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• 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]

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]

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 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]

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]

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]

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

• 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]

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]

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]

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]

The TetraEther indeX of 86 carbon atoms (TEX 86) is widely used as a proxy to reconstruct past sea surface temperatures. Most current applications of TEX 86 are primarily based on analyzing the composition of isoprenoid glycerol dialkyl glycerol tetraethers (isoGDGTs) that comprise TEX 86 in sediments, with the assumption that the sedimentary isoGDGTs are mainly derived from the surface mixed layer. Here we report on the variations in the isoGDGT distribution, archaeal abundance and community through the water column of the Western Pacific Ocean, directly testing the export depth of isoGDGTs and constraining the temperature records of TEX 86. Our data show that maximum isoGDGT concentrations occurred in subsurface waters (150–200 m) with maximum archaeal abundances. The ratio between isoGDGTs bearing 2 vs. 3 cyclopentane moieties, i.e. [2/3] ratio, increased with depth, which is likely related to the shift of the archaeal community from Ca. Nitrosopelagicus-dominance to norank_f__Nitrosopumilaceae -dominance. Models based on the [2/3] ratios in the water column predicted an average export depth of isoGDGTs to sediments of around 150–200 m, consistent with the robust relationship between the compiled sedimentary TEX 86 and the annual mean subsurface temperature. Taken together, our findings support that TEX 86 records subsurface rather than surface temperatures in the open ocean. [ABSTRACT FROM AUTHOR]

Exposure to bisphenol A (BPA) during gestation leads to fetal growth restriction (FGR), whereby the underlying mechanisms remain unknown. Here, we found that FGR patients showed higher levels of BPA in the urine, serum, and placenta; meanwhile, trophoblast ferroptosis was observed in FGR placentas, as indicated by accumulated intracellular iron, impaired antioxidant molecules, and increased lipid peroxidation products. To investigate the role of ferroptosis in placental and fetal growth, BPA stimulation was performed both in vivo and in vitro. BPA exposure during gestation was associated with FGR in mice; also, it induces ferroptosis in mouse placentas and human placental trophoblast. Pretreatment with ferroptosis inhibitor ferritin-1 (Fer-1) alleviated BPA-induced oxidative damage and cell death. Notably, BPA reduced the trophoblastic expression of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which regulated tissue growth and organ size. YAP or TAZ siRNA enhanced BPA-induced ferroptosis, suggesting that trophoblast ferroptosis is dependent on YAP/TAZ downregulation after BPA stimulation. Consistently, the protein levels of YAP/TAZ were also reduced in FGR placentas. Further results revealed that silencing YAP/TAZ promoted BPA-induced ferroptosis through autophagy. Pretreatment with autophagy inhibitor chloroquine (CQ) attenuated BPA-induced trophoblast ferroptosis. Ferritinophagy, an autophagic degradation of ferritin (FTH1), was observed in FGR placentas. Similarly, BPA reduced the protein level of FTH1 in placental trophoblast. Pretreatment with iron chelator desferrioxamine (DFO) and NCOA4 (an autophagy cargo receptor) siRNA weakened the ferroptosis of trophoblast after exposure to BPA, indicating that autophagy mediates ferroptosis in BPA-stimulated trophoblast by degrading ferritin. In summary, ferroptosis was featured in BPA-associated FGR and trophoblast injury; the regulation of ferroptosis involved the YAP/TAZ-autophagy-ferritin axis. [ABSTRACT FROM AUTHOR]

Accurately evaluating plaque characteristics is essential because lesions with lipid-rich plaque put patients at risk of thromboembolic complications from carotid artery stenting. Near-infrared spectroscopy (NIRS) is a diagnostic imaging modality that identifies lipid components from the near-infrared absorption pattern but does not reveal the distribution of calcification. The purpose of this study was to investigate the calcification characteristics of unstable carotid plaques, focusing on relationships between the calcification characteristics revealed by computed tomography angiography and the lipid core distribution derived from NIRS. Participants in this retrospective analysis comprised 35 patients (29 men, 6 women; mean age, 76.0 years; range, 52–89 years) who underwent carotid artery stenting in our institute between January 2021 and December 2022. We evaluated the thickness and length of carotid calcifications at the minimal lumen level from preoperative computed tomography angiography and analyzed the relationship with maximum lipid core burden index (max-LCBI) from NIRS. Strong negative linear correlations were observed between the thickness of calcification and max-LCBI at Area (any segment in a target lesion) (r = −0.795, P < 0.001), max-LCBI at minimal lumen area (r = −0.795, P < 0.001) and lipid core burden index (LCBI) at lesion (rate of LCBI in entire plaque lesion) (r = −0.788, P < 0.001), respectively. Significant negative linear correlations were observed between distribution of calcification length and max-LCBI at area (r = −0.429, P = 0.01), max-LCBI at minimal lumen area (r = −0.373, P = 0.027), and LCBI at lesion (r = −0.443, P = 0.008). Thin and ubiquitous carotid calcification was associated with LCBI values derived from NIRS indicative of carotid lipid plaque distribution, implying the possibility of predicting lesion instability. [ABSTRACT FROM AUTHOR]

Chaenomeles sinensis (Thouin) Koehne fruit is a rich source of medicinally and nutritionally important natural phytochemicals that benefit human health. Based on the information provided, we hypothesized that Chaenomeles sinensis (Thouin) Koehne fruit polyphenols (CSFP) possessed in vivo protective effect of on high-fat diet (HFD)–induced obesity and hepatic steatosis. Specific pathogen-free male C57BL/6J mice were randomly divided into 3 groups and fed with a low-fat diet, HFD, or HFD supplemented with CSFP by intragastric administration for 14 weeks. Obesity-related biochemical indexes and hepatic gene expression profile were determined. The findings of this study demonstrated notable reductions in body weight gain, serum triglycerides, total cholesterol, low-density lipoprotein cholesterol, and steatosis grade in the group supplemented with CSFP compared with the HFD group. Gene expression analysis provided insights into the molecular mechanisms, demonstrating that CSFP downregulated the expression of key genes involved in lipogenesis (e.g., Fas, Fads2, Scd1) and upregulated the genes associated with fatty acid oxidation (e.g., Pparα, Cpt1a, Acox1), while also suppressing genes implicated in cholesterol homeostasis (e.g., HMGCoR, Insig1, AdipoR2). These molecular changes suggest that CSFP exerts protective effects by modulating hepatic lipid metabolism pathways, thereby mitigating the metabolic derangements associated with HFD-induced obesity and hepatic steatosis. In mice with obesity, Chaenomeles sinensis (Thouin) Koehne fruit polyphenols downregulated the expression of key genes involved in lipogenesis and upregulated the genes associated with fatty acid oxidation, while also suppressing genes implicated in cholesterol homeostasis. The findings suggested that Chaenomeles sinensis (Thouin) Koehne fruit polyphenols may have beneficial effects on obesity-related molecular dysregulation. Abbreviations: Acox1 , acyl-coenzyme A oxidase 1; AdipoR2 , adiponectin receptor 2; Cpt1 a , carnitine palmitoyltransferase 1a; Fads2 , fatty acid desaturase 2; Fas , fatty acid synthase; HMGCoR , 3-hydroxy-3-methyl-glutaryl CoA reductase; Insig1 , insulin-induced gene 1; Pparα , peroxisome proliferator-activated receptor α; Scd1 , stearoyl-CoA desaturase 1. [Display omitted] [ABSTRACT FROM AUTHOR]

Lipid metabolism play an essential role in occurrence and development of asthma, and it can be disturbed by phthalate esters (PAEs) and organophosphate flame retardants (OPFRs). As a chronic inflammatory respiratory disease, the occurrence risk of childhood asthma is increased by PAEs and OPFRs exposure, but it remains not entirely clear how PAEs and OPFRs contribute the onset and progress of the disease. We have profiled the serum levels of PAEs and OPFRs congeners by liquid chromatography coupled with mass spectrometry, and its relationships with the dysregulation of lipid metabolism in asthmatic, bronchitic (acute inflammation) and healthy (non-inflammation) children. Eight PAEs and nine OPFRs congeners were found in the serum of children (1 – 5 years old) from Shenzhen, and their total median levels were 615.16 ng/mL and 17.06 ng/mL, respectively. Moreover, the serum levels of mono-methyl phthalate (MMP), tri-propyl phosphate (TPP) and tri- n -butyl phosphate (TNBP) were significant higher in asthmatic children than in healthy and bronchitic children as control. Thirty-one characteristic lipids and fatty acids of asthma were screened by machine-learning random forest model based on serum lipidome data, and the alterations of inflammatory characteristic lipids and fatty acids including palmitic acids, 12,13-DiHODE, 14,21-DiHDHA, prostaglandin D2 and LysoPA(18:2) showed significant correlated with high serum levels of MMP, TPP and TNBP. These results imply PAEs and OPFRs promote the occurrence of childhood asthma via disrupting inflammatory lipid and fatty acid metabolism, and provide a novel sight for better understanding the effects of plastic additives on childhood asthma. [Display omitted] [ABSTRACT FROM AUTHOR]

XK-related 8 (XKR8), in complex with the transmembrane glycoprotein basigin, functions as a phospholipid scramblase activated by the caspase-mediated cleavage or phosphorylation of its C-terminal tail. It carries a putative phospholipid translocation path of multiple hydrophobic and charged residues in the transmembrane region. It also has a crucial tryptophan at the exoplasmic end of the path that regulates its scrambling activity. We herein investigated the tertiary structure of the human XKR8-basigin complex embedded in lipid nanodiscs at an overall resolution of 3.66 Å. We found that the C-terminal tail engaged in intricate polar and van der Waals interactions with a groove at the cytoplasmic surface of XKR8. These interactions maintained the inactive state of XKR8. Point mutations to disrupt these interactions strongly enhanced the scrambling activity of XKR8, suggesting that the activation of XKR8 is mediated by releasing the C-terminal tail from the cytoplasmic groove. We speculate that the cytoplasmic tail region of XKR8 functions as a plug to prevent the scrambling of phospholipids. [ABSTRACT FROM AUTHOR]

Eukaryotic elongation factor 1A1 (EEF1A1) is canonically involved in protein synthesis but also has noncanonical functions in diverse cellular processes. Previously, we identified EEF1A1 as a mediator of lipotoxicity and demonstrated that chemical inhibition of EEF1A1 activity reduced mouse liver lipid accumulation. These findings suggested a link between EEF1A1 and metabolism. Therefore, we investigated its role in regulating metabolic substrate preference. EEF1A1-deficient Chinese hamster ovary (2E2) cells displayed reduced media lactate accumulation. These effects were also observed with EEF1A1 knockdown in human hepatocyte-like HepG2 cells and in WT Chinese hamster ovary and HepG2 cells treated with selective EEF1A inhibitors, didemnin B, or plitidepsin. Extracellular flux analyses revealed decreased glycolytic ATP production and increased mitochondrial-to-glycolytic ATP production ratio in 2E2 cells, suggesting a more oxidative metabolic phenotype. Correspondingly, fatty acid oxidation was increased in 2E2 cells. Both 2E2 cells and HepG2 cells treated with didemnin B exhibited increased neutral lipid content, which may be required to support elevated oxidative metabolism. RNA-seq revealed a >90-fold downregulation of a rate-limiting glycolytic enzyme, hexokinase 2, which we confirmed through immunoblotting and enzyme activity assays. Pathway enrichment analysis identified downregulations in TNFA signaling via NFKB and MYC targets. Correspondingly, nuclear abundances of RELB and MYC were reduced in 2E2 cells. Thus, EEF1A1 deficiency may perturb glycolysis by limiting NFKB- and MYC-mediated gene expression, leading to decreased hexokinase expression and activity. This is the first evidence of a role for a translation elongation factor, EEF1A1, in regulating metabolic substrate utilization in mammalian cells. [ABSTRACT FROM AUTHOR]

Lipid biomarker analysis focused on steroids has shown to have great potential for discriminating between animal faecal inputs in archaeology. This is particularly interesting when applied to stabling deposits to assess herding strategies and livestock composition. Here we present the results of a sedimentary faecal biomarker study conducted at Belmaco Cave, a pre-European archaeological site in La Palma (Canary Islands). The site was occupied by indigenous pastoralist groups over the course of five centuries prior to the first arrival of the Europeans in the 15th century. Previous soil micromorphological data indicates recurrent sheep and/or goat penning and periodic burning of the pen in the central area of the cave. We selected bulk sediment samples from unburned, charred and ashed dung layers and carried out sterol, stanol and bile acid analysis. Our results suggest that the main source of faecal matter is sheep. We also found that even though charred and dung ash layers contained lower concentrations of the biomarker compounds, these were still sufficient to provide information on the origin of the faecal remains. These data add to our current knowledge of the aboriginal Canary Island pastoralist economy. [ABSTRACT FROM AUTHOR]

Autophagy, which is responsible for removing damaged molecules, prevents their accumulation in cells, thus maintaining intracellular homeostasis. It is also responsible for removing the effects of oxidative stress, so its activation takes place during increased reactive oxygen species (ROS) generation and lipid peroxidation. Therefore, the aim of this review was to summarize all the available knowledge about the effect of protein modifications by lipid peroxidation products on autophagy activation and the impact of this interaction on the functioning of cells. This review shows that reactive aldehydes (including 4-hydroxynonenal and malondialdehyde), either directly or by the formation of adducts with autophagic proteins, can activate or prevent autophagy, depending on their concentration. This effect relates not only to the initial stages of autophagy, when 4-hydroxynonenal and malondialdehyde affect the levels of proteins involved in autophagy initiation and phagophore formation, but also to the final stage, degradation, when reactive aldehydes, by binding to the active center of cathepsins, inactivate their proteolytic functions. Moreover, this review also shows how little research exists on analyzing the impact of lipid peroxidation products and their protein adducts on autophagy. Such knowledge could be used in the therapy of diseases related to autophagy disorders. [Display omitted] • Lipid peroxidation products by forming adducts with proteins may regulate autophagy. • 4-HNE and MDA activate or prevent autophagy depending on their concentration. • 4-HNE/MDA affects proteins involved in autophagy initiation and phagophore creation. • 4-HNE by binding to cathepsins B and D inactivate their proteolytic activity. [ABSTRACT FROM AUTHOR]

Rhodotorula kratochvilovae has shown to be a promising species for microbial oil production from lignin-derived compounds. Yet, information on R. kratochvilovae's detoxification and microbial oil production is scarce. This study investigated the growth and microbial oil production on the phenolic-containing effluent from poplar steam explosion and its detoxification with five R. kratochvilovae strains (EXF11626, EXF9590, EXF7516, EXF3697, EXF3471) and compared them with Cutaneotrichosporon oleaginosum. The R. kratochvilovae strains reached a maximum growth rate up to four times higher than C. oleaginosum. Furthermore, all R. kratochvilovae strains generally degraded phenolics more rapidly and to a larger extent than C. oleaginosum. However, the diluted substrate limited the lipid production by all strains as the maximum lipid content and titre were 10.5% CDW and 0.40 g/L, respectively. [Display omitted] • All R. kratochvilovae strains are preferred to C. oleaginosum for detoxification. • R. kratochvilovae strains grow rapidly on lignocellulosic effluent. • R. kratochvilovae strains removed at least 91% of the phenolics after seven days. • The yeasts produced mainly unsaturated fatty acids on the effluent. [ABSTRACT FROM AUTHOR]

Exposure to bisphenol A (BPA) during gestation leads to fetal growth restriction (FGR), whereby the underlying mechanisms remain unknown. Here, we found that FGR patients showed higher levels of BPA in the urine, serum, and placenta; meanwhile, trophoblast ferroptosis was observed in FGR placentas, as indicated by accumulated intracellular iron, impaired antioxidant molecules, and increased lipid peroxidation products. To investigate the role of ferroptosis in placental and fetal growth, BPA stimulation was performed both in vivo and in vitro. BPA exposure during gestation was associated with FGR in mice; also, it induces ferroptosis in mouse placentas and human placental trophoblast. Pretreatment with ferroptosis inhibitor ferritin-1 (Fer-1) alleviated BPA-induced oxidative damage and cell death. Notably, BPA reduced the trophoblastic expression of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which regulated tissue growth and organ size. YAP or TAZ siRNA enhanced BPA-induced ferroptosis, suggesting that trophoblast ferroptosis is dependent on YAP/TAZ downregulation after BPA stimulation. Consistently, the protein levels of YAP/TAZ were also reduced in FGR placentas. Further results revealed that silencing YAP/TAZ promoted BPA-induced ferroptosis through autophagy. Pretreatment with autophagy inhibitor chloroquine (CQ) attenuated BPA-induced trophoblast ferroptosis. Ferritinophagy, an autophagic degradation of ferritin (FTH1), was observed in FGR placentas. Similarly, BPA reduced the protein level of FTH1 in placental trophoblast. Pretreatment with iron chelator desferrioxamine (DFO) and NCOA4 (an autophagy cargo receptor) siRNA weakened the ferroptosis of trophoblast after exposure to BPA, indicating that autophagy mediates ferroptosis in BPA-stimulated trophoblast by degrading ferritin. In summary, ferroptosis was featured in BPA-associated FGR and trophoblast injury; the regulation of ferroptosis involved the YAP/TAZ-autophagy-ferritin axis. [Display omitted] • Gestational BPA exposure induced fetal growth restriction in mice. • Ferroptosis occurs in animal models of BPA-induced fetal growth restriction. • BPA promotes placental trophoblast ferroptosis via autophagic degradation of ferritin. • BPA promotes autophagy via downregulation of YAP/TAZ expression. • YAP/TAZ reduction, ferritinophagy, and ferroptosis occur in FGR placentae. [ABSTRACT FROM AUTHOR]

Many metabolic diseases are caused by disorders of lipid homeostasis. CIDEC, a lipid droplet (LD)-associated protein, plays a critical role in controlling LD fusion and lipid storage. However, regulators of CIDEC remain largely unknown. Here, we established a homogeneous time-resolved fluorescence (HTRF)-based high-throughput screening method and identified LPXN as a positive regulatory candidate for CIDEC. LPXN and Hic-5, the members of the Paxillin family, are focal adhesion adaptor proteins that contribute to the recruitment of specific kinases and phosphatases, cofactors, and structural proteins, participating in the transduction of extracellular signals into intracellular responses. Our data showed that Hic-5 and LPXN significantly increased the protein level of CIDEC and enhanced CIDEC stability not through triacylglycerol synthesis and FAK signaling pathways. Hic-5 and LPXN reduced the ubiquitination of CIDEC and inhibited its proteasome degradation pathway. Furthermore, Hic-5 and LPXN enlarged LDs and promoted lipid storage in adipocytes. Therefore, we identified Hic-5 and LPXN as novel regulators of CIDEC. Our current findings also suggest intervention with Hic-5 and LPXN might ameliorate ectopic fat storage by enhancing the lipid storage capacity of white adipose tissues. [ABSTRACT FROM AUTHOR]

This study investigated the time course of lipid accumulation during IVM and assessed the role of lipid modulators added during IVM on lipid content, nuclear maturation, oxidative stress, mitochondrial activity, gene expression, and cryosurvival of cat oocytes. First, the lipid content of immature COCs was compared to those subjected to different IVM duration times (24, 28, and 32 h). Then, the lipid content was investigated after the use of different lipid modulators [conjugated linoleic acid (CLA), forskolin (FSK), l -carnitine (LC)]. Subsequently, both the CONTROL group and MIX 18 (CLA+FSK+LC) were compared regarding nuclear maturation, mitochondrial activity, reactive oxygen 19 species (ROS), and glutathione (GSH) levels, to the expression of SDHA, GDF9, BMP15, ZAR-1, 20 PRDX1, SIRT1, and SIRT3 genes (normalized by ACTB and YWHAZ genes); and to vitrification and 21 post-warming viability assessment. When not using any lipid modulator, an increase (P < 0.05) in lipid content could be observed after 28 h of IVM. The MIX group showed the greatest (P < 0.05) reduction in oocyte lipid content after 28 h of IVM. No difference (P > 0.05) was observed in the MII rate in the CONTROL (45%) and MIX (41%) groups and in mitochondrial activity ((1.00 ± 0.35 A U vs 1.19 ± 0.14 A U). Although ROS and GSH levels were higher (P < 0.05) in MIX than in CONTROL, the redox balance (ROS/GSH) was greater (P < 0.05) in the latter (C:1.00 ± 0.20b vs M:0.26 ± 0.06 a A.U). The GDF9, HSP70, PRDX1 , and SIRT1 transcripts were downregulated (P < 0.05) in MIX-oocytes, compared to the CONTROL. After vitrification, MIX (74%) presented a higher (P < 0.05) viability compared to control (53%). In conclusion, MIX can reduce the total lipid content and improve viability after cryopreservation, however, it seems to affect the oocyte metabolism in a way that still needs to be better understood in the cat biological model. • The use of a cocktail (MIX) of lipid modulators during IVM was able to reduce the lipid content of cat oocytes. • The use of MIX did not impact the nuclear maturation rates of cat oocytes. • MIX increased GSH and ROS levels and reduced the redox balance. • MIX increased the oocyte viability after cryopreservation. [ABSTRACT FROM AUTHOR]

Deep eutectic solvents (DES) can be a green alternative extraction technology for microalgae lipids, acting simultaneously as a pre-treatment agent and solvent. However, due to the low vapor pressure of both DES and lipid solute, the recovery of lipids and solvent regeneration remains difficult. In this study, we developed a novel strategy to separate the dissolved sunflower and model algae oil from imidazole/hexanoic acid DES by using polar antisolvents (water, methanol, and ethanol). The polarity and the amount of antisolvent influenced the lipid solubility in DES. While the water was the strongest antisolvent, the alcohols were easier to evaporate, ensuring easy DES regeneration. By adding small amounts of water and methanol, more than 90% of the lipids were recovered in the form of high-purity oils (>90%). In the case of ethanol, a large amount of ethanol was required, which diluted the solvent-rich phase and solubilized more lipids in it. Based on three repeated cycles with the selected antisolvent methanol, > 90% of the eutectic solvent could be regenerated. [ABSTRACT FROM AUTHOR]

Nucleic acid therapeutics have demonstrated substantial potential in combating various diseases. However, challenges persist, particularly in the delivery of multifunctional nucleic acids. To address this issue, numerous gene delivery vectors have been developed to fully unlock the potential of gene therapy. The advancement of innovative materials with exceptional delivery properties is critical to propel the clinical translation of nucleic acid drugs. Cationic vector materials have received extensive attention, while zwitterionic materials remain relatively underappreciated in delivery. In this review, we outline a diverse range of zwitterionic material nucleic acid carriers, predominantly encompassing zwitterionic lipids, polymers and peptides. Their respective chemical structures, synthesis approaches, properties, advantages, and therapeutic applications are summarized and discussed. Furthermore, we highlight the challenges and future opportunities associated with the development of zwitterionic vector materials. This review will aid to understand the zwitterionic materials in aiding gene delivery, contributing to the continual progress of nucleic acid therapeutics. [Display omitted] [ABSTRACT FROM AUTHOR]

Lipid nanoparticles (LNPs) hold great promise as carriers for developing drug delivery systems (DDSs) aimed at managing ischemic stroke (IS). Previous research has highlighted the vital role played by the lipid composition and biophysical characteristics of LNPs, influencing their interactions with cells and tissues. This understanding presents an opportunity to engineer LNPs tailored specifically for enhanced IS treatment. We previously introduced the innovative concept of reconstituted lipid nanoparticles (rLNPs), which not only retain the advantages of conventional LNPs but also incorporate lipids from the originating cell or tissue. Brain-derived rLNPs (B-rLNPs) exhibit significantly superior accumulation within the cerebral ischemic region when compared to liver-derived rLNPs (L-rLNPs). The homing effect of B-rLNPs was then employed to construct 3-n-butylphthalide (NBP) loaded DDS (B-rLNPs/NBP) for the treatment of IS. Our results demonstrated that compared with free NBP, B-rLNPs/NBP can significantly reduce infarct volume, neurological deficits, blood-brain barrier (BBB) leakage rate, brain water content, neutrophil infiltration, alleviate pathological structures, and improve the motor function in MCAO/R model. We also proved that B-rLNPs/NBP showed further reinforced protective effects on the same model than free NBP through the regulation of TLR4/MyD88/NF-κB (anti-inflammation) and Bax/Bcl-2 (anti-apoptosis) pathways. This study offers a promising tool towards improved IS treatment. [Display omitted] • B-rLNPs show selective homing to cerebral ischemic area. • B-rLNPs/NBP significantly improves the protective effect of NBP on MCAO/R model. • B-rLNPs/NBP functions through TLR4/MyD88/NF-κB and Bax/Bcl-2 pathways. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis (NASH) is a prevalent metabolic disease, characterized by the hepatic steatosis, inflammation, and fibrosis, which is lack of effective treatment currently. Protectin D1 (PTD1), a lipid mediator from omega-3 fatty acid docosahexaenoic acid (DHA), has displayed wide pharmacological actions including anti-inflammation in a variety of diseases, but the role of PTD1 on NASH remains unclear. In this study, using the methionine and choline deficient (MCD) fed NASH model, we explored the effect and underlying mechanism of PTD1 on NASH in mice. Our results showed PTD1 improved MCD-induced steatosis, hepatocellular injury, inflammation and fibrosis. Furthermore, PTD1 inhibited MCD-induced activation of TLR4 downstream molecules (TAK1, p38 and p65) without affecting the levels of TLR4 and phosphorylated IRAK-1. Notably, the levels of IRAK-M protein and the binding between IRAK-M and TRAF6 in the liver were also increased by PTD1 in NASH mice. Moreover, IRAK-M knockout remarkedly reverted the beneficial effects of PTD1 on the NASH in mice. Thus, these results demonstrated that PTD1 could protect mice from NASH by inhibiting the activation of TLR4 downstream signaling pathway, which might be related to the upregulation of IRAK-M, indicating that PTD1 may provide a new treatment for NASH. [Display omitted] • Protectin D1 (PTD1) has shown the anti-inflammatory effect, but little is known about its role on Non-alcoholic steatohepatitis (NASH). • PTD1 improved steatosis, liver injury, hepatic inflammation and liver fibrosis in NASH mice. • PTD1 inhibited the activation of TLR4 downstream molecules (TAK1, p38 and p65) without affecting TLR4 and IRAK-1 phosphorylation levels in NASH mice. • PTD1 upregulated IRAK-M and IRAK-M knockout reversed the protective effect of PTD1 in NASH mice. • PTD1 could attenuate NASH by inhibiting the activation of TLR4 downstream signaling pathway, which is related to the upregulation of IRAK-M. [ABSTRACT FROM AUTHOR]

Lipids are important in multiple cellular functions, with most having structural or energy storage roles. However, a small fraction of lipids exert bioactive roles through binding to G protein-coupled receptors and induce a plethora of processes including cell proliferation, differentiation, growth, migration, apoptosis, senescence and survival. Bioactive signalling lipids are potent modulators of metabolism and energy homeostasis, inflammation, tissue repair and malignant transformation. All these events are involved in the initiation and progression of chronic liver diseases. In this review, we focus specifically on the roles of bioactive lipids derived from phospholipids (lyso -phospholipids) and poly-unsaturated fatty acids (eicosanoids, pro-resolving lipid mediators and endocannabinoids) in prevalent chronic liver diseases (alcohol-associated liver disease, non-alcoholic fatty liver disease, viral hepatitis and hepatocellular carcinoma). We discuss the balance between pathogenic and beneficial bioactive lipids as well as potential therapeutic targets related to the agonism or antagonism of their receptors. [ABSTRACT FROM AUTHOR]

Fatty acid handling and complex lipid synthesis are altered in the kidney cortex of diabetic patients. We recently showed that inhibition of the renin-angiotensin system without changes in glycemia can reverse diabetic kidney disease (DKD) and restore the lipid metabolic network in the kidney cortex of diabetic (db/db) mice, raising the possibility that lipid remodeling may play a central role in DKD. However, the roles of specific enzymes involved in lipid remodeling in DKD have not been elucidated. In the present study, we used this diabetic mouse model and a proximal tubule epithelial cell line (HK2) to investigate the potential relationship between long-chain acyl-CoA synthetase 1 (ACSL1) and lipid metabolism in response to fatty acid exposure and inflammatory signals. We found ACSL1 expression was significantly increased in the kidney cortex of db/db mice, and exposure to palmitate or tumor necrosis factor-α significantly increased Acsl1 mRNA expression in HK-2 cells. In addition, palmitate treatment significantly increased the levels of long-chain acylcarnitines and fatty acyl CoAs in HK2 cells, and these increases were abolished in HK2 cell lines with specific deletion of Acsl1(Acsl1KO cells), suggesting a key role for ACSL1 in fatty acid β-oxidation. In contrast, tumor necrosis factor-α treatment significantly increased the levels of short-chain acylcarnitines and long-chain fatty acyl CoAs in HK2 cells but not in Acsl1KO cells, consistent with fatty acid channeling to complex lipids. Taken together, our data demonstrate a key role for ACSL1 in regulating lipid metabolism, fatty acid partitioning, and inflammation. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) are essential for cellular pathophysiology. In two recent reports, Kim et al. and Boutagy et al. show that accumulation of LDs in endothelial cells (ECs) elevates blood pressure and accelerates progression of atherosclerosis. These findings identify a novel mechanism of EC lipid metabolism which drives cardiometabolic diseases. Lipid droplets (LDs) are essential for cellular pathophysiology. In two recent reports, Kim et al. and Boutagy et al. show that accumulation of LDs in endothelial cells (ECs) elevates blood pressure and accelerates progression of atherosclerosis. These findings identify a novel mechanism of EC lipid metabolism which drives cardiometabolic diseases. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunctions predominantly cause encephalomyopathies with muscle atrophy and neurodegeneration. However, their impact on other tissues, particularly the gastrointestinal tract, requires further investigation. In a recent report in Nature , Moschandrea et al. used mice deficient in the mitochondrial aminoacyl-tRNA synthetase DARS2 to investigate the role of enterocytic mitochondria in dietary lipid processing and transport. Their work sheds light on the development of gastrointestinal disorders as a result of mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

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