the high RC group, the IS patientsin the low RC group had a lower incidence of all-causedeath, IS death and other causes of death and a higher survival rate. An RC<0.72 mmol/L at admission is associated with an increased risk of all-cause death and longterm IS death after discharge. Show less

This study aimed to evaluate the effects of phytosterols (PSs) alone and in combination with phospholipids (PLs) on blood lipid levels, erythrocyte membrane fluidity (EMF) and lipid profiles in subjects with borderline hyperlipidemia in a randomized, double-blind, placebo-controlled clinical trial. Among 144 initially screened participants, 87 were enrolled and randomly assigned to three groups receiving PSs (2 g of PSs), PSs and PLs (2 g of PSs plus 0.825 g of PLs), or placebo for 60 days, respectively. A total of 83 subjects completed the entire trial. After 60 days of intervention, the levels of total cholesterol (TC) and apolipoprotein B (ApoB) in the combined PSs and PLs group decreased by 7.8% and 6.4% ( Show less

Apolipoprotein B (apoB) is a well-known risk factor for atherosclerosis. However, studies examining its relation to atrial fibrillation (AF) have produced conflicting results and suggested possible sex-specific differences. This study investigated the sex-specific associations between serum apoB concentrations and incident AF and offer insight into the inconsistencies in previous research. A prospective analysis of 26,803 participants without pre-existing AF was performed using data from the Malmö Diet and Cancer Study. Sex-specific associations between apoB and AF were assessed using multivariable Cox proportional hazards models. To ensure the robustness of the results, several sensitivity analyses, such as restricted cubic spline modeling, competing risks regression, alternative adjustment strategies, subgroup analyses, follow-up time restrictions, and multiple imputation for missing data, were conducted. For median follow-up periods of 21.2 and 24.8 years in men and women, respectively, 2,768 and 2,968 incident cases of AF were recorded, respectively. Among women, unadjusted models showed a strong positive association between apoB and AF, with the highest versus lowest quartile showing a hazard ratio (HR) of 1.65 (95% confidence interval [CI] 1.49–1.84; Results show sex-specific observational links between apoB concentrations and risk of AF. In women, higher apoB levels were linearly inversely associated with AF, whereas in men, the association was borderline non-linear, with inverse effects seen mainly at lower apoB concentrations. These sex differences in AF susceptibility may partly reflect underlying atrial electrophysiological variations and hormonal influences, though whether these factors directly mediate the apoB-AF association remains speculative. The online version contains supplementary material available at 10.1186/s12944-026-02905-6. Show less

Staphylococcus aureus is a significant pathogen that poses a threat to both human and animal health. Its pathogenicity in humans has been extensively studied, however, the signaling pathways and key genes in Koi Carp responding to S. aureus from human rhinitis remain unclear. In this study, we established an intraperitoneal infection model in koi carp (Cyprinus carpio) using an S. aureus isolate from patients with rhinitis and integrated RNA-seq, qPCR, and ELISA to dissect the host response. Our findings reveal a dual-module immune evasion strategy employed by S. aureus in koi carp. Module I: The pathogen down-regulated the entire complement coagulation cascade (C3, C9, CFH, F7/9/10) and apolipoprotein-mediated opsonins (APOA1, APOB, APOC1/2), thereby crippling innate clearance. Module II: The host mounted a restricted but potent counter-response, characterized by type I IFN signalling (gvin1, MHC-I), NK/T-cell co-stimulation (CD244, SLAMF5), and the selective induction of IL-8 and IL-1β, while IL-6, IL-10, and TNF-α remained unchanged. Functionally, serum superoxide dismutase (SOD), catalase (CAT), and lysozyme (LZM) activities surged, confirming an oxidative burst, whereas splenic CD22R protein decreased, indicating B-cell disinhibition. These results establish a molecular basis for understanding the interaction between human-derived S. aureus and the immune system of aquatic organisms. Show less

The prevalence of atrial fibrillation (AF) and coronary events (CEs) overlap, yet their differential associations with risk factors and reciprocal mediation remain poorly characterized. In a large Swedish cohort study (baseline: 1991-1996), subjects without preexisting AF, CEs, stroke, or heart failure were analyzed. Associations between baseline risk factors (age, sex, body mass index or waist circumference, smoking, alcohol intake, systolic blood pressure, diabetes, apoA1 (apolipoprotein A1) and apoB (apolipoprotein B) levels, leukocyte counts, education, physical activity, and medications) and incident AF or CEs were assessed using multivariable-adjusted Cox models, with association strengths compared using competing risk analysis. For each risk factor, we performed multivariable-adjusted mediation models for survival data separately, first with AF as a time-varying mediator for CEs, then reciprocally with CEs for AF, to estimate bidirectional mediation pathways. Among 25 963 subjects (aged 58.0±7.60 years, 62.0% women), 5447 incident AF and 3462 incident CEs occurred (1125 overlapped cases) over a median follow-up of 24.6 and 24.9 years, respectively. Various traditional risk factors were predominantly associated with CEs, whereas certain ones, particularly adiposity indices, demonstrated stronger associations with AF. Notably, higher apoA1 levels were associated with higher AF risk but lower CEs risk, whereas higher apoB showed opposite associations ( AF and CEs demonstrated divergent risk profiles and bidirectional mediation effects. These findings inform risk stratification for AF, CEs, and their co-occurrence, and highlight the need for integrated prevention strategies for the comorbidity of AF and CEs. Show less

Low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL are generally considered normal. We tested the controversial hypothesis that a subset of individuals with 'normal' LDL-C levels may have a non-negligible risk of coronary artery disease (CAD) due to inherited factors, including monogenic variants and polygenic risk scores (PGS). A retrospective analysis of a prospective cohort from the Genomic Health Initiative at Endeavor Health, including 7880 participants without a prior diagnosis of CAD and not on statins at recruitment. Participants were stratified by baseline LDL-C levels and followed for incident CAD. The association of CAD risk with carrier status for pathogenic/likely pathogenic (P/LP) variants in Among participants, 31.2 % had LDL-C <100 mg/dL (normal), 39.5 % had LDL-C 100-129 mg/dL, and 29.3 % had LDL-C ≥130 mg/dL. Over a median follow-up of 8 years, CAD was diagnosed in 5.3 %, 6.9 %, and 7.6 % of participants in these LDL-C groups, respectively. Among those with normal LDL-C, CAD incidence rose to 9.5 % in individuals with high genetic risk (P/LP variants and/or high PGS). Genetic risk was significantly associated with CAD in multivariable models ( Individuals with 'normal' LDL-C levels can have substantial CAD risk if they carry high genetic risk. These findings underscore the importance of incorporating genetic information into CAD risk assessment, even among those with traditionally normal lipid profiles. Show less

The effects of lipid traits on colorectal cancer (CRC) risk and the extent to which obesity may modify these effects remain unclear. To examine the associations between lipid traits and CRC risk using an observational study and Mendelian randomization (MR) analyses, and the role of weight status in the potential associations. In the Guangzhou Biobank Cohort Study (GBCS), lipid profiles were measured during 2003-2008, and CRC events were identified through record linkage with the cancer registry. MR analyses assessed the causal effects of lipid traits on CRC using a genome-wide association study meta-analysis of 185,616 Europeans. Among 28,576 GBCS participants followed until 2020, 599 CRC events occurred. Participants in the highest quartile of apolipoprotein B (apoB) had a higher CRC risk (hazard ratio [HR] 1.43, 95% CI 1.02-2.01). This association remained in those with overweight/obesity (HR 2.21, 95% CI 1.28-3.83). MR analyses supported a detrimental effect of apoB on CRC (odds ratio 1.12 per 1 SD, 95% CI 1.02-1.22). MR analyses also showed positive associations for total cholesterol and the apoB/apolipoprotein A-I ratio, which were not significant in the observational study. Higher apoB levels were associated with an increased CRC risk in both observational and MR analyses, suggesting a potential role of apoB in CRC prevention, especially among participants with overweight/obesity. However, the limitations of single-time lipid measurements and the use of different ancestries across study designs indicate the need for further research to confirm the robustness and generalizability of the findings. Show less

The mechanisms by which Polycyclic Aromatic Hydrocarbons (PAHs) induce lipid metabolic disorder and inflammation in marine invertebrates remain poorly understood. This study utilized the clam Ruditapes philippinarum during its reproductive stage as a model organism, integrating high-throughput omics, computational simulation, and confocal microscopy to elucidate the accumulation characteristics and toxicological pathways of PAHs. The results demonstrated that PAHs significantly accumulated in the digestive gland and gonads, primarily sequestered within lipid droplets. This tissue distribution was found to be dependent on a lipid-dependent transport mechanism mediated by ApoB, FATP, and FABP4. Mechanistically, PAHs activated SREBP1 and PPARα, β nuclear receptors by interfering with the neuroendocrine system and endoplasmic reticulum stress pathways. This activation resulted in dysregulated lipid metabolism (favoring synthesis over degradation) and subsequent abnormal lipid (TG, PL) deposition. Furthermore, PAHs induced low-grade inflammation by synergistically activating the NF-κB and AP-1 pathways, a response driven by both lipotoxicity and cellular organelle stress. This finding provides important scientific evidence for contaminant risk assessment in aquatic organisms. Show less

Fibroblast growth factor 21 (FGF21) is a hepatokine that regulates systemic metabolism. Here, we delineate a novel regulatory pathway for FGF21 orchestrated by the small GTPase Rab2A. Our previous findings demonstrated that liver-specific deficiency of Rab2A impairs very low-density lipoprotein lipidation and promotes apolipoprotein B (APOB) accumulation. We now show that accumulated APOB drives the cleavage and activation of cAMP-responsive element-binding protein H (CREBH), a key hepatic transcription factor for FGF21 expression. Mechanistically, hepatic Rab2A inhibition protected mice from high-fat diet-induced obesity and was associated with markedly elevated circulating FGF21, the phenotype largely rescued by adenovirus-mediated knockdown of either CREBH or APOB. Collectively, we define a Rab2A-APOB-CREBH axis that is potentially essential for the hepatic regulation of FGF21. Show less

Diabetic lower extremity arterial disease (LEAD) is a manifestation of diabetic lower extremity vascular complications. This study aimed to screen the key single nucleotide polymorphism (SNP) gene signature in patients with type 2 diabetes mellitus (T2DM) and LEAD. A total of 147 patients with T2DM complicated by LEAD and 144 patients with T2DM without LEAD were enrolled for transcriptome sequencing. The Plink software was used to preprocess the data. Five machine learning methods were adopted to build the SNP diagnosis models. The receiver operating characteristic (ROC) curve was used to quantify the predicted probabilities of the model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the cluster Profiler package. Finally, regression statistical analysis was used to correlate the key SNPs with clinical information and biochemical indicators. A total of 24 SNPs were retained and 10 SNPs were risk allele genes. Nine SNPs (rs7412, rs1800629, rs699947, rs3918242, rs668, rs1800470, rs1800449, rs1800469, and rs1024611) were identified as the key SNPs sites. GO and KEGG pathway analyses revealed that these genes are mainly enriched in fluid shear stress and atherosclerosis. Finally, rs1800449 was associated with low-density lipoprotein cholesterol (LDL-C). With high density lipoprotein cholesterol (HDL-C), related site was rs1024611. The sites associated with total cholesterol (CHOL) were rs1800449 and rs7412.The site associated with apolipoprotein B (APOB) and apolipoprotein A1 (APOA1) were rs1800470 and rs1800469. This study authenticated nine SNPs for the diagnosis of T2DM patients with LEAD, which will be of great significance in the development of diagnostic molecular biomarkers for T2DM patients. Show less

BackgroundThe prevalence of peripheral arterial disease (PAD) is on the rise globally, leading to adverse clinical outcomes. Our aim was to investigate the causal relationship between apolipoprotein and PAD, as well as the potential mediating role of smoking, diabetes, hypertension, myocardial infarction, and ischemic stroke.MethodsWe employed two-sample Mendelian randomization (TSMR) to assess the causal effect of apoB/A1 on the risk of PAD and potential mediators (smoking, diabetes mellitus, hypertension, myocardial infarction, and ischemic stroke), as well as the causal effect of those mediators on PAD. The use of multivariate MR (MVMR) allowed us to explore and quantify the mediating role of these factors in the causal association between apoB/A1 and the risk of PAD.ResultsOur MR analysis showed that each standard deviation increase in apoB/A1 increased the risk of PAD by 46% (OR = 1.460, 95% CI: 1.255-1.697, Show less

Vascular calcification (VC) is prevalent in patients with chronic renal failure (CRF), and it is closely related to the morbidity and mortality of cardiovascular diseases; however, no medical treatments are available for this condition. Recent clinical studies have shown that plasma apolipoprotein C3 (ApoC3) levels are positively correlated with VC. However, whether ApoC3 is involved in VC remains unclear. Sections of calcified renal arteries from CRF patients were immunostained to measure calcium deposition and ApoC3 expression. VC was induced in ApoC3 transgenic (Tg) and knockout (KO) mice by both 5/6 nephrectomy and vitamin D ApoC3 expression levels were increased in calcified arteries from mice and patients with CRF. ApoC3 overexpression exacerbated calcium deposition in the calcified aortas from Tg mice in vivo, and in calcified aortic rings of Tg mice ex vivo and VSMCs infected by adenovirus of ApoC3 in vitro. Consistently with these findings, ApoC3 deficiency alleviated these effects. Furthermore, ApoC3 overexpression increased ferroptosis in calcified aortas and VSMCs, whereas ApoC3 deficiency suppressed ferroptosis. Further investigation revealed that ApoC3 inhibited the AMPK/NRF2 signaling pathway through toll-like receptor 2 (TLR2) in calcified VSMCs, downregulated the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), subsequently increased lipid peroxidation and promoted ferroptosis, ultimately exacerbating calcification in the VSMCs. Furthermore, we found that knockdown of ApoC3 by siRNA remarkably attenuated calcification of renal arterial rings in humans. We demonstrated that ApoC3 exacerbated VC and increased the osteogenic transdifferentiation in VSMCs by increasing ferroptosis. ApoC3 might be a potential target for VC treatment. Show less

Gene editing technologies have revolutionized therapeutic development, offering potentially curative and preventative strategies for cardiovascular disease (CVD), which remains a leading global cause of morbidity and mortality. This review provides an introduction to the state-of-the-art gene editing tools-including ZFNs, TALENs, CRISPR/Cas9 systems, base editors, and prime editors-and evaluates their application in lipid metabolic pathways central to CVD pathogenesis. Emphasis is placed on targets such as Show less

Atherosclerosis (AS) is a central pathological driver underlying most cardiovascular diseases. Gut microbiota and related metabolites participate in regulating atherosclerosis. Fifty C57BL/6J ApoE Atherosclerotic plaques accumulated in the aorta and aortic sinus after HFD, while statin and high-dose GP alleviated this burden. TC, TG, LDL-C, MCP-1, MCP-3 and IL-2 showed significant increase after HFD, while statin and GP decreased LDL-C, MCP-1 and MCP-3. The goblet cells, ZO-1 and Occludin decreased after HFD, while statin and GP increased them, indicating that the intestinal barrier integrity was improved. Additionally, the composition of gut microbiota was modulated by GP. Some candidate taxa were identified, such as This study suggests that GP is beneficial for alleviating atherosclerosis in HFD-induced ApoE Show less

Atherosclerosis is the inflammatory consequence of lipid accumulation with plaque formation in the vascular intima and is a common condition to develop into various cardiovascular diseases. Current therapies do not always lead to satisfactory treatment outcomes. Enterolactone, a mammalian lignan produced by bacterial transformation from plant lignans, has a preventive effect against cardiovascular disease. However, its effect on atherosclerosis and the underlying mechanism of action remain unclear. To explore the therapeutic effect of ENL on atherosclerosis and elucidate the underlying mechanism. We established a model of atherosclerosis on ApoE-/- C57BL/6 mice by high fat diet. The aortic root was collected and sectioned to assess arterial plaque area, collagen fibrillar proliferation, and lipid content. RT-qPCR was used to determine the inflammatory response in the artery of mice. The serum from mice was isolated to measure lipid levels, and the fecal microbiota was analyzed by 16S rDNA. H In the animals, enterolactone significantly improved lipid metabolism, attenuated ferroptosis occurring in the intima, facilitated the antioxidant mechanisms, and promoted healing of the endothelial lesions, by interacting with Nrf2. Of great importance, enterolactone massively altered the gut microbiota toward a curative outcome by elevating the abundance of beneficial bacteria, such as the SCFA-producing taxa. Additionally, ENL suppresses lipid peroxidation and inflammatory activation in HUVECs by regulating the Keap1/Nrf2/GPX4 pathway, and knocking down Nrf2 attenuates the treatment effect of ENL. Enterolactone effectively resolves intimal inflammation and redresses atherosclerosis by ameliorating the gut microbiome and modulating lipid metabolism via the Keap1/Nrf2/GPX4 pathway. Show less

Lecanemab binds "protofibrils," which are poorly characterized in human brain. It is unknown why lecanemab caused fewer amyloid-related imaging abnormalities (ARIAs) than other antibodies in trials. The apolipoprotein E (APOE) ε4 allele increases ARIA risk through unknown mechanisms. Equilibrium binding constants (K Lecanemab and aducanumab had indistinguishable preference for "protofibrils." Antibody preference for plaque-enriched versus CAA-enriched Aβ did not differ in soluble extracts or by IF staining but differed slightly in insoluble extracts. The APOE ε4 allele was associated with more soluble antibody-accessible Aβ. Lecanemab's binding target is similar to other antibodies'. Differences in antibody preference for plaque versus CAA Aβ may not explain differences in ARIA with edema rates. Show less

The Apolipoprotein E ε4 (APOE ε4) allele and white matter hyperintensities (WMH) have been implicated in the pathogenesis of Alzheimer's disease (AD). To investigate the dual roles of WMH in statistically moderating and mediating the relationship of APOE ε4 with AD and related phenotypes, as well as the potential biological correlates. Data were derived from 34,783 non-demented participants in the UK Biobank (UKB; mean age = 55 years; follow-up = 4.3 years) and 863 in the Alzheimer's disease Neuroimaging Initiative (ADNI; mean age = 71.9 years; follow-up = 3.8 years). Multivariable models evaluated associations of APOE ε4 status, WMH, and their interaction with cognition, neurodegeneration, core pathologies, and AD risk. Mediation analyses were performed to quantify the extent to which WMH statistically explained ε4-outcome associations. Cerebrospinal fluid proteomic and bioinformatic analyses were used to explore biological clues in a subsample of ADNI (n = 708). APOE ε4 carriers exhibited larger WMH volumes (p < 0.001, UKB) and faster WMH change rates (p = 0.019, ADNI). In UKB, WMH statistically mediated a small proportion of associations between APOE ε4 and poorer numeric memory performance, smaller hippocampal volume, increased incident AD and all-cause dementia (ACD). In ADNI, WMH showed statistical mediation signals in the associations of APOE ε4 with faster rates of cognitive decline, amyloid-β (Aβ) deposition, and neurodegeneration. Notably, WMH interacted with APOE ε4 to exacerbate cognitive decline, hippocampal atrophy, and Aβ deposition. Proteomic analyses suggested that neuroinflammatory and axonal injury pathways may be associated with the observed mediating and moderating patterns. WMH mediated and enhanced the associations of APOE ε4 with AD-related phenotypes. These findings warrant further studies to clarify the underlying mechanisms and clinical implications. Show less

This study examined the effects of APOE gene polymorphisms on body composition changes following high-intensity interval training (HIIT) in non-athletic Han Chinese university students from plain regions and identified genetic loci associated with HIIT sensitivity. A total of 236 Han Chinese undergraduates from non-physical education majors completed a 12-week HIIT program (three sessions/week). Body composition was assessed before and after the intervention. Genomic DNA from white blood cells was genotyped using Illumina chips. Single nucleotide polymorphism (SNP) quality control and association analyses with body composition indices were performed using PLINK (v1.09) and SPSS 25.0, applying linear regression and ANOVA with least significant difference (LSD) (1) Of 22 initial APOE SNPs, five passed quality control; the rs405509 locus was associated with HIIT-induced changes in body composition. (2) The GG genotype at rs405509 was associated with higher baseline BMI overall and with higher baseline weight, BMI, and waist-to-hip ratio in females than the TT genotype. (3) After training, GG carriers showed greater reductions in overall body fat than GT/TT carriers ( The rs405509 locus of the APOE gene is associated with body composition responses to HIIT, and female GG carriers show heightened responsiveness. Show less

Vascular remodeling involves structural and functional vascular changes in response to injury, aging, and disease. A key pathological feature is vascular smooth muscle cells (VSMCs) phenotypic switching, which is accompanied by mitochondrial dysregulation. Metabolic reprogramming resembling the Warburg effect alongside mitochondrial oxidative damage collectively drive this pathological VSMC transdifferentiation. We hypothesized that targeting mitochondrial ROS could restore mitochondrial integrity and enhance oxidative phosphorylation (OXPHOS) to counteract both oxidative damage and metabolic reprogramming in cardiovascular diseases associated with vascular remodeling. We proposed that the uncharacterized membrane-associated protein FAM177A1 drives VSMC mitochondrial oxidative impairment and metabolic reprogramming, thereby promoting VSMC phenotypic switching and vascular dysfunction. We modeled vascular remodeling using global We identify FAM177A1 as a key mitochondrial regulator that drives VSMC switching through SIRT3-SOD2 axis disruption. Targeting FAM177A1 restores redox-metabolic homeostasis through scavenging ROS and improving OXPHOS, establishing it as a novel therapeutic target against vascular remodeling. Show less

This study investigates the independent and interactive effects of apolipoprotein E (APOE) genotypes and white matter hyperintensities (WMH) on distinct neuropsychiatric symptom (NPS) phenotypes in patients with Alzheimer's disease (AD). We enrolled 325 AD patients consecutively diagnosed at a specialized memory clinic between May 2024 and May 2025. All participants underwent comprehensive clinical assessments-including the Chinese Mini-Mental State Examination (CMMSE), Activities of Daily Living (ADL) scale, and the Neuropsychiatric Inventory (NPI)-as well as 3T brain MRI for WMH quantification and APOE genotyping. First, we compared NPS profiles and cognitive/functional scores across APOE genotype groups (ϵ2/ϵ2-ϵ2/ϵ3, ϵ3/ϵ3, ϵ3/ϵ4, ϵ4/ϵ4) using analysis of variance (ANOVA) or Kruskal-Wallis tests, as appropriate. Second, we applied mediation analysis (PROCESS macro Model 4, 5,000 bootstrap samples) to examine whether WMH burden mediates the association between APOE genotype (X) and outcomes including CMMSE total score and domain-specific NPS subscores (delusions, agitation, irritability, euphoria). Significant differences emerged across APOE genotypes in both cognition (CMMSE, p < 0.05) and functional status (ADL, p < 0.05). At the symptom level, carriers of at least one ϵ4 allele exhibited higher agitation scores than non-carriers (p < 0.05); notably, the ϵ4/ϵ4 homozygotes showed significantly greater severity in delusions, agitation, irritability, and euphoria compared with all other genotype groups (all p < 0.05). Mediation analyses revealed no statistically significant indirect effect of APOE genotype on any outcome via WMH, indicating that WMH does not mediate these associations. Instead, APOE genotype exerted robust direct effects on both cognitive performance and specific NPS domains. APOE genotype-particularly the ϵ4/ϵ4 homozygous status-is associated with more pronounced cognitive decline and a distinct, severe NPS profile in AD, especially involving delusions, agitation, Euphoria, and irritability. These associations are independent of WMH burden, suggesting that APOE exerts direct neurobiological effects on neuropsychiatric manifestations. Thus, APOE genotyping holds dual clinical value: not only as a well-established biomarker for AD risk and diagnosis but also as a potential prognostic indicator for behavioral and psychological symptoms-offering actionable insights beyond conventional neuroimaging markers. Show less