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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]

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]

This review aimed to assess the effectiveness of interventions for type 2 diabetes (T2D) management in New Zealand on clinical outcomes, and explore the factors impacting their feasibility and acceptability. Scoping review. Three databases (PubMed, Web of Science and Scopus) were searched between January 2000 and July 2023. Reference lists of included studies were hand searched to identify additional articles. The search yielded 550 publications, of which 11 were included in the final review. Most interventions (n = 10) focussed on education and seven were delivered by health professionals. Supporting factors for interventions included clinical/peer support (n = 8) and whānau (family) involvement (n = 6). Hindering factors included non-adherence (n = 4) and high drop-out (n = 4). Most studies reported modest improvement in HbA1c and weight at six months, but minimal change in HbA1c, weight, lipids, renal profile, and blood pressure by two years. Future interventions should involve culturally appropriate approaches to improve engagement and acceptability while addressing lifestyle and medication adherence for T2D management. T2D interventions not widely disseminated via academic channels need to be further identified. [ABSTRACT FROM AUTHOR]

Seipin, a crucial protein for cellular lipid droplet (LD) assembly, oligomerizes at the interface between the endoplasmic reticulum and LDs to facilitate neutral lipid packaging. Using proximity labeling, we identified four proteins—Ldo45, Ldo16, Tgl4, and Pln1—that are recruited to the vicinity of yeast seipin, the Sei1-Ldb16 complex, exclusively when seipin function is intact, hence termed seipin accessory factors. Localization studies identified Tgl4 at the endoplasmic reticulum-LD contact site, in contrast to Ldo45, Ldo16, and Pln1 at the LD surface. Cells with compromised seipin function resulted in uneven distribution of these proteins with aberrant LDs, supporting a central role of seipin in orchestrating their association with the LD. Overexpression of any seipin accessory factor causes LD aggregation and affects a subset of LD protein distribution, highlighting the importance of their stoichiometry. Although single factor mutations show minor LD morphology changes, the combined mutations have additive effects. Lastly, we present evidence that seipin accessory factors assemble and interact with seipin in the absence of neutral lipids and undergo dynamical rearrangements during LD formation induction, with Ldo45 acting as a central hub recruiting other factors to interact with the seipin complex. [ABSTRACT FROM AUTHOR]

The CD1 family of antigen-presenting molecules adopt a major histocompatibility complex class I (MHC-I) fold. Whereas MHC molecules present peptides, the CD1 family has evolved to bind self- and foreign-lipids. The CD1 family of antigen-presenting molecules comprises four members—CD1a, CD1b, CD1c, and CD1d—that differ in their architecture around the lipid-binding cleft, thereby enabling diverse lipids to be accommodated. These CD1–lipid complexes are recognized by T cell receptors (TCRs) expressed on T cells, either through dual recognition of CD1 and lipid or in a new model whereby the TCR directly contacts CD1, thereby triggering an immune response. Chemical syntheses of lipid antigens, and analogs thereof, have been crucial in understanding the underlying specificity of T cell–mediated lipid immunity. This review will focus on our current understanding of how TCRs interact with CD1–lipid complexes, highlighting how it can be fundamentally different from TCR-MHC-peptide corecognition. [ABSTRACT FROM AUTHOR]

The central nervous system continuously detects circulating concentrations of lipids such as fatty acids and troglycerides. Once information has been detected, the central nervous system can in turn participate in the control of energy balance and blood sugar levels and in particular regulate the secretion and action of insulin. Neurons capable of detecting circulating lipid variations are located in the hypothalamus and in other regions such as the nucleus accumbens, the striatum or the hippocampus. An excess of lipids will have deleterious effects and may induce central lipotoxicity, in particular following local production of ceramides and the appearance of neuroinflammation which may lead to metabolic diseases such as obesity and type 2 diabetes. • Both specialized neurons and non-neuronal cells can sense circulating lipids. • lipoprotein lipase in neurons and astrocytes sense triglycerides-enriched lipoproteins. • Ceramides can induce brain lipotoxicity associated with neuroinflammation. [ABSTRACT FROM AUTHOR]

The central control of energy homeostasis is a regulatory axis that involves the sensing of nutrients, signaling molecules, adipokines, and neuropeptides by neurons in the metabolic centers of the hypothalamus. However, non-neuronal glial cells are also abundant in the hypothalamus and recent findings have underscored the importance of the metabolic crosstalk and horizontal lipid flux between glia and neurons to the downstream regulation of systemic metabolism. New transgenic models and high-resolution analyses of glial phenotype and function have revealed that glia sit at the nexus between lipid metabolism and neural function, and may markedly impact the brain's response to dietary lipids or the supply of brain-derived lipids. Glia comprise the main cellular compartment involved in lipid synthesis, lipoprotein production, and lipid processing in the brain. In brief, tanycytes provide an interface between peripheral lipids and neurons, astrocytes produce lipoproteins that transport lipids to neurons and other glia, oligodendrocytes use brain-derived and dietary lipids to myelinate axons and influence neuronal function, while microglia can remove unwanted lipids in the brain and contribute to lipid re-utilization through cholesterol efflux. Here, we review recent findings regarding glial-lipid transport and highlight the specific molecular factors necessary for lipid processing in the brain, and how dysregulation of glial-neuronal metabolic crosstalk contributes to imbalanced energy homeostasis. Furthering our understanding of glial lipid metabolism will guide the design of future studies that target horizontal lipid processing in the brain to ameliorate the risk of developing obesity and metabolic disease. • Lipid processing in the brain involves metabolic crosstalk and horizontal lipid flux between neurons and non-neuronal glia. • Disruption of this complex neuron-glia interplay has effects on neuronal function, and systemic energy balance. • Exposure to high-fat diets cause a shift towards a more inflammatory glial phenotype and away from metabolic support. • Sexual dimorphism in glial metabolism and phenotype could contribute to metabolic disease susceptibility. [ABSTRACT FROM AUTHOR]

Obesity is a chronic and debilitating disorder that originates from alterations in energy-sensing brain circuits controlling body weight gain and food intake. The dysregulated syntheses and actions of lipid mediators in the hypothalamus induce weight gain and overfeeding, but the molecular and cellular underpinnings of these alterations remain elusive. In response to changes in the nutritional status, different lipid sensing pathways in the hypothalamus direct body energy needs in a Yin-Yang model. Endocannabinoids orchestrate the crosstalk between hypothalamic circuits and the sympathetic nervous system to promote food intake and energy accumulation during fasting, whereas bile acids act on the same top-down axis to reduce energy intake and possibly storage after the meal. In obesity, the bioavailability and downstream cellular actions of endocannabinoids and bile acids are altered in hypothalamic neurons involved in body weight and metabolic control. Thus, the onset and progression of this disease might result from an imbalance in hypothalamic sensing of multiple lipid signals, which are possibly integrated by common molecular nodes. In this viewpoint, we discuss a possible model that explains how bile acids and endocannabinoids may exert their effects on energy balance regulation via interconnected mechanisms at the level of the hypothalamic neuronal circuits. Therefore, we propose a new conceptual framework for understanding and treating central mechanisms of maladaptive lipid action in obesity. • Endocannabinoids and bile acids act as Yin-Yang regulators of the body energy needs. • Master lipid sensors in the brain could integrate the actions of multiple lipid signals. • Obesity might originate from dysregulation of master lipid sensors in the brain. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are the leading cause of global mortality among non-communicable diseases. Current cardiac regeneration treatments have limitations and may lead to adverse reactions. Hence, innovative technologies are needed to address these shortcomings. Messenger RNA (mRNA) emerges as a promising therapeutic agent due to its versatility in encoding therapeutic proteins and targeting "undruggable" conditions. It offers low toxicity, high transfection efficiency, and controlled protein production without genome insertion or mutagenesis risk. However, mRNA faces challenges such as immunogenicity, instability, and difficulty in cellular entry and endosomal escape, hindering its clinical application. To overcome these hurdles, lipid nanoparticles (LNPs), notably used in COVID-19 vaccines, have a great potential to deliver mRNA therapeutics for CVDs. This review highlights recent progress in mRNA-LNP therapies for CVDs, including Myocardial Infarction (MI), Heart Failure (HF), and hypercholesterolemia. In addition, LNP-mediated mRNA delivery for CAR T-cell therapy and CRISPR/Cas genome editing in CVDs and the related clinical trials are explored. To enhance the efficiency, safety, and clinical translation of mRNA-LNPs, advanced technologies like artificial intelligence (AGILE platform) in RNA structure design, and optimization of LNP formulation could be integrated. We conclude that the strategies to facilitate the extra-hepatic delivery and targeted organ tropism of mRNA-LNPs (SORT, ASSET, SMRT, and barcoded LNPs) hold great prospects to accelerate the development and translation of mRNA-LNPs in CVD treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

In the CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Outcomes trial, treatment of statin-intolerant patients with bempedoic acid produced a 21% decrease in low-density lipoprotein cholesterol (LDL-C) relative to placebo and a 13% relative reduction in the risk of major adverse cardiovascular events. This study sought to determine whether the relationship between LDL-C lowering and cardiovascular benefit achieved with bempedoic acid resembles that observed with statins when standardized per unit change in LDL-C. To compare the treatment effect of bempedoic acid with statins, the methodology of the Cholesterol Treatment Trialists' Collaboration (CTTC) was applied to outcomes among the 13,970 patients enrolled in the CLEAR Outcomes trial. The CTTC endpoint of "major vascular event" was a composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal stroke, or coronary revascularization. HRs for CTTC-defined endpoints were normalized to 1 mmol/L differences in LDL-C levels between bempedoic acid and placebo groups. A first major vascular event occurred in 703 (10.1%) patients in the bempedoic acid group and 816 (11.7%) patients in the placebo group (HR: 0.85; 95% CI: 0.77-0.94). When normalized per 1 mmol/L reduction in LDL-C, the HR was 0.75 (95% CI: 0.63-0.90), comparable to the rate ratio of 0.78 reported for statins in the CTTC meta-analysis. Normalized risk reductions were similar for bempedoic acid and statins for the endpoints of major coronary events, nonfatal myocardial infarction, and coronary revascularization. Cardiovascular risk reduction with bempedoic acid is similar to that achieved with statins for a given absolute magnitude of LDL-C lowering. (Evaluation of Major Adverse Cardiovascular Events in Participants With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated with Bempedoic Acid [ETC-1002] or Placebo [CLEAR Outcomes]; NCT02993406). [ABSTRACT FROM AUTHOR]

• Wheat germ improved markers of glucose homeostasis in overweight adults. • Wheat germ reduced the pro-inflammatory adipokine, resistin. • Gut microbiota and gut integrity markers were unaffected by wheat germ. Wheat germ (WG), a by-product of flour milling, is rich in bioactive substances that may help improve health complications associated with increased adiposity. This study investigated the effects of WG on gut health, metabolic, and inflammatory markers in adults classified as overweight. We hypothesized that WG, because of its many bioactive components, would improve gut health and metabolic, and inflammatory markers in overweight adults. Forty adults (18–45 years old) and with a body mass index between 25 and 30 kg/m2 participated in this single-blinded randomized controlled pilot study. Participants consumed the study supplements containing 30 g of either cornmeal (control, CL) or WG daily for 4 weeks. Primary outcome variables were gut health markers including gut microbiota, gut integrity markers, and fecal short-chain fatty acids, whereas secondary outcome variables included metabolic and inflammatory parameters assessed at baseline and at the end of supplementation. Thirty-nine participants (n = 19 and 20 for CL and WG group, respectively) completed the study. The genus Faecalibacterium was significantly higher in the WG group compared to CL post-supplementation but no significant changes in other gut health markers, short-chain fatty acids, inflammatory markers, and lipid profiles were observed. Compared with baseline, WG improved markers of glucose homeostasis including insulin (P =.02), homeostatic model assessment of insulin resistance (P =.03), glycated hemoglobin (P =.07), and the pro-inflammatory adipokine, resistin (P =.04). However, these parameters after intervention were not different with control. Our findings suggest that WG supplementation have modest effects on gut health but may provide an economical option for individuals to improve glycemic control. Daily consumption of 30 g of wheat germ supplement for 4 weeks by adults classified as overweight maintained the bacterial genus Faecalibacterium and improved several markers of glucose homeostasis including insulin, HOMA-IR, and HbA1c, and reduced the pro-inflammatory adipokine, resistin. Abbreviations: HbA1c, glycated hemoglobin; HOMA-IR, homeostatic model assessment of insulin resistance. [Display omitted] [ABSTRACT FROM AUTHOR]

• Increased calcium intake reduces serum advanced glycation end products (AGEs). • AGEs/soluble receptor for AGEs (sRAGE) ratio also decreases after intervention. • ΔAGEs and ΔAGEs/sRAGE ratio are associated with a poorer metabolic profile. • ΔAGEs/ ΔsRAGE ratio is a better metabolic status marker than ΔAGEs and ΔsRAGE. The effect of calcium (Ca) on glycation markers is unknown. We hypothesized that increased Ca intake from skimmed milk associated with an energy-restricted diet intake will reduce glycation markers. This reduction will be associated with a greater improvement in markers of metabolic control in adults with type 2 diabetes, overweight, and low habitual Ca intake (<600 mg/d). In this secondary data analysis based on a crossover clinical trial, 14 adults were allocated into 2 groups: high calcium (shake containing 700 mg Ca/day) or low calcium (shake with 6.4 mg Ca/day), for 12 consecutive weeks per session. Energy-restricted diets were also prescribed (−500 kcal/d, 800 mg of dietary Ca/d) to all participants. Advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), glycemic control, and lipid profile were assessed at baseline and after 12 weeks. High-calcium serum AGE concentrations and AGE/sRAGE ratio were lower at the end of the study. ΔAGE and ΔAGE/sRAGE ratio were both positively associated with Δtriglycerides, Δtotal cholesterol, Δtriglyceride-glucose index and variations, and Δvisceral adiposity index. ΔAGE/sRAGE was positively associated with Δfructosamine and Δhigh-density lipoprotein-cholesterol, and negatively associated with male sex. Consumption of approximately 1200 mg/day of calcium (3 servings of skim milk) reduced serum AGEs concentrations and the AGE/sRAGE ratio in individuals with diabetes. In general, positive changes in glycation markers are associated with lipid profile, insulin resistance, and adiposity markers worsening. ΔAGEs/ΔsRAGE ratio seems to be a better marker of metabolic status than ΔAGEs and ΔsRAGE alone. Registered in ClinicalTrials.gov (NCT02377076). Consumption of 1200 mg/day of calcium reduces serum AGE concentrations and the AGEs/sRAGE ratio, demonstrating a potential antiglycation effect of skimmed milk in individuals with type 2 diabetes, excess body weight, and low habitual calcium intake. Negative changes on glycation markers are associated with a better metabolic profile. Created with Adobe Photoshop CS6, using vectors freely distributed by Flaticom.com. Abbreviations: AGE, advanced glycation end products; sRAGE, soluble receptor for AGE. [Display omitted] [ABSTRACT FROM AUTHOR]

Lipid oxidation is a spontaneous process in fats and, consequently, in products with significant fat content. Many cosmetics fall into this category, presenting an intrinsic relationship between the productʼs quality, oxidation capacity, and market value. This study comprehensively investigated the aging of body lotions, accentuating the role of their chemical formulations. Sensory analysis clarified that controlled temperature-induced aging significantly altered the lotions' appearance, texture, color, and, to a lesser extent, odor, hinting at the onset of rancidity. As lipid peroxidation unfolds, the emergence of secondary oxidation products like aldehydes, ketones, and alcohols becomes prominent. These secondary products indicate a potential degradation in the lotion's quality and efficacy. Quantifying the primary oxidation products was possible using methods like the quantification of Conjugated Dienes (CD) expressed in percentage and the Peroxide Index (PI) method expressed in meqO 2 /kg of a dry sample. On the other hand, methods such as the p-Anidisine Index (pAi) and the thiobarbituric acid reactive substances (TBARS) with malonaldehyde (MDA) expressed as malonaldehyde concentration (mg/g of dry sample) provided the quantification of secondary oxidation products. Regarding lipid oxidation, lotions containing sunflower and soybean oils emerged as notably susceptible. Conversely, samples that demonstrated minimal oxidation, were attributed to protective elements such as Aloe barbadensis and Calendula officinalis extracts. Examining into secondary oxidation, four samples displayed the highest TOTOX values, indicating extensive oxidation. A discernible correlation was observed between TOTOX values and natural extracts' presence (or lack), underscoring their protective or exacerbating roles. Certain natural ingredients, including A. barbadensis leaf juice powder and C. officinalis flower extract, were recognized as supporters against oxidation. Yet, components like PEG-40 hydrogenated castor oil can, paradoxically, seem to intensify the oxidative cascade. This research provides crucial insights into the interplay between natural extracts and lipid oxidation in body lotions. The elucidated results accentuate the necessity for judicious ingredient selection, balancing the inclusion of natural extracts to ensure product quality, longevity, and safety. [Display omitted] • Aloe barbadensis and Calendula officinalis extracts show protection against oxidation. • PEG-40 hydrogenated castor oil accelerates lipid oxidation acting as a pro-oxidant. • Accelerated aging tests show changes in lotion appearance, texture, color, and odor. • Sunflower and soybean oils exhibited heightened vulnerability to lipid oxidation. • A correlation between TOTOX values and antioxidant-rich natural extracts emerged. [ABSTRACT FROM AUTHOR]

In this study, milk fat globule membrane (MFGM) ingredients enriched in polar lipids were prepared using membrane filtration, including microfiltration, diafiltration, and ultrafiltration from butter serum powder. Polar lipids (phospholipids, sterols, and gangliosides) in prepared MFGM ingredients were analyzed by 31P nuclear magnetic resonance spectroscopy, GC-MS, and ultra-performance liquid chromatography (UPLC)-MS/MS, respectively. The lipolysis degree and microstructure of MFGM ingredient and soybean lecithin (SL) emulsions during in vitro digestion were also analyzed. Microfiltration showed higher concentration efficiency than ultrafiltration, which increased by 2.16% and 2.73% in phospholipids, respectively. Moreover, diafiltration concentrated more polar lipids (6.39% of phospholipids) than microfiltration. Milk fat globule membrane ingredients had high levels of sphingomyelin (1.27%–1.36%) and ratio of GD 3 to GM 3 is 9.25- to 9.88-fold. The different lipolysis behaviors between MFGM ingredient emulsions and SL emulsions were correlated with their different polar lipid compositions. Phospholipids from both MFGM ingredients and SL could help maintain the initial structure during the gastric digestion. These results could provide a scientific basis for developing high-polar-lipids food, particularly infant formulas and special functional foods. [ABSTRACT FROM AUTHOR]

There is still no consensus regarding the role of lipid modulators during in vitro embryo production. Thus, we investigated how lipid reducers during the in vitro maturation of oocytes (IVM) or in vitro culture (IVC) of embryos impact their cryotolerance. A literature search was performed using three databases, recovering 43 articles for the systematic review, comprising 75 experiments (13 performed in IVM, 62 in IVC) and testing 13 substances. In 39 % of the experiments, an increase in oocyte and/or embryo survival after cryopreservation was reported, in contrast to 48 % exhibiting no effect, 5 % causing negative effects, and 8 % influencing in a dose-dependent manner. Of the 75 experiments extracted during IVM and IVC, 41 quantified the lipid content. Of those that reduced lipid content (n = 26), 50 % increased cryotolerance, 34 % had no effect, 8 % harmed oocyte/embryo survival, and 8 % had different results depending on the concentration used. Moreover, 28 out of the 43 studies were analyzed under a meta-analytical approach at the IVC stage in cattle. There was an improvement in the cryotolerance of bovine embryos when the lipid content was reduced. Forskolin, l -carnitine, and phenazine ethosulfate positively affected cryotolerance, while conjugated linoleic acid had no effect and impaired embryonic development. Moreover, fetal bovine serum has a positive impact on cryotolerance. SOF and CR1aa IVC media improved cryotolerance, while mSOF showed no effect. In conclusion, lipid modulators did not unanimously improve cryotolerance, especially when used in IVM, but presented positive effects on cryotolerance during IVC when reaching lipid reduction. • The role of using lipid reducers during either IVM or IVC on oocyte and embryo cryotolerance was assessed. • Reduction of lipid content improves cryotolerance in bovine embryos. • Forskolin, phenazine ethosulfate, and l -carnitine improve cryotolerance in bovine IVP embryos. • The presence of fetal bovine serum improves cryotolerance in IVP bovine embryos. [ABSTRACT FROM AUTHOR]

There is an increasing requirement for the discovery of new anthelmintics with resistance to existing drugs on the rise. Current strategies focus on targeting carbohydrate metabolism, with glycolytic enzymes and transporters proving to be attractive druggable targets; however, these often show a lack of efficacy during in vivo infections and have a lack of specificity. Recent studies have unearthed the ability of helminths to manipulate short-chain fatty acid (SCFA) and bioactive lipid production, as possible alternative immunomodulatory strategies for establishing chronic infection. There is an urgent need to establish if these metabolic pathways are critical for parasite survival, as these could present as an exciting new avenue for anthelmintic discovery. Helminths can adapt to environmental conditions in the host, utilising anaerobic processes like fermentation and malate dismutation to produce energy from carbohydrate. Although targeting carbohydrate metabolism is an established therapeutic strategy to combat helminth infection, questions remain over the metabolic pathways they employ as adults to survive and evade host immunity. Helminths also use amino acid, polyunsaturated fatty acid (PUFA), and cholesterol metabolism, a possible strategy favouring the production of immunomodulatory compounds that may influence survival in the host. Here, we discuss the significance of these differing metabolic pathways and whether targeting of helminth metabolic pathways may allow for the development of novel anthelmintics. [ABSTRACT FROM AUTHOR]

Activation of pregnane X receptor (PXR) by xenobiotics has been associated with metabolic diseases. This study aimed to reveal the impact of PXR activation on hepatic metabolome and explore novel mechanisms underlying PXR-mediated lipid metabolism disorder in the liver. Wild-type and PXR-deficient male C57BL/6 mice were used as in vivo models, and hepatic steatosis was induced by pregnenolone-16α-carbonitrile, a typical rodent PXR agonist. Metabolomic analysis of liver tissues showed that PXR activation led to significant changes in metabolites involved in multiple metabolic pathways previously reported, including lipid metabolism, energy homeostasis, and amino acid metabolism. Moreover, the level of hepatic all- trans retinoic acid (ATRA), the main active metabolite of vitamin A, was significantly increased by PXR activation, and genes involved in ATRA metabolism exhibited differential expression following PXR activation or deficiency. Consistent with previous research, the expression of downstream target genes of peroxisome proliferator-activated receptor α (PPARα) was decreased. Analysis of fatty acids by Gas Chromatography-Mass Spectrometer further revealed changes in polyunsaturated fatty acid metabolism upon PXR activation, suggesting inhibition of PPARα activity. Taken together, our findings reveal a novel metabolomic signature of hepatic steatosis induced by PXR activation in mice. [Display omitted] • PXR activation and deficiency have different impact on hepatic metabolomics in mice. • PXR activation increased hepatic all- trans -retinoic acid by affecting the expression of genes involved in ATRA metabolism. • PXR activation inhibited PPARα-target genes involved in lipid metabolism and altered the composition of hepatic fatty acids. [ABSTRACT FROM AUTHOR]

The full potential of ionizable lipid nanoparticles (LNPs) as an in vivo nucleic acid delivery platform has not yet been realized given that LNPs primarily accumulate in the liver following systemic administration, limiting their success to liver-centric conditions. The engineering of LNPs with antibody targeting moieties can enable extrahepatic tropism by facilitating site-specific LNP tethering and driving preferential LNP uptake into receptor-expressing cell types via receptor-mediated endocytosis. Obstetric conditions stemming from placental dysfunction, such as preeclampsia, are characterized by overexpression of cellular receptors, including the epidermal growth factor receptor (EGFR), making targeted LNP platforms an exciting potential treatment strategy for placental dysfunction during pregnancy. Herein, an EGFR antibody-conjugated LNP (aEGFR-LNP) platform was developed by engineering LNPs with increasing densities of antibody functionalization. aEGFR-LNPs were screened in vitro in immortalized placental trophoblasts and in vivo in non-pregnant and pregnant mice and compared to non-targeted formulations for extrahepatic, antibody-targeted mRNA LNP delivery to the placenta. Our top performing LNP with an intermediate density of antibody functionalization (1:5 aEGFR-LNP) mediated a ∼twofold increase in mRNA delivery in murine placentas and a ∼twofold increase in LNP uptake in EGFR-expressing trophoblasts compared to non-targeted counterparts. These results demonstrate the potential of antibody-conjugated LNPs for achieving extrahepatic tropism, and the ability of aEGFR-LNPs in promoting mRNA delivery to EGFR-expressing cell types in the placenta. [Display omitted] • Strain-promoted azide-DBCO cycloaddition produces stable antibody-conjugated LNPs • Pregnancy alters EGFR antibody-conjugated LNP biodistribution in vivo • Intermediate EGFR antibody density enhances mRNA LNP delivery to the placenta • EGFR antibody-conjugated LNPs enhance uptake in EGFR-expressing trophoblasts [ABSTRACT FROM AUTHOR]

Lipid conjugates have advanced the field of lipid-based nanomedicine by promoting active-targeting (ligand, peptide, antibody), stability (PEGylation), controlled release (lipoid prodrug), and probe-based tracking (fluorophore). Recent findings indicate lipid conjugates dissociating from nanomedicine upon encountering a biological environment. Yet, implications for (pre)clinical outcomes remain unclear. In this study, using the zebrafish model (Danio rerio), we investigated the fate of liposome-incorporated lipid fluorophore conjugates (LFCs) after intravenous (IV) administration. LFCs having a bilayer mismatch and relatively polar fluorophore revealed counter-predictive outcomes for Caelyx/Doxil (clearance vs. circulating) and AmBisome-like liposomes (scavenger endothelial cell vs. macrophage uptake). Findings on LFC (mis)match for Caelyx/Doxil-like liposomes were supported by translational intravital imaging studies in mice. Importantly, contradicting observations suggest to originate from LFC dissociation in vivo , which was investigated by Asymmetric Flow Field-Flow Fractionation (AF4) upon liposome-serum incubation in situ. Our data suggests that LFCs matching with the liposome bilayer composition – that did not dissociate upon serum incubation – revealed improved predictive outcomes for liposome biodistribution profiles. Altogether, this study highlights the critical importance of fatty acid tail length and headgroup moiety when selecting lipid conjugates for lipid-based nanomedicine. [Display omitted] [ABSTRACT FROM AUTHOR]

• Lipid droplet (LD) accumulation in the brain depends upon ageing, oxidative stress and inflammation. • The Peridroplet mitochondria plays a vital role in lipid metabolism and regulates mitochondrial oxidative phosphorylation. • Abnormal astrocytic OXPHOS causes LD build up, which can cause neurodegeneration. Energy metabolism in the brain has been considered one of the critical research areas of neuroscience for ages. One of the most vital parts of brain metabolism cascades is lipid metabolism, and fatty acid plays a crucial role in this process. The fatty acid breakdown process in mitochondria undergoes through a conserved pathway known as β-oxidation where acetyl-CoA and shorter fatty acid chains are produced along with a significant amount of energy molecule. Further, the complete breakdown of fatty acids occurs when they enter the mitochondrial oxidative phosphorylation. Cells store energy as neutral lipids in organelles known as Lipid Droplets (LDs) to prepare for variations in the availability of nutrients. Fatty acids are liberated by lipid droplets and are transported to various cellular compartments for membrane biogenesis or as an energy source. Current research shows that LDs are important in inflammation, metabolic illness, and cellular communication. Lipid droplet biology in peripheral organs like the liver and heart has been well investigated, while the brain's LDs have received less attention. Recently, there has been increased awareness of the existence and role of these dynamic organelles in the central nervous system, mainly connected to neurodegeneration. In this review, we discussed the role of beta-oxidation and lipid droplet formation in the oxidative phosphorylation process, which directly affects neurodegeneration through various pathways. [ABSTRACT FROM AUTHOR]

[Display omitted] • High sugar, protein of sludge shows outstanding biodrying potential. • Low ventilation rate improved bio-drying cycle and water removal effect. • Revealed the contribution of different water types to water removal. • Lipid degradation role: Crucial for releasing and transforming bound water. • Energy-saving ventilation changes the degradation sequence of organic matter. The effectiveness of dehydration and utilization processes for citric acid dewatered sludge is hampered by its high concentrations of polysaccharides, proteins, and water-binding properties of microbial extracellular polymers (EPS). This research explores the efficacy and mechanisms involved in extracting water from this type of sludge using biological drying technology, with varying rates of ventilation. Especially pertinent was the use of low ventilation rates as control variables. Our results suggest that a scheduled intermittent ventilation at lower rates allows for the most efficient removal of water, achieving a rate of 41.71 % within eight days, according to the zero-order kinetic model. Remarkably, the peak temperature registered was 60 °C, reaching this threshold in just 0.1 days and maintaining high temperatures for approximately 5.9 days. Component analysis of organic matter illustrated a preferential degradation process for lipids under these ventilation conditions which is pivotal for releasing and transforming bound water for efficient extraction, as well as facilitating the breakdown of easily hydrolysable materials. Further, polysaccharide/protein (EPS) decomposition contributed to water removal, though less significantly. The periodic ventilation strategy allowed for the maximum cumulative temperature to be sustained, demonstrating superior efficiency in harnessing bio-generated heat (82.77 % for water evaporation), resulting in dry sludge suitable for self-sustained combustion at relatively low cost ($26.61/t). Highlighted by this study is the considerable potential of energy-efficient ventilation methods in the biological drying treatment of citric acid fermented sludge and similar industrial waste materials. [ABSTRACT FROM AUTHOR]

• Cardiometabolic health benefits of dairy foods vary by fat content and product fermentation • Dairy fat intakes are associated with neutral to beneficial cardiometabolic activities • Full-fat dairy intakes have no demonstrated adverse impact on cardiovascular risk • Fermented dairy intakes positively influence lipid profiles • Milk polar lipids contribute to improved blood lipid profiles • Dietary recommendations concerning dairy likely require greater precision Bovine dairy milk is a nutrient-rich matrix, but consumption of full-fat dairy food varieties has been claimed historically to be associated with poorer cardiometabolic health, a notion often attributed to the saturated fat content. However, continued investigation that includes observational studies and randomized controlled trials (RCTs) provide evidence that favorably supports full-fat dairy foods and their bioactive components on cardiometabolic health. This review addresses this controversy by examining the evidence surrounding full-fat dairy foods and their implications for human health. Dairy foods are heterogeneous, not just in their fat content but also in other compositional aspects within and between fermented (e.g., yogurt, cheese) and nonfermented products (e.g., milk) that could differentially influence cardiometabolic health. Drawing from complementary lines of evidence from epidemiological studies and RCTs, this review describes the health effects of dairy foods regarding their fat content, as well as their polar lipids that are concentrated in the milk fat globule fraction. Observational studies have limitedly supported the consumption of full-fat dairy to protect against cardiometabolic disorders. However, this framework has been disputed by RCTs indicating that dairy foods, regardless of their fat content or fermentation, are not detrimental to cardiometabolic health and may instead alleviate certain cardiometabolic risk factors. As dietary recommendations evolve, which currently indicate to avoid full-fat dairy foods, it is essential to consider the totality of evidence, especially from RCTs, while also recognizing that investigation is needed to evaluate the complexity of dairy foods within diverse dietary patterns and their impacts on cardiometabolic health. This review examines the cardiometabolic effects of dairy, comparing full-fat and low-fat types. It starts with observational study findings on total dairy intake and its fat content, then explores the health benefits of specific dairy types, considering fat content and whether they are fermented. Next, it presents evidence from controlled trials to establish efficacy of the correlative outcomes suggested by observational studies. This approach offers insights for future dietary recommendations. [Display omitted] [ABSTRACT FROM AUTHOR]

A commercial lipase from Rhizopus japonicus was activated and utilized for triglyceride (TG) modification for producing structured lipids via acidolysis of TGs and fatty acids. To activate the lipase, lipase powder was mixed with glass beads (GBs) in 1-dodecanol and then a buffer solution were added dropwise to form hydrated lipase aggregates. After removal of liquid phase in the mixuture, the residue consisting of hydrated lipases and GBs was lyophilized and then the hydration – aggregation-pretreated lipase loaded onto GBs was recovered. The acidolytic activity of the lipase was significantly enhanced after hydration – aggregation pretreatment, whereas untreated lipase exhibited little activity. The effects of the surface hydrophobicity, diameter, and amount of lipase loading on GBs on the acidolytic activity of the lipase were investigated. The optimal GBs and lipase loadings were 0.428 mm in diameter with a hydrophobic surface and 89.2 U/g-GB, respectively. Under these conditions, the lipase exhibited an 8-fold higher catalytic activity than that of the hydration – aggregation-pretreated lipase without GBs. Furthermore, continuous modification of olive oil with palmitic acid via acidolysis using the hydration – aggregation-pretreated lipase packed in a column reactor was achieved for 116 h. The half-life of the packed-bed reactor was 149 h. [Display omitted] ● Lyophilizing lipase aggregates with glass beads enhanced acidolytic activity. ● Activated lipase can modify olive oil with palmitic acid via acidolysis. ● A packed bed reactor was developed using the activated lipases. ● Water content affected activity and stability of lipase during continuous run. [ABSTRACT FROM AUTHOR]

Mycobacterium abscessus belongs to the largest group of mycobacteria, the rapid-growing saprophytic mycobacteria, and is one of the most difficult-to-treat opportunistic pathogen. Several features pertain to the high adaptability of M. abscessus to the host. These include the capacity to survive and persist within amoebae, to transition from a smooth to a rough morphotype that occurs during the course of the disease and to express of a wide array of virulence factors. The main objective of this narrative review consists to report major assets of M. abscessus that contribute to the virulence of these rapid-growing saprophytic mycobacteria. Strikingly, many of these determinants, whether they are from a mycobacterial origin or acquired by horizontal gene transfer, are known virulence factors found in slow-growing and strict pathogens for humans and animals. In the light of recent published work in the field we attempted to highlight major features characterizing M. abscessus pathogenicity and to explain why this led to the emergence of this mycobacterial species in patients with cystic fibrosis. M. abscessus genome plasticity, the smooth-to-rough transition, and the expression of a panel of enzymes associated with virulence in other bacteria are key players in M. abscessus virulence. In addition, the very large repertoire of lipid transporters, known as mycobacterial membrane protein large and small (MmpL and MmpS respectively), deeply influences the pathogenicity of M. abscessus , as exemplified here for some of them. All these traits largely contribute to make M. abscessus a unique mycobacterium regarding to its pathophysiological processes, ranging from the early colonization steps to the establishment of severe and chronic pulmonary diseases. [ABSTRACT FROM AUTHOR]

Mutations in RAS, a family of proteins found in all human cells, drive a third of cancers, including many pancreatic, colorectal, and lung cancers. However, there is a lack of clinical therapies that can effectively prevent RAS from causing tumor growth. Recently, a protease was engineered that specifically degrades active RAS, offering a promising new tool for treating these cancers. However, like many other intracellularly acting protein-based therapies, this protease requires a delivery vector to reach its site of action within the cell. In this study, we explored the incorporation of cationic lipids into ionizable lipid nanoparticles (LNPs) to develop a RAS protease delivery platform capable of inhibiting cancer cell proliferation in vitro and in vivo. A library of 13 LNPs encapsulating RAS protease was designed, and each formulation was evaluated for in vitro delivery efficiency and toxicity. A subset of four top-performing LNP formulations was identified and further evaluated for their impact on cancer cell proliferation in human colorectal cancer cells with mutated KRAS in vitro and in vivo , as well as their in vivo biodistribution and toxicity. In vivo , both the concentration of cationic lipid and type of cargo influenced LNP and cargo distribution. All lead candidate LNPs showed RAS protease functionality in vitro , and the top-performing formulation achieved effective intracellular RAS protease delivery in vivo , decreasing cancer cell proliferation in an in vivo xenograft model and significantly reducing tumor growth and size. Overall, this work demonstrates the use of LNPs as an effective delivery platform for RAS proteases, which could potentially be utilized for cancer therapies. [Display omitted] [ABSTRACT FROM AUTHOR]

The success of mRNA vaccines against COVID-19 has enhanced the potential of lipid nanoparticles (LNPs) as a system for the delivery of mRNA. In this review, we describe our progress using a lipid library to engineer ionizable lipids and promote LNP technology from the viewpoints of safety, controlled biodistribution, and mRNA vaccines. These advancements in LNP technology are applied to cancer immunology, and a potential nano-DDS is constructed to evaluate immune status that is associated with a cancer-immunity cycle that includes the sub-cycles in tumor microenvironments. We also discuss the importance of the delivery of antigens and adjuvants in enhancing the cancer-immunity cycle. Recent progress in NK cell targeting in cancer immunotherapy is also introduced. Finally, the impact of next-generation DDS technology is explained using the MITO-Porter membrane fusion-based delivery system for the organelle targeting of the mitochondria. We introduce a successful example of the MITO-Porter used in a cell therapeutic strategy to treat cardiomyopathy. [Display omitted] • The efficiency of lipid nanoparticles is discussed from the viewpoint of a 3-dimensinal structure of ionizable lipids. • A potential nano-DDS is designed based on a cancer immunity cycle that includes sub-cycles in a tumor microenvironment. • MITO-Porter was introduced as an organelle-targeting DDS that was successfully applied to cell transplantation therapy. [ABSTRACT FROM AUTHOR]

The advent of lipid nanoparticles (LNPs) containing ionizable cationic lipids has enabled the encapsulation, stabilization, and intracellular delivery of nucleic acid payloads, leading to FDA-approved siRNA-based therapy and mRNA-based vaccines. Other nucleic acid-based therapeutic modalities, including protein replacement and CRISPR-mediated gene knockout and editing, are being tested in clinical trials, in many cases, for the treatment of liver-related diseases. However, to fully exploit these therapies beyond the liver, improvements in their delivery to extrahepatic targets are needed. Towards this end, both active targeting strategies based on targeting ligands grafted onto LNPs and passive targeting relying on physicochemical LNP parameters such as surface composition, charge, and size are being evaluated. Often, the latter strategy depends on the interaction of LNPs with blood components, forming what is known as the biomolecular corona. Here, I discuss potential challenges related to current LNP-based targeting strategies and the studies of the biomolecular corona on LNPs. I propose potential solutions to overcome some of these obstacles and present approaches currently being tested in preclinical and clinical studies, which face fewer biological barriers than traditional organ-targeting approaches. [Display omitted] • Presents an overview of LNP-based strategies for extrahepatic RNA delivery. • Highlights potential challenges with the LNP strategies and approaches to overcome some of them. • Stresses inherent challenges associated with biomolecular corona studies of LNPs. • Highlights that LNPs are a minor subpopulation of nanoparticles in human plasma. • Advocates innovative approaches to drive progress in the LNP field. [ABSTRACT FROM AUTHOR]

Lipid-based drug formulations are promising systems for improving delivery of drugs to ocular tissues, such as retina. To develop lipid-based systems further, an improved understanding of their pharmacokinetics is required, but high-quality in vivo experiments require a large number of animals, raising ethical and economic questions. In order to expedite in vivo kinetic testing of lipid-based systems, we propose a barcode approach that is based on barcoding liposomes with non-endogenous lipids. We developed and evaluated a liquid-chromatography-mass spectrometry method to quantify many liposomes simultaneously in aqueous humor, vitreous, and neural retina at higher than ±20% precision and accuracy. Furthermore, we showed in vivo suitability of the method in pharmacokinetic evaluation of six different liposomes after their simultaneous injection into the rat vitreal cavity. We calculated pharmacokinetic parameters in vitreous and aqueous humor, quantified liposome concentrations in the retina, and quantitated retinal distribution of the liposomes in the rats. Compared to individual injections of the liposome formulations, the barcode-based study design enabled reduction of animal numbers from 72 to 12. We believe that the proposed approach is reliable and will reduce and refine ocular pharmacokinetic experiments with liposomes and other lipid-based systems. [Display omitted] • A method to quantify many liposome formulations and study their ocular pharmacokinetics within the same animal was developed. • The ocular pharmacokinetics of six barcoded liposomes were successfully evaluated within the same animal. • The barcode lipid method reduced the number of animals required for a pharmacokinetic study from 72 to 12. [ABSTRACT FROM AUTHOR]

The cryo-EM resolution revolution has heralded a new era in our understanding of eukaryotic lipid flippases with a rapidly growing number of high-resolution structures. Flippases belong to the P4 family of ATPases (type IV P-type ATPases) that largely follow the reaction cycle proposed for the more extensively studied cation-transporting P-type ATPases. However, unlike the canonical P-type ATPases, no flippase cargos are transported in the phosphorylation half-reaction. Instead of being released into the intracellular or extracellular milieu, lipid cargos are transported to their destination at the inner leaflet of the membrane. Recent flippase structures have revealed multiple conformational states during the lipid transport cycle. Nonetheless, critical conformational states capturing the lipid cargo “in transit” are still missing. In this review, we highlight the amazing structural advances of these lipid transporters, discuss various perspectives on catalytic and regulatory mechanisms in the literature, and shed light on future directions in further deciphering the detailed molecular mechanisms of lipid flipping. [ABSTRACT FROM AUTHOR]

There are no FDA-approved lipid inhibitors for cancer treatment despite promising preclinical data to suggest their utility. Only fatty acid synthase (FASN) inhibitors have reached clinical-stage testing. New results suggest central nervous system (CNS)-resident tumors are primed for FASN and stearoyl-CoA desaturase 1 (SCD1) inhibitors due the paucity of microenvironmental lipids. SCD1 is an emerging therapeutic target due to the central role that monounsaturated fatty acids play in preventing cell death. Cluster of differentiation 36 (CD36) inhibitory antibodies are poised for a clinical breakthrough based on their seemingly unanimous pro-tumorigenic function in the tumor microenvironment (TME), and CD36 inhibition may enhance the activity of immune checkpoint inhibitors. Alterations in dietary lipids through prescribed diets have shown exciting activity in preclinical testing, although more optimization of diet composition and molecular targets is required. Cancer cells perturb lipid metabolic pathways for a variety of pro-tumorigenic functions, and deregulated cellular metabolism is a hallmark of cancer cells. Although alterations in lipid metabolism in cancer cells have been appreciated for over 20 years, there are no FDA-approved cancer treatments that target lipid-related pathways. Recent advances pertaining to cancer cell fatty acid synthesis (FAS), desaturation, and uptake, microenvironmental and dietary lipids, and lipid metabolism of tumor-infiltrating immune cells have illuminated promising clinical applications for targeting lipid metabolism. This review highlights emerging pathways and targets for tumor lipid metabolism that may soon impact clinical treatment. [ABSTRACT FROM AUTHOR]

Human iPSC-derived airway organoids (iPSC-AOs) exhibit cellular heterogenicity resembling the human native airway. Bioinformatics analysis revealed a robust dysregulation in inflammation, lipid-metabolism pathway, and alternative splicing in SARS-CoV-2 infected airway organoids. Manipulating lipid homeostasis using cholesterol-lowering drugs (e.g. Statins) relocated the viral entry receptor angiotensin-converting enzyme-2 (ACE-2), leading to the reduction of SARS-CoV-2 entry and replication. [Display omitted] • Single-cell RNA sequencing showed that iPSC-AOs exhibition of the genetic profiles highly resembling the genotypes of human airways. • iPSC-AOs are susceptible to SARS-COV-2 infection and the expressions of S and N proteins after viral infection. • Bioinformatics analysis indicated the involvement of aberrant enrichment of lipid transport and lipid pathways in infected iPSC-AOs. • Statin preincubation relocated ACE2, reduced N protein, and limited SARS-CoV-2 infection in iPSC-AOs. • Lipid modifications consistently inhibited viral entry of various SARS-CoV-2 strains (wild-type, alpha, delta, omicron). Modifications of lipid metabolism were closely associated with the manifestations and prognosis of coronavirus disease of 2019 (COVID-19). Pre-existing metabolic conditions exacerbated the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while modulations of aberrant lipid metabolisms alleviated the manifestations. To elucidate the underlying mechanisms, an experimental platform that reproduces human respiratory physiology is required. Here we generated induced pluripotent stem cell-derived airway organoids (iPSC-AOs) that resemble the human native airway. Single-cell sequencing (ScRNAseq) and microscopic examination verified the cellular heterogeneity and microstructures of iPSC-AOs, respectively. We subjected iPSC-AOs to SARS-CoV-2 infection and investigated the treatment effect of lipid modifiers statin drugs on viral pathogenesis, gene expression, and the intracellular trafficking of the SARS-CoV-2 entry receptor angiotensin-converting enzyme-2 (ACE-2). In SARS-CoV-2-infected iPSC-AOs, immunofluorescence staining detected the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins and bioinformatics analysis further showed the aberrant enrichment of lipid-associated pathways. In addition, SARS-CoV-2 hijacked the host RNA replication machinery and generated the new isoforms of a high-density lipoprotein constituent apolipoprotein A1 (APOA1) and the virus-scavenging protein deleted in malignant brain tumors 1 (DMBT1). Manipulating lipid homeostasis using cholesterol-lowering drugs (e.g. Statins) relocated the viral entry receptor angiotensin-converting enzyme-2 (ACE-2) and decreased N protein expression, leading to the reduction of SARS-CoV-2 entry and replication. The same lipid modifications suppressed the entry of luciferase-expressing SARS-CoV-2 pseudoviruses containing the S proteins derived from different SARS-CoV-2 variants, i.e. wild-type, alpha, delta, and omicron. Together, our data demonstrated that modifications of lipid pathways restrict SARS-CoV-2 propagation in the iPSC-AOs, which the inhibition is speculated through the translocation of ACE2 from the cell membrane to the cytosol. Considering the highly frequent mutation and generation of SARS-CoV-2 variants, targeting host metabolisms of cholesterol or other lipids may represent an alternative approach against SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Mitochondrial fatty acid oxidation (mtFAO) plays an important role in hepatic energy metabolism. Severe mtFAO injury leads to nonalcoholic fatty liver disease (NAFLD) and liver failure. Several drugs have been withdrawn owing to safety issues, such as induction of fatty liver disease through mtFAO disruption. For instance, the antimicrobial triclocarban (TCC), an environmental contaminant that was removed from the market due to its unknown safety in humans, induces NAFLD in rats and promotes hepatic FAO in mice. Therefore, there are no consistent conclusions regarding the effects of TCC on FAO and lipid droplet accumulation. We hypothesized that TCC induces lipid droplet accumulation by inhibiting mtFAO in human hepatocytes. Here, we evaluated mitochondrial respiration in HepaRG cells to investigate the effects of TCC on fatty acid-driven oxidation in cells, electron transport chain parameters, lipid droplet accumulation, and antioxidant genes. The results suggest that TCC increases oxidative stress gene expression (GCLM , p62 , HO -1, and NRF2) through lipid droplet accumulation via mtFAO inhibition in HepaRG cells. The results of the present study provide further insights into the effect of TCC on human NAFLD through mtFAO inhibition, and further in vivo studies could be used to validate the mechanisms. • Triclocarban (TCC) disrupted mitochondrial fatty acid oxidation. • TCC induced lipid droplet accumulation. • TCC increased antioxidant gene expression. • TCC may enhance oxidative stress by lipid droplet accumulation via mtFAO inhibition. [ABSTRACT FROM AUTHOR]

The bioactive compounds in cardamom have been found to enhance cardiovascular health by improving blood lipids and inflammation. We hypothesized that cardamom consumption might ameliorate cardiovascular metabolic biomarkers in adults; however, there is still debate regarding its impact on cardiac metabolism. This research was therefore designed to determine if cardamom consumption had a favorable impact on lipid profiles, inflammatory markers, and oxidative stress indices as they related to cardiovascular diseases. A comprehensive search was conducted through PubMed, Scopus, Embase, Web of Science, and the Cochrane Library on July 4, 2023. Using a random-effects model pooled the weighted mean difference (WMD) and 95% confidence interval (CI). The final 12 trials containing 989 participants were included. The results illustrated that cardamom consumption could improve total cholesterol (WMD = –8.56 mg/dL; 95% CI, –14.90 to –2.22), triglycerides (WMD = –14.09 mg/dL; 95% CI, –24.01 to –4.17), high-sensitivity C-reactive protein (WMD = –1.01 ng/mL; 95% CI, –1.81 to –0.22), and interleukin-6 (WMD = –1.81 pg/mL; 95% CI, –3.06 to –0.56). However, it did not have significant influences on high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and some indicators of oxidative stress. In conclusion, cardamom consumption can improve specific cardiovascular metabolic biomarkers and potentially confer protective effects on cardiovascular health. However, more large-scale clinical research with better designs would further validate the findings, which will offer substantial evidence of cardamom as nutritional and functional products. The meta-analysis of 12 RCTs showed that 3 g/d cardamom consumption significantly reduced TC, TG, hs-CRP, and IL-6 in adults, with no significant impact on LDL-c and HDL-c. However, because of the limited number of studies, the effects on MDA, TAC, SOD, GR, ICAM-1, VCAM-1, and E-selectin were unknown. Cardamom consumption may have a potential cardiovascular protective effect in adults by improving TC, TG, hs-CRP, and IL-6 levels. Abbreviations : HDL-c, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; IL-6, interleukin-6; GR, glutathione reductase; LDL-c, low-density lipoprotein cholesterol; MDA, malondialdehyde; RCTs, randomized controlled trials; SOD, superoxide dismutase; TAC, total antioxidant capacity; TC, total cholesterol; TG, triglycerides; VCAM-1, vascular cell adhesion molecule-1. [Display omitted] [ABSTRACT FROM AUTHOR]

Rumen-protected choline (RPC) promotes benefits in milk production, immunity, and health in dairy cows by optimizing lipid metabolism during transition period management and early lactation. However, the RPC success in dairy cows depends on choline bioavailability, which is affected by the type of protection used in rumen-protected choline. Therefore, our objectives were to determine the effects of a novel RPC on dry matter intake (DMI), identify markers of metabolism and immunity, and evaluate lactation performance. Dry Holstein (n = 48) cows at 245 ± 3 d of gestation were blocked by parity and assigned to control or RPC treatment within each block. Cows enrolled in the RPC treatment received 15 g/d of CholiGEM (Kemin Industries, Cavriago RE, Italy) from 21 d prepartum and 30 g/d of CholiGEM from calving to 21 d postpartum. During the transition period, DMI was measured daily, and blood was sampled weekly for energy-related metabolites such as β-hydroxybutyrate (BHB), glucose, and nonesterified fatty acids (NEFA), as well as immune function markers such as haptoglobin (Hp) and lipopolysaccharide-binding protein (LPB). Vaginal discharge samples were collected at the calving and 7 d postpartum and stored in microcentrifuge tubes at −80°C until 16S rRNA sequencing. The main responses of body condition score, body weight, DMI, milk yield, milk components, and immune function markers were analyzed using the GLIMMIX procedure of SAS with the effects of treatment, time, parity, and relevant covariates added to the models. The relative abundance of microbiome α-diversity was evaluated by 3 indexes (Chao1, Shannon, and Simpson) and β-diversity by principal coordinate analysis and permutational multivariate ANOVA. We found no differences in DMI in the pre- and postpartum periods. Cows fed RPC increased the yields of energy- and 3.5% fat-corrected milk and fat yield in primiparous and multiparous cows, with an interaction between treatment and parity for these lactation variables. However, we found no differences in milk protein and lactose up to 150 DIM between treatments. Glucose, NEFA, and BHB had no differences between the treatments. However, RPC decreased BHB numerically (control = 1.07 ± 0.13 vs. RPC = 0.63 ± 0.13) in multiparous on the third week postpartum and tended to reduce the incidence of subclinical ketosis (12.7% vs. 4.2%). No effects for Hp and LPB were found in cows fed RPC. Chao1, Shannon, and Simpson indexes were lower at calving in the RPC treatment than in the Control. However, no differences were found 7 d later for Chao1, Shannon, and Simpson indexes. The vaginal discharge microbiome was altered in cows fed RPC at 7 d postpartum. Fusobacterium , a common pathogen associated with metritis, was reduced in cows fed RPC. Rumen-protected choline enhanced lactation performance and health and altered the vaginal discharge microbiome which is a potential proxy for uterine healthy in dairy cows. The current study's findings corroborate that RPC is a tool to support adaptation to lactation and shed light on opportunities for further research in reproductive health. [ABSTRACT FROM AUTHOR]

Lipids have key functions in the assembly of cell structures, serve as an important energy source, and are precursors for signaling molecules. Ubiquitination is one of the most common post-translational modifications in eukaryotes and is essential for cellular and tissue homeostasis. Ubiquitination is central in regulating lipid metabolism by controlling the turnover of proteins and lipids involved in lipid metabolism. Dysregulation of ubiquitination contributes to lipid abnormalities in divergent disorders, and targeting the ubiquitin-proteasome system serves as an interesting therapeutic approach. Lipids are essential molecules that play key roles in cell physiology by serving as structural components, for storage of energy, and in signal transduction. Hence, efficient regulation and maintenance of lipid homeostasis are crucial for normal cellular and tissue function. In the past decade, increasing research has shown the importance of ubiquitination in regulating the stability of key players in different aspects of lipid metabolism. This review describes recent insights into the regulation of lipid metabolism by ubiquitin signaling, discusses how ubiquitination can be targeted in diseases characterized by lipid dysregulation, and identifies areas that require further research. [ABSTRACT FROM AUTHOR]

Despite research efforts being made towards preserving (or even regenerating) heart tissue after an ischemic event, there is a lack of resources in current clinical treatment modalities for patients with acute myocardial infarction that specifically address cardiac tissue impairment. Modified messenger RNA (modRNA) presents compelling properties that could allow new therapeutic strategies to tackle the underlying molecular pathways that ultimately lead to development of chronic heart failure. However, clinical application of modRNA for the heart is challenged by the lack of effective and safe delivery systems. Lipid nanoparticles (LNPs) represent a well characterized class of RNA delivery systems, which were recently approved for clinical usage in mRNA-based COVID-19 vaccines. In this study, we evaluated the potential of LNPs for cardiac delivery of modRNA. We tested how variations in C12–200 modRNA-LNP composition affect transfection levels and biodistribution after intramyocardial administration in both healthy and myocardial-infarcted mice, and determined the targeted cardiac cell types. Our data revealed that LNP-mediated modRNA delivery outperforms the current state of the art (modRNA in citrate buffer) upon intramyocardial administration in mice, with only minor differences among the formulations tested. Furthermore, we determined both in vitro and in vivo that the cardiac cells targeted by modRNA-LNPs include fibroblasts, endothelial cells and epicardial cells, suggesting that these cell types could represent targets for therapeutic interference with these LNP formulations. These outcomes may serve as a starting point for LNP development specifically for therapeutic mRNA cardiac delivery applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Delivery to peripheral lymphatics can be achieved following interstitial administration of nano-sized delivery systems (nanoparticles, liposomes, dendrimers etc) or molecules that hitchhike on endogenous nano-sized carriers (such as albumin). The published work concerning the hitchhiking approach has mostly focussed on the lymphatic uptake of vaccines conjugated directly to albumin binding moieties (ABMs such as lipids, Evans blue dye derivatives or peptides) and their subsequent trafficking into draining lymph nodes. The mechanisms underpinning access and transport of these constructs into lymph fluid, including potential interaction with other endogenous nanocarriers such as lipoproteins, have largely been ignored. Recently, we described a series of brush polyethylene glycol (PEG) polymers containing end terminal short-chain or medium-chain hydrocarbon tails (1C2 or 1C12, respectively), cholesterol moiety (Cho), or medium-chain or long-chain diacylglycerols (2C12 or 2C18, respectively). We evaluated the association of these materials with albumin and lipoprotein in rat plasma, and their intravenous (IV) and subcutaneous (SC) pharmacokinetic profiles. Here we fully detail the association of this suite of polymers with albumin and lipoproteins in rat lymph, which is expected to facilitate lymph transport of the materials from the SC injection site. Additionally, we characterise the thoracic lymph uptake, tissue and lymph node biodistribution of the lipidated brush PEG polymers following SC administration to thoracic lymph cannulated rats. All polymers had moderate lymphatic uptake in rats following SC dosing with the lymph uptake higher for 1C2-PEG, 2C12-PEG and 2C18-PEG (5.8%, 5.9% and 6.7% dose in lymph, respectively) compared with 1C12-PEG and Cho-PEG (both 1.5% dose in lymph). The enhanced lymph uptake of 1C2-PEG, 2C12-PEG and 2C18-PEG appeared related to their association profile with different lipoproteins. The five polymers displayed different biodistribution patterns in major organs and tissues in mice. All polymers reached immune cells deep within the inguinal lymph nodes of mice following SC dosing. The ability to access these immune cells suggests the potential of the polymers as platforms for the delivery of vaccines and immunotherapies. Future studies will focus on evaluating the lymphatic targeting and therapeutic potential of drug or vaccine-loaded polymers in pre-clinical disease models. [Display omitted] • Lipidation of peptides and polymers leads to binding to serum albumin and extension of plasma half-life after injection. • Here we found that lipidated brush PEG polymers are lymphatically transported following subcutaneous (SC) injection in rats. • Lymph uptake was higher on conjugation to diacylglycerols and a short hydrocarbonchain, compared to cholesterol or medium hydrocarbon chain. • Differences in lymph uptake appeared driven by trafficking in association with both lipoproteins and albumin. • All polymers reached immune cells deep within lymph nodes suggesting potential for delivery of vaccines and immunotherapies. [ABSTRACT FROM AUTHOR]

The stability of ribosomal DNA (rDNA) is maintained through transcriptional silencing by the NAD+ -dependent histone deacetylase Sir2 in Saccharomyces cerevisiae. Alongside proteostasis, rDNA stability is a crucial factor regulating the replicative lifespan of S. cerevisiae. The unfolded protein response (UPR) is induced by misfolding of proteins or an imbalance of membrane lipid composition and is responsible for degrading misfolded proteins and restoring endoplasmic reticulum (ER) membrane homeostasis. Recent investigations have suggested that the UPR can extend the replicative lifespan of yeast by enhancing protein quality control mechanisms, but the relationship between the UPR and rDNA stability remains unknown. In this study, we found that the deletion of ARV1, which encodes an ER protein of unknown molecular function, activates the UPR by inducing lipid bilayer stress. In arv1Δ cells, the UPR and the cell wall integrity pathway are activated independently of each other, and the high osmolarity glycerol (HOG) pathway is activated in a manner dependent on Ire1, which mediates the UPR. Activated Hog1 translocates the stress response transcription factor Msn2 to the nucleus, where it promotes the expression of nicotinamidase Pnc1, a wellknown Sir2 activator. Following Sir2 activation, rDNA silencing and rDNA stability are promoted. Furthermore, the loss of other ER proteins, such as Pmt1 or Bst1, and ER stress induced by tunicamycin or inositol depletion also enhance rDNA stability in a Hog1-dependent manner. Collectively, these findings suggest that the induction of the UPR enhances rDNA stability in S. cerevisiae by promoting the Msn2-Pnc1- Sir2 pathway in a Hog1-dependent manner. [ABSTRACT FROM AUTHOR]

Lipoprotein(a) (Lp[a]) is a causal genetic risk factor for atherosclerotic cardiovascular disease (ASCVD). There are limited long-term follow-up data from large U.S. population cohorts. This study examined the relationship of Lp(a) with ASCVD outcomes in a large, pooled, multi-ethnic U.S. cohort. The study included data on Lp(a) and ASCVD outcomes from 5 U.S. prospective studies: MESA (Multi-Ethnic Study of Atherosclerosis), CARDIA (Coronary Artery Risk Development in Young Adults), JHS (Jackson Heart Study), FHS-OS (Framingham Heart Study-Offspring), and ARIC (Atherosclerosis Risk In Communities). Lp(a) levels were classified on the basis of cohort-specific percentiles. Multivariable Cox regression related Lp(a) with composite incident ASCVD events by risk group and diabetes status. The study included 27,756 persons without previous ASCVD who were aged 20 to 79 years, including 55.0% women, 35.6% Black participants, and 7.6% patients with diabetes, with mean follow-up of 21.1 years. Compared with Lp(a) levels <50th percentile, Lp(a) levels in the 50th to <75th, 75th to <90th, and ≥90th percentiles had adjusted HRs of 1.06 (95% CI: 0.99-1.14), 1.18 (95% CI: 1.09-1.28), and 1.46 (95% CI: 1.33-1.59), respectively for ASCVD events. Elevated Lp(a) predicted incident ASCVD events similarly by risk group, sex, and race or ethnic groups, but more strongly in patients with vs without diabetes (interaction P = 0.0056), with HRs for Lp(a) levels ≥90th percentile of 1.92 (95% CI: 1.50-2.45) and 1.41 (95% CI: 1.28-1.55), respectively. Lp(a) also individually predicted myocardial infarction, revascularization, stroke, and coronary heart disease death, but not total mortality. The study shows, in a large U.S. pooled cohort, that higher Lp(a) levels are associated with an increased ASCVD risk, including in patients with diabetes. [Display omitted] [ABSTRACT FROM AUTHOR]

Anti-inflammatory activities of catechin-rich green tea extract (GTE) in obese rodents protect against metabolic endotoxemia by decreasing intestinal permeability and absorption of gut-derived endotoxin. However, translation to human health has not been established. We hypothesized that GTE would reduce endotoxemia by decreasing gut permeability and intestinal and systemic inflammation in persons with metabolic syndrome (MetS) compared with healthy persons. A randomized, double-blind, placebo-controlled, crossover trial in healthy adults (n = 19, 34 ± 2 years) and adults with MetS (n = 21, 40 ± 3 years) examined 4-week administration of a decaffeinated GTE confection (890 mg/d total catechins) on serum endotoxin, intestinal permeability, gut and systemic inflammation, and cardiometabolic parameters. Compared with the placebo, the GTE confection decreased serum endotoxin (P =.023) in both healthy persons and those with MetS, while increasing concentrations of circulating catechins (P <.0001) and γ-valerolactones (P =.0001). Fecal calprotectin (P =.029) and myeloperoxidase (P =.048) concentrations were decreased by GTE regardless of health status. Following the ingestion of gut permeability probes, urinary lactose/mannitol (P =.043) but not sucralose/erythritol (P >.05) was decreased by GTE regardless of health status. No between-treatment differences (P >.05) were observed for plasma aminotransferases, blood pressure, plasma lipids, or body mass nor were plasma tumor necrosis factor-α, interleukin-6, or the ratio of lipopolysaccharide-binding protein/soluble cluster of differentiation-14 affected. However, fasting glucose in both study groups was decreased (P =.029) by the GTE confection compared with within-treatment arm baseline concentrations. These findings demonstrate that catechin-rich GTE is effective to decrease circulating endotoxin and improve glycemic control in healthy adults and those with MetS, likely by reducing gut inflammation and small intestinal permeability but without affecting systemic inflammation. • A novel green tea extract (GTE) confection was provided to healthy adults and adults with metabolic syndrome. • GTE increased circulating catechins and valerolactones regardless of health status. • GTE decreased intestinal inflammation and small intestinal permeability. • GTE decreased circulating endotoxin. • GTE decreased fasting glucose without affecting systemic inflammation. • Gut-level benefits by GTE support research translation for cardioprotection by green tea. Healthy adults and adults with metabolic syndrome were randomized to a placebo or GTE (1 g; 890 mg catechins) confection for 1 month and then crossed-over to the alternative treatment following a 1-month washout. Regardless of health status, the GTE confection decreased fecal biomarkers of intestinal inflammation (calprotectin and myeloperoxidase) and small intestinal permeability based on a differential sugar absorption test while decreasing serum endotoxin. Abbreviations: GTE, green tea extract; MetS, metabolic syndrome [Display omitted] [ABSTRACT FROM AUTHOR]

Kimchi is a traditional fermented food that contains abundant nutrients and functional ingredients with various health benefits. We previously reported that kimchi active components suppress hepatic steatosis caused by endoplasmic reticulum (ER) stress in vitro and in vivo. Therefore, we assessed the effect of kimchi on the inhibition of hepatic steatosis caused by ER stress in HepG2 cells and C57BL/6N mice to verify the hypothesis that kimchi may potentially inhibit nonalcoholic fatty liver disease. We investigated the effect of kimchi on cell viability and triglyceride concentrations in cells and on lipid profile, lipid accumulation, and expression of related genes in cells and mice with hepatic steatosis. A mechanistic study was also performed using the liver X receptor α agonist T0901317 and the AMP-activated protein kinase agonist AICAR. Kimchi was noncytotoxic and effectively reduced triglyceride concentrations and suppressed hepatic steatosis-related gene expression in cells and mice. Additionally, kimchi recovered weight loss, lowered the serum and liver tissue lipid profiles, suppressed lipid accumulation, and reduced the effects of T0901317 and AICAR on lipogenic gene expression in tunicamycin-treated mice. Our results highlight that kimchi could prevent hepatic steatosis caused by ER stress in cells and mice. ER stress commonly causes hepatic steatosis in vitro and in vivo. In this study, kimchi attenuated ER stress–induced hepatic steatosis in HepG2 cells and C57BL/6N mice. Kimchi inhibited hepatic steatosis by regulating the LXRα/AMPK pathway. Abbreviations: ACC, acetyl coenzyme-A carboxylase; AMPK, AMP-activated protein kinase; ER, endoplasmic reticulum; FAS, fatty acid synthase; GOT, oxaloacetic transaminase; GPT, glutamic pyruvic transaminase; H&E, hematoxylin and eosin; ORO, oil red O; LXRα, liver X receptor α; SCD-1, stearoyl-CoA desaturase-1; SREBP-1c, sterol regulatory element-binding transcription factor 1c. [Display omitted] [ABSTRACT FROM AUTHOR]

Heterozygous familial hypercholesterolemia (HeFH) predisposes to premature cardiovascular diseases. Since 2015, the European Atherosclerosis Society has advocated initiation of statins at 8–10 years of age and a low-density lipoprotein cholesterol (LDL-C) target of <135 mg/dL. Longitudinal data from large databases on pharmacological management of pediatric HeFH are lacking. Here, we describe treatment patterns and LDL-C goal attainment in pediatric HeFH using longitudinal real-world data. This was a retrospective and prospective multicenter cohort study (2015–2021) of children with HeFH, diagnosed genetically or clinically, aged <18 years, and followed up in the National French Registry of FH (REFERCHOL). Data on the study population as well as treatment patterns and outcomes are summarized as mean±SD. We analyzed the data of 674 HeFH children (age at last visit: 13.1 ± 3.6 years; 82.0 % ≥10 years; 52.5 % females) who were followed up for a mean of 2.8 ± 3.5 years. Initiation of lipid-lowering therapy was on average at 11.8 ± 3.0 years of age for a duration of 2.5 ± 2.8 years. At the last visit, among patients eligible for treatment (573), 36 % were not treated, 57.1 % received statins alone, 6.4 % statins with ezetimibe, and 0.2 % ezetimibe alone. LDL-C was 266±51 mg/dL before treatment and 147±54 mg/dL at the last visit (−44.7 %) in treated patients. Regarding statins, 3.3 %, 65.1 %, and 31.6 % of patients received high-, moderate-, and low-intensity statins, respectively. Overall, 59 % of children on statin therapy alone and 35.1 % on bitherapy did not achieve the LDL-C goal; fewer patients in the older age group did not reach the treatment goal. Pediatric patients with FH followed up in specialist lipid clinics in France receive late treatment, undertreatment, or suboptimal treatment and half of them do not reach the therapeutic LDL-C goal. Finding a more efficient framework for linking scientific evidence to clinical practice is needed. [ABSTRACT FROM AUTHOR]

The purpose of this study was to elucidate and compare styrene maleic acid copolymer (SMA)-coated lipid emulsions (SMA emulsions) uptake pathway in vascular endothelial cells and surrounding cancer cells under not only neutral but also acidic pH, which is often observed in tumor microenvironment. DiI-labeled SMA emulsions were prepared using 1-palmitoyl-2-oleoyl-sn‑glycero-3-phosphocholine and triolein. In murine melanoma B16-BL6 (B16) cells and human umbilical vein endothelial cells (HUVEC), DiI-labeled SMA emulsions uptake under near-neutral (pH 7.4) and acidic (pH 6.0) conditions was determined by fluorescent analysis. SMA emulsions were taken up more efficiently into HUVEC than B16 cells under acidic condition in a temperature-dependent manner. Uptake study using endocytosis inhibitors showed that SMA emulsions were taken up by macropinocytosis and clathrin-mediated endocytosis in B16 cells. In HUVEC, however, they were taken up by clathrin- and caveolae-independent, but dynamin-dependent pathway. SMA emulsions would be internalized efficiently into vascular endothelial cells as well as cancer cells under acidic microenvironment via different endocytosis pathways. SMA emulsions could be a promising drug delivery carrier for anti-angiogenic drugs. [Display omitted] • Uptake activity of SMA-coated lipid emulsions were higher in HUVEC than B16 cells at neutral pH. • Uptake activity of SMA-coated lipid emulsions were higher at acidic than neutral pH. • SMA-coated lipid emulsions were localized in lysosomes. • SMA emulsions were taken up by macropinocytosis and clathrin-mediated endocytosis in B16 cells. • SMA emulsions uptake were clathrin- and caveolae-independent, but dynamin-dependent in HUVEC. [ABSTRACT FROM AUTHOR]

All plasma membranes exhibit asymmetry, both in lipid distribution and protein topology. Cells invest significant free energy to uphold this asymmetry. Despite its critical physiological role, our quantitative understanding of membrane asymmetry is limited, due primarily to insufficient in vitro methods for creating asymmetric model membranes. New experimental protocols now allow for the preparation of vesicles with tailored, asymmetric lipid distributions. Leaflets with distinct lipid compositions can affect each other's properties, such as lateral diffusion, hydrocarbon chain ordering, and bending elasticity. Integral membrane proteins not only adapt to lipid asymmetry but also exhibit asymmetric topological orientations, which in turn can depend on lipid composition. Plasma membranes utilize free energy to maintain highly asymmetric, non-equilibrium distributions of lipids and proteins between their two leaflets. In this review we discuss recent progress in quantitative research enabled by using compositionally controlled asymmetric model membranes. Both experimental and computational studies have shed light on the nuanced mechanisms that govern the structural and dynamic coupling between compositionally distinct bilayer leaflets. This coupling can increase the membrane bending rigidity and induce order – or lipid domains – across the membrane. Furthermore, emerging evidence indicates that integral membrane proteins not only respond to asymmetric lipid distributions but also exhibit intriguing asymmetric properties themselves. We propose strategies to advance experimental research, aiming for a deeper, quantitative understanding of membrane asymmetry, which carries profound implications for cellular physiology. [ABSTRACT FROM AUTHOR]

The oleaginous yeast, Lipomyces starkeyi can have diverse industrial applications due to its remarkable capacity to use various carbon sources for the biosynthesis intracellular triacylglycerides (TAGs). In L. starkeyi , TAG synthesis is enhanced through upregulation of genes involved in citrate-mediated acyl-CoA synthesis and Kennedy pathways through the transcriptional regulator LsSpt23p. High expression of LsSPT23 can considerably enhance TAG production. Altering the regulatory factors associated with lipid production can substantially augment lipid productivity. In this study, we identified and examined the L. starkeyi homolog sucrose nonfermenting 1 SNF1 (LsSNF1) of YlSNF1 , which encodes a negative regulator of lipid biosynthesis in the oleaginous yeast Yarrowia lipolytica. The deletion of LsSNF1 enhanced TAG productivity in L. starkeyi , suggesting that LsSnf1p is a negative regulator in TAG production. The enhancement of TAG production following deletion of LsSNF1 can primarily be attributed to the upregulation of genes in the citrate-mediated acyl-CoA synthesis and Kennedy pathways, pivotal routes in TAG biosynthesis. The overexpression of LsSPT23 enhanced lipid productivity; strain overexpressing LsSPT23 and without LsSNF1 exhibited increased TAG production capacity per cell. LsSnf1p also has a significant role in the utilization of carbon sources, including xylose or glycerol, in L. starkeyi. Our study results elucidated the role of LsSnf1p in the negative regulation of TAG synthesis in L. starkeyi , which has not previously been reported. • Lipomyces starkeyi SNF1 homolog (LsSNF1) was identified and the LsSNF1 deletion mutant was constructed. • LsSnf1p had important roles in lipid production and carbon-source utilization in L. starkeyi. • The overexpression of LsSpt23p and without LsSnf1p exhibited increased TAG production capacity per cell. [ABSTRACT FROM AUTHOR]

• Exemestane administration significantly increased LDL-C. • Exemestane administration significantly decreased HDL-C and TC. • Exemestane prescription only lowered TG concentrations when it was administered for < 12 months. Postmenopausal women are prone to develop cardiovascular disorders. In addition, cardiovascular risk in women can be influenced by the long-term prescription of drugs that lead to estrogen deprivation, e.g., aromatase inhibitors, and that can cause dyslipidemia. Little is known about the impact of exemestane, an aromatase inhibitor, on serum lipids' concentration in women. Hence, we conducted a meta -analysis of randomized controlled trials (RCTs) to assess the influence of this pharmacological agent on the lipid profile in women. The Scopus, Web of Science, PubMed/Medline and EMBASE databases were searched by two surveyors for manuscripts published from the inception of these databases until April 3rd, 2023. No language restrictions were applied to the search. The random effects model was used to generate the combined results as weighted mean difference (WMD) and 95% confidence interval (CI). In total, 8 eligible RCTs were included in the meta -analysis. Overall results from the random effects model indicate that exemestane administration increases LDL-C (WMD: 4.42 mg/dL, 95 % CI: 0.44, 8.41, P = 0.02) and decreases HDL-C (WMD: −6.03 mg/dL, 95 % CI: −7.77, −4.29, P < 0.001) and TC (WMD: −5.40 mg/dL, 95 % CI: −9.95, −0.86, P = 0.02) levels, respectively. Moreover, exemestane prescription only lowered TG concentrations when it was administered for < 12 months (WMD: −14.60 mg/dL, 95 % CI: –23.57 to −5.62, P = 0.001). Currently available evidence suggests that the administration of exemestane in females increases LDL-C values and reduces HDL-C, TC, and, when prescribed for less than 12 months, TG concentrations. [ABSTRACT FROM AUTHOR]

Lipids have been previously implicated in the lifecycle of neuroinvasive viruses. However, the role of lipids in programmed cell death and the relationship between programmed cell death and lipid droplets (LDs) in neuroinvasive virus infection remains unclear. Here, we found that the infection of neuroinvasive virus, such as rabies virus and encephalomyocarditis virus could enhance the LD formation in N2a cells, and decreasing LDs production by targeting diacylglycerol acyltransferase could suppress viral replication. The lipidomics analysis revealed that arachidonic acid (AA) was significantly increased after reducing LD formation by restricting diacylglycerol acyltransferase, and AA was further demonstrated to induce ferroptosis to inhibit neuroinvasive virus replication. Moreover, lipid peroxidation and viral replication inhibition could be significantly alleviated by a ferroptosis inhibitor, ferrostatin-1, indicating that AA affected neuroinvasive virus replication mainly through inducing ferroptosis. Furthermore, AA was demonstrated to activate the acyl-CoA synthetase longchain family member 4-lysophosphatidylcholine acyltransferase 3-cytochrome P450 oxidoreductase axis to induce ferroptosis. Our findings highlight novel cross-talks among viral infection, LDs, and ferroptosis for the first time, providing a potential target for antiviral drug development. [ABSTRACT FROM AUTHOR]

While numerous observational studies have indicated an association between lipids and Sudden Sensorineural Hearing Loss (SSNHL), it remains uncertain whether dyslipidemia serves as a causal risk factor for SSNHL. Our objective is to elucidate the potential causal relationship between lipid levels and SSNHL through Mendelian randomization analysis. The primary and secondary lipid data used in this study were sourced from the UK Biobank (UKBB) and the Global Lipid Genetics Consortium results (GLGC), respectively. These datasets were obtained from large, publicly available genome-wide association studies (GWAS). The outcome data for sudden sensorineural hearing loss (SSNHL) were acquired from the Finnegan Biobank, consisting of 1491 cases and 196,592 controls. Subsequently, both single-variable Mendelian randomization (SVMR) and multivariate Mendelian randomization (MVMR) methods were employed to evaluate the causal relationship between lipids and the occurrence of SSNHL. Among the primary lipid data, SVMR analysis showed a significant correlation between high density lipoprotein cholesterol (HDL-C) (OR: 0.822, 95 %CI: 0.694–0.974, p = 0.023) and SSNHL, and triglycerides (TG) (OR: 0.997, 95 %CI: 0.836–1.188, p = 0.975), low density lipoprotein cholesterol (LDL-C) (OR: 1.067, 95 %CI: 0.861–1.322, p = 0.552) did not correlate with SSNHL. In the secondary lipid data, SVMR analysis showed that HDL-C (OR: 0.987, 95 %CI: 0.805–1.210, p = 0.903), TG (OR: 0.991, 95 %CI: 0.787–1.246, p = 0.937) and LDL-C (OR: 1.092, 95 % CI: 0.926–1.287, p = 0.294) did not correlate with SSNHL. MVMR analysis of the primary lipid data showed that HDL-cholesterol (OR: 0.755, 95 % CI: 0.596–0.956, p = 0.019) was significantly associated with SSNHL, while TG (OR: 0.808, 95 %CI: 0.611–1.068, p = 0.134) and LDL-C (OR: 1.146, 95 %CI: 0.869–1.511, p = 0.333) did not correlate with SSNHL, consistent with the results of SVMR. Inverse MR results showed that SSNHL did not correlate with TG (OR: 0.999, 95 %CI: 0.997–1.001, p = 0.835), HDL-C (OR: 1.001, 95 %CI: 0.998–1.003), LDL-C (OR: 0.999, 95 %CI: 0.997–1.002, p = 0.863). Mendelian randomization (MR) results suggest that decreased serum HDL-C levels are an independent risk factor for SSNHL. Monitoring and focusing on lipid levels may be of value in the prevention and treatment of SSNHL. [ABSTRACT FROM AUTHOR]

In neurodegeneration, neurons release lipids that accumulate in glial lipid droplets (LDs). But what controls lipid transport and how does this affect glia? A recent study by Li et al. discovered that the loss of neuronal AMP-activated protein kinase (AMPK) activity promotes lipid efflux, which drives a proinflammatory state in microglia. [ABSTRACT FROM AUTHOR]