Search Results (1,083)

Glucosylceramide (GlcCer), a central glycosphingolipid derived from ceramide, is increasingly recognized as a bioactive lipid that intersects with key metabolic, inflammatory, and oncogenic pathways. While its dysregulation has long been associated with lysosomal storage disorders such as Gaucher disease (GD), growing evidence implicates GlcCer in cancer initiation and progression, particularly within tumor-predisposing conditions. GlcCer modulates membrane microdomains, intracellular trafficking, and cell signaling, counteracting ceramide-induced apoptosis and promoting cellular survival. In cancer, aberrant upregulation of UDP-glucose ceramide glucosyltransferase (UGCG), the enzyme responsible for GlcCer synthesis, drives tumor growth, metastasis, and multidrug resistance through activation of pathways such as phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), canonical Wnt pathway (Wnt/β-catenin), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. Specific GlcCer species (e.g., C16:0, C18:0, C24:1) display tissue-dependent functions, adding structural specificity to their oncogenic potential. Moreover, emerging links between GlcCer metabolism and chronic inflammation, oxidative stress, and altered glucose utilization highlight its role as a metabolic node bridging inherited metabolic disorders and malignancy. This review integrates recent advances in GlcCer biology, emphasizing its roles in tumor-predisposing diseases and exploring its potential as a biomarker and therapeutic target in oncology. Full article

Gliomas are aggressive brain tumours with diverse histological and molecular features, complicating accurate diagnosis and treatment. Dysregulated lipid metabolism contributes to glioma progression, and analysing lipid profiles in plasma and tissue may enhance diagnostic and prognostic accuracy. This study investigated lipid dysregulation to identify key lipid signatures that distinguish glioma from other brain diseases and examined the associations between lipid biomarkers in glioma tissue and plasma. Biospecimens from 11 controls and 72 glioma patients of varying grades underwent lipidomic profiling using liquid chromatography-mass spectrometry. Univariate and multivariate analyses identified differentially abundant lipids, and correlation analysis evaluated the associations between tissue and plasma biomarkers. Lipidomic analysis revealed distinct lipid profiles in the tissues and plasma of glioma patients compared to those of controls. Prominent lipid metabolites in glioma tissues included LPC 21:3 (AUC = 0.925), DG 43:11 (AUC = 0.906), and PC 33:1 (AUC = 0.892), which served as effective biomarkers. Conversely, in plasma, lipid metabolites such as phosphatidylethanolamine (PE 21:3, AUC = 0.862), ceramide-1-phosphate (CerP 26:1, AUC = 0.861), and sphingomyelin (SM 24:3, AUC = 0.858) were identified as the most promising lipid biomarkers. Significant positive and negative correlations were observed between the tissue and plasma lipid biomarkers of glioma patients. Lipidomic profiling revealed aberrant lipid classes and pathways in glioma tissues and plasma, enhancing understanding of glioma heterogeneity and potential clinical applications. Full article

Background/Objectives: Diabetes mellitus, a prevalent metabolic disorder, causes severe complications and economic burden, requiring effective therapeutic strategies. While triglycerides and low-density lipoproteins (LDLs) have been widely studied in type 2 diabetes mellitus (T2DM) and related cardiovascular risks, the roles of other lipids, such as sphingolipids and glycerophospholipids, remain unclear. This study aimed to investigate their involvement in T2DM and its complications. Methods: We examined sphingolipid and glycerophospholipid profiles in T2DM patients to assess alterations associated with diabetes mellitus and its related complications. Results: Patients with T2DM showed significant modulations in sphingolipid and glycerophospholipid levels, suggesting these lipids contribute to metabolic dysregulation and progression of diabetes-related complications. Conclusions: Alterations in sphingolipids and glycerophospholipids play a critical role in T2DM, indicating their potential as novel targets for therapeutic intervention and risk mitigation in patients with diabetes and its complications. Full article

Endometrial carcinoma (EC) is the most common malignancy of the female reproductive tract, with increasing incidence driven by aging populations and obesity. While molecular classification has improved diagnostic precision, the identification of clinically relevant metabolic biomarkers remains incomplete, and targeted therapies are not yet standardized. In this study, we investigated metabolic alterations in four EC cell lines (AN3-CA, EFE-184, HEC-1B and MFE-296) compared to non-malignant controls under normoxic and stress conditions (hypoxia and lactic acidosis) to identify metabolomic differences with potential clinical relevance. Untargeted gas chromatography–mass spectrometry (GC/MS) and targeted liquid chromatography–mass spectrometry (LC/MS) profiling revealed two distinct metabolic subtypes of EC. Cells of metabolic subtype 1 (AN3-CA and EFE-184) exhibited high biosynthetic and energy demands, enhanced cholesterol and hexosyl-ceramides synthesis and increased RNA stability, consistent with classical cancer-associated metabolic reprogramming. Cells of metabolic subtype 2 (HEC-1B and MFE-296) displayed a phospholipid-dominant metabolic profile and greater hypoxia tolerance, suggesting enhanced tumor aggressiveness and metastatic potential. Key metabolic findings were validated via real-time quantitative PCR. This study identifies and characterizes distinct metabolic subtypes of EC within the investigated cancer cell lines, thereby contributing to a better understanding of tumor heterogeneity. The results provide a basis for potential diagnostic differentiation based on specific metabolic profiles and may support the identification of novel therapeutic targets. Further validation in three-dimensional culture models and ultimately patient-derived samples is required to assess clinical relevance and integration with current molecular classifications. Full article

Background: Carrimycin is a mixture of spiramycin derivatives with antibacterial functions. However, recent studies have shown that it possesses certain anticancer properties. The specific mechanism of the anticancer activity is unknown. Methods: To study the anticancer mechanism of carrimycin, we synthesized a derivative of spiramycin, n-hexyl spiramycin (h-SPM), and used a combination of metabolomics and transcriptomics methods. Capillary electrophoresis–mass spectrometry (CE-MS) was used to detect polar small molecule metabolites, and liquid chromatography–mass spectrometry (LC-MS) was used to detect lipid metabolites in cells. Transcriptomics was used to measure mRNA content in cells. Finally, by processing these data using specific bioinformatics methods, the mechanism underlying anticancer effect of carrimycin was determined. Results: Metabolomics and transcriptomic results showed that lipid metabolism and mitochondrial biogenesis pathways in the cells changed after hSPM treatment, NR1D1 genes and ceramide were enriched from these pathways, implicating the involvement of ROS and pro-inflammatory response. Western blotting verified that the protein levels of NR1D1 decreased after h-SPM treatment, and ROS stating and qPCR demonstrated that ROS levels and the mRNA levels of pro-inflammatory genes were greatly induced by h-SPM. Conclusions: h-SPM reduced the protein level of NR1D1, disrupted metabolic regulation, accumulating ceramide, and the subsequent increased ROS generation promoted apoptosis and pro-inflammatory-like response of cells. Our findings unveiled the anticancer mechanism of a potent anticancer derivative of spiramycin and unveiled its mechanism of action. Full article

Sperm membrane lipids play a crucial role in male fertility, influencing sperm motility, viability, and functional competence. This study comprehensively characterizes the phospholipid and sphingolipid composition in highly motile human spermatozoa obtained through the swim-up method, a widely used technique in assisted reproductive technology (ART). Using two-dimensional thin-layer chromatography and phosphorus analysis, we identified choline glycerophospholipids (CGP, 45%), ethanolamine glycerophospholipids (EGP, 26%), and sphingomyelin (SM, 17%) as predominant phospholipids, with minor components including cardiolipin, lysophospholipids, phosphatidylinositol, phosphatidylserine, phosphatidic acid, and neutral lipids. Gas chromatography analysis of glycerophospholipids (GPL) revealed a high long chain (C20–C22) polyunsaturated fatty acids (PUFA) content (46.3%), particularly docosahexaenoic acid (DHA, 22:6n-3), which was more abundant in CGP (46%) than EGP (26%). Sphingolipid analysis indicated that ceramide (Cer) and SM shared similar fatty acid profiles due to their metabolic relationship, with very-long-chain (VLC) PUFA (≥C26) being more prevalent in SM (10%) than in Cer (6%). Additionally, argentation chromatography identified highly unsaturated VLCPUFA species in Cer, including 28:3n-6, 28:4n-6, and 30:4n-6, which had not been previously quantified in motile human spermatozoa. Given the essential function of sphingolipid metabolism in spermatogenesis, capacitation, and acrosomal exocytosis, our findings suggest that the balance of VLCPUFA-containing SM and Cer could play a role in sperm performance and fertilization potential. This study provides novel insights into the lipid signature of human sperm and highlights the relevance of membrane lipid remodeling for male fertility and ART outcomes. Full article

Background/Objectives: Recent studies suggest that plasma ceramide levels may be better predictors of CVD risk than LDL cholesterol. Ceramides are part of the sphingolipid class of lipids and are the central intermediates in complex sphingolipid biosynthesis. Sphingolipids are crucial for cellular structure and have important biological roles as complex signaling lipids, structurally and functionally differentiated by their acylated fatty acid. Higher plasma concentrations of 16:0 ceramide are associated with increased risk of heart failure. In contrast, higher concentrations of 22:0 plus 24:0 ceramide are associated with lower risk. We aim to address how alterations in these lipids can affect the human cardiac hypertrophic response. Methods: We silenced the ceramide synthase genes (CERS) responsible for the production of 16:0 ceramide (CERS5/6) or 22:0 and 24:0 ceramide (CERS2) in immortalized human ventricular cardiomyocytes and examined the altered cardiac hypertrophic response to phorbol 12-myristate 13-acetate treatment by examining changes in the transcriptome. Results: We discovered that silencing CERS2 or CERS5/6 drastically altered the cardiac cell hypertrophic response. We demonstrated that human cardiomyocytes with silenced CERS2 appeared to have an exacerbated hypertrophy response, while cardiomyocytes with silenced CERS5/6 had a more favorable response, suggesting that CERS2 and CERS5/CERS6 and their gene product metabolites may have opposing roles in the development and progression of CVD. Conclusions: The exact mechanisms through which various ceramides contribute to CVD progression are still unknown. This study will help elucidate the role of specific ceramides during cardiac hypertrophy and suggests that drugs targeting specific sphingolipids can potentially be a viable treatment option for the prevention of CVD. Full article

Breast cancer (BC) is a primary cause of cancer-related mortality in women, making the development of novel therapeutic strategies essential. Altered lipid metabolism is a recognized hallmark of cancer, presenting a key therapeutic vulnerability. This study investigated the cytotoxic effects of the natural phenolic compound 2,3-DHBA on MCF-7 (luminal A) and MDA-MB-231 (triple-negative) human breast cancer cells and characterized the associated changes in their lipid profiles via an untargeted lipidomic approach. The in vitro cytotoxicity of 2,3-DHBA was assessed using the MTT assay at 24, 48, and 72 h against both cancer cell lines and non-cancerous L-929 fibroblasts. Following treatment with the 48-h IC₅₀ concentrations (8.61 mM for MCF-7, 5.84 mM for MDA-MB-231), total lipids were extracted and analyzed. The results showed that 2,3-DHBA exerted potent time- and dose-dependent cytotoxic effects against both BC cell lines, with significantly higher selectivity for cancer cells over healthy fibroblasts. The more aggressive MDA-MB-231 line exhibited greater sensitivity. The lipidomic analysis revealed that 2,3-DHBA induced profound cell-specific alterations across all major lipid classes, including fatty acids, glycerolipids (GLs), glycerophospholipids (GPs), and sphingolipids (SPs). These changes suggest a multi-pronged mechanism involving the disruption of membrane integrity through GP remodeling, the attenuation of survival signaling via the GL network, and a critical shift in the sphingolipid rheostat towards pro-apoptotic ceramide accumulation. This study establishes a direct link between the cytotoxic activity of 2,3-DHBA and its ability to comprehensively reprogram the cancer cell lipidome, highlighting its potential as a sophisticated metabolic modulator for breast cancer therapy. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) impacts nearly a quarter of the world’s population and encompasses a range of disease states, from simple steatosis to more advanced stages like metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and cirrhosis. A key driver of disease progression is mitochondrial dysfunction, characterized by impaired fatty acid oxidation and an overall decline in mitochondrial health. Emerging evidence has implicated ceramides—bioactive sphingolipids that serve roles in apoptotic pathways and as signals of nutrient excess—as important contributors to this dysfunction. Ceramide accumulation within mitochondria mirrors impairments seen in MASLD, specifically elevations in oxidative stress, disrupted fatty acid oxidation, and impaired mitochondrial dynamics. Ceramides may serve as an important molecular link between nutrient overload and mitochondrial dysfunction in the pathogenesis of MASLD. Given the limited availability of effective pharmacologic therapies for MASLD, lifestyle interventions like dietary modification and physical activity remain the cornerstone of disease management worldwide. In this review, we provide an overview of the current understanding of the role of ceramides in mediating the effects of diet and exercise on MASLD through their influence on mitochondrial health. Full article

Obesity and overweight have increasingly posed a serious challenge to public health security. This study systematically evaluated the reversal and regulatory effects of a composite flavonoid component mimicking the composition of adzuki bean flavonoids on high-fat diet (HFD)-induced obesity, related lipid metabolism disorders, and impaired liver function, based on lipid metabolomics and an HFD-induced obese mouse model. The results demonstrated that sustained HFD intake led to significant weight gain, increased adiposity index, dyslipidemia, and altered brown adipose tissue (BAT) cell status in mice, while also exerting adverse effects on hepatic lipid deposition and the lipid metabolic profile associated with liver fibrosis. Intervention with an adzuki bean flavonoid mimic (ABFM) effectively prevented further weight gain and ameliorated abnormal expression of serum lipid and liver function-related indicators. Furthermore, we found that ABFM alleviated HFD-induced liver damage and mitigated the whitening tendency of brown adipose tissue. Lipidomics analysis revealed that ABFM intake significantly improved abnormal hepatic lipid metabolic profiles, notably downregulating the expression levels of diacylglycerol (DG) and phosphatidylglycerol (PG), while markedly ameliorating sphingolipid metabolism disorders and ceramide (Cer) levels, which are highly associated with liver fibrosis. These findings further elucidate the mechanisms by which adzuki bean flavonoid components improve diet-induced obesity and associated liver injury, providing a theoretical basis for exploring safe and effective dietary intervention strategies based on plant flavonoids. Full article

Structural analysis of glycosphingolipids provides novel insights into organismal classification and reveals conserved functional roles that transcend taxonomic boundaries. To elucidate the structural characteristics of acidic glycosphingolipids (AGLs) in the adductor muscle of the Japanese giant scallop (Patinopecten yessoensis), AGLs were isolated and purified by column chromatography using anion exchange resin and silica gel. Structural characterization was performed using mass spectrometry, proton nuclear magnetic resonance spectroscopy, and immunological techniques. The sugar chain structure was identified as GlcA4Meβ1-4(GalNAc3Meα1-3)Fucα1-4GlcNAcβ1-2Manα1-3Manβ1-4Glcβ1-Cer, consistent with the mollu-series core reported for mollusks. In addition to uronic acid, the structure was distinguished by internal fucose and methylated sugars, features commonly found in bivalves. The presence of xylose in the sugar chains of AGLs was also suggested. In contrast, the ceramide moiety was composed primarily of fatty acids C16:0 and C18:0 and the long-chain base d16:1. This chemical structure provides valuable insights into the biological classification of P. yessoensis and the mollu-series glycolipids containing fucose and methylated sugars, which may serve as bioactive components shared across species in the phylum Mollusca and class Bivalvia. Full article

Cancer represents a leading cause of mortality globally, with its complex biological nature posing significant challenges for treatment. Central to cancer progression are molecular pathways that govern cellular function, among which protein phosphatase 2A (PP2A) plays a vital role. As a serine/threonine phosphatase, PP2A maintains cellular homeostasis by dephosphorylating a broad range of protein substrates and has emerged as a key tumor suppressor. However, PP2A activity can be physiologically inhibited by endogenous regulators such as the SE Translocation (SET) protein. Overexpression of SET has been associated with the loss of PP2A function, promoting hallmark features of cancer. Interestingly, targeting the PP2A/SET interaction has shown therapeutic potential. Indeed, inhibiting SET to reactivate PP2A may restore cellular regulation, induce apoptosis in tumor cells, and attenuate cancer progression. Research efforts have explored compounds such as the endogenous D-erythro-C18-ceramide and the drug fingolimod (FTY720), both known for their ability to reactivate PP2A. In this work, PP2A/SET complex models were generated through a computational approach and, using molecular docking, the interaction of potential SET inhibitors from a library of 26 alkoxy phenyl 1-propan-one derivatives (APPDs) was characterized. Additionally, absorption, distribution, metabolism, and excretion (ADME) predictions were performed to assess pharmacokinetic properties and therapeutic potential. Eventually, the predicted binding affinities were then correlated with biological data to assess the reliability of the models. These findings provide valuable insights into molecule–receptor interactions and lay the groundwork for developing inhibitors with encouraging therapeutic implications. Full article

Lipids are structurally diverse biomolecules that play essential roles in cellular function, energy storage, and signaling. The human lipidome, a dynamic and complex subset of the metabolome, is shaped by both endogenous factors, such as genetics, sex, age, and metabolic health, and exogenous influences like lifestyle, diet, and microbiota. Among these, diet stands out as one of the most modifiable and impactful determinants, influencing lipid composition across plasma, serum, and lipoprotein fractions. While traditional lipid profiling provides limited insight, lipidomics enables comprehensive characterization of lipid species, revealing mechanistic links between lipid metabolism and diseases such as cardiovascular disease (CVD), metabolic syndrome (MetS), and inflammatory disorders. This review explores: (1) the relationship between lipid profiles and CVD risk, (2) the internal and external modulators of the lipidome, and (3) current evidence on how specific dietary patterns, including Mediterranean, Nordic, low glycemic, and vegetarian diets, and individual nutrients such as omega-3 fatty acids (FAs), plant sterols, and mycoprotein, influence lipidomic profiles. Advances in lipidomics highlight that dietary fat quality, food matrix, and eating patterns can significantly modulate lipid species such as triacylglycerols (TAGs), ceramides (Cers), and phospholipids, with implications for cardiometabolic health. Notably, distinct responses are observed across plasma High-Density Lipoprotein (HDL) and Low-Density Lipoprotein (LDL) lipidomes, emphasizing the need for compartment-specific analyses. Understanding these diet-lipidome interactions offers promising avenues for precision nutrition and the development of lipid-based biomarkers for disease prevention and management. Full article

Background: Myristic acid (MA), a 14-carbon saturated fatty acid, serves as a precursor for the synthesis of non-canonical d16-sphingoid bases via its activated form, C14:0-CoA. However, its broader regulatory role in sphingolipid (SL) metabolism remains poorly defined. Methods: Using HepG2 cells treated with 50 μM MA, we found that sphingolipidomic analysis revealed reprogrammed sphingolipid metabolism. Results: In the canonical d18-SL pathway, MA directs its activated product C14:0-CoA into ceramide N-acyl chains and downstream metabolites—especially d18:1-C14:0 hexosylceramide. Concurrently, in the non-canonical d16-SL pathway, MA promotes d16-SL synthesis, especially d16:1-ceramides (Cer), d16:1-hexosylceramides (HexCer), and d16:1-C14:0 lactosylceramide. MA treatment further induced a coordinated shift in cellular sphingolipid pools, characterized by a significant increase in total ceramide levels (encompassing both d16- and d18-species) alongside concurrent reductions in total sphingomyelin (SM) contents. At the gene transcriptional level, MA significantly suppressed SPTLC2 mRNA expression while markedly upregulating SMPD2 and SMPD3 mRNA levels. Conclusions: Collectively, these findings position MA as a potent regulator of sphingolipid homeostasis, orchestrating dual pathway modulation: disrupting canonical d18-SL equilibrium through the selective enrichment of N-acyl C14:0-containing SLs, and activating non-canonical d16-SL synthesis. This dual pathway regulation reveals that dietary saturated fatty acids exploit sphingolipid subnetworks to regulate lipid metabolism. The interplay between dietary fatty acids and sphingolipid metabolism still requires deeper exploration. Our findings offer preliminary insights into their roles in regulating both normal and disease-associated lipid metabolism, setting the stage for subsequent mechanistic investigations. Full article

Background: Dark-base hair fibers with Curl Pattern (CP) types 2 and 3 from Asian and European populations, respectively, are very similar, although each presents different behaviors regarding water diffusion and cosmetic treatments, including in relation to dyeing. This study aims to identify the key drivers of water diffusion in hair, particularly the role of lipids in the diffusion processes. Methods: Virgin, externally delipidized, and internally delipidized CP2 and CP3 hair strands were subjected to Dynamic Vapor Sorption (DVS) and ATR-FTIR investigations. In addition, external and internal lipid extracts were quantified and analyzed via thin-layer chromatography–flame ionization detection (TLC/FID). Results: The results obtained indicate that CP2 hairs present lower water regain at all humidity steps and a different diffusion behavior depending on the humidity. Lower diffusion was obtained at low humidity and higher diffusion at high humidity. TLC/FID analyses indicate that CP2 fibers present a significantly higher amount of external lipids (1.4% vs. 0.4%) and internal lipids (3.2% vs. 2.6%) as compared with the CP3 fibers. Conclusions: The higher amount of internal lipids is mainly due to the greater amount of polar lipids (ceramides). Lipid extraction tends to modify the water content, leading to a more hydrated and less permeable lipid-depleted fiber. The similar water properties of the two types of lipid fiber support the fundamental role of lipids, even when present in small quantities, in the differentiation of hair types. This study highlights a potential link between the lipid composition of CP3 and CP2 hair fibers and their differences in behaviors regarding water diffusion, which could also explain varying responses to cosmetic treatments. Full article