Impaired retinal oxygen metabolism and perfusion are accompanied by plasma protein and lipid alterations in recovered COVID-19 patients.

The aim of the present study was to investigate retinal microcirculatory and functional metabolic changes in patients after they had recovered from a moderate to severe acute COVID-19 infection. Retinal perfusion was quantified using laser speckle flowgraphy. Oxygen saturation and retinal calibers were assessed with a dynamic vessel analyzer. Arterio-venous ratio (AVR) was calculated based on retinal vessel diameter data. Blood plasma samples underwent mass spectrometry-based multi-omics profiling, including proteomics, metabolomics and eicosadomics. A total of 40 subjects were included in the present study, of which 29 had recovered from moderate to severe COVID-19 within 2 to 23 weeks before inclusion and 11 had never had COVID-19, as confirmed by antibody testing. Perfusion in retinal vessels was significantly lower in patients (60.6 ± 16.0 a.u.) than in control subjects (76.2 ± 12.1 a.u., p = 0.006). Arterio-venous (AV) difference in oxygen saturation and AVR was significantly lower in patients compared to healthy controls (p = 0.021 for AVR and p = 0.023 for AV difference in oxygen saturation). Molecular profiles demonstrated down-regulation of cell adhesion molecules, NOTCH3 and fatty acids, and suggested a bisphasic dysregulation of nitric oxide synthesis after COVID-19 infection. The results of this study imply that retinal perfusion and oxygen metabolism is still significantly altered in patients well beyond the acute phase of COVID-19. This is also reflected in the molecular profiling analysis of blood plasma, indicating a down-regulation of nitric oxide-related endothelial and immunological cell functions.Trial Registration: ClinicalTrials.gov ( https://clinicaltrials.gov ) NCT05650905.

Effects of solid lipid nanocarrier containing methyl urolithin A by coating folate-bound chitosan and evaluation of its anti-cancer activity.

BACKGROUND: Nanotechnology-based drug delivery systems have received much attention over the past decade. In the present study, we synthesized Methyl Urolithin A-loaded solid lipid nanoparticles decorated with the folic acid-linked chitosan layer called MuSCF-NPs and investigated their effects on cancer cells. METHODS: MuSCF-NPs were prepared using a high-pressure homogenization method and characterized using FTIR, FESEM, DLS, and zeta potential methods. Drug encapsulation was assessed by spectrophotometry and its cytotoxic effect on various cancer cells (MDA-MB231, MCF-7, PANC, AGS, and HepG2) by the MTT method. Antioxidant activity was assessed by the ABTS and DPPH methods, followed by expression of genes involved in oxidative stress and apoptosis by qPCR and flow cytometry. RESULTS: The results showed the formation of monodisperse and stable round nanoparticles with a size of 84.8 nm. The drug loading efficiency in MuSCF-NPs was reported to be 88.6%. MuSCF-NPs exhibited selective cytotoxicity against MDA-MB231 cells (IC50 = 40 µg/mL). Molecular analysis showed a significant increase in the expression of Caspases 3, 8, and 9, indicating that apoptosis was occurring in the treated cells. Moreover, flow cytometry results showed that the treated cells were arrested in his SubG1 phase, confirming the pro-apoptotic effect of the nanoparticles. The results indicate a high antioxidant effect of the nanoparticles with IC50 values ​​of 45 µg/mL and 1500 µg/mL against ABTS and DPPH, respectively. The reduction of catalase gene expression confirmed the pro-oxidant effect of nanoparticles in cancer cells treated at concentrations of 20 and 40 µg/mL. CONCLUSIONS: Therefore, our findings suggest that the MuSCF-NPs are suitable candidates, especially for breast cancer preclinical studies.

Prevalence of dyslipidaemia within Polish nurses. Cross-sectional study - single and multiple linear regression models and ROC analysis.

BACKGROUND: Maintaining good health is vital not only for own well-being, but also to ensure high-quality patient care. The aim of this study was to evaluate the prevalence of dyslipidaemia and to determine the factors responsible for the development of this disorder among Polish nurses. Lipid profile disorders are the most prevalent and challenging risk factors for the development of cardiovascular disease. Nurses have significant potential and play a crucial role in providing care and treatment services. METHODS: This cross-sectional study involved nurses and included measurements of body weight composition (Tanita MC-980), body mass index, waist circumference, blood pressure (Welch Allyn 4200B), lipid profile, and fasting blood glucose (CardioChek PA). RESULTS: The results revealed that more than half of the nurses (60.09%) were overweight or obese, with 57.28% exhibiting elevated blood pressure, 32.25% having fasting glucose levels, and 69.14% experiencing dyslipidaemia. Multiple model evaluation using ROC curves demonstrated that multiple models accurately predicted hypercholesterolemia (AUC = 0.715), elevated LDL (AUC = 0.727), and elevated TC (AUC = 0.723) among Polish nurses. CONCLUSION: Comprehensive education programmes should be implemented that include the latest advances in cardiovascular disease prevention. Regular check-ups, as well as the promotion and availability of healthy food in hospital canteens, are essential.

Association of lipid profile and obesity in patients with polycystic ovary syndrome.

Objective. Abnormal lipid profile and obesity increase the risk of polycystic ovary syndrome (PCOS). PCOS patients may have a greater risk of infertility, metabolic syndrome (MetS) and cardiovascular disease (CVD) due to abnormal lipid profile and obesity. The aim of the study was to find the association between abnormal lipid profile and obesity in patients with PCOS. Methods. In this case-control study, a total of 102 female subjects (51 diagnosed PCOS and 51 age-matched healthy controls) were enrolled, aged between 20-40 years. Biochemical parameters such as total cholesterol (TC), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), very low-density lipoprotein-cholesterol (VLDL-C), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were estimated. Anthropometric parameters such as body mass index (BMI), waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) were recorded. A p<0.05 was considered statistically significant. Results. Mean of BMI, WC, WHR, LH, FSH, TC, TG, LDL-C, and VLDL-C was found significantly elevated in patients with PCOS as compared to controls (p<0.01). However, the mean of HDL-C was found significantly reduced in patients with PCOS as compared to controls (p<0.01). BMI has shown a significant positive correlation with WC (r=0.562, p<0.01) and WHR (r=0.580, p<0.01) among PCOS patients. LH has shown a significant positive correlation with FSH (r=0.572, p<0.01) among PCOS patients. TC has shown a significant positive correlation with TG (r=0.687, p<0.01), LDL-C (r=0.917, p<0.01), and VLDL-C (r=0.726, p<0.01) among PCOS patients. Conclusion. The results showed that abnormal lipid profile and obesity have a significant association with PCOS patients. Regular monitoring and treatment of PCOS patients are required to reduce the risk of infertility, MetS, and CVD.

The IRG1-itaconate axis protects from cholesterol-induced inflammation and atherosclerosis.

Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which is generated from the tricarboxylic acid-intermediate cis-aconitate by the enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested the therapeutic potential of the IRG1-itaconate axis for human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), we found that IRG1 is up-regulated in human coronary atherosclerotic lesions compared to patient-matched healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic Irg1-deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine interleukin (IL)-1ß. Mechanistically, absence of Irg1 increased macrophage lipid accumulation, and accelerated inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1ß release. Conversely, supplementation of the Irg1-itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1ß levels in mice. To investigate the effects of 4-OI in humans, we leveraged an ex vivo systems-immunology approach for CVD drug discovery. Using CyTOF and scRNA-seq of peripheral blood mononuclear cells treated with plasma from CVD patients, we showed that 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. Our data highlight the relevance of pursuing IRG1-itaconate axis supplementation as a therapeutic approach for atherosclerosis in humans.

Silicon Ether Ionizable Lipids Enable Potent mRNA Lipid Nanoparticles with Rapid Tissue Clearance.

The advent of mRNA for nucleic acid (NA) therapeutics has unlocked many diverse areas of research and clinical investigation. However, the shorter intracellular half-life of mRNA compared with other NAs may necessitate more frequent dosing regimens. Because lipid nanoparticles (LNPs) are the principal delivery system used for mRNA, this could lead to tolerability challenges associated with an accumulated lipid burden. This can be addressed by introducing enzymatically cleaved carboxylic esters into the hydrophobic domains of lipid components, notably, the ionizable lipid. However, enzymatic activity can vary significantly with age, disease state, and species, potentially limiting the application in humans. Here we report an alternative approach to ionizable lipid degradability that relies on nonenzymatic hydrolysis, leading to a controlled and highly efficient lipid clearance profile. We identify highly potent examples and demonstrate their exceptional tolerability in multiple preclinical species, including multidosing in nonhuman primates (NHP).

Effect of oesophagectomy on lipid profiles in patients with oesophageal cancer combined with hyperlipidaemia: a retrospective study.

BACKGROUND: Surgery is widely regarded as a pivotal therapeutic approach for treating oesophageal cancer, and clinical observations have revealed that many oesophageal cancer patients also present with concomitant hyperlipidaemia. It is surprising that few studies have been performed to determine how blood lipid levels are affected by oesophageal cancer resection. This research was designed to assess the influence of oesophageal cancer resection on lipid profiles among individuals diagnosed with both oesophageal cancer and hyperlipidaemia. METHODS: A retrospective analysis was carried out on 110 patients with hyperlipidaemia and oesophageal cancer who had undergone oesophagectomy at the 900th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army. Preoperative and postoperative serological data were collected at seven-, thirty-, sixty-day-, and one-year-long intervals. Changes in lipid levels were compared, the remission of various types of hyperlipidaemia was statistically assessed, and Pearson correlation was used to analyse the association between lipid changes and preoperative body weight. The research sought to assess the reduction in body weight and the proportion of body weight lost one year following surgery. RESULTS: Noteworthy decreases were observed in total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) levels, with TC decreasing from 6.20 mmol/L to 5.20 mmol/L, TG decreasing from 1.40 mmol/L to 1.20 mmol/L, and LDL decreasing from 4.50 mmol/L to 3.30 mmol/L. Conversely, there was a notable increase in high-density lipoprotein (HDL) levels, which increased from 1.20 mmol/L to 1.40 mmol/L (P < 0.05) compared to the preoperative levels. Notably, the remission rates for mixed hyperlipidaemia (60.9%) and high cholesterol (60.0%) were considerably greater than those for high triglycerides (16.2%). Alterations in TC at one year postoperatively correlated with preoperative weight and weight loss (r = 0.315, -0.216); changes in TG correlated with preoperative weight, percentage of total weight loss (TWL%), and weight reduction (r = -0.295, -0.246, 0.320); and changes in LDL correlated with preoperative weight, TWL%, and weight loss (r = 0.251, 0.186, and -0.207). Changes in non-high-density lipoprotein(non-HDL) were linked to preoperative weight (r = 0.300), and changes in TG/HDL were correlated with preoperative weight and TWL% (r = -0.424, -0.251). CONCLUSIONS: Oesophagectomy significantly improved lipid profiles in oesophageal cancer patients, potentially leading to a reduction in overall cardiovascular risk.

Dyslipidemia and associated factors among adult cardiac patients: a hospital-based comparative cross-sectional study.

BACKGROUND: Atherosclerotic vascular diseases are a leading global cause of morbidity and mortality. Dyslipidemia, a major modifiable risk factor for cardiovascular disease, remains poorly understood among adult cardiac patients in in the study area. This study aims to determine the prevalence of dyslipidemia and identify associated factors in this population. METHODS: Hospital-based comparative cross-sectional study was conducted from May to August 2021. A total of 319 participants (153 cardiac cases, 166 healthy controls, aged ≥ 18) were included in the study. Socio-demographic, anthropometric, behavioral, and clinical data were collected using the WHO STEPS survey instrument through systematic sampling. Overnight fasting blood samples were obtained, and serum lipid profiles were analyzed using a COBAS 6000 analyzer. Data were analyzed with SPSS version 20.0, employing bivariable and multivariable logistic regression. Statistical significance was set at p < 0.05. RESULTS: The overall prevalence of dyslipidemia, encompassing at least one lipid abnormality, was 80.3% among 256 participants. Among cardiac cases, the prevalence rates were as follows: 72.5% for low HDL-cholesterol, 12.4% for hypercholesterolemia, 9.8% for elevated LDL-cholesterol, and 30.1% for hypertriglyceridemia. In controls, corresponding rates were 69.9%, 9.6%, 7.2%, and 32.5%. Significant factors linked to low HDL- cholesterol were female gender (AOR: 2.8, 95% CI 1.7-4.7) and obesity (AOR: 2.8, 95% CI 1.1-7.5). Abdominal obesity was associated with hypercholesterolemia (AOR: 5.2, 95% CI 1.9-14.3) and elevated LDL-cholesterol (AOR: 5.1, 95% CI 1.6-15.8). High blood pressure, overweight, and abdominal obesity were significantly linked to hypertriglyceridemia (p < 0.05). CONCLUSION: Dyslipidemia was high among the study participants. Overweight, obesity, central adiposity, and high blood pressure were significantly associated with dyslipidemia in cardiac patients. This alarms the need for lipid profile assessment for patients periodically, with treatment follow-up to monitor any rising patterns and cardiovascular-related risks.

Targeted metabolomics profiling in pregnancy associated with vitamin D deficiency.

BACKGROUND: Vitamin D deficiency is common in pregnancy, however, its effects has not been fully elucidated. Here, we conducted targeted metabolomics profiling to study the relationship. METHODS: This study enrolled 111 pregnant women, including sufficient group (n = 9), inadequate group (n = 49) and deficient group (n = 53). Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS)-based targeted metabonomics were used to characterize metabolite profiles associated with vitamin D deficiency in pregnancy. RESULTS: Many metabolites decreased in the inadequate and deficient group, including lipids, amino acids and others. The lipid species included fatty acyls (FA 14:3, FA 26:0; O), glycerolipids (MG 18:2), glycerophospholipids (LPG 20:5, PE-Cer 40:1; O2, PG 29:0), sterol lipids (CE 20:5, ST 28:0; O4, ST 28:1; O4). Decreased amino acids included aromatic amino acids (tryptophan, phenylalanine, tyrosine) and branched-chain amino acids (valine, isoleucine, leucine), proline, methionine, arginine, lysine, alanine, L-kynurenine,5-hydroxy-L-tryptophan, allysine. CONCLUSIONS: This targeted metabolomics profiling indicated that vitamin D supplementation can significantly affect lipids and amino acids metabolism in pregnancy.

Polar lipids modify Alzheimer's Disease pathology by reducing astrocyte pro-inflammatory signaling through platelet-activating factor receptor (PTAFR) modulation.

BACKGROUND: Pro-inflammatory processes triggered by the accumulation of extracellular amyloid beta (Aß) peptides are a well-described pathology in Alzheimer's disease (AD). Activated astrocytes surrounding Aß plaques contribute to inflammation by secreting proinflammatory factors. While astrocytes may phagocytize Aß and contribute to Aß clearance, reactive astrocytes may also increase Aß production. Therefore, identifying factors that can attenuate astrocyte activation and neuroinflammation and how these factors influence pro-inflammatory pathways is important for developing therapeutic and preventive strategies in AD. Here, we identify the platelet-activating factor receptor (PTAFR) pathway as a key mediator of astrocyte activation. Intriguingly, several polar lipids (PLs) have exhibited anti-inflammatory protective properties outside the central nervous system through their inhibitory effect on the PTAFR pathway. Thus, we additionally investigated whether different PLs also exert inhibitory effects on the PAF pathway in astrocytes and whether their presence influences astrocytic pro-inflammatory signaling and known AD pathologies in vitro. METHODS: PLs from salmon and yogurt were extracted using novel food-grade techniques and their fatty acid profile was determined using LC/MS. The effect of PLs on parameters such as astrocyte activation and generation of oxygen species (ROS) was assessed. Additionally, effects of the secretome of astrocytes treated with these polar lipids on aged neurons was measured. RESULTS: We show that PLs obtained from salmon and yogurt lower astrocyte activation, the generation of reactive oxygen species (ROS), and extracellular Aß accumulation. Cell health of neurons exposed to the secretome of astrocytes treated with salmon-derived PLs and Aß was less affected than those treated with astrocytes exposed to Aß only. CONCLUSION: Our results highlight a novel underlying mechanism, why consuming PL-rich foods such as fish and dairy may reduce the risk of developing dementia and associated disorders.

Relationship between sarcopenia and fatty liver in middle-aged and elderly patients with type 2 diabetes mellitus.

OBJECTIVE: In this study, we investigated the relationship between sarcopenia and fatty liver in middle-aged and elderly patients diagnosed with type 2 diabetes mellitus (T2DM) to provide a theoretical foundation for the prevention and treatment of sarcopenia. METHODS: A total of 282 patients diagnosed with T2DM aged 50 and older and were admitted to the Endocrinology Department of Xin Medical University First Affiliated Hospital between December 2021 and February 2023, were selected. Body mass index (BMI), and limb and trunk muscle mass of the patients were measured, and data were collected. Patients were grouped based on the sarcopenia diagnostic criteria. All study participants underwent the same physical examinations and laboratory tests. The relationship between the onset of sarcopenia and fatty liver in middle-aged and elderly patients diagnosed with T2DM was then investigated using statistical analysis. RESULTS: Comparing the sarcopenia group to the non-sarcopenia group revealed statistically significant variations in gender, BMI, fatty liver prevalence rate, uric acid (UA), alanine aminotransferase (ALT), blood glucose, blood lipid associated indicators, and limb skeletal muscle content. There were, however, no statistically significant differences in age, disease duration, hypertension, smoking, or alcohol intake. There was a positive correlation between BMI, UA, fasting c-peptide, and Appendicular Skeletal Muscle Index (ASMI). Higher levels of BMI, ASMI, and UA were identified as protective variables against sarcopenia by multifactorial logistic regression analysis. CONCLUSION: Higher levels of BMI, ASMI, and UA can greatly reduce skeletal muscle atrophy in patients with T2DM. Patients with a fatty liver may be less vulnerable to sarcopenia. There is little evidence, however, that a fatty liver works as a preventive factor against sarcopenia.

Noninvasive evaluation of the skin barrier in reconstructed human epidermis using speckle analysis: Correlation with Raman microspectroscopy.

BACKGROUND: Reconstructed epidermis models, obtained from 3D keratinocytes culture, have gained significant prominence as prototypes for safety and efficacy testing in skin research. To effectively evaluate these models, it is essential to perform molecular and functional characterization. The skin's barrier function is one of the essential aspects of the epidermis that needs to be assessed. A noninvasive method is thus required for the evaluation of the skin barrier in these models. With this perspective, the aim of this feasibility study is to apply the speckle technique for the assessment of the skin barrier in the Reconstructed Human Epidermis (RHE). MATERIALS AND METHODS: Speckle analysis as well as Raman microspectroscopy were performed on RHE samples at two maturation days, D17 and D20. RESULTS: Between D17 and D20, our study showed an increase in various Raman parameters, including stratum corneum percentage, lateral lipid packing, lipid-to-protein ratio, and protein secondary structure. Furthermore, the degree of light polarization and the speckle grain size also increased over this period. CONCLUSION: The speckle technique proved to be effective for evaluating the skin barrier in Reconstructed Human Epidermis (RHE) models. Comparison with Raman validates this approach and provides comprehensive molecular and functional characterization of reconstructive skin models.

Lipid Membrane Topographies Are Regulators for the Spatial Distribution of Liquid Protein Condensates.

Liquid protein condensates play important roles in orchestrating subcellular organization and as biochemical reaction hubs. Recent studies have linked lipid membranes to proteins capable of forming liquid condensates, and shown that biophysical parameters, like protein enrichment and restricted diffusion at membranes, regulate condensate formation and size. However, the impact of membrane topography on liquid condensates remains poorly understood. Here, we devised a cell-free system to reconstitute liquid condensates on lipid membranes with microstructured topographies and demonstrated that lipid membrane topography is a significant biophysical regulator. Using membrane surfaces designed with microwells, we observed ordered condensate patterns. Furthermore, we demonstrate that membrane topographies influence the shape of liquid condensates. Finally, we show that capillary forces, mediated by membrane topographies, lead to the directed fusion of liquid condensates. Our results demonstrate that membrane topography is a potent biophysical regulator for the localization and shape of mesoscale liquid protein condensates.

Size exclusion chromatography of biopharmaceutical products: From current practices for proteins to emerging trends for viral vectors, nucleic acids and lipid nanoparticles.

The 21st century has been particularly productive for the biopharmaceutical industry, with the introduction of several classes of innovative therapeutics, such as monoclonal antibodies and related compounds, gene therapy products, and RNA-based modalities. All these new molecules are susceptible to aggregation and fragmentation, which necessitates a size variant analysis for their comprehensive characterization. Size exclusion chromatography (SEC) is one of the reference techniques that can be applied. The analytical techniques for mAbs are now well established and some of them are now emerging for the newer modalities. In this context, the objective of this review article is: i) to provide a short historical background on SEC, ii) to suggest some clear guidelines on the selection of packing material and mobile phase for successful method development in modern SEC; and iii) to highlight recent advances in SEC, such as the use of narrow-bore and micro-bore columns, ultra-wide pore columns, and low-adsorption column hardware. Some important innovations, such as recycling SEC, the coupling of SEC with mass spectrometry, and the use of alternative detectors such as charge detection mass spectrometry and mass photometry are also described. In addition, this review discusses the use of SEC in multidimensional setups and shows some of the most recent advances at the preparative scale. In the third part of the article, the possibility of SEC for the characterization of new modalities is also reviewed. The final objective of this review is to provide a clear summary of opportunities and limitations of SEC for the analysis of different biopharmaceutical products.

Molecular mechanism underlying SNARE-mediated membrane fusion enlightened by all-atom molecular dynamics simulations.

The SNAP receptor (SNARE) proteins syntaxin-1, SNAP-25, and synaptobrevin mediate neurotransmitter release by forming tight SNARE complexes that fuse synaptic vesicles with the plasma membranes in microseconds. Membrane fusion is generally explained by the action of proteins on macroscopic membrane properties such as curvature, elastic modulus, and tension, and a widespread model envisions that the SNARE motifs, juxtamembrane linkers, and C-terminal transmembrane regions of synaptobrevin and syntaxin-1 form continuous helices that act mechanically as semirigid rods, squeezing the membranes together as they assemble ("zipper") from the N to the C termini. However, the mechanism underlying fast SNARE-induced membrane fusion remains unknown. We have used all-atom molecular dynamics simulations to investigate this mechanism. Our results need to be interpreted with caution because of the limited number and length of the simulations, but they suggest a model of membrane fusion that has a natural physicochemical basis, emphasizes local molecular events over general membrane properties, and explains extensive experimental data. In this model, the central event that initiates fast (microsecond scale) membrane fusion occurs when the SNARE helices zipper into the juxtamembrane linkers which, together with the adjacent transmembrane regions, promote encounters of acyl chains from both bilayers at the polar interface. The resulting hydrophobic nucleus rapidly expands into stalk-like structures that gradually progress to form a fusion pore, aided by the SNARE transmembrane regions and without clearly discernible intermediates. The propensity of polyunsaturated lipids to participate in encounters that initiate fusion suggests that these lipids may be important for the high speed of neurotransmitter release.

Exercise and lipids.

Evidence from the existing literature suggests that exercise has positive effects for prevention and treatment of cardiovascular diseases by reducing risk factors such as elevated blood lipids. Based on clinical and observational clinical trials, it is well established that increased physical activity and regular exercise has a favourable impact on blood lipids and lipoprotein profiles. Exercise training significantly decreases blood triglycerides concentration and increases high density lipoprotein cholesterol levels. Though the Indian data depicting the effect of exercise on lipids is scarce, exercise directly improves "atherogenic dyslipidaemia" which is frequently present among Indians i.e. HDL-C is increased, TG is reduced and LDL-C particle size is improved. While drug therapy is key to the treatment of dyslipidaemia, lifestyle alterations such as exercise should continue to be actively promoted and encouraged by clinicians. Exercise is a low cost, non pharmacological therapeutic lifestyle change that is of value to lipid metabolism and cardiovascular fitness.

The impact of continuous and intermittent ketogenic diets on cognitive behavior, motor function, and blood lipids in TgF344-AD rats.

Studies suggest that ketogenic diets (KD) may improve memory in mouse models of aging and Alzheimer's disease (AD). This study determined whether a continuous or intermittent KD (IKD) enhanced cognitive behavior in the TgF344-AD rat model of AD. At 6 months-old, TgF344-AD and wild-type (WT) littermates were placed on a control (CD), KD, or IKD (morning CD and afternoon KD) provided as two meals per day for 2 or 6 months. Cognitive and motor behavior and circulating ß-hydroxybutyrate (BHB), AD biomarkers and blood lipids were assessed. Animals on a KD diet had elevated circulating BHB, with IKD levels intermediate to CD and KD. TgF344-AD rats displayed impaired spatial learning memory in the Barnes maze at 8 and 12 months of age and impaired motor coordination at 12 months of age. Neither KD nor IKD improved performance compared to CD. At 12 months of age, TgF344-AD animals had elevated blood lipids. IKD reduced lipids to WT levels with KD further reducing cholesterol below WT levels. This study shows that at 8 or 12 months of age, KD or IKD intervention did not improve measures of cognitive or motor behavior in TgF344-AD rats; however, both IKD and KD positively impacted circulating lipids.

Evaluation of Lipids and Lipid-Related Transcripts in Human and Ovine Theca Cells and an in Vitro Mouse Model Exposed to the Obesogen Chemical Tributyltin.

BACKGROUND: Exposure to obesogenic chemicals has been reported to result in enhanced adipogenesis, higher adipose tissue accumulation, and reduced ovarian hormonal synthesis and follicular function. We have reported that organotins [tributyltin (TBT) and triphenyltin (TPT)] dysregulate cholesterol trafficking in ovarian theca cells, but, whether organotins also exert lipogenic effects on ovarian cells remains unexplored. OBJECTIVE: We investigated if environmentally relevant exposures to organotins [TBT, TPT, or dibutyltin (DBT)] induce lipid dysregulation in ovarian theca cells and the role of the liver X receptor (LXR) in this effect. We also tested the effect of TBT on oocyte maturation and neutral lipid accumulation, and lipid-related transcript expression in cumulus cells and preimplantation embryos. METHODS: Primary theca cell cultures derived from human and ovine ovaries were exposed to TBT, TPT, or DBT (1, 10, or 50 ng/ml). The effect of these chemical exposures on neutral lipid accumulation, lipid abundance and composition, lipid homeostasis-related gene expression, and cytokine secretion was evaluated using liquid chromatography-mass spectrometry (LC-MS), inhibitor-based methods, cytokine secretion, and lipid ontology analyses. We also exposed murine cumulus-oocyte complexes to TBT and evaluated oocyte maturation, embryo development, and lipid homeostasis-related mRNA expression in cumulus cells and blastocysts. RESULTS: Exposure to TBT resulted in higher intracellular neutral lipids in human and ovine primary theca cells. In ovine theca cells, this effect was dose-dependent, independent of cell stage, and partially mediated by LXR. DBT and TPT resulted in higher intracellular neutral lipids but to a lesser extent in comparison with TBT. More than 140 lipids and 9 cytokines were dysregulated in TBT-exposed human theca cells. Expression of genes involved in lipogenesis and fatty acid synthesis were higher in theca cells, as well as in cumulus cells and blastocysts exposed to TBT. However, TBT did not impact the rates of oocyte maturation or blastocyst development. DISCUSSION: TBT induced dyslipidemia in primary human and ovine theca cells, which may be responsible for some of the TBT-induced fertility dysregulations reported in rodent models of TBT exposure. https://doi.org/10.1289/EHP13955.

Electron videography of a lipid-protein tango.

Biological phenomena, from enzymatic catalysis to synaptic transmission, originate in the structural transformations of biomolecules and biomolecular assemblies in liquid water. However, directly imaging these nanoscopic dynamics without probes or labels has been a fundamental methodological challenge. Here, we developed an approach for "electron videography"-combining liquid phase electron microscopy with molecular modeling-with which we filmed the nanoscale structural fluctuations of individual, suspended, and unlabeled membrane protein nanodiscs in liquid. Systematic comparisons with biochemical data and simulation indicate the graphene encapsulation involved can afford sufficiently reduced effects of the illuminating electron beam for these observations to yield quantitative fingerprints of nanoscale lipid-protein interactions. Our results suggest that lipid-protein interactions delineate dynamically modified membrane domains across unexpectedly long ranges. Moreover, they contribute to the molecular mechanics of the nanodisc as a whole in a manner specific to the protein within. Overall, this work illustrates an experimental approach to film, quantify, and understand biomolecular dynamics at the nanometer scale.

Induction of neutralizing antibodies against SARS-CoV-2 variants by a multivalent mRNA-lipid nanoparticle vaccine encoding SARS-CoV-2/SARS-CoV Spike protein receptor-binding domains in mice.

To address the need for multivalent vaccines against Coronaviridae that can be rapidly developed and manufactured, we compared antibody responses against SARS-CoV, SARS-CoV-2, and several variants of concern in mice immunized with mRNA-lipid nanoparticle vaccines encoding homodimers or heterodimers of SARS-CoV/SARS-CoV-2 receptor-binding domains. All vaccine constructs induced robust anti-RBD antibody responses, and the heterodimeric vaccine elicited an IgG response capable of cross-neutralizing SARS-CoV, SARS-CoV-2 Wuhan-Hu-1, B.1.351 (beta), and B.1.617.2 (delta) variants.