African ancestry-derived APOL1 risk genotypes show proximal epigenetic associations.

Apolipoprotein L1 (APOL1) coding variants, termed G1 and G2, are established genetic risk factors for a growing spectrum of diseases, including kidney disease, in individuals of African ancestry. Evidence suggests that the risk variants, which show a recessive mode of inheritance, lead to toxic gain-of-function changes of the APOL1 protein. Disease occurrence and presentation vary, likely due to modifiers or second hits. To understand the role of the epigenetic landscape in relation to APOL1 risk variants, we performed methylation quantitative trait locus (meQTL) analysis to identify differentially methylated CpGs influenced by APOL1 risk variants in 611 African American individuals. We identified five CpGs that were significantly associated with APOL1 risk alleles in discovery and replication studies, and one CpG-APOL1 association was independent of other genomic variants. Our study highlights proximal DNA methylation alterations that may help explain the variable disease risk and clinical manifestation of APOL1 variants.

Lipids, apolipoproteins and gestational diabetes mellitus: a Mendelian randomization study.

BACKGROUND: This study investigates the causal relationship between lipid traits and GDM in an effort to better understand the aetiology of GDM. METHODS: Employing a two-sample Mendelian Randomization (MR) framework, we used Single Nucleotide Polymorphisms (SNPs) as instrumental variables to examine the impact of lipids and apolipoproteins on GDM. The research comprised univariable and multivariable MR analyses, with a prime focus on individual and combined effects of lipid-related traits. Statistical techniques included the fixed-effect inverse variance weighted (IVW) method and supplementary methods such as MR-Egger for comprehensive assessment. RESULTS: Our findings revealed the following significant associations: apoA-I and HDL cholesterol were inversely correlated with GDM risk, while triglycerides showed a positive correlation. In multivariable analysis, apoA-I consistently exhibited a strong causal link with GDM, even after adjusting for other lipids and Body Mass Index (BMI). CONCLUSION: The study demonstrates a significant causal relationship between apoA-I and GDM risk.

Exploration of the application potential of serum multi-biomarker model in colorectal cancer screening.

Analyzing blood lipid and bile acid profile changes in colorectal cancer (CRC) patients. Evaluating the integrated model's diagnostic significance for CRC. Ninety-one individuals with colorectal cancer (CRC group) and 120 healthy volunteers (HC group) were selected for comparison. Serum levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and apolipoproteins (Apo) A1, ApoA2, ApoB, ApoC2, and ApoC3 were measured using immunoturbidimetric and colorimetric methods. Additionally, LC-MS/MS was employed to detect fifteen bile acids in the serum, along with six tumor markers: carcinoembryonic antigen (CEA), carbohydrate antigens (CA) 125, CA19-9, CA242, CA50, and CA72-4. Group comparisons utilized independent sample t-tests and Mann-Whitney U tests. A binary logistic regression algorithm was applied to fit the indicators and establish a screening model; the diagnostic accuracy of individual Indicators and the model was analyzed using receiver operating characteristic (ROC) curves. The CRC group showed significantly lower levels in eight serum lipid indicators and eleven bile acids compared to the HC group (P < 0.05). Conversely, serum levels of TG, CA19-9, and CEA were elevated (P < 0.05). Among the measured parameters, ApoA2 stands out for its strong correlation with the presence of CRC, showcasing exceptional screening efficacy with an area under the curve (AUC) of 0.957, a sensitivity of 85.71%, and a specificity of 93.33%. The screening model, integrating ApoA1, ApoA2, lithocholic acid (LCA), and CEA, attained an impressive AUC of 0.995, surpassing the diagnostic accuracy of individual lipids, bile acids, and tumor markers. CRC patients manifest noteworthy alterations in both blood lipids and bile acid profiles. A screening model incorporating ApoA1, ApoA2, LCA, and CEA provides valuable insights for detecting CRC.

Deciphering thyroid function and CIMT: a Mendelian randomization study of the U-shaped influence mediated by apolipoproteins.

Background: Carotid Intima-Media Thickness (CIMT) is a key marker for atherosclerosis, with its modulation being crucial for cardiovascular disease (CVD) risk assessment. While thyroid function's impact on cardiovascular health is recognized, the causal relationship and underlying mechanisms influencing CIMT remain to be elucidated. Methods: In this study, Mendelian Randomization (MR) was employed to assess the causal relationship between thyroid function and CIMT. Thyroid hormone data were sourced from the Thyroidomics Consortium, while lipid traits and CIMT measurements were obtained from the UK Biobank. The primary analysis method was a two-sample MR using multiplicative random effects inverse variance weighting (IVW-MRE). Additionally, the study explored the influence of thyroid hormones on lipid profiles and assessed their potential mediating role in the thyroid function-CIMT relationship through multivariate MR analysis. Results: The study revealed that lower levels of Free Thyroxine (FT4) within the normal range are significantly associated with increased CIMT. This association was not observed with free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), or TPOAb. Additionally, mediation analysis suggested that apolipoprotein A-I and B are involved in the relationship between thyroid function and CIMT. The findings indicate a potential U-shaped curve relationship between FT4 levels and CIMT, with thyroid hormone supplementation in hypothyroid patients showing benefits in reducing CIMT. Conclusion: This research establishes a causal link between thyroid function and CIMT using MR methods, underscoring the importance of monitoring thyroid function for early cardiovascular risk assessment. The results advocate for the consideration of thyroid hormone supplementation in hypothyroid patients as a strategy to mitigate the risk of carotid atherosclerosis. These insights pave the way for more targeted approaches in managing patients with thyroid dysfunction to prevent cardiovascular complications.

Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity.

Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its capacity to inhibit lipoprotein lipase (LPL) catalytic activity and its ability to detach LPL from binding sites within capillaries. However, the sequences in APOA5 that are required for suppressing ANGPTL3/8 activity have never been defined. A clue to the identity of those sequences was the presence of severe hypertriglyceridemia in two patients harboring an APOA5 mutation that truncates APOA5 by 35 residues ("APOA5Δ35"). We found that wild-type (WT) human APOA5, but not APOA5Δ35, suppressed ANGPTL3/8's ability to inhibit LPL catalytic activity. To pursue that finding, we prepared a mutant mouse APOA5 protein lacking 40 C-terminal amino acids ("APOA5Δ40"). Mouse WT-APOA5, but not APOA5Δ40, suppressed ANGPTL3/8's capacity to inhibit LPL catalytic activity and sharply reduced plasma TG levels in mice. WT-APOA5, but not APOA5Δ40, increased intracapillary LPL levels and reduced plasma TG levels in Apoa5-/- mice (where TG levels are high and intravascular LPL levels are low). Also, WT-APOA5, but not APOA5Δ40, blocked the ability of ANGPTL3/8 to detach LPL from cultured cells. Finally, an antibody against a synthetic peptide corresponding to the last 26 amino acids of mouse APOA5 reduced intracapillary LPL levels and increased plasma TG levels in WT mice. We conclude that C-terminal sequences in APOA5 are crucial for suppressing ANGPTL3/8 activity in vitro and for regulating intracapillary LPL levels and plasma TG levels in vivo.

Relationships of apolipoprotein E genotypes with a cluster of seven in persons with type 2 diabetes.

OBJECTIVE.: The objective of the study was to determine if there would be statistically significant differences or trends among apolipoprotein E genotypes (2/2, 2/3, 2/4, 3/3, 3/4, and 4/4) for each member of the cluster of seven associated with type 2 diabetes (T2D). The cluster of seven includes abdominal obesity, hypertension, platelet hyperaggregability, hyperglycemia, dyslipidemia (decreased plasma levels of high-density lipoprotein cholesterol (HDL-C) and increased plasma levels of triglycerides)), increased low-density lipoprotein (LDL) oxidation, and increased inflammation. METHODS.: Forty-six patients with well-controlled T2D participated in the study. Abdominal obesity (assessed by waist circumference), hypertension (measured by manual sphygmomanometry), platelet hyperaggregability (measured by bleeding time), hyperglycemia (by enzymatic kit and spectrophotometry), decreased plasma levels of HDL-C and increased plasma levels of triglycerides (by enzymatic kit and spectrophotometry), increased LDL oxidation (measured by LDL conjugated dienes using spectrophotometry) and increased inflammation measured by C-reactive protein (CRP) (by EIA kit) were determined. RESULTS.: All genotypes, except 2/2 were found in the population studied. Abdominal obesity did not vary significantly across the five genotypes. However, glucose levels trended progressively higher going from 2/3 to 2/4 to 3/4 to 4/4. Systolic blood pressure was higher in 3/4 compared to 2/4 and trended higher in 3/4 compared to 3/3. Diastolic blood pressure trended higher in 3/3 vs 2/4 and significantly higher in 3/4 compared to 2/4. Triglycerides trended higher in 3/4 vs 3/3 while HDL-C came close to trending downward in 4/4 compared to 2/4. Bleeding time was unaffected by genotype. Plasma LDL conjugated dienes trended higher in 3/4 vs 2/4 and were significantly higher in 3/4 vs 3/3. CRP trended higher in 4/4 vs 2/3. CONCLUSION.: We can conclude that those with at least one 4 allele in the presence of another allele being 2, 3 or 4 is potentially (in the case of trends) deleterious or is deleterious in terms of hyperglycemia, hypertension (systolic and diastolic blood pressure), dyslipidemia, LDL conjugated dienes and CRP levels.

Contactin 5 and Apolipoproteins Interplay in Alzheimer's Disease.

Background: Apolipoproteins and contactin 5 are proteins associated with Alzheimer's disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and phospholipids during synaptic turnover and terminal proliferation. Contactin 5 is a neuronal membrane protein involved in key processes of neurodevelopment. Objective: To investigate the interactions between contactin 5 and apolipoproteins in AD, and the role of these proteins in response to neuronal damage. Methods: Apolipoproteins (measured by Luminex), contactin 5 (measured by Olink's proximity extension assay), and cholesterol (measured by liquid chromatography mass spectrometry) were assessed in the cerebrospinal fluid (CSF) and plasma of cognitively unimpaired participants (n = 93). Gene expression was measured using polymerase chain reaction in the frontal cortex of autopsied-confirmed AD (n = 57) and control subjects (n = 31) and in the hippocampi of mice following entorhinal cortex lesions. Results: Contactin 5 positively correlated with apolipoproteins B (p = 5.4×10-8), D (p = 1.86×10-4), E (p = 2.92×10-9), J (p = 2.65×10-9), and with cholesterol (p = 0.0096) in the CSF, and with cholesterol (p = 0.02), HDL (p = 0.0143), and LDL (p = 0.0121) in the plasma. Negative correlations were seen between CNTN5, APOB (p = 0.034) and APOE (p = 0.015) mRNA levels in the brains of control subjects. In the mouse model, apoe and apoj gene expression increased during the reinnervation phase (p <  0.05), while apob (p = 0.023) and apod (p = 0.006) increased in the deafferentation stage. Conclusions: Extensive interactions were observed between contactin 5 and apolipoproteins and cholesterol, possibly due to neuronal damage. The alterations in gene expression of apolipoproteins suggest a role in axonal, terminal, and synaptic remodeling in response to entorhinal cortex damage.

Amyloid-ß prediction machine learning model using source-based morphometry across neurocognitive disorders.

Previous studies have developed and explored magnetic resonance imaging (MRI)-based machine learning models for predicting Alzheimer's disease (AD). However, limited research has focused on models incorporating diverse patient populations. This study aimed to build a clinically useful prediction model for amyloid-beta (Aß) deposition using source-based morphometry, using a data-driven algorithm based on independent component analyses. Additionally, we assessed how the predictive accuracies varied with the feature combinations. Data from 118 participants clinically diagnosed with various conditions such as AD, mild cognitive impairment, frontotemporal lobar degeneration, corticobasal syndrome, progressive supranuclear palsy, and psychiatric disorders, as well as healthy controls were used for the development of the model. We used structural MR images, cognitive test results, and apolipoprotein E status for feature selection. Three-dimensional T1-weighted images were preprocessed into voxel-based gray matter images and then subjected to source-based morphometry. We used a support vector machine as a classifier. We applied SHapley Additive exPlanations, a game-theoretical approach, to ensure model accountability. The final model that was based on MR-images, cognitive test results, and apolipoprotein E status yielded 89.8% accuracy and a receiver operating characteristic curve of 0.888. The model based on MR-images alone showed 84.7% accuracy. Aß-positivity was correctly detected in non-AD patients. One of the seven independent components derived from source-based morphometry was considered to represent an AD-related gray matter volume pattern and showed the strongest impact on the model output. Aß-positivity across neurological and psychiatric disorders was predicted with moderate-to-high accuracy and was associated with a probable AD-related gray matter volume pattern. An MRI-based data-driven machine learning approach can be beneficial as a diagnostic aid.

Elevated Lp(a): Guidance for Identifying and Managing Patients.

Lipoprotein(a) (Lp(a)) is a unique low-density lipoprotein-like lipoprotein that is considered an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis. The Lp(a) molecule also contains apolipoprotein A and apolipoprotein B, which collectively promote atherosclerosis, thrombosis, and inflammation. Lp(a) is highly genetic and minimally responsive to nonpharmacological measures. Lp(a) serum levels ≥125 nmol/L are associated with increased ASCVD risk, but this threshold has not been accepted universally. Elevated Lp(a) is the most common genetic dyslipidemia affecting approximately 20% of the general population. Certain currently available lipid-lowering drugs, including the proprotein convertase subtilisin/kexin type 9 therapies, produce moderate reductions in Lp(a); however, none are indicated for the treatment of elevated Lp(a). There are currently four investigational RNA-based therapeutic agents that reduce Lp(a) by 70% to 100%. Two of these agents are being evaluated for ASCVD risk reduction in adequately powered outcomes trials, with results expected in 2 to 3 years. Until such therapies become available and demonstrate favorable clinical outcomes, strategies for elevated Lp(a) primarily involve early and intensive ASCVD risk factor management.

The Janus-faced functions of Apolipoproteins L in membrane dynamics.

The functions of human Apolipoproteins L (APOLs) are poorly understood, but involve diverse activities like lysis of bloodstream trypanosomes and intracellular bacteria, modulation of viral infection and induction of apoptosis, autophagy, and chronic kidney disease. Based on recent work, I propose that the basic function of APOLs is the control of membrane dynamics, at least in the Golgi and mitochondrion. Together with neuronal calcium sensor-1 (NCS1) and calneuron-1 (CALN1), APOL3 controls the activity of phosphatidylinositol-4-kinase-IIIB (PI4KB), involved in both Golgi and mitochondrion membrane fission. Whereas secreted APOL1 induces African trypanosome lysis through membrane permeabilization of the parasite mitochondrion, intracellular APOL1 conditions non-muscular myosin-2A (NM2A)-mediated transfer of PI4KB and APOL3 from the Golgi to the mitochondrion under conditions interfering with PI4KB-APOL3 interaction, such as APOL1 C-terminal variant expression or virus-induced inflammatory signalling. APOL3 controls mitophagy through complementary interactions with the membrane fission factor PI4KB and the membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). In mice, the basic APOL1 and APOL3 activities could be exerted by mAPOL9 and mAPOL8, respectively. Perspectives regarding the mechanism and treatment of APOL1-related kidney disease are discussed, as well as speculations on additional APOLs functions, such as APOL6 involvement in adipocyte membrane dynamics through interaction with myosin-10 (MYH10).

A targeted proteomics method for quantifying plasma apolipoprotein kinetics in individual mice using stable isotope labeling.

Altered apolipoprotein kinetics play a critical role in promoting dyslipidemia and atherogenesis. Human apolipoprotein kinetics have been extensively evaluated, but similar studies in mice are hampered by the lack of robust methods suitable for the small amounts of blood that can be collected at sequential time points from individual mice. We describe a targeted liquid chromatography tandem mass spectrometry method for simultaneously quantifying the stable isotope enrichment of several apolipoproteins represented by multiple peptides in serial blood samples (15 µl each) obtained after retro-orbital injection of 13C6,15N2-lysine (Lys8) in mice. We determined apolipoprotein fractional clearance rates (FCRs) and production rates (PRs) in WT mice and in two genetic models widely used for atherosclerosis research, LDL receptor-deficient (Ldlr-/-) and apolipoprotein E-deficient (Apoe-/-) mice. Injection of Lys8 produced a unique and readily detectable mass shift of labeled compared with unlabeled peptides with sensitivity allowing robust kinetics analyses. Ldlr-/- mice showed slower FCRs of APOA1, APOA4, total APOB, APOB100, APOCs, APOE and APOM, while FCRs of APOA1, APOB100, APOC2, APOC3, and APOM were not lower in Apoe-/- mice versus WT mice. APOE PR was increased in Ldlr-/- mice, and APOB100 and APOA4 PRs were reduced in Apoe-/- mice. Thus, our method reproducibly quantifies plasma apolipoprotein kinetics in different mouse models. The method can easily be expanded to include a wide range of proteins in the same biospecimen and should be useful for determining the kinetics of apolipoproteins in animal models of human disease.

Analysis of the association between testosterone and cardiovascular disease potential risk factor apolipoprotein B in adult males without cancer: national health and nutrition examination survey 2011-2016.

Background: Over the years, there has been extensive exploration of the association between testosterone and lipid profiles, yet the precise mechanisms underlying their interaction remain incompletely elucidated. Similarly, there is a dearth of research on the correlation between serum apolipoprotein B (apoB) and serum total testosterone (TT), particularly within specific populations. Methods: We conducted a cross-sectional study to assess the relationship between serum TT concentration and serum apoB concentration. Using the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2016, we employed weighted generalized linear models, weighted univariate, weighted multivariate analysis, and smooth curve fitting to assist in exploring the relationship between serum TT and apoB. Serum apoB concentration served as the independent variable, and serum TT concentration as the dependent variable. ApoB was divided into four quartiles-Q1 (<0.7g/L, N=691), Q2 (≥0.7g/L to <0.9g/L, N=710), Q3 (≥0.9g/L to <1.1g/L, N=696), and Q4 (≥1.1g/L, N=708)-thereby further solidifying the stable association between the two. Additionally, the application of smooth curve fitting will contribute to a more detailed elucidation of the specific relationship between serum TT concentration and serum apoB concentration under different factors (Drinking, Smoke, Diabetes, Hypertension, and High cholesterol level.). Results: The results indicate a negative correlation between serum TT concentration and apoB concentration (ß=-113.4; 95% CI: -146.6, -80.2; P<0.001). After adjusting for confounding variables, the negative correlation between apoB concentration and TT concentration remains significant (ß=-61.0; 95% CI: -116.7, -5.2; P=0.040). When apoB concentration was converted from a continuous variable to a categorical variable (quartiles: Q1<0.7g/L; Q2:≥0.7g/L to<0.9g/L; Q3:≥0.9g/L to <1.1g/L; Q4: ≥1.1g/L), TT level of participants in the highest quartile (≥1.1g/L) was -47.2 pg/mL (95% CI: -91.2, -3.3; P=0.045) lower than that in the lowest quartile (<0.7g/L). The smooth curve fitting diagram revealed differences in the relationship between TT concentration and apoB among individuals with different cardiovascular disease (CVD) risk factors. Conclusions: This study elucidates a robust inverse correlation between serum TT concentration and apoB concentration, maintaining statistical significance even upon adjustment for confounding factors. These findings present a promising avenue for addressing the prevention and treatment of low testosterone and CVD.

Apolipoprotein E is enriched in dense deposits and is a marker for dense deposit disease in C3 glomerulopathy.

C3 glomerulopathy (C3G) is a rare disease resulting from dysregulation of the alternative pathway of complement. C3G includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), both of which are characterized by bright glomerular C3 staining on immunofluorescence studies. However, on electron microscopy (EM), DDD is characterized by dense osmiophilic mesangial and intramembranous deposits along the glomerular basement membranes (GBM), while the deposits of C3GN are not dense. Why the deposits appear dense in DDD and not in C3GN is not known. We performed laser microdissection (LCM) of glomeruli followed by mass spectrometry (MS) in 12 cases each of DDD, C3GN, and pretransplant kidney control biopsies. LCM/MS showed marked accumulation of complement proteins C3, C5, C6, C7, C8, C9 and complement regulating proteins CFHR5, CFHR1, and CFH in C3GN and DDD compared to controls. C3, CFH and CFHR proteins were comparable in C3GN and DDD. Yet, there were significant differences. First, there was a six-to-nine-fold increase of C5-9 in DDD compared to C3GN. Secondly, an unexpected finding was a nine-fold increase in apolipoprotein E (ApoE) in DDD compared to C3GN. Most importantly, immunohistochemical and confocal staining for ApoE mirrored the dense deposit staining in the GBM in DDD but not in C3GN or control cases. Validation studies using 31 C3G cases confirmed the diagnosis of C3GN and DDD in 80.6 % based on ApoE staining. Overall, there is a higher burden of terminal complement pathway proteins in DDD compared to C3GN. Thus, our study shows that dense deposits in DDD are enriched with ApoE compared to C3GN and control cases. Hence, ApoE staining may be used as an adjunct to EM for the diagnosis of DDD and might be valuable when EM is not available.

An ELISA-based method for Galleria mellonella apolipophorin-III quantification.

Mammalian models, such as murine, are used widely in pathophysiological studies because they have a high degree of similarity in body temperature, metabolism, and immune response with humans. However, non-vertebrate animal models have emerged as alternative models to study the host-pathogen interaction with minimal ethical concerns. Galleria mellonella is an alternative model that has proved useful in studying the interaction of the host with either bacteria or fungi, performing drug testing, and assessing the immunological response to different microorganisms. The G. mellonella immune response includes cellular and humoral components with structural and functional similarities to the immune effectors found in higher vertebrates, such as humans. An important humoral effector stimulated during infections is apolipophorin III (apoLp-III), an opsonin characterized by its lipid and carbohydrate-binding properties that participate in lipid transport, as well as immunomodulatory activity. Despite some parameters, such as the measurement of phenoloxidase activity, melanin production, hemocytes counting, and expression of antimicrobial peptides genes are already used to assess the G. mellonella immune response to pathogens with different virulence degrees, the apoLp-III quantification remains to be a parameter to assess the immune response in this invertebrate. Here, we propose an immunological tool based on an enzyme-linked immunosorbent assay that allows apoLp-III quantification in the hemolymph of larvae challenged with pathogenic agents. We tested the system with hemolymph coming from larvae infected with Escherichia coli, Candida albicans, Sporothrix schenckii, Sporothrix globosa, and Sporothrix brasiliensis. The results revealed significantly higher concentrations of apoLp-III when each microbial species was inoculated, in comparison with untouched larvae, or inoculated with phosphate-buffered saline. We also demonstrated that the apoLp-III levels correlated with the strains' virulence, which was already reported. To our knowledge, this is one of the first attempts to quantify apoLp-III, using a quick and easy-to-use serological technique.

Sinomenine protects against atherosclerosis in apolipoprotein E-knockout mice by inhibiting of inflammatory pathway.

Atherosclerosis, a multifaceted and persistent inflammatory condition, significantly contributes to the progression of cardiocerebrovascular disorders, such as myocardial infarctions and cerebrovascular accidents. It involves the accumulation of cholesterol, fatty deposits, calcium and cellular debris in the walls of arteries, leading to the formation of plaques. Our aim is to investigate the potential of sinomenine to counteract atherosclerosis in mice lacking Apolipoprotein E (ApoE-/-) Mice. We employed the high-fat diet-induced method to induce atherosclerosis in ApoE-/- mice, and the mice were treated with sinomenine (5, 10, and 15 mg/kg) and simvastatin (0.5 mg/kg) for 12 weeks. Body weight, water intake, and food intake were assessed. Lipid parameters, oxidative stress, inflammatory cytokines, and mRNA levels were estimated. Sinomenine treatment remarkably (P < 0.001) suppressed body weight, along with food and water intake. Sinomenine altered the levels of total cholesterol (TC), high-density lipoprotein (HDL), triglyceride (TG), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL), which were modulated in the atherosclerosis group. Sinomenine treatment also altered the levels of oxidative stress parameters such as glutathione peroxidase (GPx), catalase (CAT), malonaldehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH). In addition, it modulated cardiac parameters like C-reactive protein (CRP), endothelin-1 (ET-1), thromboxane B2 (TXB2), nitric oxide (NO), cardiac troponin I (cTnI), lactate dehydrogenase (LDH), and creatinine kinase isoenzymes (CK-MB). Inflammatory cytokines interleukin (IL)-1α, IL-1ß, TNF-α, IL-6, and IL-10 were also affected. Sinomenine further suppressed the mRNA expression of IL-6, IL-17, IL-10, tumor necrosis factor-α (TNF-α), Il-1ß, monocyte chemoattractant protein-1 (MCP-1), MCP-2, MCP-3, transforming Growth Factor-1ß (TGF-1ß), vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1). The results suggest that sinomenine remarkably suppressed the development of atherosclerosis in the early stage.

A genome-wide cross-trait analysis identifies shared loci and causal relationships of obesity and lipidemic traits with psoriasis.

Background: Obesity and dyslipidemia, major global health concerns, have been linked to psoriasis, but previous studies faced methodological limitations and their shared genetic basis remains unclear. This study examines various obesity-related and lipidemic traits as potential contributors to psoriasis development, aiming to clarify their genetic associations and potential causal links. Methods: Summary statistics from genome-wide association studies (GWAS) conducted for obesity-related traits (body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-hip ratio adjusted for the body mass index (WHRadjBMI)) and lipidemic traits (high-density lipoprotein (HDL), LDL, triglyceride (TG), total Cholesterol (TC), apolipoprotein A1 (apoA1), apolipoprotein B (apoB), and apolipoprotein E (apoE)) and psoriasis, all in populations of European ancestry, were used. We quantified genetic correlations, identified shared loci and explored causal relationship across traits. Results: We found positive genetic correlation between BMI and psoriasis (rg=0.22, p=2.44×10-18), and between WHR and psoriasis (rg=0.19, p=1.41×10-12). We further found the positive genetic correlation between psoriasis and WHRadjBMI(rg=0.07, p=1.81×10-2) the genetic correlation, in while the effect of BMI was controlled for. We identified 14 shared loci underlying psoriasis and obesity-related traits and 43 shared loci between psoriasis and lipidemic traits via cross-trait meta-analysis. Mendelian randomization (MR) supported the causal roles of BMI (IVW OR=1.483, 95%CI=1.333-1.649), WHR (IVW OR=1.393, 95%CI=1.207-1.608) and WHRadjBMI (IVW OR=1.18, 95%CI=1.047-1.329) in psoriasis, but not observe any significant association between lipidemic traits and the risk of psoriasis. Genetic predisposition to psoriasis did not appear to affect the risk of obesity and lipidemic traits. Conclusions: An intrinsic link between obesity-related traits and psoriasis has been demonstrated. The genetic correlation and causal role of obesity-related traits in psoriasis highlight the significance of weight management in both the prevention and treatment of this condition.

APOE-ε4 is not associated with pure-tone hearing thresholds, visual acuity or cognition, cross-sectionally or over 3 years of follow up in the Canadian Longitudinal Study on Aging.

INTRODUCTION: Hearing loss and diminished visual acuity are associated with poorer cognition, but the underlying mechanisms are not understood. The apolipoprotein (APOE) ε4 allelic variant may drive the associations. We tested whether APOE-ε4 allele count (0, 1, or 2) was associated with declines in memory, executive function, pure-tone hearing threshold averages, and pinhole-corrected visual acuity among participants in the Canadian Longitudinal Study on Aging (CLSA). METHODS: Multivariable linear mixed regression models were utilized to assess associations between APOE-ε4 allele count and each of the outcome variables. For each main effects model, interactions between APOE-ε4 and sex and age group (45-54-, 55-64-, 65-74-, and 75-85 years) respectively, were analyzed. RESULTS: Significant associations were not observed in main effects models. Models including APOE-ε4 * age (but not APOE-ε4 * sex) interaction terms better fit the data compared to main effects models. In age group-stratified models, however, there were minimal differences in effect estimates according to allele count. CONCLUSION: APOE-ε4 allele count does not appear to be a common cause of sensory-cognitive associations in this large cohort.

Associations between birth weight and adult apolipoproteins: The LifeGene cohort.

BACKGROUND: Early life factors may predict cardiovascular disease (CVD), but the pathways are still unclear. There is emerging evidence of an association of early life factors with apolipoproteins, which are linked to CVD. The study objective was to assess the associations between birth variables and adult apolipoproteins (apoA1 and apoB, and their ratio) in a population-based cohort. METHODS: The LifeGene Study is a prospective cohort comprising index participants randomly sampled from the general population. Blood samples were collected between 2009 and 2016. In this sub-study, we used birth variables, obtained from a national registry for all participants born 1973 or later, including birth weight and gestational age, while adult CVD risk factors included age, sex, body mass index (BMI), lipids, and smoking history. We employed univariate and multivariate general linear regression to explore associations between birth variables, lipid levels and other adult CVD risk factors. The outcomes included non-fasting apoA1 and apoB and their ratio, as well as total cholesterol and triglycerides. A total of 10,093 participants with both birth information and lipoprotein levels at screening were included. Of these, nearly 42.5% were men (n = 4292) and 57.5% were women (n = 5801). RESULTS: The mean (standard deviation) age of men was 30.2 (5.7) years, and for women 28.9 (5.8) years. There was an increase of 0.022 g/L in apoA1 levels per 1 kg increase in birth weight (p = 0.005) after adjusting for age, sex, BMI, gestational age, and smoking history. Similarly, there was a decrease of 0.023 g/L in apoB levels per 1 kg increase in birth weight (p<0.001) after adjusting for the same variables. There were inverse associations of birth weight with the apoB/apoA1 ratio. No independent association was found with total cholesterol, but with triglyceride levels (ẞ-coefficient (95% Confidence Interval); -0.067 (-0.114, -0.021); p-value 0.005). CONCLUSIONS: Lower birth weight was associated with an adverse adult apolipoprotein pattern, i.e., a higher apoB/apoA1 ratio, indicating increased risk of future CVD manifestations. The study highlights the need of preconception care and pregnancy interventions that aim at improving maternal and child outcomes with long-term impacts for prevention of cardiovascular disease by influencing lipid levels.

The long coiled-coil protein NECC2 regulates oxLDL-induced endothelial oxidative damage and exacerbates atherosclerosis development in apolipoprotein E -/- mice.

Oxidized low density lipoprotein (oxLDL)-induced endothelial oxidative damage promotes the development of atherosclerosis. Caveolae play an essential role in maintaining the survival and function of vascular endothelial cell (VEC). It is reported that the long coiled-coil protein NECC2 is localized in caveolae and is associated with neural cell differentiation and adipocyte formation, but its role in VECs needs to be clarified. Our results showed NECC2 expression increased in the endothelium of plaque-loaded aortas and oxLDL-treated HUVECs. Down-regulation of NECC2 by NECC2 siRNA or compound YF-307 significantly inhibited oxLDL-induced VEC apoptosis and the adhesion factors expression. Remarkably, inhibition of NECC2 expression in the endothelium of apoE-/- mice by adeno-associated virus (AAV)-carrying NECC2 shRNA or compound YF-307 alleviated endothelium injury and restricted atherosclerosis development. The immunoprecipitation results confirmed that NECC2 interacted with Tyk2 and caveolin-1(Cav-1) in VECs, and NECC2 further promoted the phosphorylation of Cav-1 at Tyr14 b y activating Tyk2 phosphorylation. On the other hand, inhibiting NECC2 levels suppressed oxLDL-induced phosphorylation of Cav-1, uptake of oxLDL by VECs, accumulation of intracellular reactive oxygen species and activation of NF-κB. Our findings suggest that NECC2 may contribute to oxLDL-induced VEC injury and atherosclerosis via modulating Cav-1 phosphorylation through Tyk2. This work provides a new concept and drug target for treating atherosclerosis.