PubMed

Cell Signal. 2025 Mar 28:111775. doi: 10.1016/j.cellsig.2025.111775. Online ahead of print.ABSTRACTSmall extracellular vesicles (sEVs) from tumour cells mediate intercellular communication and signalling to regulate the progression of pancreatic ductal adenocarcinoma (PDAC). While we and others have shown that PDAC-derived sEVs comprise oncogenic protein and nucleic acid cargo, understanding the lipid landscape of these sEVs remains unknown. Lipids influence both the composition of sEVs and their roles in lipid metabolism and signalling pathways within the tumour microenvironment and tumorigenesis. We hypothesised that specific lipids in oncogenic sEVs might provide insights into PDAC. Comprehensive mass spectrometry-based lipidomic analysis was performed using liquid chromatography-electrospray ionisation-tandem mass spectrometry on sEVs isolated from PDAC and non-malignant pancreatic cell lines, patient-derived xenograft cell lines and plasma from the PDAC transgenic mouse model KPC (KRASWT/G12D/ TP53WT/R172H/Pdx1-Cre+/+). The sEV lipidomic analyses identified over 700 lipid species from 25 lipid classes and subclasses. Our results showed that, compared to non-malignant cells, PDAC-derived sEVs were enriched in specific lysophospholipids, particularly sphingosine-1-phosphate (S1P), a lipid known for its pivotal role in cancer pathogenesis. S1P enrichment was validated in plasma-derived sEVs from KPC mice compared to WT. To explore the functional implications of S1P enrichment, we conducted assays demonstrating that S1P in sEVs facilitated tubule formation in human microvascular endothelial cells and promoted cancer-associated fibroblast cell migration. We show that PDAC-derived sEVs are differentially enriched in specific lipids associated with cancer phenotype. Our findings highlight that PDAC-derived sEVs are enriched in specific lipids, particularly S1P, which plays a crucial role in promoting cancer progression.PMID:40158707 | DOI:10.1016/j.cellsig.2025.111775

Metab Eng. 2025 Mar 28:S1096-7176(25)00050-3. doi: 10.1016/j.ymben.2025.03.014. Online ahead of print.ABSTRACTMethanol is a promising sustainable alternative feedstock for green biomanufacturing. The yeast Yarrowia lipolytica offers a versatile platform for producing a wide range of products but it cannot use methanol efficiently. In this study, we engineered Y. lipolytica to utilize methanol by overexpressing a methanol dehydrogenase, followed by the incorporation of methanol assimilation pathways from methylotrophic yeasts and bacteria. We also overexpressed the ribulose monophosphate (RuMP) and xylulose monophosphate (XuMP) pathways, which led to significant improvements in growth with methanol, reaching a consumption rate of 2.35 g/L in 24 hours and a 2.68-fold increase in biomass formation. Metabolomics and Metabolite Flux Analysis confirmed methanol assimilation and revealed an increase in reducing power. The strains were further engineered to produce the valuable heterologous product resveratrol from methanol as a co-substrate. Unlike traditional methanol utilization processes, which are often resource-intensive and environmentally damaging, our findings represent a significant advance in green chemistry by demonstrating the potential of Y. lipolytica for efficient use of methanol as a co-substrate for energy, biomass, and product formation. This work not only contributes to our understanding of methanol metabolism in non-methylotrophic organisms but also paves the way for achieving efficient synthetic methylotrophy towards green biomanufacturing.PMID:40158687 | DOI:10.1016/j.ymben.2025.03.014

Plant Physiol Biochem. 2025 Mar 26;223:109835. doi: 10.1016/j.plaphy.2025.109835. Online ahead of print.ABSTRACTIn early spring, bleeding is a common occurrence in A. arguta when local temperatures reach 8 °C-10 °C. In this study, changes in the composition of bleeding sap and effect of bleeding on A. arguta were determined by analyzing the variation in the composition of bleeding sap from different periods. Accordingly, the bleeding sap was analyzed by gas chromatography-mass spectrometry (GC-MS), and the related physiological indexes in the stem were measured. The results revealed that in annual early spring, bleeding seriously affected A. arguta. In addition, annual branches had a stronger capacity for scavenging free radicals than biennial or barren branches. The metabolomics analysis identified a total of 153 differential metabolites, mainly involved in glycolysis and the tricarboxylic acid cycle. Bleeding decreased the number and length of new shoots and basal stems, as well as the size of the phloem, phloem fibers, and xylem. In contrast, the proline, soluble protein, soluble sugar, and malondialdehyde contents, as well as the activities of superoxide dismutase, catalase, and peroxidase, increased in treated stems compared with untreated controls. This study was the first to analyze the metabolomic profile of bleeding sap in A. arguta and investigate the effects of bleeding on its growth and development. The results will provide a theoretical basis for explaining the physiological changes occurring in stems after bleeding and lay a foundation for further research on understanding the underlying mechanism and repairing bleeding.PMID:40158483 | DOI:10.1016/j.plaphy.2025.109835

Plant Physiol Biochem. 2025 Mar 24;223:109828. doi: 10.1016/j.plaphy.2025.109828. Online ahead of print.ABSTRACTLight quality exerts a vital influence on the accumulation of secondary metabolites in medicinal plants. Atropa belladonna L. serves as a primary source plant of tropane alkaloids (TAs). Nevertheless, in agricultural production, its application is restricted due to the relatively low content of alkaloids. This study explored the impacts of red, yellow, blue, and white light on the growth of A. belladonna and the biosynthesis of TAs. Through phenotypic and physiological analyses, it was found that red-light had the most significant effect on A. belladonna. Red-light remarkably increased the content of TAs, enlarged the leaf area, extended the stomatal length, and elevated the ammonium nitrogen level. It also enhanced the activities of ornithine decarboxylase, nitrate reductase, and glutamine synthetase, which are essential for nitrogen assimilation. Transcriptomic analysis identified GDHA, At2g42690, and PAO5 as key genes with upregulated expression in the putrescine biosynthesis pathway, where putrescine is an important precursor of TAs. Metabolomic data confirmed that the levels of scopolamine, hyoscyamine, and their precursors increased under red-light. Subsequent qPCR verification under red/white light treatments consistently showed the upregulation of these genes, further confirming their roles in the synthesis of TAs. Moreover, red-light activated photosynthesis-related genes and transcription factors, indicating a coordinated regulatory relationship between light signal transduction and metabolic pathways. This study has preliminarily elucidated the potential mechanism by which red-light promotes the accumulation of TAs through enhancing nitrogen metabolism and precursor synthesis, providing a theoretical basis for improving the quality of A. belladonna and optimizing agricultural production.PMID:40158482 | DOI:10.1016/j.plaphy.2025.109828

Environ Health. 2025 Mar 29;24(1):14. doi: 10.1186/s12940-025-01162-x.ABSTRACTBACKGROUND: Prenatal exposure to air pollution has been associated with an increased risk of low birth weight. Disrupted metabolism may serve as an underlying mechanism, but the specific metabolic pathways involved remain unclear.METHODS: In the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) study, 382 third-trimester maternal serum samples were analyzed for untargeted metabolomics using liquid chromatography with Fourier transform high-resolution mass spectrometry. Ambient concentrations of fine particulate matter (PM2.5), particulate matter ≤ 10 μm in diameter (PM10), nitrogen dioxide (NO2), and ozone (O3) were estimated using inverse-distance-squared weighted spatial interpolation based on daily residential histories. Birth weight was retrieved from medical records. Linear regression identified metabolomic features associated with air pollution exposure or birth weight, followed by Mummichog pathway enrichment and mediation analyses for the selected features.RESULTS: Second-trimester PM2.5 exposure was associated with lower birth weight. Fourteen metabolic pathways were significantly associated with second-trimester PM2.5 exposure, with C21-steroid hormone biosynthesis and metabolism showing the most significant association. Sixteen metabolic pathways were significantly associated with birth weight, with vitamin A (retinol) metabolism being the most significantly enriched pathway. Seven pathways were associated with both PM2.5 exposure and birth weight, including C21-steroid hormone biosynthesis and metabolism, bile acid biosynthesis, tyrosine metabolism, ascorbate (vitamin C) and aldarate metabolism, vitamin D3 (cholecalciferol) metabolism, vitamin A (retinol) metabolism, and pyrimidine metabolism. Overweight or obese women exhibited more metabolomic features and metabolic pathways associated with PM2.5 exposure compared to underweight or normal-weight women. No associations were observed between PM10, NO2, or O3 and birth weight.CONCLUSIONS: Maternal metabolic pathways involving steroid metabolism, oxidative stress and inflammation, vitamin metabolism, and DNA damage may link prenatal PM2.5 exposure to lower birth weight, with overweight or obese women potentially more susceptible to these metabolic disruptions.PMID:40158186 | DOI:10.1186/s12940-025-01162-x

Nutr J. 2025 Mar 29;24(1):50. doi: 10.1186/s12937-025-01116-6.ABSTRACTThe gut microbiome can modulate nutrient metabolism to produce many metabolites interacting with the host. However, the intricate interactions among dietary intake, the gut microbiome and metabolites, and host metabolites need to be further explored although some studies have been devoted to it. Here, in a cross-sectional studies, 88 children aged 2-12 years were enrolled from northwestern China. The dietary intake data were collected via a designed food frequency questionnaire to calculate plant-based diet indices (PDIs). Stool and plasma samples were collected for metagenomic and broad-targeted metabolomic analysis. Spearman's rank correlation was used to describe the associations between nutrients/PDIs and the gut microbiota and metabolites. PDI was significantly positively associated with Bilophila wadsworthia, Bacteroides thetaiotaomicron, and Alistipes indistinctus, etc., but was obviously negatively correlated with Roseburia intestinalis, Faecalibacterium prausnitzii, etc. However, these species showed no significant associations with either healthy PDI (hPDI) or unhealthy PDI (uPDI). Interestingly, hPDI was significantly positively related to species, including Ruminococcus bicirculans, and was significantly negatively associated with uPDI, and vice versa. The above correlation trends were also observed between PDIs and predicted gut microbial functional pathways, microbial metabolites and the host metabolome. Notably, the significantly related pathways were focused mainly on substances and energy metabolism. PDI was significantly positively associated with the fecal contents of P-aminobenzoate, chenodeoxycholic acid, 4,6-dihydroxyquinoline, quinoline-4,8-diol, etc., but was significantly negatively associated with those of TMAO, FFA, creatine phosphate, etc. In plasma, PDI was significantly positively associated with sarcosine, ornithine, L-histidine, etc., but was distinctly negatively correlated with FFAs, carnitine C2:0, etc. Strikingly, the healthy plant-based diet index (hPDI) is correlated with increased levels of metabolites related to tryptophan metabolism, whereas the unhealthy PDI (uPDI) is linked to increased levels of metabolites associated with tyrosine and sphingolipid metabolism, which are pathways commonly associated with Western diets. Our studies provide reliable data support and a comprehensive understanding of the effects of dietary intake on the gut microbiome and microbial and host metabolites and lay a foundation for further studies of the diet-gut microbiota-microbial metabolites and host metabolism.PMID:40158160 | DOI:10.1186/s12937-025-01116-6

Hum Genomics. 2025 Mar 29;19(1):34. doi: 10.1186/s40246-025-00743-8.ABSTRACTBACKGROUND: Mitochondria are small organelles inside our cells crucial for producing energy and heat, cell signaling, production and degradation of important molecules, as well as cell death. The number of mitochondria in each cell is a marker for mitochondrial function, which generally declines with increasing age. However, we found that there is also a considerable seasonal variation of mitochondrial abundance, which warrants further research.METHODS: We leveraged data from individuals participating in the UK Biobank study and computed their mitochondrial abundance from Exome sequencing reads mapping to the mitochondrial genome. The seasonal effect was modelled as a sine-cosine function across the year and changes in amplitude, acrophase and displacement of mitochondrial abundance due to various demographic, lifestyle, genetic, proteomic, and metabolomic markers were investigated with multivariate regression.RESULTS: We found that mitochondrial DNA (mtDNA) abundance was higher in winter than in summer. This difference is related to advanced age, a higher BMI and smoking behavior which resulted in a reduced amplitude of mtDNA abundance. A higher education reduced the acrophase (i.e., shifted the distribution to earlier in the year) and a higher BMI and lack of physical activity led to a later acrophase. Generally, increased immune cell count resulted in lower amplitude, and an increased platelet and lymphocyte count was found to increase the acrophase. Importantly, a reduced seasonal amplitude was associated with increased risk for cardiovascular, digestive, genitourinary, and respiratory diseases as well as all-cause mortality. Most of the metabolomic and proteomic markers were associated with mtDNA displacement (i.e., increase of the baseline level) but not acrophase or amplitude. Similarly, we found that there are multiple genetic variants influencing displacement, but none reached genome-wide significance when investigating acrophase or amplitude.CONCLUSION: Seasonal variation of mtDNA abundance is influenced by environmental, lifestyle and immune parameters. Differences in the seasonal oscillation of mitochondrial abundance could potentially explain discrepancies of previous associations results and might be useful to improve future risk prediction.PMID:40158147 | DOI:10.1186/s40246-025-00743-8

J Neurodev Disord. 2025 Mar 29;17(1):16. doi: 10.1186/s11689-025-09601-z.ABSTRACTBACKGROUND: Despite the power and promise of early detection and treatment in autism spectrum disorder (ASD), early-life biomarkers are limited. An early-life risk biosignature would advance the field's understanding of ASD pathogenies and targets for early diagnosis and intervention. We therefore sought to add to the growing ASD biomarker literature and evaluate whether fetal metabolomics are altered in idiopathic ASD.METHODS: Banked cord blood plasma samples (N = 36 control, 16 ASD) were analyzed via gas chromatography and mass spectrometry (GC-MS). Samples were from babies later diagnosed with idiopathic ASD (non-familial, non-syndromic) or matched, neurotypical controls. Metabolite set enrichment analysis (MSEA) and biomarker prediction were performed (MetaboAnalyst).RESULTS: We detected 76 metabolites in all samples. Of these, 20 metabolites differed significantly between groups: 10 increased and 10 decreased in ASD samples relative to neurotypical controls (p < 0.05). MSEA revealed significant changes in metabolic pathways related to carbohydrate metabolism and glycemic control. Untargeted principle components analysis of all metabolites did not reveal group differences, while targeted biomarker assessment (using only Fructose 6-phosphate, D-Mannose, and D-Fructose) by a Random Forest algorithm generated an area under the curve (AUC) = 0.766 (95% CI: 0.612-0.896) for ASD prediction.CONCLUSIONS: Despite a high and increasing prevalence, ASD has no definitive biomarkers or available treatments for its core symptoms. ASD's earliest developmental antecedents remain unclear. We find that fetal plasma metabolomics differ with child ASD status, in particular invoking altered carbohydrate metabolism. While prior clinical and preclinical work has linked carbohydrate metabolism to ASD, no prior fetal studies have reported these disruptions in neonates or fetuses who go on to be diagnosed with ASD. Future work will investigate concordance with maternal metabolomics to determine maternal-fetal mechanisms.PMID:40158086 | DOI:10.1186/s11689-025-09601-z

Sci Rep. 2025 Mar 29;15(1):10897. doi: 10.1038/s41598-025-95633-3.ABSTRACTLung cancer is the leading cause of cancer-related deaths globally, with radiotherapy as a key treatment modality for inoperable cases. Lactate, once considered a by-product of anaerobic cellular metabolism, is now considered critical for cancer progression. Lactate dehydrogenase B (LDHB) converts lactate to pyruvate and supports mitochondrial metabolism. In this study, a re-analysis of our previous transcriptomic data revealed that LDHB silencing in the NSCLC cell lines A549 and H358 dysregulated 1789 genes, including gene sets associated with cell cycle and DNA repair pathways. LDHB silencing increased H2AX phosphorylation, a surrogate marker of DNA damage, and induced cell cycle arrest at the G1/S or G2/M checkpoint depending on the p53 status. Long-term LDHB silencing sensitized A549 cells to radiotherapy, resulting in increased DNA damage and genomic instability as evidenced by increased H2AX phosphorylation levels and micronuclei accumulation, respectively. The combination of LDHB silencing and radiotherapy increased protein levels of the senescence marker p21, accompanied by increased phosphorylation of Chk2, suggesting persistent DNA damage. Metabolomics analysis revealed that LDHB silencing decreased nucleotide metabolism, particularly purine and pyrimidine biosynthesis, in tumor xenografts. Nucleotide supplementation partially attenuated DNA damage caused by combined LDHB silencing and radiotherapy. These findings suggest that LDHB supports metabolic homeostasis and DNA damage repair in NSCLC, while its silencing enhances the effects of radiotherapy by impairing nucleotide metabolism and promoting persistent DNA damage.PMID:40158058 | DOI:10.1038/s41598-025-95633-3

Sci Rep. 2025 Mar 29;15(1):10870. doi: 10.1038/s41598-025-92690-6.ABSTRACTThe impact of testosterone administration on the circulating lipidome in females remains unexplored, despite its relevance to understanding metabolic disorders like polycystic ovary syndrome (PCOS). This study addresses this gap by examining the effects of testosterone gel on the plasma lipidome of healthy women over three menstrual cycles. A cohort of 14 women aged 22-37 years with regular cycles was analyzed, with plasma samples collected at baseline, during peak testosterone levels (D45), and post-treatment (D59, D80). Testosterone gel treatment lasted 28 days, administered between day 29 and day 57 of the study. Using a deep-targeted lipidomic approach, 597 lipids were quantified to provide a detailed profile of the lipidome and capture subtle changes in lipid species and their associations with testosterone fluctuations. Extensive profiling revealed a significant decrease in 17 lipid species, especially ether- and ester-linked lysophosphatidylcholines (LPC), at peak testosterone. These lipid reductions were strongly negatively correlated with free and total testosterone, as well as dihydrotestosterone (DHT), and positively correlated with SHBG levels. Notably, intra-individual lipid variability was consistently lower than inter-individual variability, indicating a highly personalized lipidome regulation. Despite testosterone-induced changes, overall plasma lipidome alterations were minimal, suggesting mechanisms that maintain lipid homeostasis. This study highlights the complex interplay between testosterone and lipid metabolism in women. The minimal overall lipidome changes and high inter-individual variability point to the need for further research to assess the clinical relevance of these findings, particularly in hyperandrogenic conditions like PCOS. Clinical Trial Registration number: This study was registered on https://www.isrctn.com/ (ISRCTN10122130) on 09/01/2019.PMID:40157992 | DOI:10.1038/s41598-025-92690-6

NPJ Sci Food. 2025 Mar 29;9(1):45. doi: 10.1038/s41538-025-00387-x.ABSTRACTPingyin rose herbal tea is favored in the market for its unique quality and health benefits. Thus, researchers have explored a range of different rose products. This study evaluated the effect of processing methods and different forms on the flavor of rose herbal tea combined with sensory evaluation and metabolite profiles. Sensory evaluation showed that low-temperature drying (LTD) roses have a distinct floral and sweet aroma, while vacuum freeze drying (VFD) roses exhibit a fruity and woody aroma. Metabolomics analysis indicated that each type of rose herbal tea has its characteristic accumulation of non-volatile compounds and volatile organic compounds (VOCs). The VFD rose corollas had the highest contents of AAs, OAs, SSs, flavonoids, and VOCs. Furthermore, correlation analysis revealed key nonvolatile and volatile compounds related to aroma and taste. This study provides a scientific foundation for future investigations on the processing and quality improvement of rose herbal tea.PMID:40157961 | DOI:10.1038/s41538-025-00387-x

Int J Biol Macromol. 2025 Mar 27:142512. doi: 10.1016/j.ijbiomac.2025.142512. Online ahead of print.ABSTRACTPolysaccharide from Atractylodes macrocephala Koidz. (PAMK), a bioactive component of Atractylodes macrocephala Koidz. (AMK), demonstrates a wide range of pharmacological activities, including the enhancement of gastrointestinal function and regulation of internal homeostasis. This study explores the potential of PAMK in alleviating pyrotinib-induced diarrhea and modulating gut microbiota and its metabolites. Pyrotinib is a tyrosine kinase inhibitor used in cancer treatment, is known for its side effect of diarrhea, which significantly diminishes patients' quality of life. Our prior research suggests that pyrotinib-induced diarrhea may be linked to CFTR-mediated dysregulation of chloride secretion. The present findings indicate that PAMK alleviates pyrotinib-induced diarrhea by reducing cAMP levels, activating the LKB1/AMPK pathway, and inhibiting CFTR activity, as confirmed by enzyme-linked immunosorbent assay (ELISA), qRT-PCR, and western blot analyses. PAMK effectively decreased CFTR-mediated chloride ion secretion in pyrotinib-treated cells, as shown by the MQAE assay. At specific doses, PAMK alleviated pyrotinib-induced diarrhea in rats and significantly restored intestinal barrier integrity. Furthermore, PAMK treatment rebalanced the gut microbiota, reversing the pyrotinib-induced increase in Clostridium and Erysipelotrichi species. Metabolomic profiling further highlighted the involvement of the AMPK signaling pathway. These findings provide a basis for future research aimed at developing cancer treatments with reduced side effects.PMID:40157659 | DOI:10.1016/j.ijbiomac.2025.142512

Biochim Biophys Acta Mol Basis Dis. 2025 Mar 27:167818. doi: 10.1016/j.bbadis.2025.167818. Online ahead of print.ABSTRACTFibrinolysis-angiogenesis coupling is crucial for successful fracture healing, in which type H vessels play an indispensable role. However, the metabolic control of fibrinolysis-type H angiogenesis coupling in fracture healing remains unclear. We used a metabolomics approach to gain metabolic insights from mouse fracture models (0.3 mm and 1.0 mm femur defects). Furthermore, human umbilical vein endothelial cells (HUVECs) and MC3T3-E1 cells were employed as in vitro models to examine the effects of identified metabolites on endothelial events and osteogenesis, respectively. CD31 and endomucin (Emcn) were used for detecting type H markers, and tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) for fibrinolysis. A femur defect of 1.5 mm in mice was included to validate the therapeutic potential of identified metabolites by bone imaging and micro-CT. Purine metabolism is the most significant pathway in fracture healing; three purinergic metabolites, adenosine, adenine, and inosine, are regulated in mouse serum. According to the in vivo results, CD31HiEmcnHi type H vessels are upregulated near the defect site in mouse femur and are associated with tPA expression, but not PAI-1. Additionally, in vitro experiments examining the endothelial functions of HUVECs demonstrated that these three metabolites promote cell migration and tube formation rather than proliferation. Fibrinolytic activity and type H phenotype in HUVECs were induced only by inosine through activation of the adenosine A2A receptor. Inosine, regulated during fracture healing, has the capacity to synchronously induce fibrinolysis and type H phenotype in line with osteogenesis, indicating its role in enhancing fracture healing.PMID:40157654 | DOI:10.1016/j.bbadis.2025.167818

Nitric Oxide. 2025 Mar 27:S1089-8603(25)00029-1. doi: 10.1016/j.niox.2025.03.006. Online ahead of print.ABSTRACTSulfur-containing amino acids are involved in the regulation of vascular activity and blood pressure. Clinically, a positive correlation was found between serum homocysteine levels and blood pressure. On the other hand, methionine and cysteine levels were reduced in hypertensive patients. Recently, the redox state of sulfur-containing amino acids has emerged as potential diagnostic marker of cardiovascular health. Metabolomic studies have revealed a shift in thiol/disulfide ratio toward oxidized forms and overproduction of thiyl radicals in hypertensive patients. Although accumulating evidence confirms that sulfur-containing amino acids are essential for the maintaining redox homeostasis and blood pressure control, their hypotensive and antioxidant properties have been primarily demonstrated in animal studies. While several groups are developing new targeted and triggered sulfur-based donors, standardized pharmacological interventions for hypertensive patients are largely absent and pose a challenge for future research. In this review, we summarize recent studies that investigate the role of sulfur-containing amino acids and their redox-active metabolites, including glutathione and sulfide, in blood pressure control and the development of systemic hypertension.PMID:40157636 | DOI:10.1016/j.niox.2025.03.006

Exp Eye Res. 2025 Mar 27:110361. doi: 10.1016/j.exer.2025.110361. Online ahead of print.ABSTRACTThis study aimed to use metabolomics to accurately reveal alterations in metabolites and potential regulatory mechanisms in patients with diabetic cortical cataracts (DCC). We first collected cortical samples from different pathological areas of the same lens in DCC patients for metabolomics. Then, we used transcriptomic analysis to study lactate's effect on gene expression in human lens epithelial cells (HLECs). An in vitro rat lens culture assay evaluated lactate's impact on lens transparency, and WB and immunofluorescence assessed lactate-induced apoptosis and oxidative damage in rat LECs. Furthermore, CHIP sequencing and LC-MS identified H3K18la separately modified genes and potential lactylation proteins in HLECs. Immunoprecipitation validated lactylation levels of proteins. Our findings identified 11 upregulated and 18 downregulated metabolites in the opacity zone of LFCs (OZ-LFCs) compared to the clear zone (CZ-LFCs) in DCC patients. We confirmed the differential lactate content between OZ-LFCs and CZ-LFCs and, through transcriptomic analysis, discovered that lactate affects gene expression, protein metabolism, and DNA repair in primary Human Lens epithelial cells (HLECs). Lactate-induced apoptosis and DNA repair hastened lens opacity in a high-sugar rat lens culture model. Lactylation-MS and H3K18la-ChIP sequencing revealed 591 H3K18la-modified genes and 953 lactylation proteins in HLECs. PKM2 and NPM1 lactylation was confirmed through immunoprecipitation. These findings improve our grasp of spatial dynamics in DCC patient metabolomics and suggest a new research path into lactylation modification to understand lactate's role in cataract formation.PMID:40157629 | DOI:10.1016/j.exer.2025.110361

Food Chem Toxicol. 2025 Mar 27:115419. doi: 10.1016/j.fct.2025.115419. Online ahead of print.ABSTRACTThe health implications of genetically modified (GM) crops remain controversial relative to their non-GM counterparts, particularly regarding long-term dietary exposure. Although the gut microbiome is a key health indicator, studies investigating the impact of GM crop consumption on intestinal microbiota remain limited. This study presents a comprehensive 7-year evaluation of GM maize expressing cry1Ab/cry2Aj and G10evo-EPSPS proteins through metagenomic and metabolomic analyses. We assessed the effects of GM maize consumption on gut microbiota diversity and metabolite profiles in cynomolgus macaques (Macaca fascicularis) compared with non-GM maize. Three diet regimens were implemented: a conventional compound feed (CK group), diet formulation containing 70% non-GM maize (Corn group), and diet formulation containing 70% GM maize (Tg group). The results demonstrated that feeding GM maize to the first (F0) and second (F1) generations of monkeys did not substantially affect the composition, community structure, or function of the intestinal microbiome, as indicated by species composition and diversity analyses. Minor differences in intestinal metabolites were observed but were not directly linked to transgenic maize consumption. Collectively, long-term intake of maize with cry1Ab/cry2Aj and g10evo-epsps genes had no adverse effects on macaques or their offspring.PMID:40157594 | DOI:10.1016/j.fct.2025.115419

J Thromb Haemost. 2025 Mar 27:S1538-7836(25)00202-8. doi: 10.1016/j.jtha.2025.03.022. Online ahead of print.ABSTRACTBACKGROUND: Venous thromboembolism (VTE) is a significant global health burden, and metabolic alterations play a key role in its pathogenesis. However, previous studies have been constrained by several limitations, hindering clarification of the causal role of metabolites.METHODS: Genetic associations involving 690 plasma and 211 urinary metabolites were analyzed as exposures, while the outcomes for VTE were derived from a large-scale meta-analysis of genome-wide association studies. Metabolome-wide Mendelian randomization (MR) and colocalization analyses were performed to assess the causal role of metabolites in VTE. Metabolic pathway analysis was performed using MetOrigin, and druggability assessments were conducted to prioritize potential therapeutic targets. Additionally, a two-step MR framework was employed to elucidate the mediating effects of metabolites on the relationships between modifiable risk factors and VTE.RESULTS: After Bonferroni correction, 51 plasma metabolites and 18 urinary metabolites were significantly associated with VTE risk. Colocalization evidence supported causal relationships for 37 metabolites with VTE. Eleven metabolic pathways were identified for VTE-related metabolites, and six metabolites were prioritized as potential therapeutic targets. Twenty-four modifiable risk factors were associated with 28 VTE-related metabolites, seven of which were linked to VTE risk. Mediation analyses further revealed significant mediating effect of 8 metabolites on how 6 modifiable factors influenced VTE.CONCLUSION: This study identifies potential metabolite biomarkers associated with VTE risk and uncovered the metabolic mediators between modifiable risk factors and VTE, offering new insights for future prevention and treatment strategies.PMID:40157505 | DOI:10.1016/j.jtha.2025.03.022

Environ Pollut. 2025 Mar 27:126157. doi: 10.1016/j.envpol.2025.126157. Online ahead of print.ABSTRACTMicroplastics, particularly polymethyl methacrylate (PMMA), have emerged as significant environmental pollutants, with growing concerns about their impact on various biological processes. However, the effects of chronic PMMA exposure on hepatic lipid metabolism remain insufficiently studied. This research aimed to examine the consequences of chronic exposure to PMMA particles of different sizes (100 nm and 2 μm) on hepatic lipid metabolism in mice. Female C57BL/6J mice were administered PMMA particles in drinking water over an 8-week period, and the effects on intestinal and liver morphology and function were evaluated. Histopathological analyses, gut microbiota profiling, and serum and liver assays were conducted to assess oxidative stress, lipid metabolism-related biomarkers, and liver metabolomics. The results revealed that PMMA particles accumulated in both the liver and colon, causing liver injury characterized by elevated ALT and AST levels. The exposure also induced oxidative stress by inhibiting the NRF2/HO-1 signaling pathway. Furthermore, PMMA exposure resulted in significant alterations to the gut microbiota and hepatic metabolism. These changes were linked to increased microbial diversity, which impacted cholesterol metabolism through the gut-liver axis. Additionally, the activation of the PI3K/AKT/PPARγ signaling pathway disrupted hepatic lipid metabolism, leading to increased cholesterol synthesis and hepatic lipid accumulation. This study underscores the potential of PMMA to disrupt both hepatic lipid metabolism and gut microbiota composition, suggesting a novel mechanism by which PMMA exposure could contribute to metabolic disorders and liver disease.PMID:40157484 | DOI:10.1016/j.envpol.2025.126157

Toxicol In Vitro. 2025 Mar 27:106058. doi: 10.1016/j.tiv.2025.106058. Online ahead of print.ABSTRACTBlue-green algae (cyanobacteria), an ancient phylum of bacteria, produce a wide array of secondary metabolites that are toxic to humans. Rapid growth of cyanobacteria in an aquatic environment can result in algal blooms capable of turning waterways green and increasing toxin levels in the environment. Cyanobacterial toxins were first linked to the high incidence of a complex neurodegenerative disorder reported on the island of Guam in the 1940s but more recently have been linked to clusters of sporadic amyotrophic lateral sclerosis (sALS) worldwide. The non-protein amino acid β-N-methylamino-L-alanine (BMAA) and its isomer L-2,4-diaminobutyric acid (2,4-DAB) are produced concurrently by most cyanobacterial species. We carried out proteomic analysis on human neuroblastoma cells treated with BMAA and 2,4-DAB to determine the underlying mechanisms of toxicity resulting from exposure to these cyanotoxins and identified significant changes in the l-serine biosynthesis pathway as well as pathways associated with energy production in the cell such as fatty acid ß-oxidation and glycolysis. The impact on the serine biosynthetic pathway was supported by demonstrating a significant decrease in both mRNA and protein levels of the enzyme 3-phosphoglycerate dehydrogenase (PHGDH) the first committed step in serine biosynthesis. PHGDH uses 3-phospho-D-glycerate (3PG) an intermediate in the glycolytic pathway as a substrate, and co-incubation of cells with l-serine restored expression levels of PHGDH as did cell pre-treatment with the glycolytic product pyruvate. This is the first study to link exposure to BMAA and 2,4-DAB to impairments in the l-serine biosynthesis pathway and broad disturbances in energy metabolism.PMID:40157434 | DOI:10.1016/j.tiv.2025.106058

Immunity. 2025 Mar 21:S1074-7613(25)00096-2. doi: 10.1016/j.immuni.2025.03.002. Online ahead of print.ABSTRACTThe combination of immune checkpoint blockade and chemotherapies is the standard of care for triple-negative breast cancer (TNBC). However, initially, responsive tumors can still develop recurrences, suggesting acquired resistance mechanisms that remain poorly understood. Herein, we discover that TNBC cells surviving anti-programmed cell death protein-1 (anti-PD-1) and chemotherapy treatment accumulate neutral lipids. Disrupting lipid droplet formation in cancer cells reverses resistance and mitigates the immunosuppressive microenvironment. Single-cell RNA sequencing reveals a subset of neutrophils exhibiting a lipid-laden phenotype similar to adjacent tumor cells. Mechanistically, tumor-derived extracellular vesicles carrying lipids, including arachidonic acid (AA), mediate neutrophil reprogramming. Blocking dietary intake of omega-6 fatty acids or inhibiting fatty acid elongation for AA synthesis restores anti-tumor immunity and re-sensitizes the resistant tumors to anti-PD-1 and chemotherapy treatment. In human patients, AA metabolism-related pathways correlates with neutrophil enrichment. Overall, we demonstrate how lipid accumulation in TNBC cells leads to immune suppression and therapy resistance.PMID:40157359 | DOI:10.1016/j.immuni.2025.03.002