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Familial hypercholesterolemia (FH) is an inherited metabolic disorder that increases cardiovascular risk from childhood. Despite its frequency, pediatric diagnosis and treatment remain limited, particularly in developing countries. Retrospective analysis of pediatric patients with genetically confirmed heterozygous FH (HeFH). Genetic testing included sequencing of the genes Among the cohort of 124 patients only 28.2% of patients were diagnosed via routine lipid screening, though 90.3% had a positive family history. After diagnosis, 16.1% declined treatment and 41.1% were lost to follow-up. Most genetic diagnoses involved pathogenic This is the first large pediatric HeFH cohort study from Türkiye and provides data on both genetic background and treatment outcome. Despite genetic confirmation, significant gaps remain in early diagnosis, treatment acceptance, and long-term follow-up. Both atorvastatin and pitavastatin proved to be safe and effective. These results suggest a need for national screening programmes, family education, dietary counselling, and consistent follow-up. Show less

Alterations in lipids and apolipoproteins contribute to cardiovascular disease (CVD) and are common in people with HIV. The aim of our study was to compare lipid profiles and body composition between people with and without HIV and to explore whether any associations with HIV could be explained by socio-demographic, clinical characteristics and body composition. Cross-sectional analysis of a cohort study enrolling people with HIV and HIV-negative controls. Apolipoproteins [ApoB-100, ApoA1, Lp(a)] were analysed by immunoturbidimetry. Lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL]), clinical/demographic data and dual-energy X-ray absorptiometry (DXA)-measured body composition parameters were collected. Between-group differences were assessed with Student's T-test. Linear regression models assessed associations of lipids and apolipoproteins with HIV status and associations with socio-demographic, clinical characteristics and body composition. We included 108 people with HIV on treatment (93.5% with viral suppression) and 96 controls. People with HIV were younger, more likely to be male, with obesity, of African ethnicity, smokers and with a higher representation of CVD, hypertension, diabetes and statin use. ApoB-100, TC, HDL and LDL were significantly lower in people with HIV, with no between-group difference in ApoA, Lp(a) and body composition. HIV infection remained independently associated with lower TC and LDL after adjustment for possible confounders. People with HIV from a contemporary cohort had lower pro-atherogenic lipid parameters compared to controls, and no differences in body composition between people with HIV and controls were observed. Traditional risk factors for CVD and chronic inflammation might have a greater impact than dyslipidaemia itself on the increased CVD risk in people with HIV. Show less

Infiltration of T cell acute lymphoblastic leukemia (T-ALL) into the meninges worsens prognosis, underscoring the need to understand mechanisms driving meningeal involvement. Here, we show that T-ALL cells expressing CXCR3 exploit normal T cell function to infiltrate the inflamed meninges. CXCR3 deletion hampered disease progression and extramedullary dissemination by reducing leukemic cell proliferation and migration. Conversely, forced expression of CXCR3 facilitated T-ALL trafficking to the meninges. We identified the ubiquitin-specific protease 7 as a key regulator of CXCR3 protein stability in T-ALL. Furthermore, we discovered elevated levels of CXCL10, a CXCR3 ligand, in the cerebrospinal fluid from patients with T-ALL and leukemia-bearing mice. Our studies demonstrate that meningeal stromal cells, specifically pericytes and fibroblasts, induce CXCL10 expression in response to leukemia and that loss of CXCL10 attenuated T-ALL influx into the meninges. Moreover, we report that leukemia-derived proinflammatory cytokines, TNF-α, IL-27, and IFN-γ, induced CXCL10 in the meningeal stroma. Pharmacological inhibition or deletion of CXCR3 or CXCL10 reduced T-ALL cell migration and adhesion to meningeal stromal cells. Finally, we reveal that CXCR3 and CXCL10 upregulated VLA-4/VCAM-1 signaling, promoting cell-cell adhesion and thus T-ALL retention in the meninges. Our findings highlight the pivotal role of CXCR3-CXCL10 signaling in T-ALL progression and meningeal colonization. Show less

Residual cardiovascular risk after percutaneous coronary intervention (PCI) remains a concern despite optimal low-density lipoprotein cholesterol (LDL-C) management. The LDL-C/apolipoprotein B (ApoB) ratio is a potential marker for LDL particle size and atherogenicity. This study investigated the prognostic value of the pre-treatment LDL-C/ApoB ratio for major adverse cardiac events (MACE) in patients with coronary artery disease who underwent PCI. Among 2116 consecutive patients enrolled between 2015 and 2022 in the Fukuoka University PCI prospective registry, this study analyzed 1682 individuals who were divided into two groups according to their LDL-C/ApoB ratio (< 1.2 vs. ≥ 1.2). The primary outcome was 3-year MACE. After propensity score matching (315 pairs), the low LDL-C/ApoB ratio (< 1.2) was associated with higher MACE (Adjusted HR 1.50, 95% CI 1.04-2.16, p = 0.030). Restricted cubic spline analysis in the matched cohort revealed a significant continuous inverse association between the LDL-C/ApoB ratio and MACE risk. Notably, this predictive value persisted even after propensity score matching balanced for triglyceride-rich lipoprotein-related markers (triglycerides, remnant-like particle cholesterol) and HDL-C. The pre-treatment LDL-C/ApoB ratio is an independent predictor of MACE after PCI, demonstrating a continuous inverse relationship with risk, even when accounting for other atherogenic lipoproteins. This easily calculable ratio may enhance risk stratification by identifying residual risk associated with LDL particle characteristics. Show less

This study aimed to identify risk factors and develop statistical models to predict cerebral amyloid angiopathy (CAA). Associations between demographic, cognition, cardiovascular, and AD-related neuropathology and CAA were analyzed using data from three longitudinal cohorts of aging and dementia. Logistic regression with LASSO was used for feature selection. Predictive performance was assessed using ROC-AUC and decision curve analysis (DCA). Predictor importance was quantified using Shapley Variable Importance Cloud (ShapleyVIC), which provides a robust estimate of individual feature contribution in prediction. Stratified analyses showed that the strength of association between episodic memory or tau pathology and CAA was greater in males, while the amyloid pathology-CAA association was stronger in females. Among APOE ε4 carriers, the amyloid/tau pathology-CAA associations were pronounced. Episodic memory and amyloid/tau pathology were identified as key factors in our predictive model. DCA demonstrated the model’s clinical utility, and SHAP values confirmed the importance of individual features. We identified sex- and APOE-specific risk factors for CAA and developed models to support CAA risk stratification. The online version contains supplementary material available at 10.1186/s13195-025-01948-8. Show less

Physical inactivity post-stroke increases risk of recurrent stroke. Adaptive physical activity (PA) interventions are recommended, and alternative designs, such as sequential multiple assignment randomized trials (SMARTs) can be used. This SMART investigates the feasibility of a mobile health (mHealth) PA intervention post-stroke. People post-stroke are randomized to 12-week online exercise (EX) or lifestyle PA (LPA). Six-week daily step count data are used to classify participants as responders or nonresponses. Nonresponders are re-randomized to switch or augment their mHealth intervention, responders continue unchanged. Primary outcomes include recruitment, retention and adherence rates. Secondary outcomes include PA, sedentary behavior, fatigue, quality of life, psychological distress, and activities of daily living. General linear models estimate trends regarding first-stage interventions, nonresponse strategies, and adaptive interventions are examined using weighted and replicated regressions. Fifty participants are included. Recruitment, retention, and adherence rates are 85%, 84%, and 82%. Positive trends are seen for nonresponse strategies, switching interventions, on step count, fatigue, and quality of life. Starting with EX and switching to LPA show potential benefits for fatigue, quality of life and return to normal living. Potential benefits of these interventions are preliminary and require validation in a full-scale trial. This SMART offers novel evidence supporting the design of adaptive mHealth PA interventions post-stroke, confirming the feasibility of a definitive SMART. Show less

Lp(a) (lipoprotein[a]) is associated with cardiovascular disease, but neither the causal nature nor the underlying mechanisms are fully documented. This study investigated whether Lp(a) triggers atherogenesis by dysregulating vascular redox-sensitive inflammatory state. Plasma Lp(a) was measured in 1027 patients with advanced coronary artery disease undergoing cardiac surgery. These patients were genotyped, and a modified Increased plasma Lp(a) ( This study demonstrates for the first time that a genetically determined increase in plasma Lp(a) results in dysregulated vascular redox/nitrosative signaling in patients with atherosclerosis. Show less

In recent years, except for the well-known heart failure with reduced ejection fraction (HFrEF), the incidence of heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) among the classification of heart failure (HF) has been increasing. However, due to their complex mechanisms, current research remains insufficient to address clinical needs. Utilizing wild-type (WT), miR-30a-5p knockout (KO), and overexpression (OE) murine models combined with estrogen modulation and ovariectomy (OVX), this study delineates sex-specific regulatory networks in HF pathogenesis. Female KO mice lost the inherent resistance of WT females to HFpEF induction via 24-week HFD/L-NAME, whereas males exhibited comparable HFpEF susceptibility regardless of genotype, developing hallmark phenotypes including diastolic dysfunction (E/E'), myocardial hypertrophy (heart weight/tibia length), cardiac fibrosis, and hepatic steatosis. Particularly, due to the reduced ejection fraction in KO mice, combined with HFD/L-NAME, the HF phenotype was ultimately manifested as impaired diastolic function and slightly reduced ejection fraction (with the characteristics of HFpEF and HFmrEF). Mechanistically, KO-HF females displayed significant estrogen axis disruption (plasma estradiol and the expression of ERα, ERβ, ESRRA, and PELP1 expression). OVX in WT females validated the importance of estrogen for HFpEF resistance. Transcriptomic profiling identified convergent targets across cardiac (ITGAD, ITGAM, FGA, and FGB) and hepatic tissues (APOA1 and APOB), revealing miR-30a-5p's orchestration of extracellular matrix remodeling (via ITGAD/ITGAM mechanotransduction),fibrinogen-mediated microvascular homeostasis, and APOB-driven metabolic dysregulation. Notably, OE intervention failed to mitigate OVX-induced cardiac/hepatic pathology, implicating estrogen-dependent miR-30a-5p functionality. These findings establish miR-30a-5p as a crucial sex-specific regulator of HF (mainly HFpEF), operating through estrogen signaling to balance cardiac compliance and metabolic adaptation. Show less

Dysregulation of low-density lipoprotein (LDL) cholesterol is strongly correlated with the risk of metabolic dysfunction-associated steatotic liver disease. Endogenous molecules targeting LDL clearance play crucial roles in the progression of liver steatosis. Human cathelicidin LL-37 can form complexes with lipoproteins, but whether these complexes regulate lipoprotein-driven cholesterol metabolism is not clear. Here, we find that cathelicidin LL-37 binds to LDL via apolipoprotein (Apo)B-100 domains, enhancing the solubility of ApoB-100 and inhibiting the modifications and aggregation of LDL. LL-37-LDL interaction promotes LDL uptake through LDL receptor (LDLR) both in hepatocytes and macrophages. This interaction also promotes LDL cholesterol clearance by facilitating cholesterol excretion and cholesterol efflux. In Apoe Show less

Due to its proximity to cells of the central nervous system, cerebrospinal fluid (CSF) is an important source of novel biomarkers for neurological diseases. Membrane-bound extracellular vesicles (EVs) are enriched for proteins of intracellular and membrane origin, implicated in the pathogenesis of some neurological diseases, and secreted into CSF. Proteomic profiling of CSF-EVs, however, is limited by the large volumes required for typical EV isolation protocols. We appraised the performance of tetraspanin (CD81, CD63, CD9)-based immunocapture for EV isolation from 200 to 1000 µL CSF sample and compared to size-exclusion chromatography (SEC). EVs were profiled by library-free data independent-acquisition (DIA) mass spectrometry to assess protein depth and abundance of specific EV markers and known co-isolates. Abundance and precursor peptide locations for potential neuronal-specific immunocapture targets described in the literature were also assessed. Immunocapture was effective using CSF volumes as low as 200 µL, consistently detecting core EV markers and reducing relative levels of non-vesicular proteins such as Apolipoprotein B (APOB) and galectin 3 binding protein (LGALS3BP) compared with size-exclusion chromatography (SEC). Proteomic depth reached 811 ± 14 protein groups in EVs from 200 µL CSF, increasing to 1285 ± 224 when using feature alignment across runs with up to 1000 µL starting volume. These included eleven candidate biomarkers of neurological diseases that were detected in all preparation methods, with additional candidates detected by immunocapture only. Increased depth was observed for both transmembrane and secreted proteins using immunocapture compared with SEC, with proportional enrichment of transmembrane proteins. This work demonstrates the effectiveness of tetraspanin immunocapture for proteomic profiling of EVs in small volumes of CSF that can be adapted to use with cell-type-specific markers of choice. Show less

MN-001 (tipelukast), a compound with lipid-modulating and anti-inflammatory properties, and its active metabolite MN-002, have been suggested to influence cholesterol metabolism. This study aimed to investigate whether MN-001 and MN-002 enhance cholesterol efflux via ABCA1 and ABCG1, thereby reducing foam cell formation. We also evaluated cholesterol efflux capacity in patients with diabetes before and after MN-001 administration. Cholesterol efflux was assessed in THP-1 macrophages treated with MN-001 and MN-002 in the presence of ApoA-I or HDL. ABCA1 and ABCG1 expression were evaluated using western blot and qPCR analyses. A 12-week observational study in patients with diabetes evaluated the cholesterol efflux capacity using ApoB-depleted serum and radiolabeled J774.1 macrophages. Molecular docking simulations were conducted to explore MN-002 binding affinities, aiming to identify potential target proteins and elucidate the molecular mechanisms underlying their effects on cholesterol metabolism. MN-002 enhanced ABCA1-mediated cholesterol efflux and upregulated ABCA1 expression independently of PKA. It also increased ABCG1 expression; however, neither MN-001 nor MN-002 influenced HDL-mediated efflux. MN-001 showed no significant improvement in cholesterol efflux capacity (p = 0.6507) in patients with diabetes. Molecular docking simulations indicated that MN-002 may bind to PPAR-alpha, suggesting a potential mechanism for its effects. MN-002 offers a novel therapeutic approach for atherosclerosis by upregulating ABCA1 and ABCG1 expression and enhancing ApoA-I-mediated cholesterol efflux. Further studies are required to clarify the underlying mechanisms and assess their clinical potential in atherosclerosis and metabolic disorders. Show less

Familial hypercholesterolaemia (FH) is a genetic disorder due to pathogenic variants in LDLR, APOB, and PCSK9 genes, characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentration and a significantly increased risk of premature coronary heart disease. Annotating whole genome sequencing data of 536 FH patients using the VEP plugin UTRannotator, we identified a novel variant c.-35C > G in the 5' untranslated region (5'UTR) of LDLR, predicted to introduce an upstream translation initiation codon and upstream open reading frame (uORF) that is out of frame with the LDLR coding sequence. Using promoter and epitope reporter assays, we demonstrate that the c.-35C > G variant leads to the preferential utilisation of the upstream AUG codon over the wild-type LDLR translation start site. We additionally conducted reporter assays for a previously reported variant that introduces a novel AUG codon through a deletion at position -22 of the 5'UTR (c.-22del) and obtained similar results. These findings confirm a novel type of FH-causing LDLR variants, leading to a premature start of translation and a truncation, underscoring the need for expanded genetic screening beyond coding regions. Future studies should focus on further characterising 5'UTR variants to better understand their role in FH. Show less

Hypertriglyceridemia and hypercholesterolemia are well-known risk factors for atherosclerotic cardiovascular disease (ASCVD), especially in patients already at elevated cardiovascular risk. Despite current treatment approaches, including lifestyle changes and medication, many individuals do not reach ideal lipid levels, emphasizing the need for new therapeutic options. Olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (ApoC-III) synthesis, has emerged as a promising candidate to reduce residual cardiovascular risk in these patients. This systematic review and meta-analysis aimed to assess the effectiveness and safety of different dosages of Olezarsen in patients with high-risk hypertriglyceridemia. Additionally, it explored whether varying dosage regimens impacted lipid outcomes and adverse events. Following PRISMA guidelines, a comprehensive search was conducted in PubMed, Scopus, Web of Science, and Cochrane Library for randomized controlled trials (RCTs) published in English. The studies included compared different doses of Olezarsen with placebo in high-risk hypertriglyceridemia patients. Primary outcomes were changes in triglycerides (TG), very-low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and treatment-emergent adverse events (TEAE). Secondary outcomes included changes in non-HDL-C and total cholesterol (TC). The data were analyzed as mean differences (MD) or odds ratios (OR) using a random-effects model. Four RCTs (309 participants) were included. The pooled analysis demonstrated significant reductions in TG (MD = -76.11), VLDL-C (MD = -54.95 mg/dL), ApoB (MD = -12.40 mg/dL), non-HDL-C (MD = -18.03 mg/dL), and LDL-C (MD = -10.09 mg/dL) with Olezarsen treatment compared to placebo. Olezarsen also significantly increased HDL-C levels (MD = + 22.60 mg/dL), while total cholesterol remained unchanged. No significant differences in overall adverse events or drug-related adverse events were observed compared to placebo. Subgroup analysis revealed a dose-dependent effect on several lipid parameters without an increase in adverse events with higher doses. Olezarsen effectively improves key lipid parameters, including TG, VLDL-C, ApoB, non-HDL-C, and LDL-C, while also safely raising HDL-C in patients with high-risk hypertriglyceridemia. Total cholesterol remained stable, and no increase in adverse events was noted. Further studies are needed to determine optimal dosing and long-term cardiovascular benefits. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious chronic liver disease with limited therapeutic options. Fibroblast growth factor (FGF) analogs show promising therapeutic benefits for MASLD, yet the underlying mechanisms remain incompletely understood. Here, we studied the mechanism underlying the anti-steatotic properties of FGF1, the prototype member of the FGF family. The effect of FGF1 was studied in human and rodent hepatocytes and in obese mouse models exhibiting acute or chronic endoplasmic reticulum (ER) stress characteristic of MASLD. Metabolic analysis and proteomics were applied to evaluate liver physiology, ER stress and signaling. We show that FGF1 reduces hepatic triglyceride (TG) levels in obese mice (51%, These results define ER stress-dependent modulation of VLDL secretion as a mechanism underlying the anti-steatotic activity of FGF1. Targeting the FGF-UPR pathway may thus have therapeutic potential for treating MASLD. Fibroblast growth factors show therapeutic potential in both preclinical models and clinical trials for treating metabolic dysfunction-associated steatotic liver disease, a highly prevalent condition with limited treatment options. Identifying the mechanisms underlying their anti-steatotic effects may accelerate clinical development. Our finding that triglyceride secretion is the major driver of the anti-steatotic action of FGF1, together with the involvement of an adaptive unfolded protein response, provides deeper insight into the therapeutic potential of this pathway. These results also highlight possible implications for liver physiology and for the circulating lipoprotein profile, with relevance for both efficacy and safety considerations. Show less

Hyperlipidemia remains a leading modifiable risk factor for cardiovascular morbidity and mortality. Statins are considered the cornerstone of treatment; however, their adverse effects and limited efficacy in certain patient populations necessitate exploration of novel therapeutic avenues. Epiafzelechin (EZN), a flavanol with established antioxidant and anti-inflammatory properties, was investigated for its potential role in lipid metabolism using an integrative approach combining network pharmacology, molecular docking, and in vivo validation. Putative EZN targets were predicted through SuperPred, Way2Drug, and PharmMapper, and intersected with hyperlipidemia-related genes from GeneCards, DisGeNET, and CTD. Overlapping genes were subjected to protein-protein interaction (PPI) mapping, hub gene identification, and pathway enrichment analysis. Molecular docking was conducted to assess the binding affinity of EZN to lipid-regulating proteins. Therapeutic efficacy of EZN was also evaluated in a TWR-1339-induced hyperlipidemic rat model using biochemical assays and real-time PCR for gene expression profiling. A total of 105 genes were identified, involved in lipid transport, inflammatory signaling, and metabolic regulation. Functional enrichment and PPI analysis highlighted HMGCR, PCSK9, PPAR- Show less

Dyslipidemia is common in patients with MASLD, but the frequency and significance of inherited disorders of dyslipidemia are unclear. We investigated the prevalence and significance of pathogenic variants associated with selected monogenic disorders of dyslipidemia in 3358 patients with well-characterised MASLD. We identified clinically relevant variants in APOB, MTTP, PCSK9, ANGPTL3, LDLR and LDLRAP1 genes which can cause hypobetalipoproteinemia (HBL) and familial hypercholesterolemia (FH). Using ClinVar annotations as initial variant selection, we identified 2027 variants in those 6 genes which are reported as 'pathogenic' or 'likely pathogenic' (P/LP). We first assessed for the presence of P/LP variants in the study cohort and then investigated the effect of carrying P/LP variants on liver histology, by comparing ~4 matched controls for each APOB and LDLR carrier. As interpretative analyses, we also looked at the difference between liver enzymes, lipid measures and outcomes between the carriers and matched controls. Twenty-two variants among these 2027 P/LP variants were present in 24 out of 3358 patients (12 ApoB, 10 LDLR, 1 ANGPTL3 and 1 MTTP variant carriers). Compared to controls, APOB carriers had higher steatosis grade (2.4 vs. 1.7, p-value 0.0028), higher NAFLD activity score (NAS) (4.9 vs. 3.8, p-value 0.04), and numerically higher but statistically not significant fibrosis stage (1.2 vs. 1.1, p-value 0.75) and ALT (87.4 vs. 58.1 U/L, p-value 0.06). Their LDL-c (51 vs. 147.8 mg/dL, p-value 6.1E-09) and triglycerides (91.5 vs. 160.6 mg/dL, p-value 2.8E-03) were significantly lower. Compared to controls, LDLR carriers had numerically higher steatosis grade, NAS, fibrosis stage and LDL-c levels, but these were not statistically different. Monogenic disorders of dyslipidemia are rarely present in patients with MASLD and are sometimes associated with worse liver histology. Testing for these conditions may be considered on a case-by-case basis. Show less

Apolipoprotein B (apoB) is essential for lipoprotein assembly and secretion and plays a central role in the development of cardiovascular disease and metabolic dysfunction-associated steatotic liver disease. Although apoB protein degradation during very-low-density lipoprotein maturation has been extensively studied, the regulation of A forward genetic screen in randomly mutagenized mice identified HELZ2 (helicase with zinc finger 2) as a critical regulator of lipid metabolism. The metabolic effects of HELZ2 mutations or deficiency were evaluated in mice maintained on a chow diet or a high-fat diet. We also used a doxycycline-inducible, liver-specific HELZ2 overexpression model to test the sufficiency of hepatocyte We discovered a unique gain-of-function mutation in HELZ2 (L1833P, called HELZ2 is a key regulator of Show less

The therapeutic effects of different combination therapies containing cholesteryl ester transfer protein (CETP) inhibitors vary. Evidence from head-to-head comparisons is scarce and inconsistent. This study aimed to evaluate the impact of CETP inhibitor-based combination therapy on lipid levels and explore its adverse events (AEs). Randomized controlled trials (RCTs) were retrieved from PubMed, Embase, Cochrane Library, and Web of Science up to August 30, 2025. Thirteen RCTs were analyzed through STATA 14.0. This systematic review and network meta-analysis of 13 studies (9248 participants) evaluated CETP inhibitor-based combination therapies. For HDL-C elevation, obicetrapib + ezetimibe + statin ranked highest (SUCRA = 95.1%). Evacetrapib + statin achieved reduction in LDL-C (SUCRA = 94.3%). Obicetrapib + ezetimibe + statin excelled in reducing TC (SUCRA = 100.0%) and TG (SUCRA = 99.9%). Obicetrapib + statin was most effective for ApoAI increase (SUCRA = 100.0%), while obicetrapib + ezetimibe + statin best reduced ApoB (SUCRA = 100.0%). Regarding safety, obicetrapib + statin had the optimal profile for all grade AEs (SUCRA = 19.2%) and severe AEs (SUCRA = 22.5%), conversely, evacetrapib + statin had the worst profile (SUCRA = 83.1% and 66.3%, respectively). Our meta-analysis demonstrated that CETP inhibitor combination therapies offer distinct lipid-modulating benefits and safety profiles. The obicetrapib + ezetimibe + statin triple therapy showed superior comprehensive efficacy, while obicetrapib + statin exhibited the optimal safety. Evacetrapib + statin provided potent LDL-C reduction but had the poorest safety. These findings facilitate personalized treatment selection for dyslipidemia management. PROSPERO CRD420251145396 ( https://www.crd.york.ac.uk/prospero/ ). Show less

Oxidized phospholipids (OxPL) are bioactive lipid species that circulate bound to apolipoprotein B-100 [apoB] and apolipoprotein(a) [apo(a)] and have been widely studied as biomarkers of oxidative lipid burden. When bound to apolipoprotein B-100 [OxPL-apoB] and apolipoprotein(a) [OxPL-apo(a)], they serve as informative biomarkers for CVD risk prediction, risk reclassification, and therapeutic monitoring, particularly in studies involving RNA-targeted therapies against lipoprotein(a). To date, measurement of OxPL-apoB and OxPL-apo(a) has been limited to research-use assays performed in an academic laboratory without formal clinical laboratory validation. Here we report the first full CLIA-compliant analytical validation of chemiluminescent ELISA methods for OxPL-apoB and OxPL-apo(a), enabling their implementation in a regulated clinical reference laboratory setting. The OxPL-apoB ELISA employs murine monoclonal IgG antibody MB47 to capture apoB-100-containing lipoproteins, while the OxPL-apo(a) employs murine monoclonal IgG antibody LPA4 to capture apo(a)-containing particles. In both assays, OxPL is detected by murine monoclonal IgM antibody biotin-E06. The concentration of OxPL is determined against a standard curve of phosphocholine (PC) equivalents using PC-modified bovine serum albumin. The analytical measuring range of both assays is 1.48-148.48 nmol/L PC-OxPL. Serum and plasma matrices showed minimal bias and were analytically equivalent. In healthy donors, OxPL-apoB levels ranged from <1.48 to 25.23 nmol/L PC-OxPL (mean 4.18, median 1.79 nmol/L), while OxPL-apo(a) levels ranged from <1.48 to 126.94 nmol/L PC-OxPL (mean 31.04, median 6.90 nmol/L), with strong correlation to Lp(a) concentrations (R Show less

Long-chain fatty acids in the blood are prevented from unfettered movement into nonfenestrated tissues or the arterial wall. During fasting, nonesterified FAs are released from adipose tissue into the circulation and bind to albumin, forming a complex >65 kDa, with limited ability to efficiently cross endothelial cell (EC) barriers without a specific receptor. For this reason, nonhepatic tissue distribution of circulating FA parallels EC expression of the FA-binding protein CD36 (cluster of differentiation 36). The deletion of CD36 in ECs reduces nonesterified FA uptake by the heart, muscle, and brown adipose tissue. The other major transport system for FAs is via lipoproteins. Circulating FAs are contained within TRLs (triglyceride-rich lipoproteins), chylomicrons during the postprandial period, and VLDL (very low-density lipoprotein) both postprandially and during fasting. LPL (lipoprotein lipase) on capillary ECs releases FAs from TRLs and likely allows their passage into tissues, in part, via a CD36-independent process. ECs can also internalize lipoprotein particles, followed by the transendothelial movement of lipids. In this review, we will discuss the pathways of EC uptake of FAs from circulation, how this process affects both EC and tissue biology, and the importance of these processes for systemic metabolism and vascular health. We will conclude with speculations on methods to modulate EC FA uptake and their implications for human health. Show less

This study aimed to investigate the effects of glycerol monolaurate (GML) on lipid metabolism in young broilers, with focus on the AMPKα1 protein and the cecal microbiota. A total of 144 one-day-old male Arbor Acres broilers were randomly assigned to two groups, with each group consisting of six replicates of twelve birds. The groups were fed diets supplemented with either 0 or 1,200 mg/kg of GML for a period of 14 d. The results showed that GML increased high-density lipoprotein cholesterol levels in the serum (P < 0.05) while reducing total cholesterol, triglyceride, low-density lipoprotein cholesterol, and aspartate aminotransferase levels (P < 0.05). GML also decreased liver lipid droplets and increased the mRNA levels of AMPKα1, CPT1, ApoB, and LXR (P < 0.05). Molecular docking results indicated that GML exhibited good binding affinity with AMPKα1. Root-mean-square deviation values for AMPKα1 and the AMPKα1/GML complex remained stable at 1 to 2 Å within the first 50 ns. The residues in the AMPKα1/GML complex exhibited root-mean-square fluctuation values of less than 2 Å, and the binding energy of the complex was -133.515 kJ/mol. Moreover, GML significantly increased the expression levels of GPR119 and AMPKα1 in the jejunum (P < 0.05). Notably, the genera CHKC1001, Coprobacter, and Ruminococcaceae_UCG₀₀₅ were significantly enriched in the GML group (P < 0.05). PICRUSt2 function prediction revealed that GML-induced alterations in the cecal microbiota primarily involved fatty acid degradation (P < 0.05). In conclusion, dietary supplementation with 1200 mg/kg GML enhanced lipid metabolism in young broilers. Show less

Lipoprotein(a) (Lp(a)) is an independent cardiovascular risk factor, primarily determined by genetic factors. This study assessed Lp(a) concentrations in presumably healthy subjects and evaluated its association with age, sex, and cardiometabolic risk factors. The study included presumably healthy 1046 adults and 276 children. Laboratory parameters: lipid profile, Lp(a), apolipoprotein B (apoB), glucose, HbA1c, C-reactive protein and creatinine were measured. Contributions of Lp(a)-apoB to apoB (%Lp(a)/apoB) and of Lp(a)-cholesterol to LDL-cholesterol (%Lp(a)-C/LDL-C) were calculated. Lipoprotein(a) concentrations were significantly higher in adults than in children (P = 0.014) and in women than in girls (P = 0.003), but showed no overall sex differences. In women, Lp(a) was higher after age 50, while in men a slight rise occurred after age 60. Lipid indices %Lp(a)/apoB and %Lp(a)-C/LDL-C declined in men until their 40s and was higher after 50 in both sexes. In a multivariable logistic regression model increased LDL-C concentration was a significant predictor of Lp(a) ≥ 0.30 g/L in women (odds ratio, OR = 1.77; P = 0.021) and children (OR = 2.83; P = 0.009). Boys had twofold higher probability of Lp(a) ≥ 0.30 g/L than girls (OR = 2.17; P = 0.024). Lipoprotein(a) concentrations increase with age, especially after 50 in women and 60 in men, and are significantly associated with LDL-C. Rising %Lp(a)/apoB and %Lp(a)-C/LDL-C alongside falling apoB and LDL-C suggest greater atherogenicity in older individuals, particularly men. These findings support including Lp(a) in lipid profile for better cardiovascular risk assessment. Show less

Sepsis is a syndrome caused by the host's inflammatory response to an infection with an unknown mechanism. This study aimed to identify differentially expressed genes (DEGs) potentially involved in the development and recovery of tracheal injury from septic shock. Nine New Zealand white rabbits were randomized to control (CON), septic shock model (SS), and septic shock norepinephrine treatment (SSNE) groups (each group n = 3). The SS and SSNE groups were injected with lipopolysaccharide to induce septic shock. The SSNE group was administered Ringer lactate with norepinephrine to maintain normal blood pressure. All animals underwent cuffed endotracheal intubation for 2 h. The injured tracheal segment was harvested. RNA sequencing was performed to identify the DEGs, followed by bioinformatics analysis, and pathological staining (both HE and Masson) was performed for pathological evaluation. Bioinformatics analysis included principal component analysis (PCA), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network construction. Key findings were validated by qRT-PCR and immunohistochemistry. We obtained 124 upregulated and 28 downregulated DEGs in SS vs. CON groups, along with 60 upregulated and 178 downregulated DEGs in SSNE vs. SS groups. The pathological score showed that trachea tissue in the SS group had the highest score. The protein-protein interaction (PPI) prediction identified APOB and CD36 as the hub genes. The molecular experiments further confirmed that at mRNA and protein levels, APOB was significantly upregulated, while CD36 was significantly downregulated. Subsequent qRT-PCR and immunohistochemical analyses confirmed that APOB expression was significantly upregulated while CD36 was downregulated in the septic shock group, a trend partially reversed by norepinephrine treatment. Our study results suggest that APOB and CD36 may be involved in the pathogenesis of tracheal injury recovery in septic shock patients treated with NE. Not applicable. Show less

Familial hypercholesterolemia (FH) is a genetic disorder characterised by elevated plasma LDL-cholesterol, predisposing to premature atherosclerotic cardiovascular disease. Most cases follow an autosomal dominant pattern (ADH) caused by pathogenic variants in LDLR, APOB or PCSK9. In contrast, the rare autosomal recessive form (ARH) results from biallelic mutations in LDLRAP1, leading to defective LDL receptor-mediated endocytosis. Despite the high rate of consanguinity in Tunisia, LDLRAP1 variants have not yet been reported in this population. In this study, Whole Exome Sequencing of two consanguineous Tunisian families, identified distinct pathogenic variants. In the first family (FH-A), a recurrent LDLR splice-site variant (c.1845+1G>A) was detected in both heterozygous and homozygous states, consistent with an autosomal dominant inheritance pattern. In the second family (FH-B), a novel homozygous LDLRAP1 missense variant (c.161G>A; p.Gly54Asp) was identified, confirming autosomal recessive inheritance. In silico analyses using MutationTaster, DynaMut2, MUpro, DDGun, NetSurfP-2.0, ConSurf and PyMOL predicted that the p.Gly54Asp substitution destabilises the PTB domain of LDLRAP1 by disrupting key hydrogen bonds and hydrophobic interactions, thereby likely impairing LDLR internalisation. According to ACMG guidelines, this variant is classified as likely pathogenic. Clinically, ARH patients exhibited early-onset xanthomas and an unusual quadricuspid aortic valve (QAV). Targeted analysis of valvulogenesis genes (NOTCH1, GATA4, NKX2-5, TBX5, AGTR1, BMP2) revealed no co-segregating pathogenic variants, suggesting that QAV may result from embryonic LDL accumulation disrupting Notch1 signalling rather than a monogenic defect. Comparison with other ADH Tunisian families carrying the same LDLR mutation showed phenotypic variability, likely influenced by genetic modifiers, treatment response and environmental factors. These findings provide the first evidence of LDLRAP1-associated ARH in Tunisia and highlight the genetic heterogeneity of FH, emphasising the importance of integrating molecular, structural and functional analyses for accurate diagnosis, personalised management and early prevention. Show less

Lynch syndrome is a genetic cancer-predisposing syndrome caused by pathogenic mutations in DNA mismatch repair (path_MMR) genes. Due to the elevated cancer risk, novel screening methods, alongside current surveillance techniques, could enhance cancer risk stratification. Here we show how bi-omics integration could be utilized to pinpoint potential cancer-predicting biomarkers in Lynch syndrome. We studied which blood-based circulating microRNAs and metabolites could predict Lynch syndrome cancer occurrence within a 5.8-year prospective surveillance period. We used single- and bi-omics bioinformatic analyses and identified omics-level patterns and associations across these biological layers. Lasso Cox regression was used to highlight the most promising cancer-predicting biomarkers. Our findings revealed distinct circulating metabolite landscapes among path_MMR variant carriers and a circulating microRNA co-expression module significantly associated with future cancer incidence. These microRNAs regulate cancer-related pathways, including the PI3K/Akt signaling pathway. Additionally, a metabolite module consisting of ApoB-containing lipoproteins (low-, intermediate-, and very low-density lipoproteins) showed distinct levels across path_MMR variants. Notably, three biomarkers-hsa-miR-101-3p, hsa-miR-183-5p, and triglycerides in high-density lipoprotein particles (HDL_TG)-significantly predicted cancer risk, achieving a Harrel's Concordance Index (C-index) of 0.76 (p = .0007). Elevated levels of these biomarkers indicated increased cancer risk. Internal validation of the model yielded a C-index of 0.72. The bi-omics approach and the identified biomarkers offer promising insights for future studies regarding cancer risk identification in Lynch syndrome. 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

The gut microbiota is a diverse and abundant microbial community in animals; it plays a key role in nutrient absorption and immune defense and is an important factor affecting chicken health and growth performance. Understanding the composition of chicken gut microbiota and its influencing factors can provide a theoretical foundation for maintaining the diversity and microecological balance of beneficial microbial communities in the chicken intestinal tract. This review aimed to explore the recent advancements in understanding the non-genetic e.g. environmental and host genetic factors that influence the chicken gut microbiome, focusing on the gut microbial composition including host genetic kinship, heritability, microbial quantitative loci, and candidate genes. Studies on host genetic factors have identified several genes associated with gut microbial composition including lipid droplet associated hydrolase (LDAH) and apolipoprotein B (APOB) associated with Staphylococcus; TOX high mobility group box family member 2 (TOX2) significant locus linked to Veillonella, and reelin (RELN), lumican (LUM), and S-phase cyclin A associated protein in the ER (SCAPER) associated with intestinal microbial abundance. These factors are involved in host growth, development, and immune system regulation, collectively indicating that host genes play a significant role in regulating chicken gut microbiota. Furthermore, a comprehensive exploration of both non-genetic and host genetic factors could provide a solid foundation and practical strategies for improving chicken health and production performance by regulating the gut microbiota. Show less

Prior studies indicate that allyl isothiocyanate (AITC) alleviates metabolic dysfunction-associated steatotic liver disease (MASLD). The vitamin D receptor (VDR) is known to exert protective effects in MASLD; however, whether AITC alleviates MASLD through VDR remains unclear. To clarify the function and underlying mechanisms of AITC in MASLD AML-12 cells were exposed to 300 μM palmitate acid (PA) for 24 hours to establish an To establish an AITC provides a robust molecular basis for improving MASLD by activating hepatic VDR and driving the downstream HNF-4α/MTTP/ApoB signaling pathway. This pathway reduces hepatic lipid accumulation, promotes FA β-oxidation, and improves insulin resistance, establishing AITC as a promising treatment for MASLD. Show less

Chronic inflammation constitutes a well-established driver of colorectal carcinogenesis, yet the molecular circuitry linking inflammatory receptor signalling to tumour cell survival remains incompletely delineated. Here we demonstrate that the HMG-CoA reductase inhibitors atorvastatin and rosuvastatin modulate inflammatory survival pathways in colorectal cancer cells in a manner consistent with targeted interference with the protease-activated receptor 2 (PAR-2)-extracellular signal-regulated kinase (ERK)-tumour necrosis factor-α (TNF-α) signalling axis. Using lipopolysaccharide-stimulated HT-29 and Caco-2 cells as complementary models of inflammatory colorectal malignancy, we show that both statins selectively attenuate PAR-2 expression at the protein and transcript levels while leaving structurally related PAR-1 unaffected. This pattern of receptor modulation is accompanied by suppression of total ERK1/2 expression, ERK1/2 phosphorylation, and the transcriptional target DUSP6, together with attenuation of TNF-α secretion. Importantly, these signaling shifts are associated with dual apoptotic programs; the extrinsic pathway, reflected by transcriptional upregulation and proteolytic activation of caspase-8; and the intrinsic mitochondrial pathway, evidenced by reciprocal modulation of Bcl-2 family proteins favoring Bax over Bcl-2. Both pathways converge upon activation of executioner caspase-3 and an increase in Annexin V-defined apoptotic fractions, indicating re-engagement of programmed cell death under inflammatory stress. Notably, rosuvastatin consistently demonstrates superior potency across signaling endpoints, achieving comparable biological effects at lower concentrations than atorvastatin. Collectively, these data indicate that clinically deployed statins target the PAR-2-ERK axis and are associated with re-activation of apoptotic pathways in inflammatory colorectal cancer models, while leaving open the possibility that additional statin-responsive networks contribute to their pro-apoptotic effects. This mechanistic framework provides biological plausibility for epidemiologic observations linking statin use with reduced colorectal cancer risk and improved outcomes, and supports further translational evaluation of PAR-2-directed statin strategies in colorectal malignancy. Show less