Human APOB-expressing mice translate molecular phenotypes across the Alzheimer's disease spectrum.

On modeling two-dimensional time-dependent low-density lipoprotein (LDL) transport to the arterial intima: Effect of anisotropic permeability and diffusivity

To compare bioelectrical impedance analysis (BIA)-derived body composition between women with polycystic ovary syndrome (PCOS) and body mass index (BMI)-matched controls, and to investigate associations with metabolic, hormonal, and inflammatory markers. This cross-sectional study included 35 women with PCOS and 37 BMI-matched healthy controls, aged 18-40 years, with BMI <35 kg/m2. Clinical, anthropometric, metabolic, hormonal, and inflammatory parameters were assessed. Body composition was determined by direct segmental multifrequency BIA, including fat mass (FM), trunk fat mass (trunk FM), lean mass (LM), FM index, fat-to-lean mass ratio (F/L ratio), and trunk-to-peripheral fat ratio. Women with PCOS (28 ± 5.3 years, 26.6 ± 3.6 kg/m2) had higher FM index, trunk FM, and F/L ratio, while LM did not differ. They also showed higher fasting insulin, homeostatic model assessment for insulin resistance (HOMA-IR), glycated hemoglobin type A1c (HbA1c), low-density lipoprotein cholesterol, free androgen index, testosterone, androstenedione, and dehydroepiandrosterone sulfate, and lower sex hormone-binding globulin (SHBG). Among BIA parameters, FM, FM index, and F/L ratio showed more consistent associations with insulin resistance and selected inflammatory markers than trunk FM. In women with PCOS, these measures were positively correlated with fasting insulin and HOMA-IR and inversely correlated with SHBG. Associations with HbA1c and IL-6 were modest and not uniformly observed across all adiposity measures. No significant correlations were found with fasting glucose, HDL-c, triglycerides, or androgen levels. Women with PCOS exhibit higher adiposity, particularly reflected by FM index and F/L ratio, which show closer associations with metabolic and inflammatory dysfunction than trunk FM. These findings support the potential use of BIA as an accessible, low-cost, and noninvasive tool for the cross-sectional assessment of metabolic dysfunction in PCOS. Longitudinal studies are needed to clarify the clinical relevance of these associations.

CD36 serves as a potential drug-target to alleviate inflammation in atherosclerosis via leonurine-mediated blockade of its activation pocket.

Hypoxia-induced endothelial exosomal MSTRG.12883.2 enhances ox-LDL- induced phenotypic switching of vascular smooth muscle cells.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are globally prevalent conditions with limited therapeutic options. While macrophage scavenger receptor 1 (MSR1) is implicated in lipid uptake and inflammation, its role in MASLD pathogenesis remains poorly defined. MSR1 expression was analyzed using public databases and diet-induced animal models. Myeloid-specific Msr1 knockout (Msr1ΔMφ) mice were generated to investigate the specific function of MSR1. Invitro, oxidized low-density lipoprotein (ox-LDL)-stimulated primary mouse hepatic macrophages and bone marrow-derived macrophages were analyzed to explore potential mechanisms. Finally, an MSR1 inhibitor was employed to demonstrate therapeutic potential. MSR1 was upregulated in liver tissues and hepatic macrophages of MASLD/MASH patients and mice. Msr1ΔMφ mice exhibited significant attenuation of steatosis, inflammation, and fibrosis in comparison to wild-type littermates. Invitro, ox-LDL induced MSR1 expression, triggering lipid accumulation and pro-inflammatory cytokine release. Mechanistically, Msr1 deficiency upregulated the antioxidant enzyme superoxide dismutase 3 (SOD3) by inhibiting the PI3K/AKT/FoxO3a pathway, and these protective effects were blunted by Sod3 knockdown. Conversely, Sod3 overexpression ameliorated metabolic inflammation. Notably, pharmacological inhibition of MSR1 by fucoidan markedly attenuated the progression of diet-induced MASLD in mice. MSR1 promotes MASLD progression by mediating ox-LDL uptake in hepatic macrophages, which in turn exacerbates hepatic inflammation and fibrosis via PI3K/AKT/FoxO3a-dependent suppression of SOD3. Targeting MSR1 or its downstream pathway represents a promising novel therapeutic strategy for treating MASLD and MASH.

Egg yolk phospholipid peptides as dual-functional nanocarriers for curcumin: Enhanced hypolipidemic effects and mechanism.

MYLIP-dependent ubiquitination and degradation of LDLR in acute myeloid leukemia and MAPK signaling.

Growing evidence suggests that abnormal lipid metabolism occurs in amyotrophic lateral sclerosis, even in the presymptomatic stage, implying an etiologic link. However, the genetic mechanism underlying altered lipid levels in amyotrophic lateral sclerosis remains elusive. Therefore, in this study, we performed genetic correlation analysis, a cross-trait meta-analysis, tissue-specific enrichment analysis, and bidirectional two-sample Mendelian randomization analysis of European population to explore whether there is a genetic and causal relationship between lipids and amyotrophic lateral sclerosis. The effect of lipid-lowering drugs on amyotrophic lateral sclerosis was also evaluated using a drug target Mendelian randomization approach. The results showed a positive genetic correlation between amyotrophic lateral sclerosis and both high-density lipoprotein cholesterol and apolipoprotein A1 and identified 71 independent shared loci between amyotrophic lateral sclerosis and high-density lipoprotein cholesterol, as well as 55 independent shared loci between amyotrophic lateral sclerosis and apolipoprotein A1. These shared loci were enriched in the lipid metabolic pathway and the alcohol metabolic pathway. Further Mendelian randomization analysis targeting lipid-lowering drugs showed that single nucleotide polymorphisms within the ACLY and PCSK9 genes had a protective effect against amyotrophic lateral sclerosis risk by decreasing low-density lipoprotein cholesterol. The combination of ACLY and PCSK9 inhibitors has a greater protective effect on amyotrophic lateral sclerosis risk than that of PCSK9 inhibitors alone. In summary, there is a common genetic structure between lipids and amyotrophic lateral sclerosis. Mendelian randomization analysis supports an association between elevated blood lipids and the risk of developing amyotrophic lateral sclerosis, and the use of ACLY or PCSK9 inhibitors may improve disease prognosis.

Matrix metalloproteinase-14 promotes LRP6 shedding in vascular smooth muscle cells and its expression is elevated in the tibial arteries from peripheral artery disease.

UFM1 suppresses VSMCs phenotypic switching and attenuates atherosclerosis by inhibiting AKT phosphorylation.

A multi-level characterization of TfR, Mfsd2a and LRP1 in a stem cell derived in vitro model of the blood-brain barrier.

SUMOylation plays critical roles in both initiation and development of atherosclerosis. SUMO-specific protease 3 (SENP3), a SUMO-specific protease that targets SUMO2/3 for deSUMOylation, is involved in vascular remodeling and the modulation of macrophage functions. Here, we probed for the role of SENP3 in macrophages in the development of atherosclerosis. Stable and unstable plaques were collected from patients with atherosclerosis. A macrophage-specific SENP3 knockout mouse (Senp3Mac-KO) was generated and performed for a murine atherosclerosis model. Transcriptional sequencing was performed to identify potential mechanisms. SENP3 expression in macrophages was increased in unstable plaques, compared to stable plaques. The mean fluorescence intensity of SENP3 in macrophages infiltrating carotid plaques was positively correlated with circulating pro-inflammatory cytokines, low density lipoprotein (LDL-C), and triglycerides in atherosclerosis patients. Senp3Mac-KO mice exhibited a markedly reduced atherosclerotic plaque area in the aorta, compared to wild-type mice. Knockdown of SENP3 in macrophages resulted in decreased secretion of pro-inflammatory cytokines, increased secretion of anti-inflammatory factors, and reduced foam cell formation. Transcriptional analysis identified significant enrichment in Toll-like receptor (TLR4) signaling pathway modulated by SENP3. Genetic deletion of either TLR4 (Tlr4-/-) or Sterol O-Acyltransferase 2 (SOAT2) (Soat2-/-) attenuated the exacerbation of atherosclerosis development induced by SENP3 overexpression. Furthermore, SENP3 regulated TLR4 and SOAT2 expression indirectly via the transcription factor MYC rather than through direct deSUMOylation of TLR4 or SOAT2 themselves. Downregulation of SENP3 in macrophages suppresses pro-inflammatory cytokine release by inhibiting TLR4 signaling and reduces foam cell formation by impeding SOAT2 expression, both mediated by the transcription factor MYC, thereby attenuating the development of atherosclerosis. Hence, SENP3 may represent a potential therapeutic target in atherosclerosis.

Macrophage foam cell formation is the mark of atherosclerosis (AS). Krüppel-like factor (KLF)11 prevented the development of AS in diabetic conditions. However, it is not clear whether KLF11 inhibits macrophage foam cell formation. High-fat diet (HFD) was administered to ApoE-/- mice to build an invivo AS model. An adeno-associated virus (AAV) vector incorporating the macrophage-specific promoter CD68 was utilized to construct the macrophage-specific KLF11 overexpression mouse model. Treatment of RAW264.7 cells with oxidized low-density lipoprotein (ox-LDL) elicited foam cell formation. Dual luciferase reporter gene assays, ChIP, and RIP were applied to detect interactions between molecules. Pathological changes in arterial tissue were detected by HE staining, and the area of collagenous fibers was measured by Masson staining. Cholesterol efflux and cholesterol uptake were analyzed using NBD-cholesterol and Dil-ox-LDL methods, respectively. Lipid and inflammation levels were assessed using commercially available kits. Adipogenesis was assayed via Oil red O staining. KLF11 expression was downregulated, and overexpression of KLF11 suppressed inflammation, cholesterol levels, and lipid accumulation in AS. Meanwhile, overexpression of KLF11 inhibited ox-LDL-induced foam cell formation. Mechanistically, IGF2BP3 promoted KLF11 stabilization and expression in an m6A-dependent manner, and KLF11 transcriptionally inhibited ATP5B, which prevented NLRP3 inflammasome activation. IGF2BP3 mediated KLF11 stabilization to inhibit macrophage foam cell formation and alleviate AS through transcriptional inhibition of ATP5B to block NLRP3 inflammasome activation.

Late-life dementia has a strong heritable component. While the APOE ɛ4 allele is the strongest genetic risk factor of Alzheimer disease (AD), polygenic risk factors also play a significant role. Cardiometabolic diseases (CMDs) and their risk factors predict dementia in many cohorts, but how genetic predictors of CMD influence dementia-related outcomes remains unclear. In this study, we examined the associations of polygenic risk scores (PRSs) for major CMDs and the established APOE risk alleles with dementia-related outcomes in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, which is enriched for Black participants underrepresented in late-life dementia research. We constructed PRSs for AD and related dementias (ADRDs) and CMDs, including stroke, coronary artery disease, venous thromboembolism, type 2 diabetes, atrial fibrillation, blood pressure (systolic blood pressure, diastolic blood pressure, and pulse pressure), and circulating lipid levels (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides), using lead genome-wide significant genetic variants from the latest genome-wide association studies. We evaluated the predictive performance of each PRS on their primary end point and tested their associations with incident cognitive impairment (ICI), assessed using the 6-item screener and enhanced cognitive battery, and dementia as a contributing cause of death (DCCD). In addition, we explored the impact of APOE variants and, based on previous reports, local genetic ancestry at the APOE locus on these dementia-related outcomes. Up to 8,818 participants were analyzed (mean age 63.7 years; 58.9% female; 83.3% Black). For CMD PRS, we identified a significant association between PRS for pulse pressure and DCCD (hazard ratio [HR] 1.16, 95% CI 1.06-1.28, p < 1.76 × 10-3). We observed that the PRS for ADRD was associated nominally with DCCD (HR 1.12, 95% CI 1.00-1.25), but not with ICI among REGARDS participants, suggesting heterogeneity in associations across different cognitive-related end points. Furthermore, we identified a nominally significant (p < 0.1) attenuated effect of APOE risk alleles on ICI among those with African ancestry at the APOE locus, similar to previous reports. Higher PRS for pulse pressure was associated with increased DCCD risk, supporting shared genetic underpinnings between CMD and dementia.

Pharmacological inhibition of TRPM4 channel stabilizes atherosclerotic plaque via inhibiting AMPK-Beclin1-mediated autophagy.

To explore the genetic variant spectrum and epidemiological characteristics of Familial hypercholesterolemia (FH) patients in a regional population. A retrospective analysis was carried out on exome data from 15 841 unrelated patients undergoing trio-whole exome sequencing and couples undergoing comprehensive carrier screening at the Affiliated Women and Children's Hospital of Ningbo University from January 2022 to June 2025. The analysis focused on FH-associated LDLR, APOB, and PCSK9 genes recommended by the American College of Medical Genetics and Genomics (ACMG) as secondary findings with clinical actionability. Pathogenic and likely pathogenic variants with clear pathogenic effects were reported based on the latest ACMG variant interpretation standards. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: NBFE-2025-KY-178). Through the analysis of 15 841 exome sequencing datasets, 145 FH-associated gene variant carriers were identified, with a carrier rate of 0.92%, and 46 distinct variant sites were detected. Among these, LDLR gene variants accounted for 75.17%, comprising 37 variant sites, with c.268G>A (p.Asp90Asn), c.1747C>T (p.His583Tyr) and c.1879G>A (p.Ala627Thr) being high-frequency variants. APOB gene variants accounted for 22.76%, comprising 6 variant sites, with c.10579C>T (p.Arg3527Trp) being a high-frequency variant. PCSK9 gene variants accounted for 2.07%, comprising 3 variant sites. Three previously unreported variants were identified, including one in the LDLR gene, namely c.394_397delinsGA (p.R132Efs*47), and two in the APOB gene, namely c.10696del (p.Ser3566ValfsTer8) and c.2517del (p.Thr840Leufs*23). The two APOB variant carriers exhibited low levels of low-density lipoprotein cholesterol, consistent with the diagnosis of familial hypobetalipoproteinemia (FHBL). Above findings revealed the characteristics of FH-associated gene variant spectrum in a large regional population, which provided evidence-based support for proactive prevention and precision treatment.

Atherosclerosis is a progressive inflammatory process involving the arteries of the body that is driven by cumulative exposure to low-density lipoprotein cholesterol and other lipoprotein particles. Although clinical manifestations typically occur later in life, the atherosclerotic process can begin decades earlier if lipid levels are not well controlled. Despite this, current prevention strategies do not adequately account for young adults at elevated lifetime cardiovascular risk. This review examined multiple studies evaluating statin use in young adults and found that many high-risk individuals are not identified or treated under current approaches. The studies demonstrate that 2013 and 2018 American College of Cardiology and American Heart Association guidelines excluded a substantial proportion of young adults who experienced myocardial infarction and may have benefited from therapy prior to their event. In addition to this, statin therapy remains underutilized even in individuals who meet guideline-based criteria. Recent guideline updates in 2026 have emphasized cumulative lifetime exposure to atherogenic lipoproteins and expanded consideration of statin therapy to younger populations, reflecting an important shift toward earlier identification and prevention of cardiovascular risk. This review examines contemporary evidence regarding statin therapy in young adults, identifies barriers to treatment, and discusses potential strategies to improve early cardiovascular prevention.

LDL and non-HDL cholesterol with the lowest mortality in the general population in 1991-2018.

Plants have long been used as natural remedies for various diseases. Withania somnifera and Syzygium cumini are known for their potential therapeutic effects, particularly in managing lipid disorders. To evaluate the synergistic effects of Withania somnifera and Syzygium cumini on lipid profile in hyperlipidemic patients. This study included 60 patients, equally divided into four groups. Pre- and post-treatment assessments were conducted over 3 months. Group A (control) received Atorvastatin 10 mg HS; Group B received Withania somnifera (500 mg BD); Group C received Syzygium cumini (500 mg BD); and Group D received a combination of both (1000 mg QD). Data were analyzed using SPSS version 21 through paired sample t-test. Withania somnifera showed significant improvement in low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL). Syzygium cumini significantly reduced cholesterol, triglycerides and systolic blood pressure. The combination therapy demonstrated the most pronounced effects, significantly reducing LDL, VLDL, cholesterol and triglycerides, while also improving high-density lipoproteins (HDL), without adverse effects. The combination of Withania somnifera and Syzygium cumini may be an effective and safe approach for managing hyperlipidaemia due to its beneficial impact on lipid profile.