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Cholesterol (Chol) plays a crucial role in shaping the intricate physicochemical attributes of biomembranes, exerting a considerable influence on water molecules proximal to the membrane interface. In this study, we conducted molecular dynamics simulations on the bilayers of two lipid species, dipalmitoylphosphatidylcholine (DPPC) and palmitoyl sphingomyelin; they are distinct with respect to the structures of the hydrogen-bond (H-bond) acceptors. Our investigation focuses on the dynamic properties and H-bonds of water molecules in the lipid-membrane systems, with a particular emphasis on the influence of Chol at varying temperatures. Notably, in the gel phase at 303 K, the presence of Chol extends the lifetimes of H-bonds of the oxygen atoms acting as H-bond acceptors within DPPC with water molecules by a factor of 1.5–2.5. In the liquid-crystalline phase at 323 K, on the other hand, H-bonding dynamics with lipid membranes remain largely unaffected by Chol. This observed shift in H-bonding states serves as a crucial key to unraveling the subtle control mechanisms governing water dynamics in lipid-membrane systems. [ABSTRACT FROM AUTHOR]

Dyslipidemia is a major contributor to the development of atherosclerotic cardiovascular disease. Despite high level of physical activity, athletes are not immune from dyslipidemia, but longitudinal data on the variation of lipids are currently lacking. We sought to assess lipid profile changes over time in Olympic athletes practicing different sports disciplines (power, skills, endurance, and mixed). We enrolled 957 consecutive athletes evaluated from London 2012 to Beijing 2022 Olympic Games. Dyslipidemia was defined as low-density lipoprotein (LDL) ≥115 mg/dl, high-density lipoprotein (HDL) <40 mg/dl for males, or HDL <50 mg/dl for females. Hypertriglyceridemia was defined as triglycerides >150 mg/dl. At the follow-up, a variation of ±40 mg/dl for LDL, ±6 mg/dl for HDL, and ±50 mg/dl for triglycerides was considered relevant. Athletes with follow-up <10 months or taking lower lipid agents were excluded. Follow-up was completed in 717 athletes (74.9%), with a mean duration of 55.6 months. Mean age was 27.2 ± 4.8 years old, 54.6% were male (n = 392). Overall, 19.8% (n = 142) athletes were dyslipidemic at both blood tests, being older, practicing nonendurance sports, and predominantly male. In 69.3% (n = 129) of those with elevated LDL at t0, altered values were confirmed at follow-up, while the same occurred in 36.5% (n = 15) with hypo-HDL and 5.3% (n = 1) in those with elevated triglycerides. Weight and fat mass percentage modifications did not affect lipid profile variation. LDL hypercholesterolemia tends to persist over time especially among male, older, and nonendurance athletes. LDL hypercholesterolemia detection in athletes should prompt early preventive intervention to reduce the risk of future development of atherosclerotic disease. [ABSTRACT FROM AUTHOR]

Purpose: Previous literature has demonstrated the mediating role of adiposity in the association between cardiorespiratory fitness (CRF) and cardiometabolic risk as well as the potential role of CRF in attenuating the adverse consequences associated with excess weight. This study aimed to evaluate the mediating role of CRF and adiposity in the possible association with cardiometabolic risk. Method: Observational 3-year longitudinal study that included 420 children and adolescents (10.50 [2.05] y of age at baseline; 56.2% girls). Body mass index (BMI) was calculated, and CRF was evaluated using field assessments. A clustered cardiometabolic risk score (cMetS) was calculated from glucose, systolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, and triglycerides z scores. Analyses evaluated the mediating role of BMI in the association between CRF and cMetS as well as whether CRF mediated the association between BMI and cMetS. Results: BMI at baseline was directly associated with the cMetS at follow-up (0.102; 95% confidence interval, 0.020 to 0.181), independently of CRF, whereas CRF was only indirectly associated with cMetS at follow-up through BMI (−0.036; 95% confidence interval, −0.070 to −0.009), meaning that the association between CRF and cMetS was explained via the mediation role of BMI. Conclusions: BMI presented direct association with cMetS, whereas CRF exhibited indirect association with cMetS mediated via BMI. [ABSTRACT FROM AUTHOR]

BACKGROUND: A bioactive myelin basic protein (MBP) fragment, comprising MBP84-104, is released in sciatic nerve after chronic constriction injury (CCI). Intraneural injection (IN) of MBP84-104 in an intact sciatic nerve is sufficient to induce persistent neuropathic pain-like behavior via robust transcriptional remodeling at the injection site and ipsilateral dorsal root ganglia (DRG) and spinal cord. The sex (female)-specific pronociceptive activity of MBP84-104 associates with sex-specific changes in cholesterol metabolism and activation of estrogen receptor (ESR)1 signaling. METHODS: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP84-104 interactors by mass spectrometry of MBP84-104 pull-down; and (iii) liver X receptor (LXR)α protein expression by immunoblotting. To test the effect of LXRα stimulation on IN MBP84-104-induced mechanical hypersensitivity, the LXRα expression was confirmed along the segmental neuraxis, in DRG and spinal cord, followed by von Frey testing of the effect of intrathecally administered synthetic LXR agonist, GW3965. In cultured male and female rat DRGs exposed to MBP84-104 and/or estrogen treatments, transcriptional effect of LXR stimulation by GW3965 was assessed on downstream cholesterol transporter Abc, interleukin (IL)-6, and pronociceptive Cacna2d1 gene expression. RESULTS: CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP84-104 interacted with nuclear receptor coactivator (Ncoa)1, known to activate LXRα, injury-specific in nerves of both sexes. LXR stimulation suppressed ESR1-induced IL-6 and Cacna2d1 expression in cultured DRGs of both sexes and attenuated MBP84-104-induced pain in females. CONCLUSION: The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of MBP fragments is prevalent in females due to high circulating estrogen levels in females relative to males. Restoring LXR activity presents a promising therapeutic strategy in management of neuropathic pain induced by bioactive MBP.

BACKGROUND: According to the Physical Activity Guidelines Advisory Committee Scientific Report, limited evidence is available on sedentary behaviors (screen time) and their joint associations with physical activity (steps) for cardiovascular health in adolescence. The objective of this study was to identify joint associations of screen time and physical activity categories with cardiovascular disease (CVD) risk factors (blood pressure, hemoglobin A1c, cholesterol) in adolescence. METHODS: This study analyzed data from the Adolescent Brain Cognitive Development (ABCD) Study, comprising a diverse sample of 4,718 U.S. adolescents aged 10-15 years between 2018 and 2021. Steps were measured by a Fitbit wearable device and levels were categorized as low (1,000-6,000), medium (> 6,000-12,000), and high (> 12,000) averaged daily step counts. Self-reported recreational screen time hours per day were classified as low (0-4), medium (> 4-8), and high (> 8) hours per day. CVD risk factors including blood pressure, hemoglobin A1c, and cholesterol (total and HDL) were measured. RESULTS: The analytical sample averaged 6.6 h of screen time per day and 9,722 steps per day. In models including both screen time and steps, the high screen time category was associated with a 4.27 higher diastolic blood pressure percentile (95% CI 1.83-6.73) and lower HDL cholesterol (B= -2.85, 95% CI -4.77 to -0.94 mg/dL) compared to the low screen time category. Medium (B = 3.68, 95% CI 1.24-6.11) and low (B = 7.64, 95% CI 4.07-11.20) step categories were associated with higher diastolic blood pressure percentile compared to the high step category. The medium step category was associated with lower HDL cholesterol (B= -1.99, 95% CI -3.80 to -0.19 mg/dL) compared to the high step category. Findings were similar when screen time and step counts were analyzed as continuous variables; higher continuous step count was additionally associated with lower total cholesterol (mg/dL). CONCLUSIONS: Combinations of low screen time and high steps were generally associated with favorable cardiovascular health markers including lower diastolic blood pressure and higher HDL cholesterol, which can inform future adolescent health guidelines.

BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

This study aimed to assess the antioxidant capacity of lemon flavonoid extract Eriomin® (LE) and its impact on cholesterol metabolism in the context of healthy aging. We orally treated 24-month-old male Wistar rats with an LE (40 mg/kg) suspended in 0.3 mL of sunflower oil. At the same time, control groups received an equal volume of sunflower oil (CON) or remained untreated (ICON) daily for 4 weeks. We examined LEs effects on superoxide dismutase and catalase- and glutathione-related enzyme activities, the concentration of lipid peroxides and protein carbonyls, total oxidant status (TOS) and antioxidant status (TAS), and oxidative stress index (OSI) in the liver, jejunum, and ileum. We also measured total cholesterol, its biosynthetic precursors (lanosterol, lathosterol, desmosterol), its degradation products (bile acid precursors) in the serum, liver, jejunum, and ileum, and serum phytosterols (intestinal absorption markers). LE reduced TOS, TAS, and OSI (p < 0.05) compared with control values, indicating its consistent antioxidant action in all examined organs. LE lowered hepatic desmosterol (p < 0.05) while also reducing 7α- and 24-hydroxycholesterol levels in the liver and ileum (p < 0.01). Serum cholesterol, hepatic gene expression, and the immunostaining intensity of CYP7A1 were unchanged. In conclusion, LE exerted non-enzymatic antioxidant effects and reduced cholesterol degradation, reducing its biosynthesis products, thereby maintaining serum cholesterol levels.

Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL-C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline-recommended LDL-C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes. With atherosclerotic cardiovascular disease-related mortality increasing globally, there remains a need for additional therapeutic options for lowering LDL-C as part of an atherosclerotic cardiovascular disease prevention strategy. Following the identification of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a promising therapeutic target, inclisiran was developed using the natural process of RNA interference for robust, sustained prevention of hepatic PCSK9 synthesis. Twice-yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL-C levels by ≈50% versus placebo when added to maximally tolerated statins. Long-term safety and tolerability of inclisiran have been assessed, with studies underway to evaluate the effects of inclisiran on cardiovascular outcomes and to provide additional safety and effectiveness data. In 2021,

Three Prime Repair Exonuclease 1 (TREX1) gene mutations have been associated with Aicardi-Goutières Syndrome (AGS) - a rare, severe pediatric autoimmune disorder that primarily affects the brain and has a poorly understood etiology. Microglia are brain-resident macrophages indispensable for brain development and implicated in multiple neuroinflammatory diseases. However, the role of TREX1 - a DNase that cleaves cytosolic nucleic acids, preventing viral- and autoimmune-related inflammatory responses - in microglia biology remains to be elucidated. Here, we leverage a model of human embryonic stem cell (hESC)-derived engineered microglia-like cells, bulk, and single-cell transcriptomics, optical and transmission electron microscopy, and three-month-old assembloids composed of microglia and oligodendrocyte-containing organoids to interrogate TREX1 functions in human microglia. Our analyses suggest that TREX1 influences cholesterol metabolism, leading to an active microglial morphology with increased phagocytosis in the absence of TREX1. Notably, regulating cholesterol metabolism with an HMG-CoA reductase inhibitor, FDA-approved atorvastatin, rescues these microglial phenotypes. Functionally, TREX1 in microglia is necessary for the transition from gliogenic intermediate progenitors known as pre-oligodendrocyte precursor cells (pre-OPCs) to precursors of the oligodendrocyte lineage known as OPCs, impairing oligodendrogenesis in favor of astrogliogenesis in human assembloids. Together, these results suggest routes for therapeutic intervention in pathologies such as AGS based on microglia-specific molecular and cellular mechanisms.

Circulating levels of the soluble ligand-binding ectodomain of the LDL receptor (sLDLR) that is proteolytically cleaved from the cell surface have been shown to correlate with plasma triglycerides, but the lipid and lipoprotein effects of longitudinal changes in sLDLR have not been examined. We sought to assess associations between changes in sLDLR and detailed lipoprotein measurements between baseline and 6 months in participants in the DIETFITS (Diet Intervention Examining The Factors Interacting with Treatment Success) weight loss trial who were randomly assigned to the low-fat (n = 225) or low-carbohydrate (n = 236) diet arms. sLDLR was assayed using a proteomic procedure, lipids and apoprotein (apo) B and apoAI were measured by standard assays, and lipoprotein particle subfractions were quantified by ion mobility methodology. Changes in sLDLR were significantly positively associated with changes in plasma cholesterol, triglycerides, apoB, large-sized and medium-sized VLDL, and small and very small LDL, and inversely with changes in large LDL and HDL. The lipoprotein subfraction associations with sLDLR were independent of age, sex, diet, and BMI, but all except for large LDL were reduced to insignificance when adjusted for triglyceride change. Principal component analysis identified three independent clusters of changes in lipoprotein subfractions that accounted for 78% of their total variance. Change in sLDLR was most strongly correlated with change in the principal component that was loaded positively with large VLDL and small and very small LDL and negatively with large LDL and HDL. In conclusion, sLDLR is a component of a cluster of lipids and lipoproteins that are characteristic of atherogenic dyslipidemia.

Patients with chronic inflammatory disorders such as psoriasis have an increased risk of cardiovascular disease and elevated levels of LL37, a cathelicidin host defense peptide that has both antimicrobial and proinflammatory properties. To explore whether LL37 could contribute to the risk of heart disease, we examined its effects on lipoprotein metabolism and show that LL37 enhanced LDL uptake in macrophages through the LDL receptor (LDLR), scavenger receptor class B member 1 (SR-B1), and CD36. This interaction led to increased cytosolic cholesterol in macrophages and changes in expression of lipid metabolism genes consistent with increased cholesterol uptake. Structure-function analysis and synchrotron small-angle x-ray scattering showed structural determinants of the LL37-LDL complex that underlie its ability to bind its receptors and promote uptake. This function of LDL uptake is unique to cathelicidins from humans and some primates and was not observed with cathelicidins from mice or rabbits. Notably, Apoe-/- mice expressing LL37 developed larger atheroma plaques than did control mice, and a positive correlation between plasma LL37 and oxidized phospholipid on apolipoprotein B (OxPL-apoB) levels was observed in individuals with cardiovascular disease. These findings provide evidence that LDL uptake can be increased via interaction with LL37 and may explain the increased risk of cardiovascular disease associated with chronic inflammatory disorders.

Aster proteins mediate the nonvesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). However, the importance of nonvesicular sterol movement for physiology and pathophysiology in various tissues is incompletely understood. Here we show that loss of Aster-B leads to diet-induced obesity in female but not in male mice, and that this sex difference is abolished by ovariectomy. We further demonstrate that Aster-B deficiency impairs nonvesicular cholesterol transport from the PM to the ER in ovaries in vivo, leading to hypogonadism and reduced estradiol synthesis. Female Aster-B-deficient mice exhibit reduced locomotor activity and energy expenditure, consistent with established effects of estrogens on systemic metabolism. Administration of exogenous estradiol ameliorates the diet-induced obesity phenotype of Aster-B-deficient female mice. These findings highlight the key role of Aster-B-dependent nonvesicular cholesterol transport in regulating estradiol production and protecting females from obesity.

BACKGROUND: Dyslipidemia is among the leading risk factors for cardiovascular diseases (CVDs), with an increasing global burden, especially in developing countries. We investigated the prevalence of dyslipidemia and abnormal lipid profiles in Tehran. METHODS: We used data from 8072 individuals aged≥35 from the Tehran Cohort Study (TeCS) recruitment phase. Fasting serum total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and triglyceride were measured. Dyslipidemia was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria, and high LDL/HDL was defined as a ratio>2.5. The age-sex standardized prevalence rates were calculated based on the 2016 national census. Furthermore, the geographical distribution of dyslipidemia and lipid abnormalities was investigated across Tehrans zip code districts. RESULTS: The age-sex standardized prevalence was 82.7% (95% CI: 80.1%, 85.0%) for dyslipidemia, 36.9% (95% CI: 33.8%, 40.1%) for hypertriglyceridemia, 22.5% (95% CI: 19.9%, 25.4%) for hypercholesterolemia, 29.0% (95% CI: 26.1%, 32.1%) for high LDL-C, 55.9% (95% CI: 52.6%, 59.2%) for low HDL-C, and 54.1% (95% CI: 50.9%, 57.3%) for high LDL/HDL ratio in the Tehran adult population. The prevalence of dyslipidemia, low HDL-C, and high LDL/HDL ratio was higher in the northern regions, hypercholesterolemia was higher in the southern half, and high LDL-C was more prevalent in the middle-northern and southern areas of Tehran. CONCLUSION: We found a high prevalence of dyslipidemia, mainly high LDL/HDL in the Tehran adult population. This dyslipidemia profiling provides important information for public health policy to improve preventive interventions and reduce dyslipidemiarelated morbidity and mortality in the future.

Glaucoma is a group of ocular diseases that cause irreversible blindness. It is characterized by multifactorial degeneration of the optic nerve axons and retinal ganglion cells (RGCs), resulting in the loss of vision. Major components of glaucoma pathogenesis include glia-driven neuroinflammation and impairment of mitochondrial dynamics and bioenergetics, leading to retinal neurodegeneration. In this review article, we summarize current evidence for the emerging role of apolipoprotein A-I binding protein (AIBP) as an important anti-inflammatory and neuroprotective factor in the retina. Due to its association with toll-like receptor 4 (TLR4), extracellular AIBP selectively removes excess cholesterol from the plasma membrane of inflammatory and activated cells. This results in the reduced expression of TLR4-associated, cholesterol-rich lipid rafts and the inhibition of downstream inflammatory signaling. Intracellular AIBP is localized to mitochondria and modulates mitophagy through the ubiquitination of mitofusins 1 and 2. Importantly, elevated intraocular pressure induces AIBP deficiency in mouse models and in human glaucomatous retina. AIBP deficiency leads to the activation of TLR4 in Müller glia, triggering mitochondrial dysfunction in both RGCs and Müller glia, and compromising visual function in a mouse model. Conversely, restoring AIBP expression in the retina reduces neuroinflammation, prevents RGCs death, and protects visual function. These results provide new insight into the mechanism of AIBP function in the retina and suggest a therapeutic potential for restoring retinal AIBP expression in the treatment of glaucoma.

BACKGROUND: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system using mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (MACE). METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndrome. We compared risk of a MACE in the placebo group and MACE risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by Siemens N-latex nephelometric immunoassay (IA-mass; mg/dL), Roche Tina-Quant turbidimetric immunoassay (IA-molar; nmol/L), and a noncommercial mass spectrometry-based test (MS; nmol/L). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay. RESULTS: Among 11 970 trial participants with results from all 3 tests, baseline median (Q1, Q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/L for IA-mass, IA-molar, and MS, respectively. The strongest correlation was between IA-molar and MS (r=0.990), with nominally weaker correlations between IA-mass and MS (r=0.967) and IA-mass and IA-molar (r=0.972). Relationships of lipoprotein(a) with MACE risk in the placebo group were nearly identical with each test, with estimated cumulative incidences differing by ≤0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol levels (all spline P≤0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the 3 tests, with estimated treatment hazard ratios differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all 3 tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles. CONCLUSIONS: In patients with recent acute coronary syndrome, 3 lipoprotein(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Pulmonary alveolar proteinosis (PAP) is a life-threatening, rare lung syndrome for which there is no cure and no approved therapies. PAP is a disease of lipid accumulation characterized by alveolar macrophage foam cell formation. While much is known about the clinical presentation, there is a paucity of information regarding temporal changes in lipids throughout the course of disease. Our objectives were to define the detailed lipid composition of alveolar macrophages in PAP patients at the time of diagnosis and during treatment. We performed comprehensive mass spectrometry to profile the lipid signature of alveolar macrophages obtained from three independent mouse models of PAP and from PAP and non-PAP patients. Additionally, we quantified changes in macrophage-associated lipids during clinical treatment of PAP patients. We found remarkable variations in lipid composition in PAP patients, which were consistent with data from three independent mouse models. Detailed lipidomic analysis revealed that the overall alveolar macrophage lipid burden inversely correlated with clinical improvement and response to therapy in PAP patients. Specifically, as PAP patients experienced clinical improvement, there was a notable decrease in the total lipid content of alveolar macrophages. This crucial observation suggests that the levels of these macrophage-associated lipids can be utilized to assess the efficacy of treatment. These findings provide valuable insights into the dysregulated lipid metabolism associated with PAP, offering the potential for lipid profiling to serve as a means of monitoring therapeutic interventions in PAP patients.

BackgroundStatins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained.MethodsTo identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 µM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (ZNF335), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335).ResultsThe statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR = 5%). The two genes with the strongest correlations were zinc finger protein 335 (ZNF335 aka NIF-1, rho = 0.237, FDR-adj p = 0.0085) and CCR4-NOT transcription complex subunit 3 (CNOT3, rho = 0.233, FDR-adj p = 0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild-type C57BL/6J mice in a sex combined model (p = 0.04). Furthermore, male (but not female) mice carrying the Zfp335R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43 ± 18% and -23 ± 19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335R1092W allele(s) exhibited a significantly blunted LDL statin response.ConclusionsOur in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.

Common noncoding variants at the human 1p13.3 locus associated with SORT1 expression are among those most strongly associated with low-density lipoprotein cholesterol (LDL-C) in human genome-wide association studies. However, validation studies in mice and cell lines have produced variable results regarding the directionality of the effect of SORT1 on LDL-C. This, together with the fact that the 1p13.3 variants are associated with expression of several genes, has raised the question of whether SORT1 is the causal gene at this locus. Using whole exome sequencing in members of an Amish population, we identified coding variants in SORT1 that are associated with increased (rs141749679, K302E) and decreased (rs149456022, Q225H) LDL-C. Further, analysis of plasma lipoprotein particle subclasses by ion mobility in a subset of rs141749679 (K302E) carriers revealed higher levels of large LDL particles compared to noncarriers. In contrast to the effect of these variants in the Amish, the sortilin K302E mutation introduced into a C57BL/6J mouse via CRISPR/Cas9 resulted in decreased non-high-density lipoprotein cholesterol, and the sortilin Q225H mutation did not alter cholesterol levels in mice. This is indicative of different effects of these mutations on cholesterol metabolism in the two species. To our knowledge, this is the first evidence that naturally occurring coding variants in SORT1 are associated with LDL-C, thus supporting SORT1 as the gene responsible for the association of the 1p13.3 locus with LDL-C.

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women. Dyslipidemia is a prevalent metabolic abnormality in individuals with PCOS. Moreover, vitamin D deficiency is widespread across all societal strata, with a particularly heightened prevalence observed in patients afflicted with PCOS. The present study aimed to investigate the level of vitamin D and its correlation with lipid profiles in Iranian women diagnosed with PCOS. Methods: This cross-sectional study was carried out at the PCOS and infertility clinic of Arash Women's Hospital in Tehran. The study encompassed the medical records of PCOS patients who attended the clinic from March 2021 to December 2023. All patients underwent blood tests, which included assessments of fasting blood sugar levels, lipid profiles, and 25-hydroxyvitamin D (25(OH)D) levels. The investigation focused on evaluating the relationship between vitamin D levels and lipid profiles. Statistical analyses, including the chi-square test and Spearman's correlation coefficient, were employed to analyze the data. Results: A total of 1004 women diagnosed with PCOS were included in the study. The age range of the participants was 14 to 46 years. The majority of the participants had a body mass index (BMI) within the normal range (n = 555, 55.3%). The median vitamin D level among the participants was 26.00 (IQR: 19.00–34.00). The relationship between vitamin D levels and lipid profile parameters was assessed, revealing no significant correlation between vitamin D levels and low-density lipoprotein (LDL) (r = 0.021, p = 0.505), high-density lipoprotein (HDL) (r = 0.011, p = 0.719), or triglyceride (TG) (r = -0.026, p = 0.417) levels, both in non-adjusted and age-adjusted analyses. Conclusion: According to the present study, there was no significant correlation between serum 25(OH)D deficiency and elevated TG or LDL levels or decreased HDL levels in PCOS patients. Nevertheless, further prospective studies are needed to determine whether there is a causal relationship between vitamin D deficiency and lipid profile alterations, specifically among PCOS patients. [ABSTRACT FROM AUTHOR]

Summary Unhealthy dietary patterns are a major contributor to obesity worldwide, leading to various adverse metabolic effects such as elevated liver enzyme levels and increased cholesterol concentrations. This study investigates the potential of cascara kombucha as a functional beverage to provide health benefits in both in vitro and in vivo models. Our results indicate that kombucha fermentation enhances the bioactive compounds in cascara, including polyphenols and flavonoids. The in vitro study found that cascara kombucha effectively decreased free radicals (DPPH and ABTS) levels, α‐amylase, and lipase activity, suggesting its potential to act as an antioxidant and modulate carbohydrate and lipid metabolism. In a mouse model, oral administration of cascara kombucha at a dose of 300 mg/kg body weight for 28 days successfully decreased fasting blood glucose levels, improved liver health by reducing aspartate transaminase and alanine transaminase levels, and lowered serum cholesterol content induced by a fat‐enriched diet compared to the untreated group. The levels of superoxide dismutase and catalase, suppressed by the fat‐enriched diet, were restored to normal. Additionally, cascara kombucha downregulated genes associated with inflammation induced by a fat‐enriched diet, including tnf‐α, IL‐6, IL‐1β, and cox‐2. It also positively affected the balance of intestinal microflora in mice by reducing coliform density and enhancing probiotic populations. These findings highlight the potential of cascara kombucha as a promising approach to addressing health issues caused by poor dietary habits and metabolic imbalances. [ABSTRACT FROM AUTHOR]

Background: Cholesterol granuloma (CG) is a benign entity characterized by the presence of cholesterol crystals and foreign body giant cells. This condition can be attributed to cholesterol crystals that are deposited in the tissues and react with foreign body giant cells, resulting in granuloma formation. Lesions commonly develop in the otolaryngeal region, such as the middle ear. However, crystals rarely form in the thymus, accounting for 1% of all mediastinal tumors. Herein, we present five cases of mediastinal CG. Case presentation: The patients were aged 49–61 (mean, 55.4) years. Among them, three were men and two women. One patient had fever, and four patients were asymptomatic. The patients' lesions were detected during follow-up of other diseases or medical examinations showing the presence of abnormal chest shadows. The patients did not have a history of trauma or surgery. All lesions were located within the thymus gland. Three patients presented with multifocal lesions and two with a single lesion. Four patients had contrast effect on computed tomography scan. Four patients had abnormal fluorodeoxyglucose accumulation (mean maximum standardized uptake value, 4.67) on positron emission tomography-computed tomography. Four patients underwent complete surgical resection. The size of the resected lesions ranged from 1.8 to 5.1 (mean, 3.24) cm. Histologically, all patients presented with small nodules with cholesterol clefts and foreign body giant cells and histiocyte infiltration within the thymic tissue. The postoperative course was excellent. None of the patients who underwent complete resection presented with recurrence. Moreover, the patient who underwent partial resection did not have lesion enlargement. Conclusions: CG in the thymus is clinically challenging to differentiate from malignant lesions, and histologic diagnosis via surgical resection is required. [ABSTRACT FROM AUTHOR]

Objectives: To explore the relationship between estradiol (E2) and the incidence of hyperuricemia (HUA) in adult women and to explore whether glucolipid metabolism disorders play a mediating role in mediating this relationship. Methods: A total of 2,941 participants aged 20-65 years were included in the National Health and Nutrition Examination Survey (NHANES) 2013-2016. Multivariate logistic regression analysis was performed to evaluate the correlations of E2 with HUA. Multivariate linear regression analysis was performed to evaluate the associations between E2 and triglyceride (TG), total cholesterol (TC), and the triglyceride-glucose index (TyG). The restricted cubic spline (RCS) model was used to further explore the association between E2 and HUA and between TG, TC, and TyG and HUA. Mediation analyses were performed to examine whether TC, TG, and TyG mediated the relationship between E2 and HUA. Results: After adjusting for covariates, logistic regression revealed that ln(E2) was significantly associated with HUA in the female subgroup (p = 0.035) and that the incidence of HUA tended to increase with decreasing ln(E2) (p for trend = 0.026). Linear regression showed that E2 was significantly associated with TC (p = 0.032), TG (p = 0.019), and TyG (p = 0.048). The RCS model showed that ln(E2) was linearly correlated with the incidence of HUA (p-overall = 0.0106, p-non-linear = 0.3030). TC and TyG were linearly correlated with HUA (TC: p-overall = 0.0039, p-non-linear = 0.4774; TyG: p-overall = 0.0082, p-non-linear = 0.0663), whereas TG was non-linearly correlated with HUA. Mediation analyses revealed that TC, TG, and TyG significantly mediated the relationship between ln(E2) and HUA (TC, indirect effect: -0.00148, 7.5%, p = 0.008; TG, indirect effect: -0.00062, 3.1%, p = 0.004; TyG, indirect effect: -0.00113, 5.6%, p = 0.016). Conclusion: In conclusion, this study demonstrated that compared with women aged 20-45 years, women aged 45-55 years and 55-65 years had lower E2 levels and a greater incidence of HUA. E2 levels and the incidence of HUA were negatively associated in female individuals but not in male individuals. In addition, TC, TG, and TyG, which are markers of glucolipid metabolism, played a mediating role in the association between E2 and HUA. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is one of the leading causes of death worldwide. Evidence suggests that alterations in the gut microbiome could play a role in cardiovascular diseases, including heart failure. The purpose of this study was to evaluate the effect of synbiotics on serum paraoxonase 1(PON1), soluble CD163/soluble TNF-like weak inducer of apoptosis (sCD163/sTWEAK), and lipid profile, which are involved in heart failure in patients with chronic heart failure. In this triple-blind randomized clinical trial, 90 eligible patients were included in the study. They were randomly assigned to receive one capsule (500 mg) of synbiotics or a placebo daily for ten weeks. Serum PON1, sCD163/sTWEAK, and lipid profiles were measured at the beginning and end of the study. The data were analyzed by SPSS 24, and the p-value < 0.05 was considered statistically significant. Among 90 patients who met the inclusion criteria, 80 completed the study. The primary outcomes showed a small effect on sTWEAK, with an adjusted standard mean difference (SMD) of 0.2. However, no significant changes were observed in sCD163/sTWEAK (SMD: 0.16). Secondary outcomes indicated no changes in PON1, total cholesterol (TC), or LDL-C levels. However, there was an increase in HDL-C levels (adjusted SMD: 0.46, 95% CI: 0.02–0.91) and a decrease in TG and TC/HDL levels (adjusted SMD: − 0.5 and − 0.3, respectively) in the synbiotic group. A favorable effect of synbiotics on sTWEAK, HDL, TG, and TC/HDL of patients with heart failure was observed, but no statistically significant effect was found on sCD163/sTWEAK, PON1, LDL, and TC factors. [ABSTRACT FROM AUTHOR]

The controversy surrounding whether serum total cholesterol is a risk factor for the graded progression of knee osteoarthritis (KOA) has prompted this study to develop an authentic prediction model using a machine learning (ML) algorithm. The objective was to investigate whether serum total cholesterol plays a significant role in the progression of KOA. This cross-sectional study utilized data from the public database DRYAD. LASSO regression was employed to identify risk factors associated with the graded progression of KOA. Additionally, six ML algorithms were utilized in conjunction with clinical features and relevant variables to construct a prediction model. The significance and ranking of variables were carefully analyzed. The variables incorporated in the model include JBS3, Diabetes, Hypertension, HDL, TC, BMI, SES, and AGE. Serum total cholesterol emerged as a significant risk factor for the graded progression of KOA in all six ML algorithms used for importance ranking. XGBoost algorithm was based on the combined best performance of the training and validation sets. The ML algorithm enables predictive modeling of risk factors for the progression of the KOA K–L classification and confirms that serum total cholesterol is an important risk factor for the progression of KOA. [ABSTRACT FROM AUTHOR]

Background: Dysferlin-deficient limb-girdle muscular dystrophy type 2B (Dysf) mice are notorious for their mild phenotype. Raising plasma total cholesterol (CHOL) via apolipoprotein E (ApoE) knockout (KO) drastically exacerbates muscle wasting in Dysf mice. However, dysferlinopathic patients have abnormally reduced plasma high-density lipoprotein cholesterol (HDL-C) levels. The current study aimed to determine whether HDL-C lowering can exacerbate the mild phenotype of dysferlin-null mice. Methods: Human cholesteryl ester transfer protein (CETP), a plasma lipid transfer protein not found in mice that reduces HDL-C, and/or its optimal adapter protein human apolipoprotein B (ApoB), were overexpressed in Dysf mice. Mice received a 2% cholesterol diet from 2 months of age and characterized through ambulatory and hanging functional tests, plasma analyses, and muscle histology. Results: CETP/ApoB expression in Dysf mice caused reduced HDL-C (54.5%) and elevated ratio of CHOL/HDL-C (181.3%) compared to control Dysf mice in plasma, but without raising CHOL. Compared to the severe muscle pathology found in high CHOL Dysf/ApoE double knockout mice, Dysf/CETP/ApoB mice did not show significant changes in ambulation, hanging capacity, increases in damaged area, collagen deposition, or decreases in cross-sectional area and healthy myofibre coverage. Conclusions: CETP/ApoB over-expression in Dysf mice decreases HDL-C without increasing CHOL or exacerbating muscle pathology. High CHOL or nonHDL-C caused by ApoE KO, rather than low HDL-C, likely lead to rodent muscular dystrophy phenotype humanization. [ABSTRACT FROM AUTHOR]

Porokeratoses (PK) are a group of uncommon dermatoses characterized by abnormal epidermal differentiation due to a disorder of the mevalonate metabolic pathway. Several clinical subtypes exist that can be associated with the same patient or affect different patients within a family and could, therefore, be different expressions of one disease. All PK subtypes share a common histopathologic finding, the cornoid lamella, a vertical stack of parakeratotic corneocytes embedded in an orthokeratotic horny layer. PK often affects immunosuppressed patients, in whom the course may parallel the level of immunosuppression. The pathogenesis of PK, which had long remained mysterious, has been recently unraveled after discovering pathogenic variants of genes involved in the mevalonate metabolic pathway. The disease is due to germline pathogenic variants of genes of this pathway but requires a second‐hit event to manifest; therefore, PK is considered a dominantly inherited but recessively expressed condition. The prognosis of PK is usually favorable, even though the lesions progress to keratinocyte carcinomas in 7%–16% of patients. The treatment of PK was based on physical (ablative) procedures and various (topical or systemic) treatments, whose efficacy is nevertheless inconsistent and often temporary. The discovery of the metabolic pathway involved in the pathogenesis of PK paved the way for the elaboration of new topical treatments (combination of statins and cholesterol), which are more regularly efficacious compared with older treatments, even though the management of some patients with PK may still be challenging. [ABSTRACT FROM AUTHOR]

Introduction: Data on sodium glucose co-transporter 2 inhibitors impact on lipids in patients with diabetes are available and only a handful of studies have explored this effect in individuals with both diabetes and renal impairment; lipid parameters were not the primary focus of those earlier studies. However, there is a significant research gap specifically addressing the influence of SGLT2 inhibitors on cholesterol fractions in patients exclusively with chronic kidney disease. This aim constitutes the central objective in this particular study. Methods: In this 3-month randomized controlled study, 30 patients with stage 3 chronic kidney disease and dyslipidemia were randomly assigned to receive either dapagliflozin 10 mg or placebo. Lipid profiles, renal function, and urinary albumin levels were assessed at baseline and after 3 months. Results: Compared to baseline, patients receiving dapagliflozin for 3 months showed significant improvements in serum creatinine (p <.001) and eGFR (p =.001). Total cholesterol and LDL-C levels decreased significantly (p =.010 and.006, respectively). While albumin-creatinine ratio also decreased, this change was not statistically significant. Additionally, HDL-C and TG not significantly increased. The control group without intervention experienced deterioration in serum creatinine and eGFR (p =.008, and.011, respectively), but no statistically significant lipid changes were observed. Furthermore, post-intervention total cholesterol moderately correlated with BMI (p =.032, R =.554), yet no predictors significantly influenced lipid levels in the multiple linear regression analysis. Conclusions: Dapagliflozin has a favorable effect on cholesterol fractions in stage 3 CKD patients without diabetes mellitus and this effect was different from that observed in patients with diabetes alone. [ABSTRACT FROM AUTHOR]

The objective were to evaluate the effects of supplementation of standardized dry extract of Rosmarinus officinalis (RO) and the application of aesthetic radiofrequency on the oxidative stress markers catalase (CAT), superoxide dismutase (SOD), non-protein thiols (NP-SH), and thiobarbituric acid reactive species (TBARS) and the biochemical markers triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, glutamic-oxaloacetic transaminase (TGO/AST), pyruvic-glutamic transaminase (TGP/ALT), gamma glutamyl transpeptidase (gamma-GT), and creatinine. This study included 32 women received the aesthetic therapy to reduce localized fat. They were divided into the control group (n = 8) receiving placebo capsules and the intervention group (n = 24) subdivided into Group A, B, and C, each with eight members receiving supplementation with 100, 500, and 1000 mg/day of standardized dry extract of RO, respectively. The Universal Trial Number (UTN) – U1111-1274-6255. Supplementation with RO (500 mg/day) demonstrated a reduction in oxidative stress (quantified with through a significant increase in NP-SH and a reduction in SOD and CAT enzymes). The radiofrequency aesthetic treatment did not promote an increase in oxidative stress; however, it caused significant changes in total cholesterol, HDL cholesterol, and creatinine. RO is a plant with antioxidant effects and its oral consumption is safe in selected women subjects in hepatic and renal markers. [ABSTRACT FROM AUTHOR]

Introduction: We aim to report the clinical course of a patient with pachychoroidopathy who experienced regression of subfoveal drusen during cholesterol treatment using PCSK9 inhibitors. Case Presentation: A 62-year-old woman who was visually asymptomatic complained of recent visual loss in the left eye (OS). She was diagnosed with foveal pachydrusen (OS) that had remained stable for 10 years. Three months after starting cholesterol treatment with a PCSK9 inhibitor, the latest class of lipid-lowering medication, her vision improved in parallel with gradual regression of material deposited beneath the retinal pigment epithelium (RPE). Recurrence of drusen was observed after discontinuing the drug. Conclusions: Use of PCSK9 inhibitors may improve the retina’s lipid homeostasis by increasing the number of RPE-LDL receptors and partly contribute to the improvement of ocular phenotypes associated with dysfunctional RPE in pachychoroidopathy. [ABSTRACT FROM AUTHOR]

Background: Despite significant progress in cardiovascular disease (CVD) management, it remains a public health priority and a global challenge. Within the disease process, health care after a cardiovascular event (secondary prevention) is essential to prevent recurrences. Nonetheless, evidence has suggested the existence of gender disparities in CVD management, leaving women in a vulnerable situation. The objective of this study is to identify all available evidence on the existence of gender differences in health care attention after a major adverse cardiovascular event. Methods: A scoping review following the structure of PRISMA-ScR was conducted. To define the inclusion criteria, we used Joanna Briggs Institute (JBI) population, concept, context framework for scoping reviews. A systematic search was performed in MEDLINE (PubMed), EMBASE and Cochrane. The methods of this review are registered in the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) (INPLASY202350084). Results: The initial search retrieved 3,322 studies. 26 articles were identified manually. After the reviewing process, 93 articles were finally included. The main intervention studied was the pharmacological treatment received (n = 61, 66%), distantly followed by guideline-recommended care (n = 26, 28%) and cardiac rehabilitation (CR) referral (n = 16)". Literature described gender differences in care and management of secondary prevention of CVD. Women were less frequently treated with guideline-recommended medications and seem more likely to be non-adherent. When analysing guideline recommendations, women were more likely to make dietary changes, however, men were more likely to increase physical activity. Studies also showed that women had lower rates of risk factor testing and cholesterol goals attainment. Female sex was associated with lower rates of cardiac rehabilitation referral and participation. Conclusions: This review allowed us to compile knowledge on the existence of gender inequalities on the secondary prevention of CVD. Additional research is required to delve into various factors influencing therapeutic disparities, referral and non-participation in CR programs, among other aspects, in order to improve existing knowledge about the management and treatment of CVD in men and women. This approach is crucial to ensure the most equitable and effective attention to this issue. [ABSTRACT FROM AUTHOR]

The mevalonate pathway plays an important role in breast cancer and other tumor types. However, many issues remain obscure as yet regarding its mechanism of regulation and action. In the present study, we report that the expression of mevalonate pathway enzymes is mediated by the RHO guanosine nucleotide exchange factors VAV2 and VAV3 in a RAC1‐ and sterol regulatory element‐binding factor (SREBF)‐dependent manner in breast cancer cells. Furthermore, in vivo tumorigenesis experiments indicated that the two most upstream steps of this metabolic pathway [3‐hydroxy‐3‐methylglutaryl‐coenzyme A synthase 1 (HMGCS1) and 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR)] are important for primary tumorigenesis, angiogenesis, and cell survival in breast cancer cells. HMGCR, but not HMGCS1, is also important for the extravasation and subsequent fitness of breast cancer cells in the lung parenchyma. Genome‐wide expression analyses revealed that HMGCR influences the expression of gene signatures linked to proliferation, metabolism, and immune responses. The HMGCR‐regulated gene signature predicts long‐term tumor recurrence but not metastasis in cohorts of nonsegregated and chemotherapy‐resistant breast cancer patients. These results reveal a hitherto unknown, VAV‐catalysis‐dependent mechanism involved in the regulation of the mevalonate pathway in breast cancer cells. They also identify specific mevalonate‐pathway‐dependent processes that contribute to the malignant features of breast cancer cells. [ABSTRACT FROM AUTHOR]

The colon is the largest compartment of the immune system, with innate immune cells exposed to antigens in the environment. However, the mechanisms by which the innate immune system is instigated are poorly defined in colorectal cancer (CRC). Here, a population of CD16+ neutrophils that specifically accumulate in CRC tumor tissues by imaging mass cytometry (IMC), immune fluorescence, and flow cytometry, which demonstrated pro‐tumor activity by disturbing natural killer (NK) cells are identified. It is found that these CD16+ neutrophils possess abnormal cholesterol accumulation due to activation of the CD16/TAK1/NF‐κB axis, which upregulates scavenger receptors for cholesterol intake including CD36 and LRP1. Consequently, these region‐specific CD16+ neutrophils not only competitively inhibit cholesterol intake of NK cells, which interrupts NK lipid raft formation and blocks their antitumor signaling but also release neutrophil extracellular traps (NETs) to induce the death of NK cells. Furthermore, CD16‐knockout reverses the pro‐tumor activity of neutrophils and restored NK cell cytotoxicity. Collectively, the findings suggest that CRC region‐specific CD16+ neutrophils can be a diagnostic marker and potential therapeutic target for CRC. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have revealed the role of dietary fatty acids in human health. However, few studies have evaluated dietary fatty acid patterns and their association with metabolic parameters. The current study aimed to explore the association between dietary fatty acid patterns and risk factors for metabolic syndrome (MetS) among overweight and obese adults. Methods: This cross-sectional study involved 340 participants who were overweight or obese. The study included assessments of body composition and anthropometric measurements. Dietary fatty acid consumption was evaluated using a validated Food Frequency Questionnaire (FFQ) containing 168 items. Additionally, biochemical parameters, including serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), fasting serum glucose (FSG), and insulin levels, were measured using enzymatic methods. Fatty acid patterns were determined by principal component analysis (PCA), and the association between these dietary FA patterns and risk factors related to MetS components was assessed using logistic regression. Results: Factor analysis conducted in this study explored three dietary fatty acid patterns: saturated fatty acids (SFA), polyunsaturated fatty acids (PUFA), and long-chain combined fatty acids (LC-CFA). Those at the highest tertile of the SFA pattern had lower diastolic blood pressure (DBP) (P = 0.03). Low-density lipoprotein cholesterol (LDL) was lower in the second and third tertiles (P ≤ 0.05). Also, higher fasting blood glucose (FBS) was observed in the second and third tertiles (P < 0.05), and the homeostatic model assessment of insulin resistance (HOMA-IR) was higher in the third tertile (P = 0.049). In the PUFA pattern, FBS was lower in the third tertile (P = 0.03). In the LC-CFA pattern, lower TC was achieved in higher tertiles (P = 0.04). Conclusion: Our findings demonstrated that consuming high and moderate SFA patterns is associated with higher FBS and HOMA-IR. Also, increased consumption of SCFAs is related to lower DPB and LDL. Individuals who consumed more PUFA, especially linoleic acid, had lower FBS. These outcomes might be beneficial in managing MetS and leading to a new field of research. [ABSTRACT FROM AUTHOR]

Purpose: We examined the associations of soy product intake with all-cause, cardiovascular disease (CVD), and cancer mortality and mediations through CVD risk factors based on the Guangzhou Biobank Cohort Study (GBCS), and conducted updated meta-analyses. Methods: A total of 29,825 participants aged 50 + years were included. Causes of death were identified through record linkage. Soy product intake was assessed by food frequency questionnaire. Cox proportional hazards regression was used to analyze the associations between soy product intake and mortality, yielding hazard ratios (HRs) and 95% confidence intervals (CIs). Mediation analyses with CVD risk factors as mediators, and updated meta-analyses were conducted. Results: During 454,689 person-years of follow-up, 6899 deaths occurred, including 2694 CVD and 2236 cancer. Participants who consumed soy product of 1–6 portions/week, versus no consumption, had significantly lower risks of all-cause and CVD mortality (adjusted HR (95% CI) 0.91 (0.86, 0.97) and 0.87 (0.79, 0.96), respectively). In participants who consumed soy product of ≥ 7 portions/week, the association of higher intake with lower CVD mortality was modestly mediated by total cholesterol (4.2%, 95% CI 1.0–16.6%). Updated meta-analyses showed that the highest level of soy product intake, versus the lowest, was associated with lower risks of all-cause and CVD mortality (pooled HR (95% CI) 0.92 (0.88, 0.96) and 0.92 (0.87, 0.98), respectively). Conclusion: Moderate and high soy product intake were associated with lower risks of all-cause and CVD mortality. Our findings provide support for current dietary guidelines recommending moderate soy product intake, and contribute additional evidence regarding the potential protective effects of high soy product intake. [ABSTRACT FROM AUTHOR]

Background: Older patients with cardiovascular disease (CVD) are highly susceptible to adverse drug reactions due to age-related physiological changes and the presence of multiple comorbidities, polypharmacy, and potentially inappropriate medications (PIMs). Objective: This study aimed to develop a predictive model to identify the use of PIMs in older patients with CVD. Methods: Data from 2012 to 2021 from the Changhua Christian Hospital Clinical Research Database (CCHRD) and the Kaohsiung Medical University Hospital Research Database (KMUHRD) were analyzed. Participants over the age of 65 years with CVD diagnoses were included. The CCHRD data were randomly divided into a training set (80% of the database) and an internal validation set (20% of the database), while the KMUHRD data served as an external validation set. The training set was used to construct the prediction models, and both validation sets were used to validate the proposed models. Results: A total of 48,569 patients were included. Comprehensive data analysis revealed significant associations between the use of PIMs and clinical factors such as total cholesterol, glycated hemoglobin (HbA1c), creatinine, and uric acid levels, as well as the presence of diabetes, hypertension, and cerebrovascular accidents. The predictive models demonstrated moderate power, indicating the importance of these factors in assessing the risk of PIMs. Conclusions: This study developed predictive models that improve understanding of the use of PIMs in older patients with CVD. These models may assist clinicians in making informed decisions regarding medication safety. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is the primary neurodegenerative disease affecting the elderly population. Despite the first description of its pathology over a century ago, its precise cause and molecular mechanism remain unknown. Numerous factors, including beta-amyloid, tau protein, the APOEε4 gene, and different metals, have been extensively investigated in relation to this disease. However, none of them have been proven to have a decisive causal relationship. Furthermore, no single theory has successfully integrated these puzzle pieces thus far. In this review article, we propose the most probable molecular mechanism for AD, which clearly shows the relationship between the main aspects of the disease, and addresses fundamental questions such as: Why is aging the major risk factor for the disease? Are amyloid plaques and tau tangles the causes or consequences of AD? Why are the distributions of senile plaques and tau tangles in the brain different and independent of each other? Why is the APOEε4 gene a risk factor for AD? Finally, why is the disease more prevalent in women? [ABSTRACT FROM AUTHOR]

Cholesterol is required to maintain the functional integrity of cellular membrane systems and signalling pathways, but its supply must be closely and dynamically regulated because excess cholesterol is toxic. Sterol regulatory element-binding protein 2 (SREBP2) and the ER-resident protein HMG-CoA reductase (HMGCR) are key regulators of cholesterol biosynthesis. Here, we assessed the mechanistic aspects of their regulation in hepatic cells. Unexpectedly, we found that the transcriptionally active fragment of SREBP2 (N-SREBP2) was produced constitutively. Moreover, in the absence of an exogenous cholesterol supply, nuclear N-SREBP2 became resistant to proteasome-mediated degradation. This resistance was paired with increased occupancy at the HMGCR promoter and HMGCR expression. Inhibiting nuclear N-SREBP2 degradation did not increase HMGCR RNA levels; this increase required cholesterol depletion. Our findings, combined with previous physiological and biophysical investigations, suggest a new model of SREBP2-mediated regulation of cholesterol biosynthesis in the organ that handles large and rapid fluctuations in the dietary supply of this key lipid. Specifically, in the nucleus, cholesterol and the ubiquitin–proteasome system provide a short-loop system that modulates the rate of cholesterol biosynthesis via regulation of nuclear N-SREBP2 turnover and HMGCR expression. Our findings have important implications for maintaining cellular cholesterol homeostasis and lowering blood cholesterol via the SREBP2-HMGCR axis. [ABSTRACT FROM AUTHOR]

Simple Summary: Nutritional status is closely related to the outcomes of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). However, the prognostic value of the Controlling Nutritional Status (CONUT) score in CRS-HIPEC has not yet been investigated. This study evaluated the predictive power of the CONUT score for mortality and postoperative complications after CRS-HIPEC. We found that patients with high CONUT score exhibited significantly higher 1-year mortality and postoperative complication rates than those with low CONUT score. Notably, a high CONUT score was identified as an independent risk factor for 1-year mortality and postoperative complications. These results suggest the potential of the CONUT score as a robust risk stratification tool for identifying high-risk patients within the CRS-HIPEC surgical demographic. The Controlling Nutritional Status (CONUT) score is a novel nutritional index that integrates the serum albumin level, peripheral blood lymphocyte count, and total cholesterol level. This retrospective study explores its prognostic significance in patients undergoing cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). We included 436 patients who underwent CRS-HIPEC, categorized into low (0–3) and high (4–12) CONUT score groups, and performed logistic regression analysis to predict one-year mortality and postoperative morbidity. Our findings revealed that high CONUT scores correlate with increased one-year mortality (47.1% vs. 20.3%, p < 0.001) and morbidity (39.2% vs. 18.2%, p < 0.001) compared to low CONUT scores. Multivariable regression analysis confirmed high CONUT scores as independent predictors of one-year mortality (odds ratio: 2.253, 95% CI: 1.014–5.005, p = 0.046) and postoperative morbidity (odds ratio: 2.201, 95% CI: 1.066–4.547, p = 0.033). These results underscore the CONUT score's effectiveness as an independent marker for evaluating risks associated with CRS-HIPEC, emphasizing its potential to improve risk stratification. [ABSTRACT FROM AUTHOR]

Childhood maltreatment influences adult physical health through cascading effects over the life course and it is critical to identify intervening processes. Marital quality has significant implications for adult physical health via cognitive, emotional, and behavioral pathways and may be a viable pathway. Given that cardiometabolic biomarkers are associated with the leading causes of death in the United States, the current study longitudinally investigated marital quality, health locus of control, and eating habits in a serial mediation model linking childhood maltreatment to high density lipoprotein (HDL) and low density lipoprotein (LDL). Using a sample of 352 adults from the study of Midlife Development in the United States, we used three waves of data to test our hypotheses. Results of structural equation models indicate that although all the hypothesized direct effects were statistically significant, the serial indirect effects were non-significant. Childhood maltreatment was associated with a lower quality marriage, marital quality was associated with higher levels of health locus of control which, in turn, was associated with healthier eating habits. Finally, healthier eating habits were associated with greater HDL, but not lower LDL. Additionally, marital quality exerted a direct effect on LDL and mediated the relationship between maltreatment and LDL, but not HDL. For researchers, marital quality appears to be a mechanism linking childhood maltreatment to cardiometabolic biomarkers, yet health locus of control and eating habits do not appear to have strong effects. For clinicians, strengthening the couple relationship among survivors of maltreatment appears to have health promotive effects over time. [ABSTRACT FROM AUTHOR]

Background and aims: The effect of breastfeeding duration on childhood lipid levels has remained controversial. In this study, we aimed to establish the long-term associations of breastfeeding duration with future levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol and low-density lipoprotein cholesterol. In addition, we report lipid levels at the age of seven months depending on the child receiving any breastmilk. Methods: The sample comprised 999 children participating in the prospective Special Turku Coronary Risk Factor Intervention Project (STRIP). Serum lipid profile was studied at the ages of seven months and 13 months, and annually thereafter until the age of 20 years. Duration of breastfeeding was inquired, and infants were divided into those who received or did not receive any breast milk at the age of seven months (n =533 and n =466, respectively). In addition, breastfeeding duration groups (any breastfeeding for 0–4 months, 4–6 months, 6–9 months, and >9 months) were formed. Results: At the age of seven months infants who at that time received breast milk had higher serum HDL cholesterol (0.95±0.21mmol/l vs. 0.90±0.19 mmol/l; p =0.0018), non-HDL cholesterol (3.38±0.78 mmol/l vs. 3.01±0.67 mmol/l; p <0.001) and total cholesterol levels (4.33±0.80 mmol/l vs. 3.91±0.69 mmol/l; p <0.001) than their peers who did not receive breast milk. From two to 20 years of age serum lipid levels showed no consistent differences between the breastfeeding duration groups. Conclusions: Our long-term data showed that duration of breastfeeding has no consistent associations with serum lipid concentrations in healthy individuals aged two to 20 years. Clinical Trial Registration: www.clinicaltrials.gov, unique identifier NCT00223600. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver ailment worldwide, in which nonpharmacological strategies have a considerable role in the treatment. Probiotic supplementation as well as physical exercise can improve cardiometabolic parameters, but further research is needed to determine the effects of combined treatment versus exercise alone in managing NAFLD-associated biomarkers, primarily liver enzymes, lipid markers, and insulin resistance. Objectives: This systematic review and meta-analysis aimed to evaluate the effects of probiotic supplementation, combined with exercise versus exercise alone, on liver enzymes and cardiometabolic markers in patients with NAFLD. Methods: A systematic review and meta-analysis of randomized clinical trials was performed by searching PubMed, Scopus, and Web of Science databases up to April 2024. The search was restricted to articles published in the English language and human studies. Random effects models were used to calculate weighted mean differences (WMD). Results: Pooled estimates (9 studies, 615 patients, intervention durations ranging from 8 to 48 weeks) revealed that probiotics plus exercise decreased aspartate transaminase (AST) [WMD=-5.64 U/L, p = 0.02], gamma-glutamyl transferase (GGT) [WMD=-7.09 U/L, p = 0.004], low-density lipoprotein (LDL) [WMD=-8.98 mg/dL, p = 0.03], total cholesterol (TC) [WMD=-16.97 mg/dL, p = 0.01], and homeostatic model assessment for insulin resistance (HOMA-IR) [WMD=-0.94, p = 0.005] significantly more than exercise only. However, probiotics plus exercise did not significantly change high-density lipoprotein (HDL) [WMD = 0.07 mg/dL, p = 0.9], fasting insulin [WMD=-1.47 µIU/mL, p = 0.4] or fasting blood glucose (FBG) [WMD=-1.57 mg/dL, p = 0.3] compared with exercise only. While not statistically significant, there were clinically relevant reductions in alanine aminotransferase (ALT) [WMD=-6.78 U/L, p = 0.1], triglycerides (TG) [WMD=-21.84 mg/dL, p = 0.1], and body weight (BW) [WMD=-1.45 kg, p = 0.5] for probiotics plus exercise compared with exercise only. The included studies exhibited significant heterogeneity for AST (I2 = 78.99%, p = 0.001), GGT (I2 = 73.87%, p = 0.004), LDL (I2 = 62.78%, p = 0.02), TC (I2 = 72.41%, p = 0.003), HOMA-IR (I2 = 93.86%, p = 0.001), HDL (I2 = 0.00%, p = 0.9), FBG (I2 = 66.30%, p = 0.01), ALT (I2 = 88.08%, p = 0.001), and TG (I2 = 85.46%, p = 0.001). There was no significant heterogeneity among the included studies for BW (I2 = 0.00%, p = 0.9). Conclusion: Probiotic supplementation combined with exercise training elicited better results compared to exercise alone on liver enzymes, lipid profile, and insulin resistance in patients with NAFLD. Systematic Review Registration: PROSPERO registration number CRD42023424290. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is often linked to chronic inflammation, which can be influenced by both lifestyle and dietary choices. However, the relationship between the inflammatory potential of diet and lifestyle factors and the risk of developing T2DM remains unclear. The present study aimed to investigate the associations of the empirical dietary inflammatory index (EDII), dietary inflammatory score (DIS), and lifestyle inflammatory score (LIS) with the risk of T2DM among Iranian adults. Methods: The current study was conducted on 5714 individuals from Yazd Health Study (YaHS) who were followed up for a mean period of six years. YaHS is a prospective cohort study which has been conducted since 2014. Dietary intakes were collected at baseline using the food frequency questionnaire. The relative risk (RR) of T2DM was calculated by Cox regression analysis across tertiles of EDII, DIS, and LIS, adjusted for potential confounders. Results: The mean ± SD for the age and body mass index of the study population were 47.0 ± 9.2 years and 26.7 ± 5.1 Kg.m2, respectively. A significant association between LIS and the risk of T2DM was observed (RR: 4.05, 95% CI: 2.61–6.27 P-trend < 0.001). Individuals in the highest compared to the lowest tertile of EDII-LIS (RR: 3.07, 95%CI: 2.01–4.68; P for trend < 0.001) and DIS-LIS (RR: 2.42, 95%CI: 1.69–3.49; P for trend < 0.001) had a higher risk of T2DM. However, no significant association was found between EDII and DIS scores and the risk of T2DM. Conclusion: Greater adherence to LIS, EDII-LIS, and DIS-LIS scores was associated with a higher risk of T2DM, while no significant association was found between EDII and DIS with T2DM risk. [ABSTRACT FROM AUTHOR]

Protein aggregation plays a crucial role in the development of several neurodegenerative diseases. It is important to understand the aggregation process for the detection of the onset of these diseases. Alzheimer's Disease (AD) is one of the most prevalent neurodegenerative diseases caused by the aggregation of Aβ-40 and Aβ-42 peptides. The smaller oligomers lead to the formation of protein plaque at the neural membranes leading to memory loss and other disorders. Interestingly, aggregation takes place at the neural membranes, therefore the membrane composition seems to play an important role in the aggregation process. Despite a large number of literatures on the effect of lipid composition on protein aggregation, there are very few concise reviews that highlight the role of membrane composition in protein aggregation. In this review, we have discussed the implication of membrane composition on the aggregation of amyloid beta peptide with a special emphasis on cholesterol. We have further discussed the role of the degree of unsaturation of fatty acids and the participation of apolipoprotein E4 (ApoE4) in the onset of AD. [ABSTRACT FROM AUTHOR]

Aims: Very few cohort studies are available about the relation between remnant cholesterol (RC) and diabetes. Based on a prospective cohort survey, this research aimed at investigating if high RC was related to a future diabetes risk in the Chinese population, as well as to compare the association between RC, high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), total cholesterol (TC), triglycerides (TG), TG/HDL‐C, LDL‐C/HDL‐C, TC/HDL‐C, and non‐high‐density lipoprotein cholesterol (non‐HDL‐C), and future diabetes risk. Materials and Methods: 6,700 baseline normoglycemic participants of the REACTION study's Beijing center were recruited in 2011–2012 and followed up in 2015. Multivariate Cox regression analyses were performed to explore the relationship of RC, HDL‐C, LDL‐C, TC, TG, LDL‐C/HDL‐C, TG/HDL‐C, TC/HDL‐C, and non‐HDL‐C and a future diabetes risk. Results: After potential confounders were adjusted for, only RC (HR 1.134, 95% CI 1.016–1.267, P = 0.025) was positively related to a future diabetes risk, and only HDL‐C (HR 0.728, 95% CI 0.578–0.918, P = 0.007) was negatively related to a future diabetes risk. The rest of the lipid parameters were not related to a future risk of diabetes. Sensitivity and stratification analyses revealed that the relation between RC and future diabetes risk was stable. RC and future diabetes risk were still positively correlated even when the HDL‐C was ≥1.04 mmol/L (HR 1.167, 95% CI 1.050–1.297, P = 0.004). Conclusions: It was RC, but not other lipid parameters, that was independently and positively related to a future risk of diabetes among the Chinese general population. Moreover, the relationship between RC and diabetes risk was stable, even with appropriate levels of HDL‐C. [ABSTRACT FROM AUTHOR]

Background: Studies concerning the negative effect of hormonal contraceptives is scarce and scanty. The main aim of this study the common health problems related to the intake of oral contraceptives (OCP) and injection contraceptives (INJ). Methods: This was a descriptive, cross-sectional study, The study was conducted in Omdurman Maternity Hospital. About 125 Sudanese women were participated in this study divided to test group which was consisted of 65 women used contraceptives, and 60 women were control group. The primary data was collected using questionnaire and laboratory investigations. Results: Sociodemographic characteristics of the two groups showed no association between residential areas and nutritional problems as it compared between control and test group (P ≤ 0.05). Level of blood pressure, cholesterol, triglycerides and Hb% among test and control group showed clear differences between the two groups (P ≤ 0.05). Conclusions: The most common side effects associated with consecutive use among test were headache, hair fall, weight increase, joint pain, fatigue, accelerated heart beats, unstable breathing and nausea. [ABSTRACT FROM AUTHOR]