Effect of very long-chain lipids on the organization of biological membranes: A simulation study.

Hot air drying is widely used in edible mushroom processing, but often leads to quality changes, including browning and flavor changes. This study focused on Phallus impudicus (P. impudicus), combining dynamic monitoring of browning-related indicators with lipidomics technology to systematically investigate the mechanism by which lipid changes influence quality during hot air drying. The results showed that drying significantly altered lipid metabolism. Encompassing 28 subclasses, five major lipid categories were identified: glycerophospholipids (GP), glycolipids (GL), sphingolipids (SP), isoprenylglycolipids (PR), and fatty acids (FA). From among these, the total content of GP remained the highest and increased significantly after drying, whereas the contents of GL and FA decreased markedly. Hydrolysis of structural lipids led to the collapse of cellular structure, and the levels of hydrolyzed lipids phosphatidic acid (PA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), and lysophosphatidic acid (LPA) increased significantly after drying, which may adversely affect long-term storage. Furthermore, increased lipid unsaturation intensified browning, and lipid oxidation also promoted the formation of volatile flavor compounds. Overall, this lipidomic research demonstrated that hot air drying determines the final quality and flavor profile of dried P. impudicus through coordinated mechanisms involving membrane lipid oxidation, structural membrane damage, browning, and flavor generation. These findings provided a new insight into the mechanism of quality changes and a theoretical basis for quality improvement and process regulation for dried edible mushroom products.

Grass carp (Ctenopharyngodon idellus), China's most valuable freshwater aquaculture species, exhibits growth and nutrient utilization efficiency that are highly dependent on feed quality. After macronutrient balancing, nano-selenium (nano-Se) supplementation becomes critical for enhancing health and profitability. Although nano-Se has been observed to alleviate oxidative stress and inflammation, the molecular mechanisms underlying its hepatoprotective effects following long-term administration remain systematically uncharacterized. To fill this gap, this study utilized transcriptomic and metabolomic technologies to investigate the beneficial alterations in the liver of grass carp following 30 weeks of nano-Se feeding. Ninety juvenile grass carp were randomly allocated to either a control group (basal diet) or a nano-Se group (basal diet + 0.6 mg/kg nano-Se); livers were harvested for omics analyses at the end of the 30-week feeding period. Transcriptomic analysis initially identified 533 differentially expressed genes (110 up-regulated, 423 down-regulated). Gene Ontology (GO) functional enrichment analysis indicated that these genes were primarily involved in biological processes such as metabolic processes, biological regulation, and stress response, suggesting that nano-Se broadly regulates hepatic metabolic activity and stress adaptability. Further Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed significant enrichment in the "protein digestion and absorption" pathway. Key genes in this pathway, including collagen VI α1/2 (COL6A1/2), elastase ELA2/3 L, and amino acid transporters SLC3A1 and SLC7A9, were significantly down-regulated, indicating that nano-Se may mitigate oxidative stress-induced micro-damage in hepatocytes, thereby reducing the liver's demand for damage repair and fibrotic processes. Metabolomic analysis detected 1404 metabolites, with 267 differentially metabolites (198 up-regulated, 69 down-regulated) spanning multiple metabolic categories such as amino acids, lipids, and cofactors. Glycerophospholipids (GP) and sphingolipids (SP) were significantly up-regulated, while bile acid metabolites were down-regulated. Related metabolic pathway analysis showed that "glycerophospholipid metabolism" and "linoleic acid metabolism" pathways were significantly activated. Glycerophospholipids and sphingolipids are major components of cell membranes; their increased levels may enhance the integrity and stability of hepatocyte membranes. Concurrently, enhanced linoleic acid metabolism may contribute to energy supply and inflammation regulation. These changes collectively suggest that nano-Se may improve hepatic redox homeostasis and metabolic balance by remodeling hepatocyte membrane lipid composition and optimizing energy metabolism pathways. Collectively, nano-Se alleviates oxidative injury and maintains metabolic homeostasis in the grass-carp liver through the coordinated modulation of amino-acid, lipid and immune-related pathways, thereby providing a theoretical basis for its long-term, safe application in aquafeeds; future work is still required to verify these findings by measuring antioxidant-enzyme activities and to optimize dosage through graded-dose experiments.

An integrative approach to studying sphingolipid metabolism reveals p53 as a master regulator of the pathway.

Emotional well-being is a multifactorial concept, which comprises not only life quality of human individuals, but also their mental and physical health. It encompasses several key parameters, many of which have behavioral representation in daily life. These include finding positive meaning of life events, ability to maintain supportive and caring social interactions, reward-oriented behavior, and many others. It is well-known that the behavioral phenotype is tightly bound to certain physiological and metabolic factors, among which sphingolipid (SL) balance of the organism and especially central nervous system might play an important role. Recent research proposes that SLs mediate multiple components of emotional well-being. The most abundant brain SL types, ceramides and gangliosides, dynamically shape the composition of protein carrying cellular membranes and overall neuronal plasticity. Multiple studies show the contribution of SLs to normal brain functioning and corresponding beneficial behavioral phenotypes, such as stress resilience, cognitive performance, and social interactions, which determine emotional well-being. On the other hand, an imbalance in SL metabolism affects normal functioning of cells and thus contributes to the development of several psychiatric disorders, such as depression, anxiety, cognitive decline, schizophrenia, and others. SLs are suggested as a potentially new mechanism of the key behavioral manifestations of emotional well-being, which might be further investigated as new biomarkers of life quality as well as physical and mental resilience.

Lipidomic analysis of Beijing-You chicken breast muscle during growth process reveals lipid changes and key lipid molecules associated with intramuscular fat.

Distinct serum metabolic profiles with supportive diagnostic value in differentiating tuberculosis and Mycobacterium avium complex pulmonary disease.

Cordyceps sinensis is a traditional medicinal fungus known for its immunomodulatory properties. Its bioactive sphingolipids (SPLs) exhibit antitumor potential, though their mechanisms remain poorly understood. This study aimed to identify the active SPLs from C. sinensis and investigate their synergistic effects with αPD-1 (anti-programmed death-1 antibody) therapy. SPLs were isolated from C. sinensis via UPLC-MS/MS-guided purification. The antitumor efficacy and immunomodulatory synergy with αPD-1 were assessed using a Lewis lung carcinoma (LLC) tumor-bearing mouse model and invitro co-culture systems. Mechanisms involving sphingosine kinase 1 (SphK1) were explored through cellular thermal shift assays, enzymatic activity tests, surface plasmon resonance, molecular docking, and molecular dynamics simulations. The combination of SPLs and αPD-1 enhanced antitumor immunity by promoting CD8+ T-cell infiltration and suppressing PD-L1 expression in the tumor microenvironment. Metabolomic and transcriptomic analyses revealed that SPLs shifted the sphingolipid balance by targeting the SphK1-mediated ceramide/sphingosine-1-phosphate (Cer/S1P) axis, promoting antitumor immunity. A novel ceramide, cordysinamide A, was identified as a key bioactive constituent and shown to bind directly to SphK1 (IC₅₀ = 28.45 μM; KD = 14.4 μM), stabilizing its structure and inhibiting S1P production. This shift increased IL-2 and IFN-γ levels and sensitized tumors to αPD-1 treatment. This study identifies C. sinensis-derived SPLs as key bioactive components that overcome αPD-1 resistance by targeting the SphK1-mediated Cer/S1P balance. Our findings propose a natural product-based strategy to change immunosuppressive metabolism in non-small cell lung cancer.

ToF-SIMS revealing sphingolipids composition in extracellular vesicles and paternal β-cells after persistent hyperglycemia.

Sphinganine-induced lysosomal membrane permeabilization: Interplay with subcellular oxidative levels.

Rice-derived glucosylceramides (GlcCer) consist of multiple molecules that comprise different types of sphingoid bases and saturated fatty acids. These GlcCer are critical for epidermal barrier function and exert anti-melanogenic effects. Regarding their effects on the immune system, a dead cell-derived GlcCer [d18:2/24:1] was shown to enhance the activation of antigen-presenting cells via Mincle receptors. However, the immunomodulatory effects of rice-derived GlcCer have yet to be examined. Therefore, we herein investigated the effects of rice-derived GlcCer on dendritic cell (DC) activation. Among rice-derived GlcCer, GlcCer[d18:2(4E,8Z)/18:0] (10μM) significantly enhanced IL-6 production by iMylc DC established from induced pluripotent stem cells. CD40 and CD80 expression was significantly upregulated by GlcCer[d18:2(4E,8Z)/18:0] in aMylc DC derived from human peripheral blood mononuclear cells. In a toll-like receptor (TLR) competitive binding assay using TLR antagonists, GlcCer[d18:2(4E,8Z)/18:0] bound to TLR2 and 4. The antigen-presenting abilities of GlcCer[d18:2(4E,8Z)/18:0] and GlcCer[d18:2(4E,8Z)/26:0] were confirmed by the mixed lymphocyte reaction test, which showed a significant T-cell proliferative effect. These results indicate that GlcCer[d18:2(4E,8Z)/18:0] activated DC being sensed by TLR2 and 4 and induced T-cell responses through the expression of CD40 and CD80. Therefore, the limited GlcCer molecules in rice appear to promote innate immune responses on DC.

Ceramides are central to stratum corneum barrier organization and hydration. Beyond topical replenishment, ceramide-stimulating strategies increasingly aim to enhance endogenous ceramide biosynthesis, processing, and homeostatic remodeling in coordination with keratinocyte differentiation. In this review, we summarize the three major metabolic routes that shape epidermal ceramide output—de novo synthesis, salvage, and sphingomyelin hydrolysis—and organize representative bioactive ingredients by their primary molecular targets rather than by origin. Specifically, we map ingredients to tractable regulatory nodes, including transcriptional “liposensors” (PPAR/LXR), the induction of biosynthetic/elongation and processing enzymes (e.g., SPT, CerS3, ELOVL4), the provision of structural substrates and precursors (e.g., linoleate-rich lipids and glycosylceramides), salvage-pathway sphingoid bases that can reshape ceramide subclass output, and metabolic sensing/stress-response pathways centered on AMPK–mTOR–SIRT1/autophagy. Across these mechanisms, agents spanning botanical and fermented extracts, vitamins, sphingoid intermediates, lipid precursors, and pathway modulators (including autophagy-focused probes) have been reported to increase ceramide abundance and, in some contexts, favor barrier-relevant ultra-long-chain species and ω-O-acylceramides that support lamellar organization and the corneocyte lipid envelope. Translational and clinical studies in dry, sensitive, and aged skin generally associate such interventions with improved barrier function and reduced dryness. Aligning ingredient selection with defined biosynthetic and processing checkpoints—and verifying outcomes with lipidomics alongside clinical endpoints—may accelerate the development of evidence-based, ceramide-stimulating cosmetics.

Lipids are essential for the skin, playing a crucial role in forming plasma membranes and maintaining the skin’s permeability barrier and hydration. Intercellular lipids fill the spaces between corneocytes and contribute to the barrier function. Lipid abnormalities in the skin have been observed in many skin diseases, including atopic dermatitis and psoriasis. However, the specific localization and roles of skin lipids at particular sites remain incompletely elucidated due to the limited methods available for comprehensive lipid analysis. This study aims to precisely determine the localization of skin lipids, especially intercellular lipids, and investigate their roles and metabolism using mass spectrometry imaging (MSI). We conducted high-resolution (spatial resolution: 5 µm) matrix-assisted laser desorption/ionization (MALDI)-MSI on the lower back and buttocks and created overlay images of skin lipids to clarify their precise localizations. Ceramide was localized in the outermost layer among intercellular lipids. Cholesterol and free fatty acids were present in the stratum corneum but were at trace levels in the outermost layer. Cholesterol sulfate was abundant in the granular layer and gradually decreased in the stratum corneum, promoting desquamation. Phospholipids were confined to the viable epidermis (stratum corneum-/epidermis+), which forms the plasma membrane. A significant increase in mass intensity in the stratum corneum was observed for ceramide, sphingoid base, cholesterol, and free fatty acids, along with a decrease in phospholipids compared with those in the viable epidermis, based on region of interest analysis (Mann–Whitney test, p < 0.0005). We clarified the precise localization of skin lipids, particularly intercellular lipids. Our findings supported the reported functions of skin lipids at specific sites. Skin lipids are metabolized to form intercellular lipids in the stratum corneum, which are essential for the skin barrier. Our current lipid localization data serve as a baseline, or healthy control dataset, for future MSI-based lipid biomarker research in disease groups.

Lung adenocarcinoma (LUAD), the most prevalent subtype of non-small cell lung carcinoma (NSCLC), commonly metastasizes to the brain, particularly in advanced stages. Since brain metastases (BMs) are a leading cause of morbidity and mortality in LUAD patients, their early detection is critical, necessitating the identification of reliable biomarkers. Gangliosides (GGs), a class of bioactive glycosphingolipids involved in cell signaling, adhesion, and immune regulation, have emerged as promising candidates for diagnostic and therapeutic targeting in LUAD-associated brain metastases (BMLA). In this context, ion mobility spectrometry mass spectrometry (IMS-MS) was employed here to analyze GG alterations in BMLA tissues compared to healthy cerebellar control. The results revealed marked differences, including a reduction in the total number of species, altered sialylation profiles, and variations in fatty acid chain length and sphingoid base hydroxylation. GM3, a monosialodihexosylganglioside, was significantly overexpressed in BMLA, supporting its role in tumor progression via immune evasion and oncogenic signaling. Elevated levels of the brain-specific GT1 ganglioside further point to its possible role as a metastasis-associated biomarker, while the presence of asialogangliosides, absent in normal brain, suggests adaptation to the brain microenvironment. Structural modifications such as O-acetylation, fucosylation, and CH3COO- were more frequent in BMLA, being associated with aggressive tumor phenotypes. Ceramide profiles revealed increased levels of proliferative C16- and C24-ceramides and decreased pro-apoptotic C18-ceramide. Additionally, GM3(d18:1/22:0) and GD3(d18:1/16:0), identified as potential BMLA biomarkers, were structurally characterized using (-) nanoelectrospray ionization (nanoESI) IMS collision-induced dissociation tandem MS (CID MS/MS). Collectively, these findings highlight the clinical potential of GGs for early diagnosis and targeted therapy in BMLA.

Plants recognize pathogen-associated molecular patterns via pattern recognition receptors, leading to the activation of pattern-triggered immunity in response to pathogen attack. Phytophthora infestans ceramide D (Pi-Cer D) is a sphingolipid from the oomycete pathogen P. infestans. Pi-Cer D is cleaved by the plant extracellular ceramidase NEUTRAL CERAMIDASE 2 (NCER2), and the resulting 9-methyl-branched sphingoid base is recognized by the plant receptor RESISTANT TO DFPM-INHIBITION OF ABSCISIC ACID SIGNALING 2 (RDA2) at the plasma membrane to transduce a defense signal. However, additional components are likely involved in sphingolipid recognition, which remain to be identified. Here, we employed a screen based on Lumi-Map technology to look for Arabidopsis (Arabidopsis thaliana) mutants with altered defense responses to Pi-Cer D. We identified three mutants showing diminished responses to Pi-Cer D and elf18, each carrying mutations in STAUROSPORIN AND TEMPERATURE SENSITIVE 3-LIKE A (STT3A), which encodes an oligosaccharyltransferase. The stt3a mutants exhibited higher susceptibility to the pathogen Colletotrichum higginsianum than the wild type. In stt3a mutants, the molecular mass of NCER2 and RDA2 proteins appeared smaller, indicating that STT3A is involved in posttranslational modification of the proteins. An enzymatic deglycosylation assay revealed that NCER2 and RDA2 are N-glycosylated. These findings suggest that STT3A contributes to plant immunity via posttranslational modification of proteins including NCER2 and RDA2. [Formula: see text] Copyright © 2025 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Sphingolipids play key roles in cellular systems both as membrane components and as signaling molecules. Their biosynthesis, which occurs in the endoplasmic reticulum (ER), begins with the condensation of an amino acid, typically serine, and a fatty acyl-CoA. Under certain pathological conditions, alanine can be substituted for serine in the condensation reaction, producing 1-deoxysphingolipids, which lack the 1-hydroxyl group on the sphingoid base. Unlike typical sphingolipids, 1-deoxysphingolipids are unable to accept a head group modification, which alters their metabolic processing and prevents their canonical degradation. The accumulation of these “headless” 1-deoxysphingolipids causes neurotoxicity in various neurological and metabolic disorders. Here, we conducted a genome-wide CRISPR-Cas9 screen to identify pathways leading to 1-deoxysphinganine–induced toxicity in SH-SY5Y cells, a model used to study neurotoxic responses. Our top genetic hits highlighted the pathway involved in synthesizing ceramides with very-long-chain fatty acids (C22–C26). Using CRISPR-Cas9–modified SH-SY5Y cells with loss-of-function (LOF) mutations in the TECR or CERS2 genes—both critical for producing very-long-chain ceramides—we validated that this pathway was essential for 1-deoxysphinganine–mediated toxicity. Furthermore, we demonstrated that the ceramide synthesis pathway is required for 1-deoxysphinganine to trigger ER stress, as evidenced by significantly increased expression of the unfolded protein response in WT, but not TECR or CERS2 LOF mutant, SH-SY5Y cells exposed to 1-deoxysphinganine. Collectively, these findings identify a specific metabolic pathway for 1-deoxysphinganine leading to very-long-chain 1-deoxyceramide production that culminates in ER stress and toxicity. The findings highlight potential therapeutic targets for neuropathological diseases caused by 1-deoxysphingolipid accumulation.

Determining carbon-carbon double bond position of unsaturated glycerophospholipids in human plasma NIST® SRM® 1950 by electron impact excitation of ions from organics-tandem mass spectrometry (EIEIO-MS/MS).

Background Porphyromonas gingivalis (P. gingivalis) is one of the few bacteria that can produce sphingolipids (SLs). Bacterial SLs have been shown to modulate the host immune response. Objective Since neutrophil activation is critical for the pathogenesis of periodontal disease, we hypothesized that SL synthesis by P. gingivalis is important for neutrophil function. Design We treated primary human neutrophils with P. gingivalis strains W83 that either produce SL (W83) or lack expression (W83 ΔSPT). We compared the phagocytosis capacity and toll-like receptor 2 (TLR2), TLR4, the adhesion molecule CD62L, and sphingosine 1 phosphate receptor 1 (S1PR1) expressions of the neutrophils. We evaluated the migration speed of neutrophils using microfluidic and transwell systems. We quantified their superoxide formation, measured neutrophil extracellular trap (NET), and inflammatory mediator release. Results When P. gingivalis cannot synthesize SLs, this promotes early neutrophil recruitment, higher levels of phagocytosis, and a decrease in bacterial survival. P. gingivalis can stimulate TLR2 expression, prevent S1PR1 expression, and suppress the production of inflammatory mediators in the presence of SL expression. Conclusions Our data suggest that SL synthesis is an efficient immune evasion mechanism of P. gingivalis, which dampens the inflammatory response of neutrophils to this endogenous pathogen.

The gut microbiota contributes to host homeostasis through the production of bioactive metabolites that regulate immune function. Some of these microbial metabolites, called short-chain fatty acids (SCFA), have been extensively associated with allergic diseases. However, this review aims to focus on other families of microbial metabolites that are also involved in regulating the immune and inflammatory responses. These include branched SCFA (BCFA), tryptophan and tyrosine (and their derivatives), secondary bile acids (BA), sphingolipids (SL), histamine, polyamines, and odd-chain fatty acid (OCFA)-containing metabolites. In addition to the canonical SCFA, BCFA are also important regulators of innate and adaptive immunity. Specifically, they appear to participate in the mechanisms underlying allergic resolution and tolerance development. Furthermore, microbial derivatives of tryptophan, such as indole-3-acetic acid and indole-3-propionic acid, have been shown to regulate T helper 17 (Th17) and regulatory T cell populations, thereby reducing the allergic response. Products of the bacterial metabolism of other aromatic amino acids, such as tyrosine, are also associated with pro- and anti-inflammatory properties. Regarding secondary BA, isolithocholic acid has recently emerged as a key inhibitor of the Th17 response. Additionally, SL help maintain epithelial integrity and modulate the inflammatory response by regulating the levels of bioactive lipids, including ceramides and sphingosine-1-phosphate. Lastly, alterations in the bacterial metabolism of polyamines, including spermidine, and OCFA-containing metabolites, including lysophosphatidylcholines (LCP), have also been reported in allergic diseases. The microbiota metabolism modulates the immune response of its host and represents a potential target for the implementation of personalized therapeutic strategies in allergic patients.

Abstract Background Heart failure (HF) has been characterized by altered metabolism including biosynthesis and accumulation of toxic lipid intermediates such as sphingolipids (SGLs). The accumulation of toxic SGLs had previously been associated with metabolic diseases such as obesity and diabetes mellitus. More recently, the accumulation of myocardial ceramides (Cer) has been associated with HF in animal models and humans. However, various circulating SGLs, such as sphingomyelin and sphingosine-1-phosphate (S1P), have also been correlated with cardiometabolic protection. Purpose Given the recent importance given to SGLs in HF development, we sought to investigate the association between serum and cardiac SGLs and myocardial recovery in advanced HF patients following left ventricular assist device (LVAD) support. Methods We analyzed 85 HF patients undergoing LVAD implantation, 47 LVAD patients undergoing heart transplantation and 13 population-based controls. Patients were retrospectively grouped as responders (R) (defined as patients with combined structural and functional myocardial improvement using a cutoff for left ventricular ejection fraction &amp;gt;40% and left ventricular end-diastolic diameter &amp;lt;6cm within 1 year of LVAD support) or non-responders (NR) (defined as the rest of the patients). Serum and tissue samples were taken upon LVAD implantation and at time of transplant. Serum and cardiac SGLs (Cer, dihydro-Cer, glucosyl-Cer, sphingomyelin, sphingosine, sphinganine, S1P and sphinganine-1-phosphate (Sa1P)) were evaluated by targeted liquid chromatography mass spectrometry and correlated with "myocardial recovery" as described above. Results R were more likely female (35%, p=0.002), had shorter HF duration (10 vs 74 months, p&amp;lt;0.05) and less likely to be taking a statin medication (9.1 vs 41.2%, p&amp;lt;0.05) than NR. HbA1c, LDL, HDL and total cholesterol did not differ between the 2 groups (p&amp;gt;0.05). Lipidomic analysis revealed lower circulating Cer, glucosyl-Cer, sphingomyelins, Sa1P and S1P in HF patients compared to controls. Myocardial lipidomics showed elevated dihydro-Cer, Cer and S1P in HF patients versus donors, with NR displaying higher myocardial S1P and Sa1P than R. Post-LVAD, NR had increased circulating very long-chain dihydro-cer and Cer, whereas R had reduced S1P. R also had decreased myocardial dihydro-Cer(16:0) and increased myocardial long-chain glucosyl-Cer and sphingomyelin, sphingosine and Sa1P than NR. Conclusion Our findings suggest that serum and cardiac sphingolipids, particularly S1P signaling, are potentially involved in HF and myocardial recovery, offering potential therapeutic targets for improving LVAD outcomes.