SARS-CoV-2 infection triggers distinct patterns of disease development, characterized by significant alterations in host regulatory responses. Severe cases exhibit profound lung inflammation and systemic repercussions. Remarkably, critically ill patients display a "lipid storm", influencing the inflammatory process and tissue damage. Sphingolipids (SL) play pivotal roles in various cellular and tissue processes, including inflammation, metabolic disorders, and cancer. In this study, we employed high-resolution mass spectrometry to investigate SL metabolism in plasma samples obtained from control subjects (n=55), COVID-19 patients (n=204), and convalescent individuals (n=77). These data were correlated with inflammatory parameters associated with the clinical severity of COVID-19. Additionally, we utilized RNAseq analysis to examine the gene expression of enzymes involved in the SL pathway. Our analysis revealed the presence of thirty-eight SL species from seven families in the plasma of study participants. The most profound alterations in the SL species profile were observed in patients with severe disease. Notably, the predominant sphingomyelin (SM d18:1) species emerged as a potential biomarker for COVID-19 severity, showing decreased levels in the plasma of convalescent individuals. Elevated SM levels were positively correlated with age, hospitalization duration, clinical score, neutrophil count, as well as the production of IL-6 and IL-8. Intriguingly, we identified a putative protective effect against disease severity mediated by SM (d18:1/24:0), while ceramide (Cer) d18:1/24:1 and d18:1/24:0 was associated with increased risk. Moreover, we observed enhanced expression of key enzymes involved in SL pathway, in blood cells from severe COVID-19 patients, suggesting a primary flow towards Cer generation in tandem with SM synthesis. These findings underscore the potential of SM as a prognostic biomarker for COVID-19 and highlight promising pharmacological targets. By targeting sphingolipid pathways, novel therapeutic strategies may emerge to mitigate the severity of COVID-19 and improve patient outcomes.

Sphingolipids are lipids derived from an 18-carbons unsaturated amino alcohol, the sphingosine. Ceramide, sphingomyelins, sphingosine-1-phosphates, gangliosides and globosides, are part of this group of lipids that participate in important cellular roles such as structural part of plasmatic and organelle membranes maintaining their function and integrity, cell signaling response, cell growth, cell cycle, cell death, inflammation, cell migration and differentiation, autophagy, angiogenesis, immune system. The metabolism of these lipids involves a broad and complex network of reactions that convert one lipid into others through different specialized enzymes. Impairment of sphingolipids metabolism has been associated with several disorders, from several lysosomal storage diseases, known as sphingolipidoses, to polygenic diseases such as diabetes and Parkinson and Alzheimer diseases. Sphingolipids are mainly located in central nervous system, and their abundance and distribution depend on brain development state and cell type. Although several studies have expanded the knowledge about sphingolipids function both in health and disease, it is still necessary to continue their study to understand the cellular implications of novel sphingolipids. These studies will also contribute to the diagnosis and treatment of diseases in which these molecules are part of their pathophysiology. In this review, we summarize the main sphingolipid characteristics and current knowledge about the synthesis, catabolism, regulatory pathways, participation in action potential and ionic channels, among other relevant functions.

Despite the increasing popularity of liquid chromatography-mass spectrometry (LC-MS)-based lipidomics, there is a lack of accepted and validated method for lipid extract quality and quantity assessment prior to LC-MS. Fourier-Transform Infrared Spectroscopy (FTIR) has been reported for quantification of pure lipids, however, the sample complexity and purity complex lipid extract quantification in lipidomics experiments could be impact quantification accuracy. Here, we report comprehensive assessment of the sample matrix on the accuracy of lipid quantification using Attenuated Total Reflectance Fourier-Transform Infrared Spectroscopy (ATR-FTIR). Pure lipids are characterized by CH-and C=O-stretching vibrations on FTIR, with quantitative range of 40–3000 ng and a limit of detection of 12 ng. Sample extraction method and local baseline subtraction during FTIR spectral processing significantly impact lipid quantification by CH-stretching. To facilitate sample quality screening, we developed the Lipid Quality (LiQ) score from a spectral library of common contaminants, using a ratio of peak heights between CH-stretching vibrations maxima and the collective vibrations from amide/amine, CH-stretching minima and sugar moieties. We evaluated LiQ score as a rapid sample quality control method by comparing to total LC-MS intensity of targeted lipidomics of 107 human plasma lipid extracts. Exclusion of poor-quality samples based on LiQ score improved the correlation between FTIR and LC-MS quantification. Finally, the uncertainty of absolute quantification by FTIR was estimated using a 795 ng SPLASH LipidoMix standard to be <10%. In summary, this study identified key parameters for accurate FTIR-based quantification of complex lipid mixture, and developed a rapid workflow requiring only 1 µL of MS-ready sample and < 5 minutes for routine lipidomics sample quality and quantity assessment.

The latest scientific literature outlines a resilient interconnection between cancer modulation and dietary polyphenols by sphingolipid-mediated mechanisms, usually correlated with a modification of their metabolism. We aim to extensively survey this relation to show how it could be advantageous in cancer treatment or prevention by nutrients. Polyphenols, chemically characterized by polyhydroxylated phenolic structure, are well known for their pervasive pharmacological properties: anti-inflammatory, antibiotic, antiseptic, antitumor, antiallergic, cardioprotective and others. Pervasive is also their distribution in food products especially in plant foods as vegetables, cereals, legumes, fruits, nuts and beverages as wine, cider, beer, tea, cocoa. Recently, sphingolipids have been correlated with cancer by a dysregulation of their rheostat emerging as mediator of cell proliferation in cancer and modulator of chemotherapeutics.

Recent COVID-19 outbreak has come into prominence the pathogenetic mechanisms underlying the Biology and Biochemistry of viral infections. COVID-19 illness is brought about by infection with the severe acute respiratory syndrome coronavirus SARS-CoV-2 [1,2], an enveloped positive single stranded RNA virus (ssRNA+). From a lipidomics viewpoint, there is a variety of mechanisms involving virus infection that encompass virus entry, disturbance of host cell lipid metabolism, and the role played by diverse lipids in regard to the infection effectiveness. All these aspects have currently been tackled separately as independent issues and focusing on the function of proteins. Here we review the role of cholesterol and other lipids in in ssRNA+ and SARS-COV-2 infection.

: Molecular targeting strategies have been used for years to control cancer progression and are often based on targeting various enzymes involved in metabolic pathways. Keeping that in mind, it is essential to know the role of each enzyme in a particular metabolic pathway. In this review, we are providing in-depth knowledge of various enzymes such as ceramidase, sphingosine kinase, sphingomyelin synthase, dihydroceramide desaturase, and ceramide synthase, which are associated with multiple types of cancer that depend on ceramide metabolism. Focus has also been given to discussing physicochemical properties of well-studied inhibitors of natural products origin and their related structures for these enzymes. Targeting ceramide metabolism exhibited promise in mono and combination therapies at preclinical stages to prevent cancer progression and paved the way for the significance of sphingolipid metabolism in cancer treatments. Targeting ceramide metabolizing enzymes will help the medicinal chemist to design potent and selective small molecules for treating cancer progression at various levels.

Niemann-Pick type C (NPC) disease is a childhood autosomal recessive inherited rare neuro-degenerative disease, characterized by the accumulation of cholesterol and glycosphingolipids, implicating the autophagy-lysosome system. Inhibition of soluble epoxide hydrolase (sEH), an enzyme that metabolizes epoxy fatty acids (EpFAs) to 1,2-diols, exerts beneficial effects in mod-ulating inflammation and autophagy, critical features of the NPC disease. This study aimed to evaluate the effects of UB-EV-52 a sEH inhibitor (sEHi) in the Npc mouse model by administering for 4 weeks (5 mg/kg/day). Behavioral and cognitive assays (open field test (OF), elevated plus maze (EPM), novel object recognition test (NORT) and object location test (OLT) demonstrated that treatment produced an improvement in short- and long-term memory as well as in spatial memory. Moreover, the treatment with UB-EV-52 increased body weight and the lifespan by 25% and re-duced gene expression of the inflammatory markers (i.e. Il-1β and Mcp1) and improved oxidative stress (OS) markers (iNOS and Hmox1) in the treated Npc mice group. Regarding the autophagic markers, we surprisingly found significantly reduced levels of the ratio LC3B-II/LC3B-I and a significant reduction of brain protein levels of lysosomal-associated membrane protein-1 (LAMP-1) in Npc mice treated group compared to non-treated. Lipid profile analysis showed a significant reduction in lipid storage in the liver and some slight changes in brain tissue in treated Npc mice compared to non-treated groups. Thus, Our results suggest that the pharmacological inhibition of sEH ameliorates most of NPC’s characteristic traits in mice, demonstrating that sEH can be considered a potential therapeutic target for this condition.

The rapid increase in metabolic diseases occurred in the last three decades in both industrialized and developing countries has been related to the rise in sugar-added foods and sweetened beverages consumption. An emerging topic in the pathogenesis of metabolic diseases related to modern nutrition is the role of Advanced Glycation Endproducts (AGEs). AGEs can be ingested with high temperature processed foods, but also endogenously formed as consequence of a high dietary sugars intake. Animal models of high sugars consumption, in particular fructose, have reported AGEs accumulation in different tissues in association with peripheral insulin resistance and lipid metabolism alterations. The in vitro observation that fructose is one of the most rapid and effective glycating agent when compared to other sugars has prompted the investigation of the in vivo fructose-induced glycation. In particular, the widespread employment of fructose as sweetener has been ascribed by many experimental and observational studies for the enhancement of lipogenesis and intracellular lipid deposition. Indeed, diet-derived AGEs have been demonstrated to interfere with many cell functions such as lipid synthesis, inflammation, antioxidant defences, and mitochondrial metabolism. Moreover, emerging evidences also in humans suggest that this impact of dietary AGEs on different signalling pathways can contribute to the onset of organ damage in liver, skeletal and cardiac muscle, and brain, affecting not only metabolic control, but global health. Indeed, the here reviewed most recent reports on the effects of high sugars consumption and diet-derived AGEs on human health suggest the need to limit the dietary sources of AGEs, including added sugars, to prevent the development of metabolic diseases and related comorbidities.

Glycosyl inositol phospho ceramides (GIPCs) are the major sphingolipids on earth as they account for a considerable fraction of the total lipids in plants and fungi which in turn represent a large portion of the biomass on earth. Despite their obvious importance, GIPC analysis remains challenging due to the lack of commercial standards and automated annotation software. In this work, we introduce a novel GIPC glycolipidomics workflow based on reversed-phase ultra-high pressure liquid chromatography coupled to high-resolution mass spectrometry. For the first time, automated GIPC assignment was performed using the open-source software Lipid Data Analyzer based on platform-independent decision rules. Four different plant samples (salad, spinach, raspberry, strawberry) were analyzed and revealed 64 GIPCs based on accurate mass, characteristic MS2 fragments and matching retention times. Relative quantification using lactosyl ceramide for internal standardization revealed GIPC t18:1/h24:0 as the most abundant species in all plants. Depending on the plant sample, GIPCs contained mainly amine, N-acetylamine or hydroxyl residues. Most GIPCs revealed a Hex-HexA-IPC core and contained a ceramide part with a trihydroxylated t18:0 or t18:1 long chain base and hydroxylated fatty acid chains ranging from 16 to 26 carbon atoms in length (h16:0 – h26:0). Interestingly, six GIPCs containing t18:2 were observed in raspberry, which was not reported so far. The presented workflow supports the characterization of different plant samples by automatic GIPC assignment potentially leading to the identification of new GIPCs. For the first time, automated high‑throughput profiling of these complex glycolipids is possible by liquid chromatography-high-resolution mass spectrometry and subsequent automated glycolipid annotation based on decision rules.