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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]

Fluorescent lipid probes such as 1-palmitoyl-2-(6-[7-nitro-2-1,3-benzoxadiazol-4-yl]amino-hexanoyl)-sn-glycero-3-phosphocholine (C6 NBD-PC) have been used extensively to study the kinetics of lipid flip-flop. However, the efficacy of these probes as reliable reporters of native lipid translocation has never been tested. In this study, sum-frequency vibrational spectroscopy (SFVS) was used to measure the kinetics of C6 NBD-PC lipid flip-flop and the flip-flop of native lipids in planar supported lipid bilayers. C6 NBD-PC was investigated at concentrations of 1 and 3 mol. % in both chain-matched 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and chain-mismatched 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) to assess the ability of C6 NBD-PC to mimic the behavior of the surrounding matrix lipids. It was observed that C6 NBD-PC exhibited faster flip-flop kinetics compared to the native lipids in both DPPC and DSPC matrices, with notably accelerated rates in the chain-mismatched DSPC system. SFVS was also used to measure the acyl chain orientation and gauche content of C6 NBD-PC in both DPPC and DSPC membranes. In the DSPC matrix (chain mismatched), C6 NBD-PC was more disordered in terms of both gauche content and acyl tilt, whereas it maintained an orientation similar to that of the native lipids in the DPPC matrix (chain matched). In addition, the flip-flop kinetics of C6 NBD-PC were also measured using second-harmonic generation (SHG) spectroscopy, by probing the motion of the NBD chromophore directly. The flip-flop kinetics measured by SHG were consistent with those obtained from SFVS. This study also marks the first instance of phospholipid flip-flop kinetics being measured via SHG. The results of this study clearly demonstrate that C6 NBD-PC does not adequately mimic the behavior of native lipids within a membrane. These findings also highlight the significant impact of the lipid matrix on the flip-flop behavior of the fluorescently labeled lipid, C6 NBD-PC. [ABSTRACT FROM AUTHOR]

Within cell plasma membranes, unsaturated lipids are asymmetrically distributed over the inner and outer leaflets, offering an attractive local structural feature. However, the mechanism to keep lipid transmembrane asymmetry and the closely related transmembrane movement (flip-flop) for unsaturated lipids remain poorly understood. Here, we applied sum frequency generation vibrational spectroscopy to investigate this lipid transmembrane asymmetry upon mimicking the cell membrane homeostatic processes. On the one hand, unsaturated lipids were found to hinder the flip-flop process and preserve lipid transmembrane asymmetry in model cell membranes, owing to the steric hindrance caused by their bent tails. On the other hand, local unsaturated lipids in the mixed unsaturated/saturated lipid bilayer were conducive to the formation of the local asymmetry. Therefore, lipid unsaturation can be recognized as an intrinsic key factor to form and maintain lipid transmembrane asymmetry in cell membranes. [ABSTRACT FROM AUTHOR]

Both sugars and lipids are important biomolecular building blocks with exceptional conformational flexibility and adaptability to their environment. Glycolipids bring together these two molecular components in the same assembly and combine the complexity of their conformational landscapes. In the present study, we have used selective double resonance vibrational spectroscopy, in combination with a computational approach, to explore the conformational preferences of two glycolipid models (3-0-acyl catechol and guaiacol α-D-glucopyranosides), either fully isolated in the gas phase or controlled interaction with a single water molecule. We could identify the preferred conformation and structures of the isolated and micro-hydrated species and evidence of the presence of a strong water pocket, which may influence the conformational flexibility of such systems, even in less controlled environments. [ABSTRACT FROM AUTHOR]

Fatty acids from cooking fumes and hypochlorous acid (HOCl) released from indoor cleaning adversely affect respiratory health, but the molecular-level mechanism remains unclear. Here, the effect of cooking oil fumes [palmitic acid (PA), oleic acid (OA), and linoleic acid (LA)] on lung model phospholipid (POPG) hydrochlorination mediated by HOCl at the air–water interface of the hanged droplets was investigated. Interfacial hydrochlorination of POPG was impeded by OA and LA, while that of POPG was facilitated by PA. The effect on POPG hydrochlorination increased with the decrease in oil fume concentration. A potential mechanism with respect to the chain length of these oil fumes, regardless of their saturation, was proposed. PA with a short carbon chain looses the POPG packing and leads to the exposure of the C=C double bonds of POPG, whereas OA and LA with a long carbon chain hinder HOCl from reaching the C=C bonds of POPG. These results for short chain and low concentration dependence suggest that the decay of oil fumes or the conversion of short-chain species by indoor interfacial chemistry might be adverse to lung health. These results provide insights into the relationship between indoor multicomponent pollutants and the respiratory system. [ABSTRACT FROM AUTHOR]

Biological lipid membranes are generally asymmetric, not only with respect to the composition of the two membrane leaflets but also with respect to the state of mechanical stress on the two sides. Computer simulations of such asymmetric membranes pose unique challenges with respect to the choice of boundary conditions and ensemble in which such simulations are to be carried out. Here, we demonstrate an alternative to the usual choice of fully periodic boundary conditions: The membrane is only periodic in one direction, with free edges running parallel to the single direction of periodicity. In order to maintain bilayer asymmetry under these conditions, nanoscale "sticky tapes" are adhered to the membrane edges in order to prevent lipid flip-flop across the otherwise open edge. In such semi-periodic simulations, the bilayer is free to choose both its area and mean curvature, allowing for minimization of the bilayer elastic free energy. We implement these principles in a highly coarse-grained model and show how even the simplest examples of such simulations can reveal useful membrane elastic properties, such as the location of the monolayer neutral surface. [ABSTRACT FROM AUTHOR]

The pH-dependent change in protonation of ionizable lipids is crucial for the success of lipid-based nanoparticles as mRNA delivery systems. Despite their widespread application in vaccines, the structural changes upon acidification are not well understood. Molecular dynamics simulations support structure prediction but require an a priori knowledge of the lipid packing and protonation degree. The presetting of the protonation degree is a challenging task in the case of ionizable lipids since it depends on pH and on the local lipid environment and often lacks experimental validation. Here, we introduce a methodology of combining all-atom molecular dynamics simulations with experimental total-reflection x-ray fluorescence and scattering measurements for the ionizable lipid Dlin-MC3-DMA (MC3) in POPC monolayers. This joint approach allows us to simultaneously determine the lipid packing and the protonation degree of MC3. The consistent parameterization is expected to be useful for further predictive modeling of the action of MC3-based lipid nanoparticles. [ABSTRACT FROM AUTHOR]

Aims: To examine the association between domain-specific physical activity (PA) and cardiometabolic factors with longitudinal data, which is limited in current literature. Methods: Participants who attended the Singapore Multi-Ethnic Cohort and follow-up surveys were included in this study (N = 3950, mean age: 44.7 y, female: 57.9%). Self-reported moderate- to vigorous-intensity PA (MVPA) for each domain (leisure-time, transportation, occupation, and household) was categorized into 4 levels: no, low, middle, and high MVPA. The longitudinal associations of domain-specific MVPA with cardiometabolic factors including systolic and diastolic blood pressures, low-density and high-density lipoprotein cholesterols, triglycerides, and body mass index were examined using Generalized Estimating Equations, accounting for confounding factors and repeated measurements. Results: There were 5.2% participants who had no MVPA. For each domain, this rate ranged from 22.6% (household) to 83.3% (occupation). Leisure-time and occupation MVPAs had positive and linear associations with high-density lipoprotein cholesterols, corresponding to 0.030 (95% confidence interval, 0.015 to 0.045) mmol/L (leisure-time) and 0.063 (95% confidence interval, 0.043 to 0.083) mmol/L (occupation), when compared high with no respective MVPA. Occupation and household MVPAs were associated with low-density lipoprotein cholesterol. Transportation and occupation exhibited a positive and linear relationship with diastolic blood pressure. None of the domains were associated with body mass index, systolic blood pressures, or triglycerides. Conclusions: This study showed that each domain had differential association with individual cardiometabolic risk factors. As occupation, transportation, or household PA had unfavorable associations with low-density lipoprotein cholesterol or diastolic blood pressure, the overall beneficial impact of higher PA levels may not necessarily hold in the context of domain-specific PA and cardiovascular health. Further investigation is needed to corroborate our findings. [ABSTRACT FROM AUTHOR]

Summary Inflammasomes are multiprotein complexes that play a crucial role in regulating immune responses by governing the activation of Caspase‐1, the secretion of pro‐inflammatory cytokines, and the induction of inflammatory cell death, pyroptosis. The inflammasomes are pivotal in effective host defense against a range of pathogens. Yet, overt activation of inflammasome signaling can be detrimental. The most well‐studied NLRP3 inflammasome has the ability to detect a variety of stimuli including pathogen‐associated molecular patterns, environmental irritants, and endogenous stimuli released from dying cells. Additionally, NLRP3 acts as a key sensor of cellular homeostasis and can be activated by disturbances in diverse metabolic pathways. Consequently, NLRP3 is considered a key player linking metabolic dysregulation to numerous inflammatory disorders such as gout, diabetes, and atherosclerosis. Recently, compelling studies have highlighted a connection between lipids and the regulation of NLRP3 inflammasome. Lipids are integral to cellular processes that serve not only in maintaining the structural integrity and subcellular compartmentalization, but also in contributing to physiological equilibrium. Certain lipid species are known to define NLRP3 subcellular localization, therefore directly influencing the site of inflammasome assembly and activation. For instance, phosphatidylinositol 4‐phosphate plays a crucial role in NLRP3 localization to the trans Golgi network. Moreover, new evidence has demonstrated the roles of lipid biosynthesis and trafficking in activation of the NLRP3 inflammasome. This review summarizes and discusses these emerging and varied roles of lipid metabolism in inflammasome activation. A deeper understanding of lipid‐inflammasome interactions may open new avenues for therapeutic interventions to prevent or treat chronic inflammatory and autoimmune conditions. [ABSTRACT FROM AUTHOR]

The lubrication process of natural joint cartilage involves a series of coordinated mechanisms, a key aspect of which is its ability to continuously extract lubricating components from synovial fluid to achieve sustained lubrication. Inspired by this natural phenomenon, this study reports a novel polyelectrolyte hydrogel, specifically integrating ε‐poly‐L‐lysine (ε‐PL), adeptly captures lipids from environment to achieve effective lubrication similar to human joints. The ε‐PL within the hydrogel facilitates the dynamic sequestration of lipids, fostering interfacial self‐assembly. This setup, enriched with highly hydrated lipid head groups, enhances boundary lubrication capabilities for extended performance. Through rigorous evaluation of friction coefficients and supramolecular interactions between the hydrogel and lipids, it identified hydrogen bonding, charge‐dipole, and hydrophobic interactions as key to this self‐assembly. The findings affirm the versatility of polyelectrolytes in synthesizing lubricating hydrogels, bridging the gap to the creation of biomimetic hydrogels that mimic natural lubrication with enhanced durability and efficiency. [ABSTRACT FROM AUTHOR]

The microtubule‐associated protein tau participates in neurotransmission regulation via its interaction with synaptic vesicles (SVs). The precise nature and mechanics of tau's engagement with SVs, especially regarding alterations in vesicle dynamics, remain a matter of discussion. We report an electrochemical method using a synapse‐mimicking nanopipette to monitor vesicle dynamics induced by tau. A model vesicle of ~30 nm is confined within a lipid‐modified nanopipette orifice with a comparable diameter to mimic the synaptic lipid environment. Both tau and phosphorylated tau (p‐tau) present two‐state dynamic behavior in this biomimetic system, showing typical ionic current oscillation, induced by lipid‐tau interaction. The results indicate that p‐tau has a stronger affinity to the lipid vesicles in the confined environment, blocking the vesicle movement to a higher degree. Taken together, this method bridges a gap for sensing synaptic vesicle dynamics in a confined lipid environment, mimicking vesicle movement near the synaptic membrane. These findings contribute to understanding how different types of tau protein regulate synaptic vesicle motility and to underlying its functional and pathological behaviours in disease. [ABSTRACT FROM AUTHOR]

The consequences of intramolecular ionic interactions in determining the reactivity of functional groups are of interest because they provide insights into how nature deploys seemingly reactive functionalities to be rather ubiquitous. Of specific interest are the quaternary ammonium ions in lipids. In this work, we investigate the effect of intramolecular electrostatic interactions in zwitterionic functionalities by judiciously incorporating them as leaving groups at the α‐position of α,β‐unsaturated ester‐based lipid head groups. We find that electrostatic stabilization indeed plays a critical role in both the reaction kinetics with nucleophiles and the thermodynamics of lipid formation. We further leverage these findings to fabricate both triggerable assembly and disassembly of liposomal supramolecular assemblies in the presence of nucleophiles. [ABSTRACT FROM AUTHOR]

The existence of life beyond Earth has long captivated humanity, and the study of extremophiles—organisms surviving and thriving in extreme environments—provides crucial insights into this possibility. Extremophiles overcome severe challenges such as enzyme inactivity, protein denaturation, and damage of the cell membrane by adopting several strategies. This feature article focuses on the molecular strategies extremophiles use to maintain the cell membrane's structure and fluidity under external stress. Key strategies include homeoviscous adaptation (HVA), involving the regulation of lipid composition, and osmolyte-mediated adaptation (OMA), where small organic molecules protect the lipid membrane under stress. Proteins also have direct and indirect roles in protecting the lipid membrane. Examining the survival strategies of extremophiles provides scientists with crucial insights into how life can adapt and persist in harsh conditions, shedding light on the origins of life. This article examines HVA and OMA and their mechanisms in maintaining membrane stability, emphasizing our contributions to this field. It also provides a brief overview of the roles of proteins and concludes with recommendations for future research directions. [ABSTRACT FROM AUTHOR]

Enantiomers of a lipid erythro-sphingosine have been quantified with ≈4% accuracy by UV cold ion spectroscopy of their non-covalent complexes with a chiral aromatic molecule. The diastereomeric configuration of such complexes enables the quantification using just a single enantiomeric lipid standard and the identification of non-racemic solutions with no standards at all. [ABSTRACT FROM AUTHOR]

Recent studies strongly suggest that gut microbiome can influence brain functions and contribute to the development of Alzheimer's disease (AD). However, reported changes in the gut microbiomes in AD patients from different countries are not similar, and more research is needed to reveal the relationships between human microbiomes and AD in diverse ethnic populations. There is also an assumption that microbiome‐associated peripheral inflammation might drive the development of sporadic AD. This cross‐sectional study is aimed at analyzing the gut microbial profile and exploring potential associations with blood cytokines and some clinical parameters among individuals diagnosed with Alzheimer's in Kazakhstan. Consistent with previous studies, we have found that the microbial landscape in AD reveals specific alterations in the gut microbiome. Specifically, the AD patient group showed a decreased Firmicutes/Bacteroidetes ratio. The differential abundance analysis highlighted a dysbiosis in the gut microbiota of AD patients, marked by a reduced presence of Bifidobacterium, particularly B. breve. In our study, AD patients' altered gut microbiota composition notably features an increased presence of Pseudomonadota like Phyllobacterium and inflammatory bacteria such as Synergistetes and the Christensenellaceae family. The metabolic profiling of the AD microbiome reveals a predominant presence of pathways related to sugar, carrier molecules, tetrapyrrole, pyrimidine biosynthesis, and nucleic acid processing. This analysis also highlighted a marked reduction in SCFA, carbohydrate, polysaccharide, polyamine, and myo‐inositol degradation pathways. The increases in the proinflammatory cytokines IL‐1a, IL‐8, IL‐17A, IL‐12p40, TNF‐β, MCP‐1, IL‐2, and IL‐12p70 and the anti‐inflammatory cytokines IL‐10 and IL‐13 were observed in AD patients. Key variables driving the separation of AD and controls include inflammatory markers (IL‐1a and IL‐8), growth factors (EGF), lipids (LDL), BMI, and gut microbes, like genus Tyzzerella and Turicibacter and species Parabacteroides distasonis and Bacteroides eggerthii. We have also demonstrated that almost all cytokines strongly correlate with serum adiponectin levels and specific microbial taxa in AD patients. Thus, our findings identify potential microbial and inflammatory signatures in an ethnically distinct cohort of AD patients. These could serve as AD biomarkers and microbiota‐based therapeutic targets for treating AD. [ABSTRACT FROM AUTHOR]

Background: Lipid levels have been suggset to be correlated with multiple myeloma (MM) risk, though causality remains unconfirmed. To explore this further, a detailed study combining meta-analysis and Mendelian randomization (MR) was conducted. Methods: Literature searches were performed on PubMed and Embase; summary data for plasma lipid traits were extracted from the IEU and MM data from the FinnGen database. Meta-analysis and MR were utilized to analyze the link of lipids with MM risk, including mediator MR to identify potential mediators. The study was conducted in accordance with PRISMA and STROBE-MR guidelines. Results: Observational studies analyzed through meta-analysis showed that elevated levels of LDL, HDL, total cholesterol (TC), and triglycerides correlate with a lower risk of MM, with HRs of 0.73, 0.59, 0.60, and 0.84, respectively. MR analysis confirmed a potential causal link of triglyceride with a reduced MM risk (OR: 0.67, 95% CI: 0.46–0.98), independent of BMI. Mediation analysis pointed to X-11,423-O-sulfo-L-tyrosine and neuropilin-2 as potential mediators. Conclusions: The findings suggest that higher lipid levels (LDL, HDL, TC, and triglycerides) are linked with a reduced MM risk, and higher triglyceride levels are causally associated with a reduced MM risk. This suggests new avenues for therapeutic interventions targeting MM. [ABSTRACT FROM AUTHOR]

Introduction & objectives: To evaluate whether cardiovascular risk factors and their management differ in primary prevention between adult males and females with type 1 diabetes (T1D) in two European countries in 2020–2022 and sex inequalities in achievement of standards of care in diabetes. Methods: We used 2020–2022 data of patients without a cardiovascular history in the Prospective Diabetes Follow-up registry (DPV) centres, in Germany, and the Société Francophone du Diabète– Cohorte Diabète de Type 1 cohort (SFDT1), in France. Results: We included 2,657 participants from the DPV registry and 1,172 from the SFDT1 study. Body mass indexes were similar in females and males with similar proportions of HbA1c < 7% (DPV: 36.6 vs 33.0%, p = 0.06, respectively; SFDT1: 23.4 vs 25.7%, p = 0.41). Females were less overweight compared to men in DPV (55.4 vs 61.0%, p < 0.01) but not in SFDT1 (48.0 vs 44.9%, p = 0.33) and were less prone to smoke (DPV: 19.7 vs 25.8%, p < 0.01; SFDT1: 21.0 vs 26.0%, p = 0.07). Systolic blood pressure was lower in females than males with a higher rate of antihypertensive therapy in case of hypertension in females in DPV (70.5 vs 63.7%, p = 0.02) but not in SFDT1 (73.3 vs 68.6%, p = 0.64). In the case of microalbuminuria, ACEi-ARB were less often prescribed in women than men in DPV (21.4 vs 37.6%, p < 0.01) but not SFDT1 (73.3 vs 67.5.0%, p = 0.43). In females compared to males, HDL-cholesterol levels were higher; triglycerides were lower in both countries. In those with LDL-cholesterol > 3.4 mmol/L (DPV: 19.9 (females) vs 23.9% (males), p = 0.01; SFDT1 17.0 vs 19.2%, p = 0.43), statin therapy was less often prescribed in females than males in DPV (7.9 vs 17.0%, p < 0.01), SFDT1 (18.2 vs 21.0%, p = 0.42). Conclusion: In both studies, females in primary prevention have a better cardiovascular risk profile than males. We observed a high rate of therapeutic inertia, which might be higher in females for statin treatment and nephroprotection with ACEi-ARB, especially in Germany. Diabetologists should be aware of sex-specific differences in the management of cardiorenal risk factors to develop more personalized prevention strategies. [ABSTRACT FROM AUTHOR]

Summary The adipose tissue is a complex organ that can play endocrine, metabolic, and immune regulatory roles in cancer. In particular, adipocytes provide metabolic substrates for cancer cell proliferation and produce signaling molecules that can stimulate cell adhesion, migration, invasion, angiogenesis, and inflammation. Cancer cells, in turn, can reprogram adipocytes towards a more inflammatory state, resulting in a vicious cycle that fuels tumor growth and evolution. These mechanisms are enhanced in obesity, which is associated with the risk of developing certain tumors. Diet, an exogenous source of lipids with pro‐ or anti‐inflammatory functions, has also been connected to cancer risk. This review analyzes how adipocytes and lipids are involved in tumor development and progression, focusing on the relationship between obesity and cancer. In addition, we discuss how diets with varying lipid intakes can affect the disease outcomes. Finally, we introduce novel metabolism‐targeted treatments and adipocyte‐based therapies in oncology. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the causal relationship between lipids and ulcerative colitis (UC) through Mendelian Randomization (MR), and to further investigate the involvement of immune cells in mediating this process. Methods: Utilizing summary statistics from genome-wide association studies (GWAS) of individuals with European ancestry, we analyzed the causal link between 179 lipid types and UC (2,569 UC cases and 453,779 controls) through Two-sample Mendelian randomization (2SMR) and Bayesian-weighted MR (BWMR). Based on this, a mediation screening of 731 immune cell phenotypes was conducted to identify exposure and mediator factors. Lastly, the role and proportion of immune cells in mediating the causal effects of lipids on UC were assessed via reverse MR (RMR) and two-step MR. Results: The results of MR showed that there was a causal relationship between the six genetically predicted lipid types and UC (P <0.05), and the four immune cell phenotypes were identified as mediators of the association between lipids and UC. Notably, Phosphatidylcholine (PC) (16:0_0:0) served as the exposure factor, and myeloid cells CD11b on CD33+ HLA DR+ CD14dim acted as the mediator. Mediation analysis showed that CD11b on CD33+ HLA DR+ CD14dim had a mediation effect of -0.0205 between PC (16:0_0:0) and UC, with the mediation effect ratio at 15.38%. Conclusion: Our findings elucidate the causal effect of lipids on UC and identify the significant mediating role of myeloid cells CD11b on CD33+ HLA DR+ CD14dim in regulating UC through PC (16:0_0:0), offering new pathways and strategies for UC clinical treatment. [ABSTRACT FROM AUTHOR]

Background: Clinical observations indicate that blood lipids may be risk factors for lateral epicondylitis (LE) of the humerus, and lipid-lowering drugs are also used for the prevention and treatment of tendon diseases, but these lack highquality clinical trial evidence and remain inconclusive. Mendelian randomization (MR) analyses can overcome biases in traditional observational studies and offer more accurate inference of causal relationships. Therefore, we employed this approach to investigate whether blood lipids are risk factors for LE and if lipidlowering drugs can prevent it. Methods: Genetic variations associated with lipid traits, including low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC), were obtained from the UK Biobank and the Global Lipids Genetics Consortium (GLGC). Data on genetic variation in LE were sourced from FinnGen, including 24,061 patients and 275,212 controls. Subsequently, MR analyses were conducted to assess the potential correlation between lipid traits and LE. Additionally, drug-target Mendelian randomization analyses were performed on 10 drug targets relevant to LE. For those drug targets that yielded significant results, further analysis was conducted using colocalization techniques. Results: No correlation was found between three blood lipid traits and LE. Lipoprotein lipase (LPL) enhancement is significantly associated with a decreased risk of LE (OR = 0.76, [95% CI, 0.65-0.90], p = 0.001). The expression of LPL in the blood is associated with LE and shares a single causal variant (12.07%), greatly exceeding the probability of different causal variations (1.93%), with a colocalization probability of 86.2%. Conclusion: The three lipid traits are not risk factors for lateral epicondylitis. LPL is a potential drug target for the prevention and treatment of LE. [ABSTRACT FROM AUTHOR]

Chemokine receptor CXCR4 is involved in diverse diseases. A comparative study was conducted on CXCR4 embedded in a POPC lipid bilayer binding with CXCL12 in full and truncated forms, hBD-3 in wildtype, analog, and mutant forms based on in total 63 µs all-atom MD simulations. The initial binding structures of CXCR4 with ligands were predicted using HADDOCK docking or random-seed method, then μs-long simulations were performed to refine the structures. CXCR4&ligand binding structures predicted agree with available literature data. Both kinds of ligands bind stably to the N-terminus, extracellular loop 2 (ECL2), and ECL3 regions of CXCR4; the C2-C3 (K32-R38) region and occasionally the head of hBD-3 bind stably with CXCR4. hBD-3 analogs with Cys11-Cys40 disulfide bond can activate CXCR4 based on the Helix3-Helix6 distance calculation, but not other analogs or mutant. The results provide insight into understanding the dynamics and activation mechanism of CXCR4 receptor binding with different ligands. The chemokine receptor CXCR4 is involved in cancers and diverse diseases, however, molecular details surrounding the binding of different ligands to this receptor remain incomplete. Here, the authors study the binding and interaction between CXCR4 with CXCL12 and hBD-3 in different forms, and find that both ligands can bind with CXCR4 at the same site, and analogs of hBD-3 with a Cys11-Cys40 disulfide bond can activate CXCR4. [ABSTRACT FROM AUTHOR]

Objective. Obesity, chronic inflammation, and oxidative stress can influence mitochondrial DNA (mtDNA) content. Our objective was to evaluate the oxidation level and content of mtDNA and its relationship with metabolic parameters in metabolically healthy obese (MHO) compared to metabolically unhealthy obese (MUO) and normal weight (NW) controls. Materials and Methods. We studied 94 NW, 95 MHO, and 97 MUO individuals between 18 and 80 years old. Relative mtDNA content and mtDNA oxidation level (8‐oxoguanine, 8‐OxoG) were determined in peripheral blood leukocytes by the SYBR Green method of real‐time PCR. One‐way ANOVA and Tukey test were used to compare biochemical, clinical, and anthropometric characteristics, as well as mtDNA content and 8‐OxoG. Results. A progressive decrease in mtDNA content was observed between NW, MHO, and MUO with significant differences in MUO vs. NW (p: 0.04). An increase in 8‐OxoG was observed in MUO patients compared to the other groups (MUO vs. MHO p: 0.01; MUO vs. NW p: 0.04). mtDNA content was directly correlated with HDL‐c (p < 0.01) and inversely with waist circumference (p: 0.01) and LDL‐c (p: 0.05). mtDNA content decreased, and the oxidation level increased concomitantly with the presence of obesity, the number of MS components, higher coronary risk, and insulin resistance parameters. Conclusion. MHO presented a similar mtDNA oxidation level to NW and mtDNA content to the MUO, placing the MHO individuals as having an intermediate phenotype. Changes in mtDNA content and oxidation were correlated to the lipid profile related to obesity and/or MS presence, probably associated with oxidative stress and chronic low‐grade inflammation. [ABSTRACT FROM AUTHOR]

Glycerol, a versatile and ubiquitous compound, plays a vital role in a plethora of metabolic pathways in both prokaryotes and eukarotyes. Relatively few glycerol analogues have previously been explored for their use as glycerol kinase inhibitors, in addition to their therapeutic potential, however their use as (pro)‐drugs in the context of parasitic diseases such as trypanosomiasis is unreported. The literature on glycerol metabolism and particular its synergic anti‐profilation behaviour with salicylhydroxamic acid (SHAM) in Trypanosoma brucei is extensive. However, utiliation of glycerol analogues has not been explored as possible superior combinatory compounds. This report describes the synthesis of various glycerol analogues and their subsequent biochemical pheotypic analysis for their effect on lipid metabolism and their possible synergic activity with SHAM on Trypanosoma brucei. The glycerol analogues caused morphological changes;, including detached flagella, cytokinesis defects and ‘big‐eye’ phenotype. All four compounds either matched or marginally increased the toxicity of SHAM when used in combination against Trypanosoma brucei. However, the compounds exhibited mostly an antagonistic relationship with SHAM rather than synergistic. This research highlights the potential of small molecule glycerol analogues for their combination use with SHAM for the treatment of parasitic disease, such as trypanosomiasis. [ABSTRACT FROM AUTHOR]

Phosphoinositides, such as PI(4,5)P2, are known to function as structural components of membranes, signalling molecules, markers of membrane identity, mediators of protein recruitment and regulators of neurotransmission and synaptic development. Phosphatidylinositol 4‐kinases (PI4Ks) synthesize PI4P, which are precursors for PI(4,5)P2, but may also have independent functions. The roles of PI4Ks in neurotransmission and synaptic development have not been studied in detail. Previous studies on PI4KII and PI4KIIIβ at the Drosophila larval neuromuscular junction have suggested that PI4KII and PI4KIIIβ enzymes may serve redundant roles, where single PI4K mutants yielded mild or no synaptic phenotypes. However, the precise synaptic functions (neurotransmission and synaptic growth) of these PI4Ks have not been thoroughly studied. Here, we used PI4KII and PI4KIIIβ null mutants and presynaptic‐specific knockdowns of these PI4Ks to investigate their roles in neurotransmission and synaptic growth. We found that PI4KII and PI4KIIIβ appear to have non‐overlapping functions. Specifically, glial PI4KII functions to restrain synaptic growth, whereas presynaptic PI4KIIIβ promotes synaptic growth. Furthermore, loss of PI4KIIIβ or presynaptic PI4KII impairs neurotransmission. The data presented in this study uncover new roles for PI4K enzymes in neurotransmission and synaptic growth. [ABSTRACT FROM AUTHOR]

This study aimed to estimate the hepatic and immune ameliorating potential of extracted bovine lactoferrin (LF), Selenium nanoparticles (SeNPs) or their combination (LF/SeNPs) against bleomycin (BLM) induced hepatic injury. Fifty adult male rats (160–200 g) were equally divided into five groups: (1) the saline control group, (2) BLM-injected (15 mg/kg twice a week, ip), and (3–5) groups treated orally with LF (200 mg/kg/day), SeNPs (0.0486 mg/kg/day) or LF/SeNPs combination (200.0486 mg/kg/day) for 6 weeks post BLM-intoxication. Blood and liver samples were subjected to biochemical, histopathological, and immunohistochemical analyses. The results revealed that BLM caused a significant increase in hepatic lipid peroxidation and nitric oxide, as well as serum markers of liver functions (AST, ALT and GGT activities), and levels of GM-CSF, CD4, TNF-α, IL-1β, TGF-β1, fibronectin, triglycerides, cholesterol and LDL-C. Additionally, hepatic glutathione, Na+/K+-ATPase, and glutathione peroxidase, as well as serum HDL-C, total protein and albumin levels were significantly reduced. Moreover, BLM injection resulted in marked histopathological alterations and severe expression of caspase 3. Post-treatment of BLM-intoxicated rats with LF, SeNPs or LF/SeNPs combination obviously improved the BLM-induced hepatic damages; this was achieved from the marked modulations in the mentioned parameters, besides improving the histopathological hepatic architecture. It is worth mentioning that LF/SeNPs exerted the greatest potency. In conclusion, the obtained results demonstrated that LF, SeNPs and LF/SeNPs succeeded in attenuating the BLM-induced hepatic dysfunction. Therefore, these supplements might be used to protect against drug-associated side effects. [ABSTRACT FROM AUTHOR]

Realizing the immense clinical potential of mRNA-based drugs will require continued development of methods to safely deliver the bioactive agents with high efficiency and without triggering side effects. In this regard, lipid nanoparticles have been successfully utilized to improve mRNA delivery and protect the cargo from extracellular degradation. Encapsulation in lipid nanoparticles was an essential factor in the successful clinical application of mRNA vaccines, which conclusively demonstrated the technology's potential to yield approved medicines. In this review, we begin by describing current advances in mRNA modifications, design of novel lipids and development of lipid nanoparticle components for mRNA-based drugs. Then, we summarize key points pertaining to preclinical and clinical development of mRNA therapeutics. Finally, we cover topics related to targeted delivery systems, including endosomal escape and targeting of immune cells, tumors and organs for use with mRNA vaccines and new treatment modalities for human diseases. [ABSTRACT FROM AUTHOR]

Migratory birds excel in phenotypic flexibility, adapting physiologically as their life histories and environments require. Discerning the metabolic processes underlying migrants' physiology, an emergent property of multiple continuous and dynamic organism–environment interactions, is therefore challenging, particularly under natural conditions. Accordingly, analyses of snapshot‐sampled serum‐circulating metabolites, versatile and readily applicable for migrating birds, have increasingly become the method of choice for such physiologic inference. However, the atemporal nature of single sampling might obscure the links between observed metabolite concentrations and the processes producing them, necessitating an analytical decoupling of focal processes from their broader biochemical background.In the present study, we examined how variation in combined fat and muscle fuel stores, traits pivotal in migratory context, relates to the serum‐circulating metabolomes of spring‐migrating Eurasian blackcaps stopping‐over. Our analyses accounted for potential spatiotemporal influences in the form of time past night's fasting and random local conditions across three sites within the Negev Desert. We shifted the focus from compound‐level analysis of preselected metabolites towards the level of inclusive metabolome, quantifying serum‐circulating lipophilic and polar molecules via UHPLC–MS/MS untargeted metabolomic technique.Our results indicated a general relationship between fuel stores and the metabolome, comprising 16 326 lipophilic and 6923 polar compounds, among which 918 and 44 were annotated, respectively. By applying generalized latent‐variable linear modeling (GLLVM) upon concentrations of annotated metabolites, we identified several candidate biomarkers, some novel in migratory context, notably the fuel‐associated increase in serum ceramides likely derived from circulating very low‐density lipoproteins (VLDLs). Relying on estimated metabolite links with fuel and foraging time and on modeled residual covariations among metabolites, we demonstrate fuel–metabolite associations generally consistent with higher fat‐ and lower protein mobilization in birds having greater stores and with decreased fuel utilization as ingested nutrients accumulate over time, thus introducing a novel approach for the physiological study of migrating birds. [ABSTRACT FROM AUTHOR]

Aim Materials and Methods Results Conclusions/Interpretation Whether apolipoproteins (apolipoprotein A1, apolipoprotein B, apolipoprotein B/apolipoprotein A1 [ApoB/ApoA1] ratio) or very‐low‐density lipoprotein (VLDL) cholesterol are better risk predictors than established lipid risk markers, and whether there are sex differences, is uncertain, both in general populations and in patients with diabetes. The aim of this study was to assess the association between established risk markers, apolipoproteins and the risk of macro‐ and microvascular disease and death in a large study of women and men with diabetes and to assess the potential sex differences in the associations.Established lipid risk markers were studied in 11 140 individuals with type 2 diabetes from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified‐Release Controlled Evaluation (ADVANCE) trial, and apolipoproteins (A1, B, ApoB/ApoA1 ratio) and VLDL cholesterol from nuclear magnetic resonance (NMR) lipid analyses in biobanked samples from 3586 individuals included in the ADVANCE case‐cohort study (ADVANCE CC). Primary outcomes were major macro‐ and microvascular events and death. Cox proportional hazards models adjusted for confounders were used to quantify the associations (hazard ratio [HR] and 95% confidence intervals [CIs]) between established lipid risk markers and apolipoproteins with study outcomes. To address potential effect modification by sex, we investigated the association between the lipid risk markers and outcomes in subgroup analyses by sex.There was a lower risk of macrovascular complications for high‐density lipoprotein (HDL) cholesterol (HR [95%CI] 0.88 [0.82–0.95]), a higher risk for total cholesterol (1.10 [1.04–1.17]), low‐density lipoprotein (LDL) cholesterol (1.15 [1.08–1.22]), non‐HDL cholesterol (1.13 [1.07–1.20]) and the total cholesterol/HDL ratio (1.20 [1.14–1.27]) but no significant associations with triglycerides from ADVANCE. There was a higher risk of macrovascular complications for the ApoB/ApoA1 ratio (1.13 [1.03–1.24]) from the ADVANCE CC. Only the ApoB/ApoA1 ratio (1.19 [1.06–1.34]), but none of the established lipid risk markers, was associated with a higher risk of microvascular complications. There were no statistically significant sex differences for any of the established lipid risk markers or apolipoproteins with any outcome. Using C‐statistics and net reclassification improvement (NRI) did not detect significant improvement in predicting all outcomes by adding lipids or apolipoproteins to the models with confounding factors only.All established lipid risk markers, except triglycerides, were predictors of macrovascular complications, but not microvascular complications, in patients with type 2 diabetes. The ApoB/ApoA1 ratio was associated with major macro‐ and microvascular complications, but there was no evidence that apolipoproteins are better than established lipid risk markers in predicting cardiovascular complications in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations. This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial. Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations. Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82). Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402) [ABSTRACT FROM AUTHOR]

The impact of premade beef patty (BBP) with red onion skin powder (OSP) at 0, 1, 2, and 3% levels on color, lipid, and protein oxidative stability, and infection degree of microorganisms during cold storage was investigated. The objective was to determine the effect of color by L*, a*, b*, and the content of MetMb. The inhibitory effect of OSP on the oxidation of lipid and protein was studied based on TBARS and the carbonyl content of protein in samples at different storage times. TVB-N content was used to characterize the degree of infection of microorganisms and their effect on meat quality. The results showed that the addition of OSP reduced the pH, L *, a*, and b * values of BBP, and improved the hardness, springiness, gumminess, and cohesiveness of BBP, but had no significant effect on the chewiness of BBP (p > 0.05). After 12 days of storage, the carbonyl group and TBARS content in the BBP supplemented with 3%OSP was significantly lower than that in the control group (p < 0.05). Furthermore, the addition of OSP significantly inhibited the TVB-N increase during beef patty storage. These results indicated that OSP has a good research prospect as a natural antioxidant or preservative. [ABSTRACT FROM AUTHOR]

Contact sites between lipid droplets and other organelles are essential for cellular lipid and energy homeostasis. Detection of these contact sites at nanometer scale over time in living cells is challenging. Here, we developed a tool kit for detecting contact sites based on Fluorogen-Activated Bimolecular complementation at CONtact sites, FABCON, using a reversible, low affinity split fluorescent protein, splitFAST. FABCON labels contact sites with minimal perturbation to organelle interaction. Via FABCON, we quantitatively demonstrated that endoplasmic reticulum (ER)- and mitochondria (mito)-lipid droplet contact sites are dynamic foci in distinct metabolic conditions, such as during lipid droplet biogenesis and consumption. An automated analysis pipeline further classified individual contact sites into distinct subgroups based on size, likely reflecting differential regulation and function. Moreover, FABCON is generalizable to visualize a repertoire of organelle contact sites including ER-mito. Altogether, FABCON reveals insights into the dynamic regulation of lipid droplet-organelle contact sites and generates new hypotheses for further mechanistical interrogation during metabolic switch. [ABSTRACT FROM AUTHOR]

Aquaporin-0 (AQP0) tetramers form square arrays in lens membranes through a yet unknown mechanism, but lens membranes are enriched in sphingomyelin and cholesterol. Here, we determined electron crystallographic structures of AQP0 in sphingomyelin/cholesterol membranes and performed molecular dynamics (MD) simulations to establish that the observed cholesterol positions represent those seen around an isolated AQP0 tetramer and that the AQP0 tetramer largely defines the location and orientation of most of its associated cholesterol molecules. At a high concentration, cholesterol increases the hydrophobic thickness of the annular lipid shell around AQP0 tetramers, which may thus cluster to mitigate the resulting hydrophobic mismatch. Moreover, neighboring AQP0 tetramers sandwich a cholesterol deep in the center of the membrane. MD simulations show that the association of two AQP0 tetramers is necessary to maintain the deep cholesterol in its position and that the deep cholesterol increases the force required to laterally detach two AQP0 tetramers, not only due to protein–protein contacts but also due to increased lipid–protein complementarity. Since each tetramer interacts with four such ‘glue’ cholesterols, avidity effects may stabilize larger arrays. The principles proposed to drive AQP0 array formation could also underlie protein clustering in lipid rafts. [ABSTRACT FROM AUTHOR]

Background: While dengue NS1 antigen has been shown to be associated with disease pathogenesis in some studies, it has not been linked in other studies, with the reasons remaining unclear. NS1 antigen levels in acute dengue are often associated with increased disease severity, but there has been a wide variation in results based on past dengue infection and infecting dengue virus (DENV) serotype. As NS1 engages with many host lipids, we hypothesize that the type of NS1-lipid interactions alters its pathogenicity. Methods: Primary human monocyte derived macrophages (MDMs) were co-cultured with NS1 alone or with HDL, LDL, LPS and/or platelet activating factor (PAF) from individuals with a history of past dengue fever (DF = 8) or dengue haemorrhagic fever (DHF = 8). IL-1β levels were measured in culture supernatants, and gene expression analysis carried out in MDMs. Monocyte subpopulations were assessed by flow cytometry. Hierarchical cluster analysis with Euclidean distance calculations were used to differentiate clusters. Differentially expressed variables were extracted and a classifier model was developed to differentiate between past DF and DHF. Results: Significantly higher levels of IL-1β were seen in culture supernatants when NS1 was co-cultured with LDL (p = 0.01, median = 45.69 pg/ml), but lower levels when NS1 was co-cultured with HDL (p = 0.05, median = 4.617 pg/ml). MDMs of those with past DHF produced higher levels of IL-1β when NS1 was co-cultured with PAF (p = 0.02). MDMs of individuals with past DHF, were significantly more likely to down-regulate RPLP2 gene expression when macrophages were co-cultured with either PAF alone, or NS1 combined with PAF, or NS1 combined with LDL. When NS1 was co-cultured with PAF, HDL or LDL two clusters were detected based on IL10 expression, but these did not differentiate those with past DF or DHF. Conclusions: As RPLP2 is important in DENV replication, regulating cellular stress responses and immune responses and IL-10 is associated with severe disease, it would be important to further explore how differential expression of RPLP2 and IL-10 could lead to disease pathogenesis based on NS1 and lipid interactions. [ABSTRACT FROM AUTHOR]

Background: Lipid droplet (LD) is a metabolically active organelle, which changes dynamically with the metabolic state and energy requirements of cells. Proteins that either insert into the LD phospholipid monolayer or are present in the cytoplasm, playing a crucial role in lipid homeostasis and signaling regulation, are known as LD-associated proteins. Methods: The keywords "lipid droplets" and "metabolic diseases" were used to obtain literature on LD metabolism and pathological mechanism. After searching databases including Scopus, OVID, Web of Science, and PubMed from 2013 to 2024 using terms like "lipid droplets", "lipid droplet-associated proteins", "fatty liver disease", "diabetes", "diabetic kidney disease", "obesity", "atherosclerosis", "hyperlipidemia", "natural drug monomers" and "natural compounds", the most common natural compounds were identified in about 954 articles. Eventually, a total of 91 studies of 10 natural compounds reporting in vitro or in vivo studies were refined and summarized. Results: The most frequently used natural compounds include Berberine, Mangostin, Capsaicin, Caffeine, Genistein, Epigallocatechin-3-gallate, Chlorogenic acid, Betaine, Ginsenoside, Resveratrol. These natural compounds interact with LD-associated proteins and help ameliorate abnormal LDs in various metabolic diseases. Conclusion: Natural compounds involved in the regulation of LDs and LD-associated proteins hold promise for treating metabolic diseases. Further research into these interactions may lead to new therapeutic applications. [ABSTRACT FROM AUTHOR]

Purpose American College of Cardiology/American Heart Association guidelines recommend high-intensity statin therapy and consideration for nonstatin therapy for patients with peripheral vascular disease (PVD); however, utilization rates remain suboptimal. The primary objective of this study was to determine whether pharmacist intervention for patients with PVD could improve the percentage of patients discharged on a high-intensity statin. Methods The study used a single-center pre/post design and included patients with PVD who underwent peripheral bypass during their admission. Postintervention patients managed with an order set including a preselected consult for a pharmacy lipid protocol were compared to preintervention patients managed using the order set without the consult. The primary outcome was the percentage of patients discharged on a high-intensity statin. Secondary outcomes included intensification of statin therapy, the addition of ezetimibe, and referral to an outpatient lipid clinic. Results A total of 175 patients were included in the analysis, with 94 patients in the preintervention group and 81 patients in the postintervention group. The primary outcome met statistical significance, with an increase in the percentage of patients discharged on a high-intensity statin in the postintervention group (70.4%) compared to the preintervention group (38.3%) (P < 0.001; 95% confidence interval, 1.37-2.46). Secondary outcomes that met statistical significance included an increase in the percentage of patients with any increase in statin intensity (35.8% vs 20.2%; P = 0.02). Conclusion The addition of a pharmacist consult led to an increase in the percentage of patients discharged on a high-intensity statin and an increase in overall statin intensification. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF-21) has been suggested as a potential therapeutic target for insulin resistance in health-related metabolic disorders such as type 2 diabetes. Despite the metabolic effects of resistance (RT) and aerobic training (AT) on diabetes symptoms, uncertainty exists regarding the superiority of effects manifested through these training approaches on FGF-21 and biochemical and physiological variables associated with metabolic disorders in men diagnosed with type 2 diabetes. This study aimed to investigate the impact of a 12-week RT and AT on FGF-21 levels and symptoms associated with metabolic disorders in male individuals diagnosed with type 2 diabetes. Thirty-six sedentary obese diabetic men (40 to 45 years old) were matched based on the level of FGF-1. They and were randomly divided into two training groups (RT, n = 12 and AT, n = 12) performing three days per week of moderate-intensity RT or AT for 12 weeks and an inactive control group (n = 12). Both training interventions significantly improved FGF-21, glucose metabolism, lipid profile, hormonal changes, strength, and aerobic capacity. Subgroup analysis revealed that RT had greater adaptive responses (p < 0.01) in fasting blood sugar (ES = -0.52), HOMA-IR (ES = -0.87), testosterone (ES = 0.52), cortisol (ES = -0.82), FGF-21 (ES = 0.61), and maximal strength (ES = 1.19) compared to AT. Conversely, AT showed greater changes (p < 0.01) in cholesterol (ES = -0.28), triglyceride (ES = -0.64), HDL (ES = 0.46), LDL (ES = -0.73), and aerobic capacity (ES = 1.18) compared to RT. Overall, both RT and AT interventions yielded significant moderate to large ES in FGF-21 levels and enhanced the management of biochemical variables. RT is an effective method for controlling FGF-21 levels and glucose balance, as well as for inducing hormonal changes. On the other hand, AT is more suitable for improving lipid profiles in overweight men with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Lipid lowering, with the use of statins after an acute coronary syndrome (ACS), is a cornerstone, well-established strategy for the secondary prevention of ischemic events in this high-risk cohort. In addition to the positive effect on lipid levels, statins have also been linked to improved atherosclerotic plaque characteristics, such as plaque regression and inflammation reduction, associated with the extent of reduction in LDL-C. The recent emergence of PCSK9 inhibitors for the management of dyslipidemia and the more extensive lipid lowering provided by these agents may provide better prevention for ACS patients when initiated after the ACS event. Several trials have evaluated the immediate post-ACS initiation of PCSK9 inhibitors, which has shown, to date, beneficial results. Furthermore, PCSK9 inhibitors have been linked with positive plaque remodeling and associated mortality benefits, which makes their use in the initial management strategy of such patients appealing. Therefore, in this review, we will analyze the rationale behind immediate lipid lowering after an ACS, report the evidence of PCSK9 inhibition immediately after the ACS event and the available data on plaque stabilization, and discuss treatment algorithms and clinical perspectives for the use of these agents in this clinical setting. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases remain the leading cause of death in the world, and that is why finding an effective and multi-functional treatment alternative to combat these diseases has become more important. Fibrates and thiazolidinediones, peroxisome proliferator-activated receptors alpha and gamma are the pharmacological therapies used to treat dyslipidemia and type 2 diabetes, respectively. New mechanisms of action of these drugs have been found, demonstrating their pleiotropic effects, which contribute to preserving the heart by reducing or even preventing myocardial damage. Here, we review the mechanisms underlying the cardioprotective effects of PPAR agonists and regulating morphological and physiological heart alterations (metabolic flexibility, mitochondrial damage, apoptosis, structural remodeling, and inflammation). Moreover, clinical evidence regarding the cardioprotective effect of PPAR agonists is also addressed. [ABSTRACT FROM AUTHOR]

Background: Concurrent Exercise Training (CET) is defined as an exercise training mode in which aerobic and resistance exercises are performed in the same session. Objectives: The effects of CET in type 2 diabetes mellitus (T2DM) are inconclusive. Therefore, the objective of the present systematic review with a meta-analysis is to evaluate the effects of CET on metabolic markers, body composition, lipid profile, inflammation, and cardiorespiratory fitness (CRF) in people with T2DM. Methods: Five electronic databases were searched from inception up to January 2023. The eligibility criteria included prospective studies that had T2DM participants aged between 35 and 65 years who performed CET at least 2 times/week for a minimum duration of 8 weeks with a control group. Results: Seven studies were identified for qualitative review. Sufficient data were not available for one study, therefore, meta-analysis was performed in six studies. A significant effect was observed in glucose level (p <.01); glycated hemoglobin (p =.02); Homeostatic Model Assessment for Insulin Resistance (p =.02); body mass index (p =.02); %body fat (p <.01); %fat-free mass (p <.01); waist circumference (p =.03); triglyceride (p <.01); peak oxygen uptake (p <.01); and tumor necrotic factor -α (p <.01). Conclusions: The CET is effective in improving metabolic markers, body composition, lipid profile, inflammation, and CRF in people with T2DM and can be included in the management of T2DM. The overall evidence for this conclusion may be influenced by bias in included studies. [ABSTRACT FROM AUTHOR]

Objective: Diabetic nephropathy (DN) is a deleterious microangiopathy of diabetes, constituting a critical determinant of fatality in diabetic patients. This work is purposed to disclose the effects and modulatory mechanism of BTG anti-proliferation factor 2 (BTG2) during the pathological process of DN. Methods: BTG2 expression in kidney tissues of diabetic mice and high glucose (HG)-exposed human proximal tubular cell line HK-2 was assessed with Western blot and RT-qPCR. The diabetic mice model was constructed by streptozotocin injection and confirmed by the blood glucose level beyond 16.7 mmol/L. Hematoxylin and eosin (H&E) staining and measurement of kidney function hallmarks were conducted to assess kidney injury. Cell counting kit (CCK)-8 method and TUNEL assay appraised cell activity and apoptosis. Oil red O staining assayed lipid accumulation. Relevant commercial kits were used to estimate oxidative stress-related factors. Co-immunoprecipitation (Co-IP) assay testified the binding relationship of BTG2 with protein arginine methyltransferase 1 (PRMT1). Results: BTG2 expression was significantly raised in renal tissues of diabetic mice and HK-2 cells exposed to HG. BTG2 deficiency improved viability and extenuated the apoptosis, lipid deposition as well as oxidative stress in HK-2 cells following HG exposure. In addition, PRMT1 was also overexpressed in HK-2 cells exposed to HG. BTG2 interacted with PRMT1 and positively modulated PRMT1 expression. The effects of BTG2 interference on viability, apoptosis, lipid deposition, and oxidative stress in HG-challenged HK-2 cells were partially abrogated by PRMT1 overexpression. Conclusion: Altogether, BTG2 might aggravate HK-2 cell injury in response to HG by binding with PRMT1, providing a novel target for the therapeutic strategy of DN. [ABSTRACT FROM AUTHOR]

This study aimed to assess the applicability of solution-state 1H NMR for molecular-level characterization of siRNA-loaded lipid nanoparticles (LNP). Dilinoleylmethyl-4-dimethylaminobutyrate (DLin-MC3-DMA, MC3) was used as an ionizable lipid, and siRNA-loaded LNPs were prepared by pre-mixing and post-mixing methods. The pre-mixing method involved mixing an acidic solution containing siRNA with an ethanolic lipid solution using a microfluidic mixer. The pre-mixed LNP was prepared by dialyzing the mixed solution into the phosphate buffered saline (PBS, pH 7.4). The post-mixed LNP was prepared by mixing the siRNA solution with empty LNP in an acidic condition with and without ethanol, resulting in post-mixed LNP (A) and (B), respectively. Both pre-mixed and post-mixed LNPs formed LNP particles with an average diameter of approximately 50 nm. Moreover, the ratio of encapsulated siRNA to lipid content in each LNP particle remained constant regardless of the preparation method. However, small-angle X-ray scattering measurements indicated structural variations in the siRNA-MC3 stacked bilayer structure formed in the LNPs, depending on the preparation method. Solution-state 1H NMR analysis suggested that the siRNA was incorporated uniformly into the LNP core for pre-mixed LNP compared to post-mixed LNPs. In contrast, the post-mixed LNPs contained siRNA-empty regions with local enrichment of siRNA in the LNP core. This heterogeneity was more pronounced in post-mixed LNP (B) than in post-mixed LNP (A), suggesting that ethanol facilitated the homogeneous mixing of siRNA with LNP lipids. The silencing effect of each siRNA-loaded LNP was reduced in the order of pre-mixed LNP, post-mixed LNP (A), and post-mixed LNP (B). This suggested that the heterogeneity of the siRNA-loaded LNP could cause a reduction in the silencing effect of the incorporated siRNA inside LNPs. The present study highlighted that NMR-based characterization of siRNA-loaded LNP can reveal the molecular-level heterogeneity of siRNA-loaded LNP, which helps to optimize the preparation conditions of siRNA-loaded LNP formulations. [Display omitted] [ABSTRACT FROM AUTHOR]

Although lipid nanoparticles (LNPs) have been FDA-approved for mRNA delivery, there is still much to learn about these fascinating multi-component delivery systems. Here, I discuss the presence of "bleb" structures on LNPs and the co-existence of mRNA-empty LNPs in LNP-mRNA-based formulations. Specifically, I discuss key articles on these structural and compositional heterogeneities, whether these features present negative or positive LNP attributes, and how to deal with them in research and quality control settings. Additionally, I present current approaches and propose novel strategies on how to study and quantify bleb and empty LNP structures. With the conflicting views on these features in the literature and limited systematic studies on their impact on safety and efficacy, I hope this Perspective will support current and bring forward new thinking about these matters. I anticipate that novel studies and insights could emerge from these lines of thinking, which could potentially enhance the development of safe and efficient LNP-based drug products that will either embrace, leverage, or mitigate the presence of blebs and empty LNPs. [Display omitted] • Presents and discusses key articles related to bleb and empty LNP structures. • Examines methods for studying and quantifying these features, including proposing new approaches. • Discusses how to deal with these features differently in research and quality control settings. • Emphasizes the significance of developing standard LNP materials to evaluate LNP analysis tools. • Presents different perspectives on whether bleb and empty LNP structures are positive or negative LNP attributes. [ABSTRACT FROM AUTHOR]

Charcot–Marie–Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy caused by a 1.5 Mb tandem duplication of chromosome 17 harbouring the PMP22 gene. This dose-dependent overexpression of PMP22 results in disrupted Schwann cell myelination of peripheral nerves. To obtain better insights into the underlying pathogenic mechanisms in CMT1A, we investigated the role of PMP22 duplication in cellular homeostasis in CMT1A mouse models and in patient-derived induced pluripotent stem cells differentiated into Schwann cell precursors (iPSC-SCPs). We performed lipidomic profiling and bulk RNA sequencing (RNA-seq) on sciatic nerves of two developing CMT1A mouse models and on CMT1A patient-derived iPSC-SCPs. For the sciatic nerves of the CMT1A mice, cholesterol and lipid metabolism was downregulated in a dose-dependent manner throughout development. For the CMT1A iPSC-SCPs, transcriptional analysis unveiled a strong suppression of genes related to autophagy and lipid metabolism. Gene ontology enrichment analysis identified disturbances in pathways related to plasma membrane components and cell receptor signalling. Lipidomic analysis confirmed the severe dysregulation in plasma membrane lipids, particularly sphingolipids, in CMT1A iPSC-SCPs. Furthermore, we identified reduced lipid raft dynamics, disturbed plasma membrane fluidity and impaired cholesterol incorporation and storage, all of which could result from altered lipid storage homeostasis in the patient-derived CMT1A iPSC-SCPs. Importantly, this phenotype could be rescued by stimulating autophagy and lipolysis. We conclude that PMP22 duplication disturbs intracellular lipid storage and leads to a more disordered plasma membrane owing to an alteration in the lipid composition, which might ultimately lead to impaired axo-glial interactions. Moreover, targeting lipid handling and metabolism could hold promise for the treatment of patients with CMT1A. [ABSTRACT FROM AUTHOR]

Purpose: Dyslipidemia is a major health issue worldwide. There is growing interest in understanding the potential role of kimchi consumption on serum lipid profiles. However, there are limited epidemiological studies available on this topic. Therefore, this study aims to investigate the association between kimchi intake and serum lipid profiles. Methods: We conducted an epidemiological study on participants (aged 40–69 years old) selected from the Health Examinees (HEXA) cohort study (n = 61,761). Four types of kimchi, including Baechu kimchi (cabbage kimchi), Kkakdugi (radish kimchi), Nabak kimchi/Dongchimi (a type of water kimchi made with fermented vegetables), and other kimchi, were assessed by a 106-food item semi-quantitative validated food frequency questionnaire (FFQ). Each kimchi intake is the average value calculated from the FFQ of the baseline and follow-up surveys. Fasting blood data were obtained at baseline and follow-up visits. Linear regression was used to examine the relationship between the intake of kimchi and the change in serum lipid profiles. Results: The mean years between the baseline survey and a follow-up survey was 4.97 years. In this study, compared to the lowest category (< 1 serving/day), Baechu kimchi intake (2− < 3 servings/day) had more negative correlations with the change in values of total cholesterol (β: −1.600, 95% confidence interval [CI, −2.744, −0.456]), triglycerides (β: −3.372, 95% CI [−5.414, −1.330]), and low-density lipoprotein cholesterol (β: −1.155, 95% CI [−2.214, −0.095]) in women. In men, Baechu kimchi intake (2− < 3 servings/day) had a more positive correlation associated with the changes in values of high-density lipoprotein cholesterol (β: 0.049, 95% CI [0.031, 0.907]) compared to the lowest intake category (< 1 serving/day). Conclusions: Among Korean adults, consumption of kimchi, particularly Baechu kimchi, was found to be associated with improvements in serum lipid profiles. Further studies are required to conduct additional interventions to confirm the association between kimchi and serum lipid profiles. [ABSTRACT FROM AUTHOR]

Purpose: The original aim of the study was to determine, in a double-blind 3-arm crossover human trial (n = 7), the effect of supplemental levels of iron (25 mg) and zinc (30 mg) on β-carotene (synthetic) bioavailability (10 h postprandial). However, despite the high dose of supplemental β-carotene (15 mg) consumed with the high fat (18 g), dairy-based breakfast test meal, there was a negligible postprandial response in plasma and triglyceride rich fraction β-carotene concentrations. We then systematically investigated the possible reasons for this low bioavailability of β-carotene. Methods: We determined (1) if the supplemental β-carotene could be micellised and absorbed by epithelial cells, using a Caco-2 cell model, (2) if the fat from the test meal was sufficiently bioavailable to facilitate β-carotene bioavailability, (3) the extent to which the β-carotene could have been metabolised and converted to retinoic acid/retinol and (4) the effect of the test meal matrix on the β-carotene bioaccessibility (in vitro digestion) and Caco-2 cellular uptake. Results: We found that (1) The supplemental β-carotene could be micellised and absorbed by epithelial cells, (2) the postprandial plasma triacylglycerol response was substantial (approximately 75–100 mg dL−1 over 10 h), indicating sufficient lipid bioavailability to ensure β-carotene absorption, (3) the high fat content of the meal (approximately 18 g) could have resulted in increased β-carotene metabolism, (4) β-carotene bioaccessibility from the dairy-based test meal was sixfold lower (p < 0.05) than when digested with olive oil. Conclusion: The low β-carotene bioavailability is probably due to a combination of the metabolism of β-carotene to retinol by BCMO1 and interactions of β-carotene with the food matrix, decreasing the bioaccessibility. Trail registration: The human trail was retrospectively registered (ClinicalTrail.gov ID: NCT05840848). [ABSTRACT FROM AUTHOR]

In this work, we demonstrate that a functional modeling the self-aggregation of stochastically distributed lipid molecules can be obtained as the Γ -limit of a family of discrete energies driven by a sequence of independent and identically distributed random variables. These random variables are intended to describe the asymptotic behavior of lipid molecules that satisfy an incompressibility condition. The discrete energy keeps into account the interactions between particles. We resort to transportation maps to compare functionals defined on discrete and continuous domains, and we prove that, under suitable conditions on the scaling of these maps as the number of random variables increases, the limit functional features an interfacial term with a Wasserstein-type penalization. [ABSTRACT FROM AUTHOR]

Depleting fossil fuel reserves and the effects of greenhouse gases on climate change have led to the investigation of alternative energy sources such as biofuel, including biodiesel and renewable diesel. Unfortunately, the cost of the feedstock exceeds 70% of the total production cost. The current work investigates the potential of utilizing a waste product (activated sludge biomass) from wastewater treatment, as an alternative feedstock for biodiesel production. The activated sludge biomass was pretreated with subcritical water to enhance the lipid yield before extracting the lipid using solvent extraction. The result showed that lipid yield from the activated sludge was 4.73–8.58%. After subcritical water pretreatment with varying residence time, temperature, and biomass loading, the lipid yield increased by 158.04–400%. Gas chromatography–mass spectrometry (GC–MS) analysis of the fatty acid methyl esters (FAME) from the transesterification of the lipid extract using calcined egg shell as a catalyst identified the following lipids: triglyceride, fatty acids, sphingolipid, phospholipid, glycerolipid, glycerophospholipid, steroid, and cholesterol. The predominant lipid was triglyceride, and the high percentage of unsaturated fatty acids, including arachidonic acid (23.54%), eicosadienoic acid (8.37%), and oleic acid (6.23%) suggest that the lipid extract is a potential feedstock for biodiesel production. [ABSTRACT FROM AUTHOR]

This research aimed to model and optimize the growth factors and enhance the lipid yield from Botryococcus braunii microalgae, and to design a system for obtaining biodiesel from these lipids as this does not compromise food security. Botryococcus braunii, grown on a modified Chu‐13 medium, reached the stationary phase after 27 days with a maximum cell count of 265 × 104 cells mL−1 after 27 days and maximum biomass yield of 725 mg L−1 after 30 days on modified Chu‐13 medium, which was higher than growth on Basal SAG medium. The maximum lipid content (18.47%) and lipid yield (4.46 mg L−1day) were obtained when B. braunii was cultivated on modified Chu‐13 medium after 30 days. Gas chromatography (GC) analysis for the lipids indicated that the highest percentages of SFAs (51.03%) and lowest percentages of monounsaturated fatty acids (MUFAs) (36.47%) and polyunsaturated fatty acids (PUFAs) (12.49%) were obtained by culturing B. braunii on modified Chu‐13 medium. The effect of different growth parameters (N2 level, NaHCO3, and CO2 concentrations) on growth yield was modeled by using D‐optimal design response surface methodology (RSM). [ABSTRACT FROM AUTHOR]

The primary objective of this study is to investigate the effects of Zinc toxicity when fishes are exposed in a controlled environment using two-dimensional correlation spectral analysis. This analysis is superior as subtle spectral changes induced by an external perturbation are not readily noticeable in conventional one-dimensional spectra. A higher decrease in protein and carbohydrates and a lesser decrease in lipids (20%–28%) against the control sample occurs due to Zn toxicity. The lowest value of the bioconcentration factor for Zn shows carbohydrate utilization, which was resolved well in our two-dimensional spectral analysis. Synchronous maps show the predominant changes in protein (1668 cm−1), phospholipids (1771 cm−1), and fatty acids (1707 cm−1). The asynchronous two-dimensional spectra show alteration in phosphodiester stretching of glycogen followed by Amide I. In addition, we explored the importance of principal component analysis coupled two-dimensional spectra analysis which shows weak amide III protein changes. The hetero asynchronous shows well-resolved cross peaks of +(1047, 1389), resulting in improved resolution. The study helps in understanding biomolecular changes of muscle tissues of G. affinis under Zn toxicity using two-dimensional correlation infrared spectral analysis. [ABSTRACT FROM AUTHOR]