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Hypertriglyceridemia is a prevalent lipid disorder that considerably increases the risk of cardiovascular diseases, pancreatitis, and metabolic syndrome. Existing treatment options, including lifestyle changes and medications, often show limited effectiveness and may cause side effects. Olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (APOC3), represents a novel therapeutic strategy for lowering triglyceride levels. This systematic review and meta-analysis assess the efficacy and safety of olezarsen in comparison to a placebo for managing hypertriglyceridemia. A systematic literature search was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines across databases such as PubMed, Google Scholar, and the Cochrane Library, incorporating clinical trials and conference proceedings. Studies that compared olezarsen with a placebo and reported outcomes related to triglyceride levels, APOC3, and other lipid parameters were included. Two independent reviewers conducted data extraction and quality assessment. Statistical analyses were performed using RevMan, employing risk ratios for dichotomous variables and standard mean differences for continuous variables, with a random-effects model. Three randomized controlled trials, comprising 334 participants, were included in the analysis. Olezarsen significantly lowered triglyceride levels at both 6 months (standard mean difference [SMD]: -1.69, 95% CI -2.22 to -1.17) and 12 months (SMD: -1.64, 95% CI -2.22 to -1.07). Very low-density lipoprotein (VLDL) levels also declined at 6 months (SMD: -1.95, 95% CI -2.38 to -1.51) and 12 months (SMD: -0.83, 95% CI -1.13 to -0.53). Additional lipid profile improvements included reductions in total cholesterol, non-HDL cholesterol, and apoB levels, along with increases in HDL cholesterol and apoA-1. The incidence of adverse events was similar between the olezarsen and placebo groups. Olezarsen effectively reduces triglyceride and VLDL levels while enhancing lipid profiles in patients with hypertriglyceridemia. Although serious adverse events were more frequent, the overall safety profile remains acceptable. Further long-term research is required to validate these findings and optimize treatment regimens. Show less

In Traditional Chinese Medicine (TCM), dampness is a pathogenic factor arising from impaired production and transportation of bodily fluids. While Fuling Zexie decoction (FLZXD) has demonstrated therapeutic efficacy in dampness constitution (DC) treatment, the material basis underlying its constitutional modulatory effects remains unclear. This study proposes objective indicators for the differentiation and therapeutic evaluation of DC and elucidates the material basis of FLZXD in DC treatment. Serum exosome proteomic profiling was conducted across two independent cohorts to identify DC-related indicators and assess the therapeutic efficacy of FLZXD in DC-associated hyperlipidemia (DC-hyperlipidemia). The bioactive compounds of FLZXD were prioritized through a comprehensive analysis of patent documentation and network pharmacology, with subsequent validation of DC-related targets using enzyme-linked immunosorbent assay (ELISA). Proteomic analysis of serum exosomes revealed signatures that differentiate individuals with a balanced constitution (BC) from those with DC. The differentially expressed proteins (DEPs) were enriched predominantly in pathways related to the complement cascade and cardiovascular diseases. FLZXD demonstrated therapeutic efficacy against DC-hyperlipidemia, as evidenced by the reversal of DEPs expression following treatment, which was supported by the patentable findings and network pharmacology analysis. Through experimental validation and pharmacological evidence, the active herbs of FLZXD (Fuling, Zexie and Baizhu, collectively referred to as FZB) were identified, and a total of 73 putative therapeutic targets involved in the dampness-resolving effects of FZB were revealed. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment further confirmed that FLZXD exerts its anti-dampness effects primarily through regulation of the complement and coagulation cascades. Among eight candidate indicators specifically associated with DC, four proteins were validated via ELISA, indicating potential utility for the differentiation of DC. The sensitivity (%), specificity (%), fold change (FC), p-value, and area under the curve (AUC) for each indicator were as follows: apolipoprotein B-100 (APOB) (100.00, 80.00, 0.63, 0.0051, 0.94), complement factor H-related protein 1 (CFHR1) (90.00, 100.00, 0.55, 0.0001, 0.98), alpha-1-acid glycoprotein 1 (ORM1) (100.00, 80.00, 0.71, 0.0043, 0.92), and pigment epithelium-derived factor (SERPINF1) (90.00, 70.00, 0.66, 0.0002, 0.87). The integrative approach, combining proteomic profiling, network pharmacology analysis, and clinical validation, establishes an integrative approach for research on TCM constitutions. This approach provides (1) molecular insights into the differentiation of DC, (2) a foundation for mechanism-based, targeted therapeutic strategies, and (3) enhanced patient stratification to support personalized treatment approaches. Show less

Increasing evidence underscores the driving role of coding and non-coding variants in cancer development. Analyzing gene sets in biological processes offers deeper insights into the molecular mechanisms of carcinogenesis. Here, we developed geMER to identify candidate driver genes genome-wide by detecting mutation enrichment regions within coding and non-coding elements. We subsequently designed a pipeline to identify a core driver gene set (CDGS) that broadly promotes carcinogenesis across multiple cancers. CDGS comprising 25 genes for 25 cancers displayed instability in DNA aberrations. Variants within the TTN enrichment region may influence the folding of the I-set domain by altering local polarity or side-chain chemistry properties of amino acids, potentially disrupting its antigen-binding capacity in LUAD. Multi-omics analysis revealed that APOB emerged as a candidate oncogene in LIHC, whose genetic alterations within the enrichment region may activate key TFs, upregulate DNA methylation levels, modulate critical histone modifications, and enhance transcriptional activity in the HepG2 and A549 cell lines compared to Panc1. Additionally, CDGS mutation status was an independent prognostic factor for the pan-cancer cohort. High-risk patients tended to develop an immunosuppressive microenvironment and demonstrated a higher likelihood of responding to ICI therapy. Finally, we provided a user-friendly web interface to explore candidate driver genes using geMER ( http://bio-bigdata.hrbmu.edu.cn/geMER/ ). Show less

Lipoprotein(a) (Lp[a]) is an apolipoprotein B100 (apoB)-containing lipoprotein with a single apolipoprotein(a) (apo[a]) covalently bound to apoB via a disulfide bond and oxidized phospholipids linked to apoB and apo(a), which is associated with proinflammatory, prothrombotic, and proatherogenic mechanisms. Elevated Lp(a) (≥125 nmol/L [≥50 mg/dL]) is an independent, causal, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD), affecting >1.4 billion individuals worldwide. There are no pharmacological Lp(a)-lowering therapies approved in the United States; however, lipoprotein apheresis may be considered under certain circumstances. Germany is the only country where apheresis is approved for patients with elevated Lp(a) and progressing ASCVD. Existing lipid-lowering therapies including proprotein convertase subtilisin/kexin type 9 inhibitors have shown modest effects on Lp(a) levels but fallen short of clinically meaningful reductions of >50 to 100 mg/dL. Several Lp(a)-lowering, RNA-targeted agents are in development, including antisense oligonucleotides (ASOs) and small interfering RNAs. Pelacarsen is a second-generation ASO that targets the production of apo(a) and includes chemical modifications such as triantennary N-acetylgalactosamine that improve biostability, decrease off-target toxicity compared with unmodified ASOs, and allow rapid, specific uptake by hepatocytes, the site of apo(a) synthesis. A phase 2b study of pelacarsen showed ≥80% reduction in Lp(a) concentration with a favorable safety profile in patients with established ASCVD. The ongoing phase 3 Lp(a)HORIZON study is evaluating whether the Lp(a)-lowering effects of pelacarsen translate into reductions in the incidence of major cardiovascular events, also in patients with established ASCVD. Herein, we review the mechanism of action of pelacarsen and evidence for its Lp(a)-lowering effects. Show less

The peri- and early post-infarction period carries an increased risk of recurrent ischemic events. Oxidized phospholipids (OxPLs) are pro-inflammatory and contribute to plaque instability and thrombosis. This study aimed to: (1) assess changes, during the early post-MI period in OxPL-apo(a) and OxPL-apoB, (2) evaluate the effect of PCSK9 inhibition on these changes, and (3) explore their relationships with the changes in Lp(a) and LDL-C. Ninety-six participants with NSTEMI or STEMI were randomized to receive placebo (n = 48) or 420 mg subcutaneous evolocumab (n = 48) within 24 h of admission. OxPL-apo(a), OxPL-apoB, Lp(a), and LDL-C levels were measured at baseline and 30 days post-MI. In the placebo group, OxPL-apo(a) increased from 52.6 [19.3, 106.5] nmol/L at baseline to 61.7 [31.5, 116.9] nmol/L at 30 days (p = 0.014), and OxPL-apoB rose from 6.7 [3.1, 21] nmol/L to 8.8 [3.7, 23] nmol/L (p = 0.0045). In contrast, no significant changes were observed for OxPL-apo(a) (p = 0.17) or OxPL-apoB (p = 0.058) in the evolocumab group. OxPL-apo(a) correlated strongly with Lp(a) at baseline (r = 0.93, p < 0.001) and 30 days (r = 0.94, p < 0.001), and OxPL-apoB correlated similarly (baseline: r = 0.92, p < 0.001; 30 days: r = 0.93, p < 0.001). No correlation was observed between OxPLs and LDL-C. OxPL-apo(a) and OxPL-apoB levels were strongly correlated with Lp(a) and increased during the early post-infarction period. This increase was prevented by in-hospital administration of a PCSK9 inhibitor. These findings provide new insights into early changes in OxPLs following acute MI and suggest a protective role for PCSK9 inhibition during this critical period. Show less

The incidence of silent myocardial infarction (SMI) is increasing. Meanwhile, due to the atypical clinical symptoms and signs associated with SMI, the prognosis for patients is often poor. This prediction model used the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression analyses to screen variables. Predictive accuracy was assessed using the area under the receiver operating characteristic (ROC) curve (AUC). The clinical decision curve analysis (DCA), alongside the calibration curve and clinical impact curve (CIC) analyses, were used to assess model validity. This study included 174 patients, 64 (36.8%) of whom experienced SMI; logistic regression analysis identified six variables: gender, age, high-density lipoprotein cholesterol (HDL-C), apolipoprotein B/apolipoprotein A1 (ApoB/A1), uric acid (UA), and triglyceride glucose-body mass index (TyG-BMI). The results identified the TyG-BMI as a predictor of SMI (odds ratios (OR) = 1.02, 95% CI: 1.01-1.03; The TyG-BMI is an independent predictor of SMI. A prediction model based on the TyG-BMI showed good predictive ability for SMI. Show less

Coronary heart disease (CHD) arises from a complex interplay of genetic and environmental factors. This study examines the influence of This retrospective case-control study enrolled 900 CHD patients and 900 control subjects. We evaluated associations between conventional cardiovascular risk factors and polymorphisms at the No significant differences were observed in the distribution of The Show less

Hypercholesterolemia and other dyslipidemias are common risk factors for cardiovascular diseases (CVD) and development of atherosclerosis. International guidelines recommend LDL-C, non-HDL-C, and apoB under some conditions for clinical use in evaluating risk of CVD. In part 2 of this review, newer risk factor data for apoA-1, and the apoB/apoA-1 ratio is presented for atherosclerotic plaques, HDL-C versus apoA-1, inflammatory diseases, cancer, and metastases. Compared to conventional lipids, these apolipoproteins add strong clinical risk information for these CVD disorders and for a range of other diseases. Prospective studies, reviews, meta-analyses, case control, nested-case, and therapeutic studies are analyzed. Searches were conducted with Google and in PubMed, and CVD journals for peer-reviewed publications. In part 1 of this review, newer risk factor data for apoA-1 and the apoB/apoA-1 ratio are presented for cardiovascular, cerebrovascular, diabetes, and other CVD manifestations of atherosclerosis. Strong associations between apoB, apoA-1 and especially the apoB/apoA-1 ratio and development of atherosclerosis-related risk of multiple CVD diseases have been documented world-wide. These data indicate that the balance, i.e. the Show less

Hypercholesterolemia and other dyslipidemias are common risk factors for cardiovascular diseases (CVD) and development of atherosclerosis. International guidelines recommend LDL-C, non-HDL-C and apoB under some conditions for clinical use in evaluating risk of CVD. In part 1 of this review newer risk factor data for apoA-1, and the apoB/apoA-1 ratio is presented for cardiovascular, cerebrovascular, diabetes and other CVD manifestations of atherosclerosis. Compared to conventional lipids, these apolipoproteins add strong clinical risk information for these CVD disorders and for a range of other diseases. Prospective studies, reviews, meta-analyses, case control, nested-case and therapeutic studies are analyzed. Searches were conducted with Google and in PubMed, and CVD journals for peer-reviewed publications. In part 2 of this review newer risk factor data for apoA-1, and the apoB/apoA-1 ratio is presented for atherosclerotic plaques, HDL-C versus apoA-1, inflammatory diseases, cancer, and metastases. Associations between apoB, apoA-1 and especially the apoB/apoA-1 ratio and development of atherosclerosis related risk of multiple CVD diseases have been documented world-wide. This data indicates that the balance, i.e. the ratio between the atherogenic apoB and the protective apoA-1, significantly improves risk evaluation and prediction of CVD, hence calling for an update of guidelines. Show less

Liu et al. (2025) analyzed UK Biobank data, using Principal Component Analysis (PCA) to identify lipid patterns associated with depression and bipolar disorder. Their work reported that the first principal component (PC1), reflecting Apolipoprotein B (ApoB), cholesterol, and low-density lipoprotein cholesterol (LDL-C), showed a protective effect against depression. However, their methodological approach warrants discussion. PCA is a linear dimensionality reduction technique. The authors noted nonlinear relationships between lipid profiles and mood disorder risk, contradicting PCA's inherent linearity assumption. Applying linear methods like PCA to nonlinear data can lead to significant distortions, systematic bias, and underfitting, failing to capture true data complexity. PC1 may have obscured genuine associations by forcing distinct biological features into a single linear equation, potentially diluting crucial signals. For future research, complementing PCA with unsupervised learning techniques like Feature Agglomeration (FA) and Highly Variable Gene Selection (HVGS) could offer a more robust approach. Additionally, using nonlinear nonparametric statistical methods such as Spearman's rho or Kendall's tau would be beneficial. These methods detect monotonic relationships without linearity assumptions, precisely capturing potentially nonlinear associations and enhancing interpretability in translational biomarker research. Show less

Primary bone marrow large B-cell lymphoma (PBM-LBCL) is a rare entity with poorly defined genetic features. We performed whole-exome sequencing on bone marrow specimens from 19 PBM-LBCL cases and compared them with 11 cases of conventional diffuse large B-cell lymphoma (DLBCL) with secondary bone marrow involvement. Clinicopathological characteristics, including hemophagocytic lymphohistiocytosis (HLH), hepatosplenomegaly, International Prognostic Index (IPI) score, treatment with chemotherapy plus rituximab, CD5 expression, histopathological patterns, germinal center B-cell-like subtype and follow-up duration, did not differ significantly between the two groups. Both IPI score and treatment regimen emerged as independent predictors of survival. Sequencing analysis revealed 7974 moderate- to high-impact variants. The MCD molecular subtype predominated in both cohorts, while the EZB subtype was observed exclusively in PBM-LBCL. A distinct 16-gene mutational signature differentiated PBM-LBCL from DLBCL. Among these, 10 genes (KMT2D, APOB, BBS9, CFAP46, EIF4G3, FAT1, MED12L, TG, TNR, ZFHX4) were uniquely mutated in PBM-LBCL, and three genes (CNTNAP3B, IL16, ZNF814) were exclusive to DLBCL. Mutations in COL5A3, PCNT, HMCN2, and OSBPL10 were associated with HLH. Notably, BTG1 mutation was significantly associated with poor prognosis in both univariate and elastic net-regularized multivariate analyses. In summary, PBM-LBCL harbors a distinct genetic profile, characterized by a unique 16-gene signature that distinguishes it from DLBCL with secondary bone marrow involvement. BTG1 mutation is associated with adverse outcomes, highlighting their potential as prognostic biomarkers or therapeutic targets. These findings advance our understanding of the molecular landscape and prognostic stratification of PBM-LBCL. Show less

Apolipoprotein B (APOB) rs676210 polymorphism has been associated with altered lipid metabolism and cardiovascular risk in various populations; however, data from Vietnamese populations remain limited. This study aimed to investigate the association of the APOB rs676210 variant with lipid profiles among Vietnamese individuals newly diagnosed with elevated low-density lipoprotein cholesterol (LDL-C). A cross-sectional study was conducted among 69 Vietnamese adults newly diagnosed with elevated LDL-C (≥130 mg/dL) at a tertiary hospital in Southern Vietnam. Participants were genotyped for APOB rs676210 using real-time polymerase chain reaction (PCR) with allele-specific probes. Lipid profile components, including LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and ApoB, were compared across genotype groups (AA vs GA/GG) and alleles (A vs G). Statistical analyses involved t tests, chi-square tests, and multivariable linear regression adjusted for age, sex, the BMI, and diabetes. P<.05 was considered statistically significant. Of the 69 participants, 32 (46.4%) carried the AA genotype, while 37 (53.6%) carried the GA or the GG genotype. The AA genotype was associated with significantly higher LDL-C (mean 5.19, SD 0.95, vs mean 4.37, SD 0.97, mmol/L; P<.001), non-HDL-C (mean 5.94, SD 1.08, vs mean 5.31, SD 1.22 mmol/L; P=.03), and ApoB (mean 149.5, SD 26.3, vs mean 136.9, SD 15.2, mg/dL; P=.02) and lower HDL-C (mean 1.26, SD 0.31, vs mean 1.44, SD 0.39, mmol/L; P=.03) compared to the GA/GG genotype. Allele-based analysis showed that carriers of the A allele (98/138, 71%) also had higher LDL-C (mean 4.91, SD 1.02, vs mean 4.36, SD 0.97, mmol/L; P=.004) and ApoB (mean 145.6, SD 23.2, vs mean 135.9, SD 16.0, mg/dL; P=.02) than G allele carriers (40/138, 29%). These associations remained significant after multivariate adjustment. APOB rs676210 polymorphism is associated with significant differences in lipid profiles among Vietnamese adults with elevated LDL-C. Specifically, the A allele and the AA genotype confer a more atherogenic profile, suggesting potential utility as a genetic marker in lipid screening and personalized cardiovascular risk management in this population. Show less

To investigate the relationship between serum lipid levels and the risk of Chronic obstructive pulmonary disease (COPD) in the UK Biobank. We performed this prospective study in 381,938 adults without COPD from UK Biobank. Serum high-density cholesterol (HDL-C), low-density cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), apolipoprotein A (ApoA) and apolipoprotein B (ApoB) were measured and classified into quintiles. Restricted cubic spline (RCS) analysis was applied to visualize the dose-response relationship between lipids and COPD risk and Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). We documented 10,443 incident COPD cases. Nonlinear relationships were found between HDL-C, LDL-C, TC, ApoA, ApoB and COPD risk with RCS analysis (P values for non-linearity < 0.05). Accordingly, multivariable-adjusted regression analysis indicated abnormal HDL-C and ApoA, and low LDL-C, TC and ApoB were associated with increased risk of COPD. Compared to intermediate quintile (Q3) group, both high or low HDL-C and ApoA were associated with risk of COPD. Corresponding HRs (95% CIs) were 1.15 (1.08-1.22), 1.16 (1.09-1.23) in Q1 group and 1.08 (1.01-1.16), 1.07 (1.00-1.14) in Q5 group. For LDL-C, TC and ApoB, there were more than 29% higher risk was observed in Q1 group with HRs (95% CIs) of 1.34 (1.27-1.42), 1.38 (1.30-1.46) and 1.29 (1.21-1.37), while HRs (95% CIs) were 0.88 (0.83-0.94), 0.92 (0.86-0.98) and 0.90 (0.84-0.95) in Q5 groups. We also observed the interactions between specific lipids and age at recruitment, sex and smoking status with stratified analysis. Our study provides the first evidence demonstrating the associations between six major serum lipids and COPD risk, revealing multiple nonlinear relationships. There were U-shaped associations between serum HDL-C, ApoA and COPD risk, and L-shaped associations between LDL-C, TC, ApoB and COPD risk. Show less

Primary Sjögren's Syndrome (pSS) is a chronic autoimmune condition affecting lacrimal and salivary glands. While previous studies suggest potential associations between dyslipidemia and autoimmune diseases, the causal relationship between lipid-lowering medications and pSS remains unclear. This study employed drug-targeted Mendelian randomization (MR) analysis to assess the impact of lipid-lowering drugs on pSS risk, focusing on genetic targets including HMGCR, PCSK9, NPC1L1, APOB, CETP, and LDLR. Data were sourced from the Global Lipids Genetics Consortium and UK Biobank. Significant single-nucleotide polymorphisms linked to LDL cholesterol were utilized as instrumental variables. Causal effects were estimated using Inverse Variance Weighted, Weighted Median, MR Egger, Simple Mode, and Weighted Mode methods. Robustness was ensured through heterogeneity and sensitivity analyses. The inhibition of HMGCR and CETP genes was found to be significantly associated with an increased risk of developing pSS (HMGCR: OR = 3.602, 95% CI [1.051, 12.344], p = 0.041; CETP: OR = 12.251, 95% CI [2.599, 57.743], p = 0.002). HMGCR and CETP may affect pSS risk via non-lipid pathways, suggesting distinct mechanisms among different lipid-lowering drug targets. This study provides compelling evidence suggesting that lipid-lowering drugs may contribute to the risk of pSS, thus offering new insights for clinical intervention strategies. Show less

To assess the association between the single nucleotide polymorphisms (SNP) rs174575 and rs2845574 of the fatty acid desaturase 2 (FADS2) gene and gestational diabetes mellitus (GDM). A total of 1 514 pregnant women who visited West China Second University Hospital of Sichuan University between January 1, 2013 and December 31, 2021 were enrolled in this study. Among them, 583 were diagnosed with gestational diabetes mellitus (GDM group), and 931 had normal pregnancies (control group). The SNPs rs174575 and rs2845574 of the FADS2 gene were analyzed using Sanger DNA sequencing. Plasma levels of insulin (INS), apolipoprotein A1 (apoA1) and apolipoprotein B (apoB) were measured using enzymatic methods, chemiluminescence and immunoturbidimetry. This study was approved by the Medical Ethics Committee of the West China Second University Hospital of Sichuan University (Ethics No.: 2020-036). The main genotype at the rs174575 C/G and rs2845574 C/T loci were CC in both GDM and control groups. No significant difference was found between the GDM and control groups regarding the genotypic or allelic frequencies of rs174575 and rs2845574 sites (P > 0.05). Among the GDM group, individuals with the GG genotype at the rs174575 site had lower plasma HDL-C levels compared to those with the CC genotype (P < 0.05), and had higher atherogenic indices (AI) compared with the CC and CG genotype (P < 0.05; P < 0.05). Individuals with the TT genotype at the rs2845574 site had higher AI compared with the CT genotype (P < 0.05). Among the control group, individuals with the GG genotype had lower diastolic blood pressure (DBP) compared to those with the CC genotype (P < 0.05). Additional subgroup analysis demonstrated that the rs174575 polymorphism was associated with AI levels in obesity subgroup of GDM, TG levels in non-obese subgroup of control and DBP levels in the obese subgroup of control (P < 0.05; P < 0.05; P < 0.05). The FADS2 rs174575 and rs2845574 polymorphisms in GDM patients are associated wit HDL-C and AI levels, and the FADS2 rs174575 polymorphisms was also associated with DBP levels in normal pregnant women. The AI and DBP levels have a BMI-dependent effect. Show less

To determine whether low-density lipoprotein cholesterol (LDL-C) levels, set by the balance of clearance and production, causally contribute to septic shock 28-day mortality. We measured LDL-C levels and genotypes in patients with septic shock. Using Genotyping and Genome-Wide Association Study summary statistics from over 150,000 Japanese participants, we genetically predicted pre-infection LDL-C levels. Two-sample Mendelian randomization was used to assess the causal relationship between predicted pre-infection LDL-C levels and 28-day mortality. We analyzed PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) genotypes to determine if LDL-C clearance or production was the underlying mechanism. Multicenter ICUs in Japan. Genotyped septic shock patients ( n = 614). None. Predicted pre-infection LDL-C levels were much higher than directly measured LDL-C levels at the onset of septic shock (141 mg/dL vs. 40 mg/dL, p < 0.001). Two-sample Mendelian randomization revealed that high predicted pre-infection LDL-C levels were causally associated with increased septic shock 28-day mortality (hazard ratio, 2.78; p = 0.039). PCSK9 genetic variants that increase LDL-C clearance via the LDL receptor (genetically proxied PCSK9 inhibitor treatment) were associated with decreased mortality ( p = 0.003) while HMGCR genetic variants that decrease LDL-C production (genetically proxied statin treatment) were not associated with decreased septic shock mortality (indeed the opposite effect was observed, p = 0.039). The two main genetic variants driving the association between high predicted pre-infection LDL-C levels and increased mortality were in apolipoprotein genes ( ApoB100 -rs13306206 and ApoE -rs7412), apolipoproteins involved in LDL-C binding to the LDL receptor. Low LDL-C clearance explains the causal association between high genetically predicted pre-infection LDL-C levels and increased septic shock mortality. PCSK9 , ApoB , and ApoE variants were identified as causal, all related to the LDL receptor or its interaction with LDL-C. Enhancing LDL receptor-mediated clearance of pathogen lipid toxins may improve septic shock outcomes. Show less

Atherosclerosis is partially driven by the accumulation of oxidised low-density lipoprotein (oxLDL), which facilitates foam cell formation and vascular inflammation. This research examines the efficacy of bamboo charcoal (BC) as a bioactive agent for neutralising oxLDL using both in silico and in vitro methodologies. Molecular docking demonstrated significant binding affinities between BC and essential constituents of oxLDL, such as oxidised cholesterol and apolipoprotein B-100, facilitated by π-π stacking and electrostatic interactions. Molecular dynamics simulations demonstrated the stability of these complexes over 300 ns, indicating sustained molecular interactions. Quantum chemical calculations employing density functional theory showed a narrow HOMO-LUMO gap of 0.45 eV and a significant dipole moment of approximately 45 D, underscoring the reactive and polar characteristics of BC. Electrostatic potential mapping and thermodynamic analyses provided additional evidence for BC's spontaneous and stable binding to oxLDL components. The Oil Red O staining and total cholesterol estimation assays were conducted on oxLDL-treated RAW 264.7 macrophages in vitro indicated that BC significantly decreased macrophage-derived foam cell formation, thereby confirming its ability to reduce oxLDL-induced lipid accumulation. The findings suggest that BC functions as a physical adsorbent and a participant in direct chemical interactions with oxLDL, providing a dual-action therapeutic approach to atherosclerosis. Show less

The combination of acute pancreatitis (AP), severe hypertriglyceridemia (HTG), and diabetic ketoacidosis (DKA) poses a life-threatening triad. Although DKA is a frequent complication in children, this triad is rare. We report a 10-year-old girl with type 1 diabetes mellitus (T1DM) for 10 months, who presented with DKA, severe HTG, and AP. Her serum was lipemic. She had HTG (1733 mg/dl, 19.5 mmol/L; reference range, 90-129 mg/dl, 1,016-1,456 mmol/L) and severe abdominal pain that did not improve despite treatment for ketoacidosis. She had high lipase levels (1581 U/L, reference range 28-100 U/L), and pancreatitis was detected on abdominal tomography. She recovered with a combination of hydration and insulin therapy. A heterozygous p.N318S (c.953A>G) variant was detected in her lipoprotein lipase (LPL) gene. Her apolipoprotein B (ApoB) was elevated at 1.44 g/L (reference range, 0.6-1.17 g/L, 60-117 mg/dl). It is well established that both the likely pathogenic LPL variants and high ApoB concentrations contribute to an increased risk of cardiovascular complications. Therefore, it is recommended to evaluate for a pathogenic variant in the LPL gene in children with T1DM who do not have dyslipidemia but exhibit the rare triad of AP, HTG, and DKA. Show less

Individuals with familial hypercholesterolemia (FH) are at high risk of premature cardiovascular disease. A healthy lifestyle and lipid-lowering medication are essential to reduce this risk. We examined if adherence to a heart healthy diet provides additional risk reduction independent of lipid-lowering medication. The Dutch Lipid Clinic Network (DLCN) criteria was used to diagnose FH (n=559 individuals with probable or definite FH) in the Copenhagen General Population Study(n=106,899) and the Copenhagen City Heart Study(n=7,451). Individuals were categorised by their level of heart healthy dietary adherence to Danish dietary guidelines, corresponding to international guidelines. Concentrations of low-density lipoprotein (LDL) cholesterol, apolipoprotein B (apoB), non-high-density lipoprotein (HDL) cholesterol, remnant cholesterol, triglycerides, and lipoprotein(a) (Lp(a)), and risk of ischaemic heart disease (IHD) were assessed by clinical FH category and level of dietary adherence. Women had a higher heart healthy dietary adherence compared to men. Mean concentrations of LDL cholesterol, apoB, non-HDL cholesterol, remnant cholesterol, and triglycerides increased stepwise by lower dietary adherence category, regardless of clinical FH category. Lp(a) concentration did not change by adherence to dietary guidelines. Results were similar in individuals taking lipid-lowering medication. Risk of ischemic heart disease (IHD) was lower in individuals with a higher dietary adherence (ranging from 8 to 57 % lower risk) compared to individuals with a very low dietary adherence regardless of clinical FH category. Adherence to a heart healthy diet is associated with lower concentrations of atherogenic lipids and lipoproteins, and lower risk of IHD in individuals with clinical FH, independent of treatment with lipid-lowering medication. Dietary adherence should be emphasised as an important tool in addition to treatment with lipid-lowering medication in individuals with FH. Show less

An abnormal accumulation of immune cells and inflammation has been described in ascending aortic aneurysm, but the factor driving disease initiation remains elusive. Interestingly, ascending aortic dilatation often occurs alongside aortic regurgitation but rarely with aortic stenosis. We sought to investigate ascending aortic aneurysm initiation by assessing the relation between aortic regurgitation and vascular activation and inflammation. In this prospective cohort study, patients with tricuspid aortic valves undergoing elective open-heart surgery were included. Aortic specimens from organ donors were obtained through the University of Miami Tissue Bank. Spatial transcriptomics measured gene expression in nondilated aortic endothelium, intima, and subintima. Immunohistochemistry determined protein expression. Aortic dimensions were recorded preoperatively and 10 years after surgery using echocardiography. Aortic gene expression affected by physiological blood flow was previously measured in Wistar rats. We show a mesenchymal activation of endothelial cells, possibly mediated by bidirectional flow, in the nondilated ascending aorta of patients with aortic regurgitation, accompanied by intimal infiltration, retention, and oxidation of apoB-containing lipoproteins. We further observed intimal upregulation of genes coding for core proteins of lipoprotein-binding proteoglycans and the Our results highlight a distinct pathological role of aortic regurgitation in ascending aortic aneurysm formation by promoting mesenchymal activation of endothelial cells and lipoprotein-related immune cell infiltration and inflammation in patients with tricuspid aortic valves. We also provide novel insights into the long-term impact of surgical aortic valve replacement on ascending aortic growth and suggest a diagnostic or therapeutic target in oxidized low-density lipoprotein cholesterol. Show less

Per- and polyfluoroalkyl substances (PFAS) pose potential health risks to lipid metabolism, but the effects of emerging PFAS alternatives, particularly in children, remain unclear. This cross-sectional study investigated the association between emerging PFAS exposure and lipid levels in 294 Chinese children aged 7-10 years, analyzing blood samples for 14 PFAS and lipid profiles, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB). Exposure to 6:2 Cl-PFESA, PFO4DA, and PFO5DoDA was associated with higher TC, TG, and LDL levels, with PFO4DA increasing the TC by 1.7% and PFO5DoDA increasing the TG by 10.7%. Weighted quantile sum (WQS) regression showed mixed PFAS exposure positively associated with TG (0.08, 95% CI: 0.007, 0.153). PFO4DA had the highest weight for TC (0.468), TG (0.327), LDL (0.57), ApoA1 (0.243), and ApoB (0.466), while PFMOAA had the highest weight for HDL (0.332). Bayesian Kernel Machine Regression (BKMR) analysis confirmed positive associations between the PFAS mixture and TC, TG, LDL, and ApoA1. Mediation analysis revealed that mtDNAcn significantly mediated PFAS exposure's effect on TG levels, explaining 27.2-74.2% of the total effect. These findings highlight the need for regulatory action to address the emerging PFAS risks. Show less

The research on Apolipoprotein A-1 (ApoA-1), Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) ratio, and preterm birth was limited to the first and second trimesters. No studies have been conducted in the third trimester, and thus this study aimed to investigate the association between ApoA-1, ApoB/ApoA-1 ratio, and preterm birth in patients with gestational diabetes mellitus (GDM) in the third trimester. This study collected the data of single pregnant women of age at pregnancy 16-49 years with GDM who were in the third trimester and gave birth in the Obstetrics department, Hangzhou Linping District Women & Children Hospital from December 1, 2023, to April 20, 2024. The patients were divided into preterm birth group and term birth group according to whether they had preterm birth or not. The restricted cubic spline analysis was used to explore whether there was a linear relationship between ApoA-1, ApoB/ApoA-1 ratio, and preterm birth. The relationship between ApoA-1, ApoB/ApoA-1 ratio, and preterm birth in patients with GDM was explored using trend analysis. The receiver operating characteristic and Decision Curve Analysis were conducted to evaluate the predictive efficacy and clinical benefits of ApoA-1, ApoB/ApoA-1 ratio in predicting preterm birth in patients with GDM. There was a linear relationship between ApoA-1, ApoB/ApoA-1 ratio, and preterm birth. The higher the ApoA-1 level, the lower the risk of preterm birth; the higher the ApoB/ApoA-1 ratio, the higher the risk of preterm birth. ApoA-1, ApoB/ApoA-1 ratio in pregnant women with GDM in the third trimester were associated with preterm birth. Show less

Obicetrapib is a next-generation, oral, selective cholesteryl ester transfer protein inhibitor known to significantly affect atherogenic lipoproteins, including low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), nonhigh-density lipoprotein cholesterol (Non-HDL-C), and lipoprotein(a) [Lp(a)]. To evaluate the lipid-lowering efficacy of obicetrapib based on available evidence. This systematic review was drafted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search was conducted to identify randomized clinical trials assessing the lipid-lowering effects of obicetrapib compared to placebo. Fixed and random-effects models were used. Five randomized clinical trials (n = 288 patients) were included in this analysis. Patients treated with obicetrapib exhibited significantly greater reductions in LDL-C (mean difference [MD]: 41.4% [95% CI: 45.7 to -37.1]; I²: 6%), ApoB (MD: 26.5% [95% CI: 31.3 to -21.6]; I²: 45%), and Non-HDL-C (MD: 34.5% [95% CI: 37.0 to -31.6]; I²: 80%) compared to those receiving a placebo. Additionally, HDL-C levels were significantly higher in the obicetrapib group (MD: 157.4% [95% CI: 142.2 to 172.6]; I²: 69%). While triglyceride levels did not differ significantly between the 2 groups, Lp(a) levels were notably reduced with obicetrapib treatment (MD: 39.5% [95% CI: 54.6 to -24.3]; I²: 67%). Obicetrapib is associated with significant reductions in key atherogenic lipoproteins, including LDL-C, ApoB, Non-HDL-C and Lp(a). Further investigation is needed to assess its impact on cardiovascular risk. Show less

Ovarian cancer presents a significant treatment challenge due to its insidious nature and high malignancy. As autophagy is a vital cellular process for maintaining homeostasis, targeting the autophagic pathway has emerged as an avenue for cancer therapy. In the present study, we identify apolipoprotein B100 (ApoB100), a key modulator of lipid metabolism, as a potential prognostic biomarker of ovarian cancer. ApoB100 functioned as a tumor suppressor in ovarian cancer, and the knockdown of ApoB100 promoted ovarian cancer progression in vivo. Moreover, ApoB100 blocked autophagic flux, which was dependent on interfering with the lipid accumulation/endoplasmic reticulum (ER) stress axis. The effects of LFG-500, a novel synthetic flavonoid, on ApoB100 induction were confirmed using proteomics and lipidomics analyses. Herein, LFG-500 induced lipid accumulation and ER stress and subsequently blocked autophagy by upregulating ApoB100. Moreover, data from in vivo experiments further demonstrated that ApoB100, as well as the induction of the lipid/ER stress axis and subsequent blockade of autophagy, were responsible for the anti-tumor effects of LFG-500 on ovarian cancer. Hence, our findings support that ApoB100 is a feasible target of ovarian cancer associated with lipid-regulated autophagy and provide evidence for using LFG-500 for ovarian cancer treatment. Show less

To evaluate whether integrating Apolipoprotein B (ApoB) into the Systematic Coronary Risk Evaluation 2 (SCORE2) cardiovascular risk prediction framework improves its predictive accuracy and clinical applicability within the UK Biobank population. A 10-year prospective cohort study was conducted with 448 303 UK Biobank participants eligible for SCORE2 calculation. Three approaches were employed: (i) threshold analysis to determine the optimal ApoB cutoff for cardiovascular disease (CVD) risk prediction using Youden's Index, (ii) assessment of the synergistic effect of SCORE2 and ApoB through concordant and discordant classifications, and (iii) recalibration of the SCORE2 model by incorporating ApoB as an additional predictor. Each 0.2 g/L increase in ApoB was associated with an increased subdistribution hazard for CVD events [subdistribution hazard ratio (SHR): 1.13; 95% CI: 1.11-1.14, P < 0.001], accounting for non-cardiovascular death as a competing risk. Threshold analysis identified an optimal ApoB cutoff at 1.18 g/L; however, it demonstrated limited discriminatory performance (area under the curve 0.54), with low sensitivity (32.4%), and moderate specificity (74.4%). Individuals with both low ApoB (<1.18 g/L) and low SCORE2 risk (<5%) had a lower CVD incidence rate (232.51 per 100 000 person-years) compared with those identified as low risk by SCORE2 alone (253.69 per 100 000 person-years). Integration of ApoB into the SCORE2 model did not significantly improve the model discrimination, calibration, and net reclassification improvement. Apolipoprotein B exhibited a dose-response relationship with cardiovascular risk but had limited standalone predictive utility within the UK Biobank population. However, combining ApoB with SCORE2 thresholds improved the identification of low-risk individuals, suggesting a complementary role for ApoB in refining cardiovascular risk stratification. Show less

Studies using machine learning to identify the target characteristics and develop predictive models for coronary artery disease severity in patients with premature myocardial infarction (PMI) are limited. In this observational study, 1111 PMI patients (≤55 years) at Tianjin Chest Hospital from 2017 to 2022 were selected and divided according to their SYNTAX scores into a low-risk group (≤22) and medium-high-risk group (>22). These groups were further randomly assigned to a training or test set in a ratio of 7:3. Lasso-logistic was initially used to screen out target factors. Subsequently, Lasso-logistic, random forest (RF), k-nearest neighbor (KNN), support vector machine (SVM), and eXtreme Gradient Boosting (XGBoost) were used to establish prediction models based on the training set. After comparing prediction performance, the best model was chosen to build a prediction system for coronary artery severity in PMI patients. Glycosylated hemoglobin (HbA1c), angina, apolipoprotein B (ApoB), total bile acid (TBA), B-type natriuretic peptide (BNP), D-dimer, and fibrinogen (Fg) were associated with the severity of lesions. In the test set, the area under the curve (AUC) of Lasso-logistic, RF, KNN, SVM, and XGBoost were 0.792, 0.775, 0.739, 0.656, and 0.800, respectively. XGBoost showed the best prediction performance according to the AUC, accuracy, F1 score, and Brier score. In addition, we used decision curve analysis (DCA) to assess the clinical validity of the XGBoost prediction model. Finally, an online calculator based on the XGBoost was established to measure the severity of coronary artery lesions in PMI patients. In summary, we established a novel and convenient prediction system for the severity of lesions in PMI patients. This system can swiftly identify PMI patients who also have severe coronary artery lesions before the coronary intervention, thus offering valuable guidance for clinical decision-making. Show less

RNA editing is a significant mechanism underlying genetic variation and protein molecule alteration; C-to-U RNA editing, specifically, is important in the regulation of mammalian genetic diversity. The ability to define and limit accesses of enzymatic machinery to avoid the modification of unintended targets is key to the success of RNA editing. Identification of the core component of the apoB RNA editing holoenzyme, APOBEC, and investigation into new candidate genes encoding other elements of the complex could reveal further details regarding APOBEC-mediated mRNA editing. Menkes disease is a recessive X-chromosome-linked hereditary syndrome in humans, caused by defective copper metabolism due to mutations in the Show less

The therapeutic value of lipid-lowering drugs in pulmonary vascular disease remains uncertain due to insufficient studies and evidence. This study aims to investigate the causal effects of lipid-lowering drugs (specifically, inhibitors of APOB, CETP, HMGCR, NPC1L1, and PCSK9) on pulmonary vascular diseases using a Mendelian randomization (MR) approach. We utilized summary-level statistics from genome-wide association studies (GWAS) to simulate the exposure to low-density lipoprotein cholesterol (LDL-C) and its outcomes on pulmonary arterial hypertension (PAH), pulmonary embolism (PE), and pulmonary heart disease (PHD). Single-nucleotide polymorphisms (SNPs) within or near drug target-associated LDL-C loci were selected as proxies for the lipid-lowering drugs. Data from the FinnGen cohort and UK Biobank (UKB) were incorporated to enhance the robustness and generalizability of the findings. The inverse variance weighted (IVW) and MR-Egger methods were employed to estimate MR effects. Our MR analysis indicated that LDL-C mediated by NPC1L1 (odds ratio [OR] = 104.76, 95% confidence interval [CI] = 2.01-5457.01, Show less