Search Results (349)

Sphingolipids, a class of lipids, are widely present in the cell membranes of all eukaryotic and some prokaryotic organisms. These lipids play crucial roles in the formation of the lipid bilayer and are categorised into several groups, including sphingomyelins, ceramides, sphingosine-1-phosphate, and glycosphingolipids. In addition to their structural significance, sphingolipids also show bioactivity, regulating various signalling pathways involved in cell growth, differentiation, ageing, and apoptosis, and are closely associated with several chronic diseases, including obesity and type 2 diabetes mellitus. Notably, dysregulated sphingolipid metabolism contributes to obesity-related metabolic dysfunction through altered lipid accumulation, insulin signalling, organelle stress, and inflammation. This review summarises the various mechanisms and recent research advances related to sphingolipids and their association with obesity. It further examines how the metabolic effects of ceramides vary according to their acyl-chain length, enzyme of origin, tissue distribution, and metabolic context, as well as how adipose depot, sex, age, and metabolic phenotype influence the sphingolipid response to obesity. It further considers plant-derived sphingolipids as a compositionally distinct exogenous input to host sphingolipid pools, comparing their structural and enzymatic features with those of mammalian sphingolipids. Pharmacological, dietary, and lifestyle approaches that modify sphingolipid metabolism are also considered. Accordingly, the review summarises our current knowledge regarding the dietary occurrence, intestinal handling, and metabolic effects of sphingolipids and identifies the evidence gaps that currently limit conclusions regarding their relevance to obesity. Full article

Epstein–Barr virus (EBV) is causally associated with various malignancies and autoimmune diseases. It establishes a lifelong latent infection in host B-lymphocytes, and can strategically manipulate host cell metabolism and cell-to-cell communication via extracellular particles (EPs). While EBV-induced changes in fatty acid and mevalonate pathways are documented, the role of the sphingolipid network in this process remains poorly understood. In this study, we characterized both the EP and the cellular sphingolipid signatures of three EBV-infected (EBV+) lymphoblastoid cell lines compared to three EBV-negative (EBV−) counterparts. Lipidomic analysis revealed a profound metabolic redirection in EBV+ cells, characterized by reduced ceramide and sphingomyelin levels, and a significant upregulation of glycosphingolipids (GSLs), particularly hexosylceramide and globotrialosylceramide. Furthermore, EBV+ cells released larger, more heterogeneous EPs that are significantly enriched in GSLs and in the viral non-coding RNA EBER1. Our findings suggest that EBV-induced reshaping of sphingolipid metabolism correlates with altered physical properties of the secretome, potentially contributing to viral pathogenesis and microenvironmental manipulation. Full article

Background/Objectives: Obesity and its metabolic comorbidities, including dyslipidemia and non-alcoholic fatty liver disease (NAFLD), are a growing global health burden, and current pharmacotherapies have limited efficacy and notable adverse effects. The gut microbiome has emerged as a key regulator of host metabolism, and its dysregulation is implicated in obesity. This study investigated the therapeutic potential of Piper sarmentosum Roxb. aqueous extract (PSRW) on metabolic dysfunction and gut microbiota composition in a high-fat diet (HFD)-induced obese rat model. Methods: HFD-induced obese male Wistar rats received PSRW, simvastatin, or their combination for 12 weeks. Serum lipids (TC, TG, HDL, LDL), liver enzymes (AST, ALT), and renal markers were measured, and gut microbiota were profiled by 16S rRNA (V4) sequencing with PICRUSt2/KEGG functional prediction. The phenolic composition of the same extract was characterized by HPLC in a companion study. Results: PSRW did not cause weight loss but significantly lowered serum TC, AST, and ALT, with efficacy comparable to simvastatin and significantly lower TG than control, though not significantly different from HFD. Co-administration of PSRW and simvastatin produced a greater reduction in TC and liver enzymes than either agent alone. HFD shifted microbial community structure and enriched pro-inflammatory phyla such as Desulfobacterota; PSRW partially reversed these changes, suppressing obesogenic Lachnospiraceae genera while enriching beneficial microbes including Dwaynesavagella, and functionally reprogrammed taxa such as Kineothrix and Muribaculum from detrimental to protective associations. HFD enriched microbial glycosphingolipid biosynthesis, whereas the PSRW simvastatin combination uniquely enhanced glycine, serine, and threonine metabolism. Conclusions:P. sarmentosum extract ameliorates HFD-induced dyslipidemia and hepatotoxicity, and these effects are accompanied by remodeling of the composition and predicted functional capacity of the gut microbiome. Its ability to act in combination with statins highlights its potential as a candidate complementary therapy for hyperlipidemia and NAFLD. Full article

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A deficiency, leading to glycosphingolipid accumulation and progressive organ damage. Beyond substrate storage, low-grade inflammation and complement activation have been increasingly implicated in FD pathogenesis, yet a comprehensive characterization of this immuno-inflammatory profile is lacking. In this exploratory cross-sectional study, fifteen patients with FD and fifteen age- and sex-matched healthy controls (HCs) were assessed using a broad panel of systemic inflammatory, humoral immunity/complement, hematological, and endothelial biomarkers, integrated through univariate analysis (Cliff’s delta, δ), penalized least absolute shrinkage and selection operator (LASSO) regression, and unsupervised hierarchical clustering. Fibrinogen (δ = 0.60, 95% confidence interval (CI) 0.24–0.88), sTNFR2 (δ = 0.48, 95% CI 0.08–0.80), complement C4 (δ = 0.53, 95% CI 0.13–0.84), and lymphocyte count (δ = 0.52, 95% CI 0.15–0.85) showed the largest between-group effect sizes among the immuno-inflammatory biomarkers assessed, with higher levels in FD. Fibrinogen and sTNFR2 were the most stable predictors in LASSO bootstrap resampling (selected in 75.0% and 69.5% of iterations, respectively), and unsupervised clustering segregated FD from HCs with high accuracy (90% FD enrichment in the high-biomarker cluster; p < 0.001). These convergent findings indicate that FD is characterized by a distinct low-grade immuno-inflammatory profile dominated by innate immune and complement activation. Full article

Fabry disease is a rare X-linked lysosomal storage disorder characterized by progressive glycosphingolipid accumulation and multisystem organ involvement. Globotriaosylsphingosine (Lyso-Gb3) has emerged as a promising biomarker of disease burden; however, its relationship with validated clinical severity scoring systems remains incompletely understood. This study aimed to evaluate the associations between serum Lyso-Gb3 concentrations and the overall scores of three validated clinical severity assessment tools—the Mainz Severity Score Index (MSSI), Disease Severity Scoring System (DS3), and Fabry Stabilization Index (FASTEX)—in patients with Fabry disease. This retrospective observational study included 18 adult patients with genetically and/or enzymatically confirmed Fabry disease who were regularly followed at a tertiary referral center. Baseline and 12-month serum Lyso-Gb3 concentrations, MSSI scores, DS3 scores, and FASTEX values were evaluated. Correlations between Lyso-Gb3 concentrations and disease severity scores were assessed using Spearman correlation analysis. Exploratory sex-stratified analyses and univariable linear regression analyses were additionally performed to examine associations with disease severity; these analyses were considered hypothesis-generating because of the limited sample size. Median baseline Lyso-Gb3 concentration was 6.77 ng/mL (IQR: 3.94–50.10), median baseline MSSI score was 27.0 (IQR: 16.3–34.3), and median baseline DS3 score was 19.0 (IQR: 15.3–22.0). Significant reductions were observed in Lyso-Gb3 concentrations, MSSI scores, and DS3 scores after 12 months of follow-up (all p < 0.001). Baseline Lyso-Gb3 concentrations demonstrated strong positive correlations with baseline MSSI (ρ = 0.845, p < 0.001) and baseline DS3 scores (ρ = 0.854, p < 0.001), while no significant correlation was observed with FASTEX scores (ρ = −0.117, p = 0.644). Similar significant correlations were identified between 12-month Lyso-Gb3 concentrations and corresponding MSSI (ρ = 0.812, p < 0.001) and DS3 scores (ρ = 0.697, p = 0.001). In sex-stratified analyses, significant correlations between Lyso-Gb3 and disease severity scores were observed predominantly among male patients. In exploratory univariable linear regression analyses, baseline Lyso-Gb3 concentrations were strongly associated with baseline MSSI (R² = 0.758) and DS3 scores (R² = 0.579); however, these estimates should be interpreted cautiously because of the small sample size. Serum Lyso-Gb3 concentrations were strongly associated with MSSI and DS3 scores in this small retrospective cohort, whereas no statistically significant association was observed with FASTEX. The observed associations, particularly those derived from sex-stratified and regression analyses, should be considered exploratory and hypothesis-generating because of the limited sample size. Larger prospective multicenter studies are required to confirm the magnitude, independence, and clinical applicability of these relationships. Full article

Glycosphingolipids (GSLs) are glycoconjugates in which a short and heterogeneous saccharide chain is attached to a lipid moiety called ceramide. Based on their sugar backbone, mammalian GSLs are primarily grouped into the ganglio-, lacto-/neolacto-, and globo-series. Sialic acid—containing GSLs are known as gangliosides. Complex ganglio-series gangliosides are particularly abundant in the brain, whereas simple ganglio-series gangliosides, as well as those belonging to other series or neutral GSLs, are less abundant and typical of non-neural tissues. Congenital disorders in the biosynthesis of the lipid moiety of sphingolipids (SLs) result from defects in enzymes and proteins involved in ceramide biosynthesis and transport. Congenital disorders in the biosynthesis of the sugar chain of GSLs specifically affect ganglio-series ganglioside biosynthesis and are caused by pathogenic variants in GM3 synthase (ST3GAL5) or GM2/GD2/asialo-GM2 synthase (B4GALNT1). Defective variants of the sialyltransferase ST3GAL3 and the galactosyltransferase B4GALT5 have been reported and proposed to impair GSL biosynthesis. The occurrence of these syndromes has provided new insights into the physiological and pathological roles of GSLs. Most of these disorders are associated with completely inactive enzyme variants, leading to severe neurological syndromes. Only a few cases highlighted variants that retained partial activity, resulting in milder phenotypes, which included non-syndromic intellectual disability. It is therefore conceivable that many undiagnosed patients, with mild neurological symptoms, may carry variants retaining residual enzyme activity, insufficient to ensure normal levels of brain GSLs. The purpose of this article is to encourage clinicians to look for additional GLS hereditary disorders associated with a milder phenotype. We also hope to boost future investigations by highlighting the most critical issues emerging from recent literature on SL and GSL biosynthesis and their related defects. Full article

Selective insertion of lipid probes from the external milieu into raft regions of the cell membrane would enable targeted studies of raft molecular organization and of raft-associated peptide and glycan components. In this work, we compared the insertion of several synthetic glycolipids into raft and non-raft membrane areas of Raji and EA.hy 926 endothelial cells. A glyco-cholesterol derivative in which the 3β oxygen atom is replaced by NH was selected as a candidate raft-selective probe. Although this glycolipid also inserted into other membrane areas, its raft-to-non-raft distribution ratio was higher than that of its O-analog (natural 3β-O-cholesterol). Full article

Fabry disease is an X-linked lysosomal storage disease that leads to the intracellular accumulation of glycosphingolipids in many tissues and fluids, including the kidneys. We report a single family with Fabry disease that includes seven patients carrying the pathogenic variant c.797A>C in the GLA gene, with remarkable variability in kidney involvement, assessed based on clinical, biological, and histological data. The patients were monitored for 2–9 years, and all received enzyme replacement therapy. Kidney involvement was variable and included severely decreased GFR with significant proteinuria, mildly to moderately decreased GFR with proteinuria, mildly decreased GFR with microalbuminuria or normoalbuminuria, hyperfiltration with normoalbuminuria, and preserved kidney function. All patients who underwent kidney biopsy presented with Fabry-specific lesions and, in some cases, chronic histological damage. This study provides valuable insights into kidney involvement evaluated through kidney biopsy, personalized management strategies for family members according to their phenotype, and long-term follow-up of kidney function. We underscore the importance of molecular screening of the GLA gene in all family members for early identification of the disease and early initiation of specific treatments that can prevent or delay the progression of this disease. Full article

Background: While sphingolipid alterations in obesity and metabolic syndrome (MS) have been extensively studied in plasma, their intracellular regulation within immune cells remains poorly characterized. Here, we introduce a PBMC-based sphingolipidomic approach that provides a novel immunometabolic perspective beyond traditional analyses of circulating lipids. Methods: Targeted sphingolipidomics was performed in peripheral blood mononuclear cells (PBMCs) from normal-weight healthy (NWH) subjects, and patients with essential obesity (EO) or MS. Multivariate integration (principal component analysis [PCA], hierarchical clustering, and partial least squares discriminant analysis [PLS-DA]) was combined with selected univariate models to explore lipid patterns and associations with cardiometabolic variables. Results: PBMC profiling identified a selective intracellular sphingolipid signature, with 10 species significantly altered across groups (FDR < 0.05), including ceramides, dihydroceramides, glycosphingolipids, and ceramide ratio indices. PCA showed that the first two components explained ~72% of total variance, with PC2 driving group separation. EO and MS displayed partial overlap, consistent with a shared metabolic phenotype, while both differed from NWH. Multivariate models highlighted ceramide ratios (e.g., CER16/24, and CER18/24) as key discriminators. Associations with cardiometabolic variables were limited and modest (adjusted R² ≈ 0.06–0.09), indicating that lipid alterations reflect integrated metabolic dysregulation rather than single clinical drivers. Conclusions: PBMC-based sphingolipidomics reveals a distinct intracellular immunometabolic remodeling in EO and MS, capturing aspects not detectable in plasma. These findings support the relevance of immune cell lipid profiling as a potential source of integrative biomarkers and provide insight into immune–metabolic crosstalk underlying metabolic disease. Full article

Glucosylceramide synthase (GCS) catalyzes ceramide glycosylation in response to cell stress that produces glucosylceramide and other glycosphingolipids. GCS overexpression is a cause of drug resistance and enriches cancer stem cells (CSCs) during cancer chemotherapy. Previous studies showed that GCS modulates the expression of p53 mutants and oncogenic gain-of-function (GOF) in heterozygous knock-in cell models (TP53 R273H^−/+). However, it is unclear whether GCS can modulate the effects of homozygous p53 mutations, which are common in many cancer cases. We report herewith that inhibition of GCS, via UGCG knockout and using an inhibitor (Genz-161), effectively re-sensitizes drug resistance and diminishes CSCs in colon cancer cells carrying the homozygous p53 R273H mutation. In aggressive WiDr cells carrying TP53 R273H mutation, knockout of UGCG gene using CRISPR/Cas9 editing or inhibition of GCS with Genz-161 sensitized cancer cells to oxaliplatin, irinotecan and paclitaxel. With decreased ceramide glycosylation in lipidomic profiling, both UGCG knockout and Genz-161 treatments substantially decreased wound healing, and diminished CSCs and tumor growth under chemotherapy. Interestingly, inhibition of RNA m⁶A methylation by neplanocin A markedly increased p53 function and reversed drug resistance. Mechanistic investigation revealed that GCS inhibition downregulated methyltransferase-like 3 (METTL3) expression and decreased RNA-m⁶A modification on mutant p53 R273H effects. Altogether, our findings demonstrate that ceramide glycosylation promotes METTL3 expression and RNA m⁶A methylation in response to drug-induced stress, thereby promoting mutant p53 expression and associated GOF. Conversely, inhibition of GCS can diminish CSCs and drug resistance via reduction in m⁶A modification and advance of p53-assocaited tumor suppressive function. GCS inhibition is an achievable approach for mutant cancer treatment. Full article

Background: Sialylation, a key terminal glycosylation modification, plays a pivotal role in tumor progression and immune evasion. The sialyltransferase ST3GAL4 is implicated in individual cancers, but its pan-cancer landscape and systemic associations remain undefined. Methods: We performed an integrated multi-omics analysis using transcriptomic, proteomic, genomic, DNA methylation, and tumor microenvironment datasets from TCGA, CPTAC, GTEx, and other public resources. Immune associations were evaluated via TIMER2.0 and TISIDB. Experimental validation included immunofluorescence staining for ST3GAL4 protein in human tumor specimens. Results: ST3GAL4 exhibited pervasive, lineage-specific dysregulation across cancers. Elevated expression correlated with adverse prognosis, genomic instability, and specific RNA modification patterns. Tumor microenvironment analyses revealed significant associations: ST3GAL4 expression positively correlated with cancer-associated fibroblast and endothelial cell infiltration but was inversely associated with cytotoxic T-cell abundance. Functional enrichment implicated ST3GAL4 within glycosphingolipid metabolism and glycan biosynthetic pathways. In experimental models, its expression demonstrated context-dependent modulation following cytokine stimulation and immunotherapy. Immunofluorescence confirmed tumor-specific protein expression and its spatial co-occurrence with stromal and immune cell markers. Conclusions: This multi-omics study delineates a comprehensive pan-cancer atlas of ST3GAL4, establishing its association with aggressive tumor behavior, an immunosuppressive microenvironment, and core glycosylation pathways. These findings position ST3GAL4 as a potential cross-tumor node linking sialylation to immune evasion, providing a rationale for future mechanistic and therapeutic exploration. Full article

The gut–skin axis is increasingly implicated in psoriasis pathogenesis, yet the cross-compartment convergence of molecular programs remains incompletely defined. We constructed a conceptual “Triple-Hit” multi-omics framework by integrating five independent public datasets spanning gut microbial functional remodeling (shotgun metagenomics), systemic immune cell methylomes (PBMC and CD8+ T-cell EPIC 850K), and lesional skin regulatory layers (miRNA and bulk RNA-seq). In the gut compartment, functional profiles exhibited a selective reduction in microbial lipid catabolic potential, including decreased fatty acid degradation and a lowered composite lipid degradation score, alongside heterogeneous shifts across SCFA-associated metabolic pathways. Systemically, PBMC methylomes revealed widespread regional remodeling (45,396 DMRs) enriched for membrane-proximal signaling and cytoskeletal programs, while CD8+ T cells showed specific epigenetic alterations in lipid- and glycosphingolipid-associated loci, suggesting a systemic metabolic–epigenetic alignment. In the skin, we identified a compact miRNA signature (168 DE-miRNAs) and a mechanistically interpretable, directionality-constrained miRNA–mRNA bridge that aligns with an AMP-dominant inflammatory transcriptome, consistent with reduced post-transcriptional restraint. Collectively, these findings support a convergent multi-omics framework linking putative microbial metabolic remodeling, systemic immune priming, and cutaneous effector programs. This study provides a systems-level perspective on psoriasis pathogenesis, highlighting the metabolic–epigenetic–transcriptional convergence as a potential avenue for therapeutic intervention. Full article

Glycosphingolipids are amphiphilic compounds that feature sugar or glycan moieties installed onto a ceramide lipid. The synthesis of glycosphingolipids by members of the human gut microbiome, and their known immune stimulating activity, have made them of interest for potential pharmaceutical roles. However, the known diversity of glycosphingolipid glycans in bacteria remains limited, highlighting the need to isolate novel glycosphingolipid-producing organisms as a source of these compounds. The order Sphingomonadales, one of the major clades of sphingolipid producing bacteria, conserves a serine palmitoyltransferase (SPT) enzyme needed for the initial biosynthetic step in sphingolipid production which can be targeted as part of isolation efforts. With these bacteria known to live in diverse environments such as soil microbiomes, soap scum biofilms, and cyanobacterial microbiomes, there are many environments to target for the isolation of these bacteria. In this work, we designed a set of polymerase chain reaction (PCR) primers for the isolation of diverse Sphingomonadales strains by targeting the SPT gene (spt), which we used to isolate strains from the genera Sphingomonas and Novosphingobium in soil, soap scum biofilms, and xenic cyanobacterial cultures. In these efforts, streptomycin improved the encounter rate, as represented by the SPT assay true-positive rate. Our isolates represent novel genomic space: with genomes from both genera that have low similarity to known genomes, suggestive of novel species, while several novel plasmids were also missing known marker sequences. Full article

Ganglioside GM3, a fundamental glycosphingolipid on the mammalian cell surface, is a key regulator of transmembrane signaling and cellular recognition. In oncology, GM3 acts as a tumor suppressor by modulating the activity of various receptor tyrosine kinases (RTKs) and their downstream pathways. Recent studies highlight its function in the tumor microenvironment (TME), specifically its ability to impede pathological angiogenesis. This review summarizes the molecular mechanisms by which GM3 interferes with pro-angiogenic signaling, such as the VEGF/VEGFR axis, and discusses how this inhibition can be used for therapy. We explore the clinical potential of GM3-based strategies, including monoclonal antibodies and cancer vaccines, discussing the potential of targeting GM3 to reshape the TME and suppress tumor-associated vascularization. Full article

Background: Obesity is associated with hypothalamic dysfunction characterized by neuroinflammation and altered transcriptional programs. While resveratrol (RSV) has shown beneficial metabolic effects in peripheral tissues, its central effects on hypothalamic gene expression in obesity remain poorly understood. This study provides the first predictive transcriptomic analysis of the hypothalamic response to RSV in a mouse model of diet-induced obesity. C57BL/6 male mice were fed a high-fat diet (HFD) to induce obesity and then subsequently treated with RSV. Methods: Hypothalamic RNA was extracted and analyzed using RNA sequencing. Differentially expressed genes (DEGs) were identified and functionally analyzed through KEGG pathway analysis. Results: Although RSV did not significantly alter body weight, it reversed the expression of several HFD-induced DEGs. Key genes modulated by RSV included Aqp7, Ccl27a, Lta, Rilp, M6pr-ps, C1ra, Snail1, Gbgt1, and Ppargc1b, which are involved in inflammation, lipid metabolism, mitochondrial function, and immune signaling. Pathway enrichment analysis revealed significant modulation of TNF and NF-κB signaling, cytokine–cytokine receptor interactions, glycosphingolipid biosynthesis, and phagosome-related activity. Remarkably, 45% of RSV-responsive transcripts were non-coding RNAs, suggesting epigenetic regulation. Conclusions: RSV reprograms the hypothalamic transcriptome in obesity, targeting both coding and non-coding RNAs associated with inflammation and metabolic regulation, independently of weight loss. These findings identify RSV as a potential central modulator of metabolic dysfunction and highlight the hypothalamus as a promising therapeutic target in obesity-related disease. Full article