Identification of Novel Human 15-Lipoxygenase-2 (h15-LOX-2) Inhibitors Using a Virtual Screening Approach.

The human 15-lipoxygenase-2 (h15-LOX-2) catalyzes mainly the regio- and stereospecific oxygenation of arachidonate to its corresponding hydroperoxide (15()-HpETE). h15-LOX-2 is implicated in the biosynthesis of inflammatory lipid mediators and plays a role in the development of atherosclerotic plaques, but it is still underexploited as a drug target. Here, to search for novel h15-LOX-2 inhibitors, we used a virtual screening (VS) approach consisting of shape-based matching, two-dimensional (2D) structural "dissimilarity", docking, and visual inspection filters, which were applied to a "curated" ZINC database (∼8 × 10 compounds).

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance.

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and begins with the uptake of the Sec carrier, selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP is metabolized via selenocysteine lyase (SCLY), producing selenide, a substrate for selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor, selenophosphate (HSePO), for the biosynthesis of the Sec-tRNA. Here, we discovered an alternative pathway in Sec metabolism mediated by peroxiredoxin 6 (PRDX6), independent of SCLY.

On the binding of auranofin to Prdx6 and its potential role in cancer cell sensitivity to treatment.

In this study, we demonstrate that ferroptosis is a component of the cell death mechanism induced by auranofin in HT-1080 cells, in contrast to the gold(III) compounds [Au(phen)Cl]PF and [Au(bnpy)Cl]. Additionally, we identify a potential role of Prdx6 in modulating the sensitivity of A-375 cells to auranofin treatment, whereas the gold(III) compounds evaluated here exhibit Prdx6-independent cytotoxicity. Finally, using mass spectrometry, we show that auranofin binds selectively to the catalytic Cys47 residue of Prdx6 in vitro under acidic conditions.

Quantitative Analysis of Glutathione and Carnosine Adducts with 4-Hydroxy-2-nonenal in Muscle in a hSOD1 ALS Rat Model.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the dysfunction and death of motor neurons through multifactorial mechanisms that remain unclear. ALS has been recognized as a multisystemic disease, and the potential role of skeletal muscle in disease progression has been investigated. Reactive aldehydes formed as secondary lipid peroxidation products in the redox processes react with biomolecules, such as DNA, proteins, and amino acids, resulting in cytotoxic effects.

Plasmalogen oxidation induces the generation of excited molecules and electrophilic lipid species.

Plasmalogens are glycerophospholipids with a vinyl ether linkage at the sn-1 position of the glycerol backbone. Despite being suggested as antioxidants due to the high reactivity of their vinyl ether groups with reactive oxygen species, our study reveals the generation of subsequent reactive oxygen and electrophilic lipid species from oxidized plasmalogen intermediates. By conducting a comprehensive analysis of the oxidation products by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS), we demonstrate that singlet molecular oxygen [O (Δ)] reacts with the vinyl ether bond, producing hydroperoxyacetal as a major primary product (97%) together with minor quantities of dioxetane (3%).

Prevention of lipid droplet accumulation by DGAT1 inhibition ameliorates sepsis-induced liver injury and inflammation.

Background & Aims: Lipid droplet (LD) accumulation in cells and tissues is understood to be an evolutionarily conserved tissue tolerance mechanism to prevent lipotoxicity caused by excess lipids; however, the presence of excess LDs has been associated with numerous diseases. Sepsis triggers the reprogramming of lipid metabolism and LD accumulation in cells and tissues, including the liver. The functions and consequences of sepsis-triggered liver LD accumulation are not well known.

Gold-Promoted Biocompatible Selenium Arylation of Small Molecules, Peptides and Proteins.

A low pKa (5.2), high polarizable volume (3.8 Å), and proneness to oxidation under ambient conditions make selenocysteine (Sec, U) a unique, natural reactive handle present in most organisms across all domains of life.

Lipidome remodeling in response to nutrient replenishment requires the tRNA modifier Deg1/Pus3 in yeast.

In the yeast Saccharomyces cerevisiae, the absence of the pseudouridine synthase Pus3/Deg1, which modifies tRNA positions 38 and 39, results in increased lipid droplet (LD) content and translational defects. In addition, starvation-like transcriptome alterations and induced protein aggregation were observed. In this study, we show that the deg1 mutant increases specific misreading errors.

Plasma oxylipin profiling by high resolution mass spectrometry reveal signatures of inflammation and hypermetabolism in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons, systemic hypermetabolism, and inflammation. In this context, oxylipins have been investigated as signaling molecules linked to neurodegeneration, although their specific role in ALS remains unclear. Importantly, most methods focused on oxylipin analysis are based on low-resolution mass spectrometry, which usually confers high sensitivity, but not great accuracy for molecular characterization, as provided by high-resolution MS (HRMS).

Oxygen-induced pathological angiogenesis promotes intense lipid synthesis and remodeling in the retina.

The retina is a notable tissue with high metabolic needs which relies on specialized vascular networks to protect the neural retina while maintaining constant supplies of oxygen, nutrients, and dietary essential fatty acids. Here we analyzed the lipidome of the mouse retina under healthy and pathological angiogenesis using the oxygen-induced retinopathy model. By matching lipid profiles to changes in mRNA transcriptome, we identified a lipid signature showing that pathological angiogenesis leads to intense lipid remodeling favoring pathways for neutral lipid synthesis, cholesterol import/export, and lipid droplet formation.

Phenotypic changes in low-density lipoprotein particles as markers of adverse clinical outcomes in COVID-19.

Background And Aims: Low-density lipoprotein (LDL) plasma concentration decline is a biomarker for acute inflammatory diseases, including coronavirus disease-2019 (COVID-19). Phenotypic changes in LDL during COVID-19 may be equally related to adverse clinical outcomes.

Methods: Individuals hospitalized due to COVID-19 (n = 40) were enrolled.

Futile cycle of β-oxidation and de novo lipogenesis are associated with essential fatty acids depletion in lipoatrophy.

Total absence of adipose tissue (lipoatrophy) is associated with the development of severe metabolic disorders including hepatomegaly and fatty liver. Here, we sought to investigate the impact of severe lipoatrophy induced by deletion of peroxisome proliferator-activated receptor gamma (PPARγ) exclusively in adipocytes on lipid metabolism in mice. Untargeted lipidomics of plasma, gastrocnemius and liver uncovered a systemic depletion of the essential linoleic (LA) and α-linolenic (ALA) fatty acids from several lipid classes (storage lipids, glycerophospholipids, free fatty acids) in lipoatrophic mice.

Orange juice intake by obese and insulin-resistant subjects lowers specific plasma triglycerides: A randomized clinical trial.

Background & Aims: Dyslipidaemia is usually common in obesity, insulin resistance, and type 2 diabetes mellitus. Clinical trials suggest that orange juice may have a positive impact on lipid metabolism and blood lipid profiles; however conflicting results have been reported. Here, we applied a combined untargeted/targeted lipidomic analysis of plasma to examine the impact of orange (Citrus sinensis) juice intake on the lipidome profile of obese and insulin-resistant subjects.

In yeast, cardiolipin unsaturation level plays a key role in mitochondrial function and inner membrane integrity.

Cardiolipin is the signature phospholipid of the mitochondrial inner membrane. It participates in shaping the inner membrane as well as in modulating the activity of many membrane-bound proteins. The acyl chain composition of cardiolipin is finely tuned post-biosynthesis depending on the surrounding phospholipids to produce mature or unsaturated cardiolipin.

Omega-3 Fatty Acids Improve Functionality of High-Density Lipoprotein in Individuals With High Cardiovascular Risk: A Randomized, Parallel, Controlled and Double-Blind Clinical Trial.

Omega-3 (ω-3) fatty acids have been extensively studied for primary and secondary prevention of cardiovascular health, but their ability to modulate HDL functionality remains unclear. The purpose of this study was to investigate the role of ω-3, rich in eicosapentaenoic (EPA) and docosahexaenoic (DHA), on HDL functionality. For that, 147 individuals with high cardiovascular risk were randomized in ω-3 (1 g of fish oil each - 370 mg of EPA and 230 mg of DHA, 3 times per day total EPA+DHA = 1,800 mg) or ω-6 groups (1 g of sunflower oil each - 760 mg of linoleic acid, 3 times per day; total linoleic acid = 2,280 mg).

Disruption of polycystin-1 cleavage leads to cardiac metabolic rewiring in mice.

Cardiovascular manifestations account for marked morbi-mortality in autosomal dominant polycystic kidney disease (ADPKD). Pkd1- and Pkd2-deficient mice develop cardiac dysfunction, however the underlying mechanisms remain largely unclear. It is unknown whether impairment of polycystin-1 cleavage at the G-protein-coupled receptor proteolysis site, a significant ADPKD mutational mechanism, is involved in this process.

Calorie restriction changes lipidomic profiles and maintains mitochondrial function and redox balance during isoproterenol-induced cardiac hypertrophy.

Typically, healthy cardiac tissue utilizes more fat than any other organ. Cardiac hypertrophy induces a metabolic shift leading to a preferential consumption of glucose over fatty acids to support the high energetic demand. Calorie restriction is a dietary procedure that induces health benefits and lifespan extension in many organisms.

Postprandial plasma lipidome responses to a high-fat meal among healthy women.

Postprandial lipemia consists of changes in concentrations and composition of plasma lipids after food intake, commonly presented as increased levels of triglyceride-rich lipoproteins. Postprandial hypertriglyceridemia may also affect high-density lipoprotein (HDL) structure and function, resulting in a net decrease in HDL concentrations. Elevated triglycerides (TG) and reduced HDL levels have been positively associated with risk of cardiovascular diseases development.

Simultaneous silencing of lysophosphatidylcholine acyltransferases 1-4 by nucleic acid nanoparticles (NANPs) improves radiation response of melanoma cells.

Radiation induces the generation of platelet-activating factor receptor (PAF-R) ligands, including PAF and oxidized phospholipids. Alternatively, PAF is also synthesized by the biosynthetic enzymes lysophosphatidylcholine acyltransferases (LPCATs) which are expressed by tumor cells including melanoma. The activation of PAF-R by PAF and oxidized lipids triggers a survival response protecting tumor cells from radiation-induced cell death, suggesting the involvement of the PAF/PAF-R axis in radioresistance.

PPARγ-induced upregulation of subcutaneous fat adiponectin secretion, glyceroneogenesis and BCAA oxidation requires mTORC1 activity.

The nutrient sensors peroxisome proliferator-activated receptor γ (PPARγ) and mechanistic target of rapamycin complex 1 (mTORC1) closely interact in the regulation of adipocyte lipid storage. The precise mechanisms underlying this interaction and whether this extends to other metabolic processes and the endocrine function of adipocytes are still unknown. We investigated herein the involvement of mTORC1 as a mediator of the actions of the PPARγ ligand rosiglitazone in subcutaneous inguinal white adipose tissue (iWAT) mass, endocrine function, lipidome, transcriptome and branched-chain amino acid (BCAA) metabolism.

Plasma lipidome profiling of newborns with antenatal exposure to Zika virus.

The 2015-2016 Zika virus (ZIKV) outbreak in Brazil was remarkably linked to the incidence of microcephaly and other deleterious clinical manifestations, including eye abnormalities, in newborns. It is known that ZIKV targets the placenta, triggering an inflammatory profile that may cause placental insufficiency. Transplacental lipid transport is delicately regulated during pregnancy and deficiency on the delivery of lipids such as arachidonic and docosahexaenoic acids may lead to deficits in both brain and retina during fetal development.