PubMed

Exp Eye Res. 2026 Sep 10:111236. doi: 10.1016/j.exer.2026.111236. Online ahead of print.ABSTRACTPURPOSE: To synthesize evidence linking one-carbon metabolism to retinal ganglion cell (RGC) vulnerability and pressure-independent neurodegeneration in glaucoma, while distinguishing direct glaucoma-relevant evidence, indirect biological support, and mechanistic hypotheses.METHODS: We conducted a critical narrative review of human ocular and systemic metabolomics, conventional biomarkers, nutritional epidemiology, experimental retinal injury and glaucoma models, and early translational studies. The metabolomics evidence base comprised 26 reports (17 ocular and 9 systemic), evaluated by glaucoma subtype, specimen, analytical platform, analyte direction, effect-size availability, and cohort independence.RESULTS: Under the operational cross-study criteria used in this review, five aqueous-humor analytes recurred across independent primary open-angle glaucoma (POAG) cohort families, all with compatible increases: threonine, lysine, histidine, arginine, and creatinine. Broader cross-study convergence was strongest at the amino-acid, membrane-lipid, energy/purine/tricarboxylic acid (TCA), and redox pathway levels. Exfoliation-related ocular studies showed no exact recurrent analyte, whereas systemic evidence was most consistent for diglyceride/triglyceride class-level associations. Direct evidence includes human glaucoma cohorts and protection with combined vitamins B6, B9, and B12 plus choline in experimental glaucoma. Non-glaucoma retinal, RGC, and glial models provide indirect support, whereas compartment-specific ocular flux, a transsulfuration-to-axon causal chain, and axis-specific choline/betaine effects remain hypotheses. Human interventional evidence is limited to an early-phase protocol.CONCLUSION: One-carbon metabolism is a candidate biological framework for mechanistic and target-engagement studies, not a validated biomarker panel or established supplementation strategy. Clinical efficacy of one-carbon pathway modulation or related supplementation in glaucoma has not been established.PMID:42722144 | DOI:10.1016/j.exer.2026.111236

JHEP Rep. 2026 Sep 10:102035. doi: 10.1016/j.jhepr.2026.102035. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Extrahepatic organ failures are key determinants of acute-on-chronic liver failure (ACLF). While the role of systemic inflammation and mitochondrial dysfunction in the pathogenesis of ACLF is well known, the contribution of the liver itself is less understood. We therefore performed transcriptome and functional analyses of the liver in order to identify hepatic drivers of ACLF.METHODS: Bulk-RNA sequencing and spatial transcriptomics were performed in liver specimens from patients with compensated cirrhosis, decompensated cirrhosis or ACLF. In addition, detailed analyses of genes involved in energy metabolism, as well as a metabolome analysis and functional analyses were performed.RESULTS: In total, 39 patients were included (9 compensated cirrhosis, 15 decompensated cirrhosis, 15 ACLF). ACLF was associated with changes in the hepatic transcriptome, clearly distinct from compensated and decompensated cirrhosis. Most strongly downregulated in ACLF were pathways involved in substrate metabolism and mitochondrial function, including downregulation of multiple genes of glucose and amino acid metabolism. In line, spatial transcriptomics revealed a breakdown of the functional liver zonation in ACLF, with decreasing proportions of hepatocytes specialized in gluconeogenesis/β-oxidation (compensated cirrhosis 68%, decompensated cirrhosis 52%, ACLF 12%; P<0.03). Branched chain ketoacid dehydrogenase kinase (BCKDK), a key regulator of branched-chain amino acid catabolism, was strongly downregulated in ACLF (0,33- fold expression vs. compensated cirrhosis, P<0.05) and may link dysregulation of branched-chain amino acid and glucose metabolism.CONCLUSION: ACLF is characterized by distinct changes in the hepatic transcriptome, which affect key pathways in substrate metabolism and mitochondrial function and are associated with loss of functional liver zonation. Downregulation of BCKDK in ACLF might be of particular interest, as it links altered branched-chained amino acid metabolism to impaired glucose production.IMPACT AND IMPLICATIONS: Extrahepatic organ failures are well known features of acute-on-chronic liver failure (ACLF), but the contribution of the liver itself to their pathogenesis is not well understood. By RNA sequencing and spatial transcriptomics of liver specimens, we could identify profoundly impaired metabolic and mitochondrial hepatic programs, suggesting that the liver might play a key role in the development of extrahepatic organ failures by compromising the body's energy supply. These findings are important since they provide a rationale for further studying molecular targets in the liver as therapeutic strategies for ACLF.PMID:42722106 | DOI:10.1016/j.jhepr.2026.102035

Environ Res. 2026 Sep 10:125657. doi: 10.1016/j.envres.2026.125657. Online ahead of print.ABSTRACTTrace-level neuroactive contaminants in aquatic environments are increasingly recognized as ecological hazards, yet the neurotoxic potential of areca alkaloids remains largely unexplored. In this study, adult zebrafish were chronically exposed to arecoline or arecaidine for 90 days to investigate long-term neurobehavioral toxicity and associated biological alterations. Behavioral assessments revealed persistent impairments in social interaction, reduced aggression, and altered exploratory activity following alkaloid exposure. Concomitantly, areca alkaloids induced intestinal injury characterized by villus atrophy, goblet cell depletion, epithelial alterations, and increased macrophage infiltration. Gut microbiota profiling revealed compositional shifts, with significant enrichment of inflammation-associated genera, including Acinetobacter, Pseudomonas and Rhodococcus, and depletion of several commensal taxa. At the central level, brain histopathology revealed neuronal damage and increased expression of apoptosis-associated markers. Brain metabolomic analysis further revealed extensive alterations in amino acid- and neurotransmitter-related metabolism, highlighted by alterations in glutamate, glycine, serine, N-acetyl-L-aspartic acid, and citrate, as well as enrichment of pathways related to alanine, aspartate and glutamate metabolism and aminoacyl-tRNA biosynthesis. Integrated correlation analyses revealed associations among altered gut bacterial genera, brain metabolic pathways, and behavioral endpoints, suggesting potential links among gut microbial alterations, brain metabolic changes, and behavioral outcomes following areca alkaloid exposure. In summary, these findings reveal that long-term exposure to areca alkaloids at environmental concentrations elicits neurobehavioral and neurotoxic effects in adult zebrafish accompanied by alterations in gut microbiota and brain metabolism, highlighting the potential of areca alkaloids as environmental neurotoxicants relevant to aquatic health risk assessment.PMID:42722099 | DOI:10.1016/j.envres.2026.125657

J Nutr Biochem. 2026 Sep 10:110503. doi: 10.1016/j.jnutbio.2026.110503. Online ahead of print.ABSTRACTWe previously investigated whether maternal high-fat diet (HFD) exposure alters lupus nephritis (LN) progression in MRL/lpr offspring. Contrary to expectation, maternally HFD-exposed offspring showed delayed and attenuated nephritic progression compared with control diet offspring. The maternal HFD developmental impact on LN remains unclear. Here, integrated amniotic fluid metabolomics and fetal liver transcriptomics revealed that maternal HFD reshaped the intrauterine molecular environment, particularly involving steroid hormone biosynthesis and Wnt/β-catenin-associated regulatory networks. Methylome profiling further demonstrated broad CpG hypomethylation, immune-related differentially methylated region enrichment, and an inverse association between global CpG methylation and oxidative genomic DNA damage. Among candidate regulatory nodes, Axin2, a canonical Wnt/β-catenin target and feedback regulator, emerged as a potential link between fetal nutritional exposure, epigenetic remodeling, and persistent pathway modulation. Although whole-locus and gene body methylation of Axin2 were not markedly altered, promoter-region methylation showed an increasing tendency under maternal HFD exposure. In adult offspring, maternal HFD was associated with reduced Axin2 protein expression, decreased Wnt-responsive transcripts, increased peripheral corticosterone levels, and attenuation of LN progression. The inverse association between Axin2 expression and corticosterone further suggested coupling between suppressed Wnt pathway output and steroid hormone remodeling. Together, these findings support a developmental model in which maternal HFD reshapes the fetal intrauterine environment and establishes a persistent Wnt-steroid hormone-epigenetic regulatory axis that unexpectedly attenuates LN progression in genetically susceptible offspring.PMID:42722094 | DOI:10.1016/j.jnutbio.2026.110503

J Dairy Sci. 2026 Sep 10:S0022-0302(26)03251-0. doi: 10.3168/jds.2026-28883. Online ahead of print.ABSTRACTThis study investigated the effects of 2 Lactobacillus paracasei strains, KL1 and BK56, on the physicochemical properties, microstructure, texture characteristics, and sensory quality of a compound fermented yogurt system (GK107: L. paracasei KL1, Leuconostoc mesenteroides G12S, Chr. Hansen Commercial Starter Culture; G56107: L. paracasei BK56, L. mesenteroides G12S, Chr. Hansen Commercial Starter Culture), and further integrated genomic and metabolomic analyses to infer their shelf-life and optimal consumption period. The results showed that GK107 yogurt maintained stable quality throughout the 28-d storage period (at d 28: pH 4.07; titratable acidity 93.25 °T; exopolysaccharide content 0.31 g/L; water-holding capacity 53.05%; sensory score 83), and rapidly formed a stable gel structure that persisted for an extended duration. In contrast, the quality of G56107 yogurt deteriorated during the later stage of storage (at d 28: pH 4.0; titratable acidity 98.4 °T; exopolysaccharide content 0.31 g/L; water-holding capacity 51.3%; sensory score 67). Genomic analysis revealed that, compared with the L. paracasei KL1 strain, the L. paracasei BK56 strain carried loss-of-function mutations in multiple key genes associated with flavor synthesis, polysaccharide metabolism, and proteolysis, including alsS, prtP, glpO, AWC33_RS01450, AWC33_RS00855, AWC33_RS01070, and AWC33_RS01805. These mutations may have played a role in the gradual flavor deterioration, and weak post-acidification control observed in G56107 yogurt during prolonged storage. Based on the above results, it is reasonable to suggest that GK107 yogurt is suitable for long-term storage with an optimal consumption period of 14 to 28 d, whereas G56107 yogurt is more suitable for short-term storage and recommended for consumption within the first 14 d.PMID:42722071 | DOI:10.3168/jds.2026-28883

Ecotoxicol Environ Saf. 2026 Sep 10;323:120770. doi: 10.1016/j.ecoenv.2026.120770. Online ahead of print.ABSTRACTThe early pathogenic mechanisms underlying human diquat (DQ) poisoning remain incompletely understood. This study integrated retrospective clinical analysis, exploratory serum metabolomics, and in vitro experiments to characterize early metabolic disturbances and investigate potential cell-death mechanisms associated with acute DQ poisoning. Clinical data from 95 patients with acute DQ poisoning were retrospectively analyzed to identify clinical variables associated with outcome. Guided by these findings, exploratory pretreatment serum metabolomics was performed in eight patients with acute DQ poisoning and eight age- and sex-matched healthy controls. Cellular experiments were subsequently conducted in DQ-exposed HepG2 cellsto examine oxidative stress, lipid peroxidation, and ferroptosis-related features using biochemical, molecular, morphological, and inhibitor-based approaches. DQ concentration and markers of multi-organ injury were among the variables most strongly associated with clinical outcome in the random-forest analysis. Serum metabolomic analysis revealed alterations in polyunsaturated fatty acid metabolism, including perturbations in linoleic acid- and α-linolenic acid-related pathways and increased levels of several ω-6 polyunsaturated fatty acids and their oxidation derivatives. Correlation analysis demonstrated associations between these lipid-related metabolites and clinical markers of renal, hepatic, and muscular injury. In HepG2 cells, DQ exposure was associated with ROS accumulation, GSH depletion, lipid peroxidation, increased intracellular Fe²⁺, time-dependent alterations in GPX4 and SLC7A11 expression, and mitochondrial ultrastructural injury, a combination of changes consistent with ferroptosis-related cellular injury. Ferrostatin-1 significantly improved cell viability, whereas Necrostatin-1 showed no comparable protective effect and Z-DEVD-FMK provided less protection than Ferrostatin-1 under the conditions tested. In conclusion, acute DQ poisoning is associated with distinct clinical and metabolic disturbances involving PUFA metabolism. The HepG2 experiments further suggested that ferroptosis-related lipid peroxidation may contribute to DQ-induced cellular injury. These findings support further investigation of lipid peroxidation and ferroptosis-related pathways as potential therapeutic targets in DQ poisoning.PMID:42721925 | DOI:10.1016/j.ecoenv.2026.120770

J Hazard Mater. 2026 Sep 1;517:143463. doi: 10.1016/j.jhazmat.2026.143463. Online ahead of print.ABSTRACTHypertensive disorders of pregnancy (HDP) are major pregnancy complications, yet their environmental correlates and associated metabolic profiles remain incompletely characterized. In this prospective study of 1432 pregnant women from the Shanghai Birth Cohort, we integrated exposome-wide prioritization, mixture analyses, untargeted metabolomics, meet-in-the-middle (MITM), and exploratory mediation analyses to investigate prenatal exposures and metabolic profiles associated with HDP, gestational hypertension (GH), and preeclampsia (PE). Eighty-one exposures were ranked using ExWAS, elastic net, random forest, sparse partial least squares, and XGBoost. Among the measured exposure domains, phenols were prominently represented among the top 15 exposures, accounting for eight, seven, and six exposures for HDP, GH, and PE, respectively. Among 10 prioritized phenols, BP-1, BP-8, 4-HBP, and BPS showed generally consistent positive associations, with supportive evidence from weighted quantile sum regression and Bayesian kernel machine regression. In 1156 women with metabolomics data, metabolome-wide association analyses identified metabolic profiles associated with prioritized phenols and HDP outcomes. MITM and exploratory mediation analyses highlighted lipid-related candidate processes, particularly biosynthesis of unsaturated fatty acids and plasmalogen synthesis, which were consistently retained across the outcomes. These findings highlight prenatal phenols as an HDP-associated exposure family and lipid metabolism as a candidate biological link.PMID:42721835 | DOI:10.1016/j.jhazmat.2026.143463

Phytomedicine. 2026 Sep 3;161:158761. doi: 10.1016/j.phymed.2026.158761. Online ahead of print.ABSTRACTBACKGROUND: The occurrence of muscle atrophy in chronic kidney disease (CKD) is a prevalent complication with serious consequences but lacks effective treatment. Modulating the gut microbiota offers a promising new therapeutic approach. Shenshuai Yingyang Jiaonang (SSYYJN) is a clinically validated prescription of traditional Chinese medicine for muscle atrophy in CKD, yet the molecular basis for its therapeutic action requires elucidation.PURPOSE: To evaluate the therapeutic efficacy of SSYYJN against CKD-induced muscle atrophy, investigate the mechanism from the perspective of the gut microbiota, and explore potential strategies for enhancing the treatment efficacy of SSYYJN.METHODS: A rat model of CKD with concomitant muscle atrophy was established by 5/6 nephrectomy. 16S rDNA sequencing and fecal microbiota transplantation (FMT) experiments were conducted to elucidate the gut microbiota's role in SSYYJN efficacy. Untargeted metabolomics profiling and the pharmacological network analysis were conducted to investigate the potential mechanism of Faecalibacterium prausnitzii (FP) probiotics on SSYYJN. The regulatory mechanism of SSYYJN in CKD-associated muscle atrophy was validated through in vitro C2C12 cell experiments.RESULTS: In patients with CKD-associated protein-energy wasting (PEW), effective SSYYJN treatment improved mid-arm muscle circumference, hand grip strength, mid-arm circumference, and serum albumin. Moreover, post-hoc microbiome analysis revealed that the abundance of FP was higher in treatment-responsive patients. In a CKD rat model, SSYYJN conferred protection against renal injury, malnutrition, and muscle atrophy, this therapeutic effect was related to the gut microbiota modulation. Of note, a higher abundance of FP was also observed in SSYYJN-treated CKD rats. Further analyses suggested that FP was associated with increased levels of carnosol and may enhance EGFR/PI3K/AKT signaling, thereby potentiating the therapeutic effect of SSYYJN against CKD-induced muscle atrophy.CONCLUSION: These findings suggest a gut microbiota-dependent mechanism underlying the action of SSYYJN against muscle atrophy in CKD. FP may be linked to the effects of SSYYJN, potentially involving the generation of carnosol and the upregulation of the EGFR/PI3K/AKT pathway, representing a targeted therapeutic strategy.PMID:42721824 | DOI:10.1016/j.phymed.2026.158761

Talanta. 2026 Sep 4;312(Pt C):130595. doi: 10.1016/j.talanta.2026.130595. Online ahead of print.ABSTRACTPorcini mushrooms have high culinary and commercial value, but species-dependent differences in their flavor-related chemical composition and rapid authentication remain insufficiently characterized. In this study, four wild porcini mushroom species, Boletus bainiugan, Butyriboletus roseoflavus, Lanmaoa asiatica, and Rugiboletus extremiorientalis, were investigated using an integrated analytical strategy combining GC-MS, LC-MS/MS, Fourier transform infrared spectroscopy (FTIR), chemometrics, deep learning, and SHAP-based model interpretation. In this workflow, GC-MS and LC-MS/MS were used as the metabolomic characterization layer to define species-associated chemical differences within the investigated sample set in volatile organic compounds (VOCs), organic acids, and amino acid-related metabolites, whereas FTIR was used as the rapid spectral acquisition layer for non-destructive classification. The metabolomic results identified 770 volatile organic compounds, 59 organic acids, and 67 amino acid metabolites, among which 200 VOCs, 27 organic acids, and 29 amino acid metabolites were screened as differential markers. These data revealed that the four porcini mushroom species differed markedly in aroma-active compounds and taste-related metabolites, including pyrazines, lipid oxidation-derived aldehydes/ketones, sulfur-containing volatiles, organic acids, and amino acid derivatives. FTIR spectra were then processed using different preprocessing methods and modeled using back propagation neural network (BPNN) and convolutional neural network (CNN) classifiers. Among the tested models, the standard normal variate (SNV)-CNN model achieved the best classification performance, with F1 scores of 0.96-1.00 for the four species. SHAP analysis further linked the key discriminative wavenumbers to characteristic molecular vibrations, mainly O-H, N-H, C-H, C-O, and C-C bands, which were consistent with the metabolomic differences revealed by GC-MS and LC-MS/MS. Therefore, this study establishes a two-level analytical platform in which chromatographic-mass spectrometric profiling provides chemical annotation, compositional interpretation, and hypothesis generation, while FTIR combined with deep learning enables rapid species discrimination. The proposed strategy offers both chemical insight and practical potential for quality evaluation of porcini mushrooms.PMID:42721737 | DOI:10.1016/j.talanta.2026.130595

Food Chem. 2026 Sep 8;528:151068. doi: 10.1016/j.foodchem.2026.151068. Online ahead of print.ABSTRACTTo investigate suitable mechanized drying technologies for tiger nut, this study compared natural drying (ND), hot-air drying (HAD), heat-pump drying (HPD), infrared drying (ID), and radio-frequency drying (RFD) in terms of drying kinetics, microstructure, texture, rehydration ratio, relative electrical conductivity, major nutritional quality, and untargeted metabolomics. The results showed that mechanical drying significantly improved drying efficiency, with HPD requiring the shortest drying time (12 h). The Modified Page model provided the better fit for describing moisture changes during tiger nut drying. HAD and HPD were more effective in maintaining tissue continuity and resulted in higher hardness and chewiness, whereas RFD caused the most severe structural disruption. ID showed greater advantages in retaining protein, starch, and ash, while HAD was more favorable for lipid retention. HPD exhibited better performance in total dietary fiber retention and overall nutritional balance. Untargeted metabolomics analysis annotated 3977 metabolites and identified five key metabolic pathways. These findings provide a reference for optimizing tiger nut drying technologies and promoting postharvest processing and utilization.PMID:42721593 | DOI:10.1016/j.foodchem.2026.151068

Food Chem. 2026 Sep 6;528:151066. doi: 10.1016/j.foodchem.2026.151066. Online ahead of print.ABSTRACTThe reduction of high fructose and glucose content without affecting other important biochemicals is a challenge for healthier pomegranate juice, which was attempted using non-alcoholic fermentation by Kluyveromyces marxianus (isolated from kefir grains). For optimization of sugar reduction, static fermentation was undertaken with varying temperature (20 to 37C), pH (3.5, 4.0), and duration (up to 21 days). The reduction of fructose, glucose and formation of ethanol was measured periodically using HPLC for 21 days. The maximum sugar reduction by 34% (glucose 42% and fructose 18%) without ethanol formation was observed on day 7 at 30 °C and pH 3.5 and insignificant change in organic acids. GC/MS analysis showed increase in esters content contributing to fruity aroma corroborating higher sensory scores. The metabolomics profiling of fresh and fermented juice using LC-MS/MS revealed enhancement in B vitamins including pantothenic acid (1.5-fold), and biotin (2.3-fold) during fermentation.PMID:42721590 | DOI:10.1016/j.foodchem.2026.151066

Clin Nutr. 2026 Sep 1;65:106778. doi: 10.1016/j.clnu.2026.106778. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Autophagy activation is a promising strategy to counteract age-related cellular dysfunction. While preclinical studies suggest dietary protein restriction can induce autophagy via mTORC1 inhibition, direct human evidence using dynamic, flux-based measurements remains limited. The aim of this study was to determine whether a low protein diet could modulate autophagic flux in humans.METHODS: We conducted a randomized crossover trial in which 74 healthy adults were randomized to receive two 4-week interventions of either average-protein (20% energy) or reduced-protein (10% energy) diets prescribed to maintain calculated energy balance, separated by a 4-week washout period. The primary outcome was autophagic flux measured in whole blood using a validated assay that preserves PBMCs in their physiological environment during lysosomal inhibition. Secondary outcomes included metabolic markers, body composition, and self-reported health metrics.RESULTS: Sixty-three participants completed both interventions (mean ± SD age 29.5 ± 7.2 yrs; BMI 24.0 ± 3.2 kg/m2). Reducing protein intake did not alter autophagic flux (adjusted mean difference: -8.46 ng LC3B-II/mg protein/h; 95% CI: -24.06 to 7.14; p = 0.28). Metabolomic profiling confirmed effective dietary separation, with lower circulating urea following reduced protein intake. Small differences in body weight and muscle mass were observed, while fat mass was unaffected. Fasting glucose, insulin, lipids, blood pressure, and quality of life did not differ between the two diets.CONCLUSIONS: Moderate protein restriction does not increase basal autophagy in circulating immune cells of healthy adults, suggesting protein reduction alone, without caloric deficit, may be insufficient to activate autophagy in human blood.CLINICAL TRIAL REGISTRY NUMBER: Australian New Zealand Clinical Trials Registry Identifier ACTRN12623000260628. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382790.PMID:42721581 | DOI:10.1016/j.clnu.2026.106778

Neurology. 2026 Oct 13;107(7):e218409. doi: 10.1212/WNL.0000000000218409. Epub 2026 Sep 10.ABSTRACTBACKGROUND AND OBJECTIVES: Lacunar stroke results from cerebral small vessel disease (SVD) and is a major cause of vascular dementia and cognitive decline. We aimed to evaluate the associations of metabolites with lacunar stroke, neuroimaging markers of SVD, and cognition to help elucidate SVD pathogenesis.METHODS: In a clinical cohort of MRI-confirmed lacunar stroke cases and unrelated hospital controls recruited from stroke centers across the United Kingdom, we assayed 250 serum metabolites using NMR spectroscopy. We investigated the association of metabolites with MRI-confirmed lacunar stroke, neuroimaging markers, and cognitive impairment. We also conducted a genome-wide association analysis for each metabolite and applied bidirectional Mendelian randomization (MR) to investigate causality.RESULTS: Among 2,408 participants, there were 1,456 lacunar stroke cases (mean age, 62 [SD 12]; 34% female) and 952 controls (mean age, 57 [SD 6]; 38% female). Observational analyses identified 211 metabolites that were significantly associated with lacunar stroke. MR analyses identified significant evidence to support causal associations of 2 of these metabolites, glycine and the proportion of cholesterol to total lipids within medium low-density lipoprotein (LDL) (%C/Total in M-LDL), with 2 distinct lacunar stroke subtypes-isolated lacunar infarcts (ILI, 1 lacunar infarct with Fazekas grade <2) and multiple lacunar infarcts and/or leukoaraiosis (MLI/LA, >1 lacunar infarct and/or Fazekas grade ≥2). Glycine was inversely associated with ILI (OR: 0.704, 95% CI 0.585-0.848), and %C/Total in M-LDL was inversely associated with MLI/LA (OR: 0.541, 95% CI 0.401-0.730). Five metabolites (Total S-high-density lipoprotein [HDL], S-HDL concentration, phospholipid (PL) in S-HDL, %CE/Total in L-LDL, and lactate) were significantly associated with executive functioning and processing speed in observational analyses. MR analyses also implicated genetically determined levels of ω-3/Total FA with 2 diffusion tensor imaging markers of SVD. Overall, the most robust and consistent associations across both observational and MR analyses were identified for glycine and %C/Total in M-LDL with lacunar stroke subtypes.DISCUSSION: We identified inverse associations of glycine and the proportion of cholesterol to total lipids within medium LDL with distinct subtypes of MRI-confirmed lacunar stroke. These findings reveal metabolomics signatures associated with lacunar stroke subtypes, which may inform future studies of SVD pathogenesis and biomarker development.PMID:42721413 | DOI:10.1212/WNL.0000000000218409

Science. 2026 Sep 10;393(6816):eaea4287. doi: 10.1126/science.aea4287. Epub 2026 Sep 10.ABSTRACTObesity increases breast cancer risk and tumor aggressiveness, yet the mechanisms underlying this association remain unclear. In this work, we identify a tumor-suppressive lipid signaling pathway in which mammary adipocytes secrete the oxylipin 9S-hydroxyoctadecadienoic acid (9S-HODE). 9S-HODE induces ferroptosis in breast cancer cells by disrupting iron homeostasis. Adipocytes in obese mammary tissue produce less 9S-HODE, and tumors in obese mice exhibit reduced ferroptosis. Accordingly, ferroptosis inhibition accelerates tumor growth in lean mice, and restoring 9S-HODE suppresses tumor growth in obese mice. In humans, mammary 9S-HODE content is inversely correlated with body mass index, and 9S-HODE inhibits patient-derived breast cancer organoid growth. These findings identify the loss of adipocyte-derived 9S-HODE as a mechanism by which obesity promotes breast cancer and suggest that the restoration of ferroptosis-inducing lipid signaling may be a therapeutic strategy.PMID:42721252 | DOI:10.1126/science.aea4287

Cell Rep. 2026 Sep 10;45(9):117962. doi: 10.1016/j.celrep.2026.117962. Online ahead of print.ABSTRACTCell protrusions (CPs) promote metastasis by coordinating cell invasion, matrix remodeling, and communication with the microenvironment. The receptor tyrosine kinase AXL, activated in brain-tropic metastatic cancers, frequently localizes to CPs. The metabolic cues regulating CP biogenesis and AXL activation remain unclear. Here, we report that in invading cancer cells, phosphatidylserine is the most enriched lipid class in CPs. Mechanistically, we demonstrate that the scramblase-like transmembrane protein SERINC2 functions as a scaffold that interacts with integrins and recruits OSBPL8, an ER-plasma-membrane phosphatidylserine transporter, to CPs. This recruitment leads to phosphatidylserine accumulation and externalization at CPs, activation of CP-localized AXL, and upregulation of cell invasion. Furthermore, extracellular vesicles enriched in phosphatidylserine in a SERINC2-dependent manner stimulate autocrine AXL activation and drive M2-like microglia polarization. Accordingly, SERINC2 enhances orthotopic brain tumor growth and microglial reprogramming in vivo. Our data reveal a SERINC2-OSBPL8 axis orchestrating spatial lipid remodeling, AXL activation, and tumor-microenvironment communication.PMID:42721038 | DOI:10.1016/j.celrep.2026.117962

Cell Rep. 2026 Sep 9;45(9):117972. doi: 10.1016/j.celrep.2026.117972. Online ahead of print.ABSTRACTThe symbiosome, a temporary plant organelle enabling nitrogen fixation in legume-rhizobia symbiosis, consists of a plant-derived symbiosome membrane (SM), symbiosome space (SS), and enclosed bacteroid. Here, we isolate and purify symbiosomes from Medicago truncatula-Sinorhizobium meliloti root nodules and perform label-free quantitative mass spectrometry to profile protein abundances in the symbiosomes. We identify 1,018 M. truncatula proteins, including 829 in the SM and 457 in the SS. Combined with transport assays, our data reveal multiple dicarboxylate transporters in the SM that potentially deliver carbon sources to bacteroids. The SM is enriched in membrane trafficking proteins, lipid raft-associated components, and receptor-like proteins, together with numerous cell wall-associated proteins, highlighting the extracellular properties of the symbiosome. Proteomic and metabolomic analyses reveal the SS as a metabolically active compartment enriched in both plant and rhizobial proteins involved in carbon and amino acid metabolism. These findings offer insights into the molecular basis of symbiotic nitrogen fixation.PMID:42721037 | DOI:10.1016/j.celrep.2026.117972

Naturwissenschaften. 2026 Sep 10;113(5):105. doi: 10.1007/s00114-026-02148-6.ABSTRACTAlthough plants require an appropriate level of zinc (Zn) for normal growth and development, excessive accumulation, and high concentrations of it can impair plant growth, and disrupt physiological and metabolic processes. In this study, we aimed to identify zinc-tolerant chickpea varieties using multivariate analysis, and to elucidate the contribution of primary metabolites to zinc tolerance. We investigated multiple growth, physiological and biochemical parameters, including plant height, fresh weight and dry weight, Zn uptake, root-to-shoot ratio, relative shoot water content, tolerance index, chlorophyll contents, hydrogen peroxide (H2O2), malondialdehyde (MDA), electrolyte leakage (EL) and enzymatic and non-enzymatic antioxidants, such as superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), glutathione reductases (GR), proline, soluble sugars, and total protein in three chickpea varieties: ICCV89310 (IC8), NC234 (NC2), and ICCV89323-B (IC8-B) under various ZnSO4 concentrations (Ck, 50, 100, and 150 µM) in a hydroponic medium. Metabolite profiling of shoot samples was performed using GC-MS, while Zn accumulation in roots and shoots was quantified with ICP-OES. The results revealed significant differences among the tested varieties. For instance, IC8 and NC2 exhibited robust growth, and physiological and biochmeical performance under elevated ZnSO4 stress, indicating greater Zn tolerance, while IC8-B was the most sensitive variety. Additionally, IC8 and NC2 exhibited greater enzymatic and non-enzymatic antioxidant capacity compared to IC8-B across the Zn treatments. Meanwhile, forty-six responsive metabolites of different categories, including organic acids, amino acids, amines, alcohols, and sugars were quantified in the shoots of three chickpea varieties. Noticeably, the relative tolerance potential of IC8 and NC2 compared to IC8-B was asociated with distinct metabolic adjusments, including changes in histidine, asparagine, tryptophan, allantoin and antioxidant-related metabolites. Overall, this study provides an integrated physiological, biochemical, and metabolomic basis for identifying Zn-tolerant, and Zn-sensitive chickpea germplasm. IC8-B may serve as a sensetive refrence variety for comparative Zn-tolerance studies or to evaluate other chickpeas tolerance capacity, while IC8 and NC2 represent promising germplasm for Zn-contaminated environments; howver, field-scale confirmation remains necessary before practical application.PMID:42720780 | DOI:10.1007/s00114-026-02148-6

Plant Cell Rep. 2026 Sep 10;45(10):288. doi: 10.1007/s00299-026-03965-9.ABSTRACTThis review synthesizes the molecular mechanisms of cold tolerance in pepper, integrating multi-omics data,genome editing, and precision breeding strategies to accelerate the development of cold-resilient cultivars. Cold stress is a significant environmental factor that affects the growth, productivity, and fruit quality of Capsicum annuum by impairing membrane integrity photosynthesis and cellular redox homeostasis. Although pepper has several endogenous cold-responsive regulators such as CaNAC035 and CabHLH035, along with antioxidant defense systems, its cold tolerance remains limited due to low transcriptional activation of key regulators, functional redundancy among cold-responsive genes, and the polygenicity of cold tolerance. These complexities, combined with low genetic diversity and linkage drag, have hindered the improvement of cold-resistant cultivars through conventional breeding. This review brings together the recent progress in understanding the molecular mechanisms of cold stress perception, signal transduction, transcriptional regulation, metabolic reprogramming, and phytohormone interactions in pepper. Precision Breeding 2.0 is a new innovation that combines the integration of multi-omics-based target identification with next-generation genome-editing techniques, allowing precise and multiplex engineering of complex and interconnected regulatory networks instead of single genes. We cover new approaches such as engineering the DREB/CBF pathway, allele-specific editing and targeted disruption of negative regulators to enhance the pathway(s) involved in cold response. Moreover, we propose a roadmap for integration of transcriptomics, proteomics, metabolomics, high-throughput phenomics, and speed breeding to accelerate the identification, validation, and deployment of superior alleles to boost cold tolerance. This review provides a foundation for developing climate-resilient pepper cultivars by connecting functional genomics with precision genome engineering approaches to maintain productivity under variable environmental conditions.PMID:42720682 | DOI:10.1007/s00299-026-03965-9

J Allergy Clin Immunol. 2026 Sep 9:S0091-6749(26)00592-0. doi: 10.1016/j.jaci.2026.07.026. Online ahead of print.NO ABSTRACTPMID:42720631 | DOI:10.1016/j.jaci.2026.07.026

CNS Neurosci Ther. 2026 Sep;32(9):e71134. doi: 10.1002/cns.71134.ABSTRACTBACKGROUND: Sleep deprivation (SD) has been increasingly implicated in age-related cognitive decline. However, the mechanisms linking SD duration to progressive disruption of glial homeostasis, synaptic vulnerability, and metabolic dysregulation remain poorly defined.METHODS: We employed 12-month-old Thy1-EGFP and Cx3CR1-EGFP mice to investigate the effects of short-term sleep deprivation (SSD) and long-term sleep deprivation (LSD) on neuronal architecture, microglial morphology, and astrocytic homeostasis. Quantitative analyses included dendritic spine density, synaptic protein expression, glial morphological and transcriptional markers, and untargeted plasma metabolomics. The neuroprotective effects of D30, a novel small molecule compound, were also evaluated.RESULTS: SSD induced relatively transient oxidative stress and glial suppression, whereas LSD led to sustained reductions in dendritic spine density, synaptic protein levels, and microglial/astrocytic morphological complexity. LSD further disrupted mitochondrial metabolism, notably involving the TCA cycle, AMPK-associated signaling, and lipid homeostasis. Treatment with D30 significantly ameliorated LSD-induced deficits by preserving glial homeostatic features, restoring synaptic protein expression, maintaining dendritic spine density, and rebalancing systemic metabolism, ultimately improving cognitive performance.CONCLUSIONS: LSD impairs glial homeostatic integrity and synaptic stability in association with systemic metabolic dysfunction in middle-aged mice. D30 effectively alleviates these impairments, highlighting its potential as a protective intervention for chronic SD-related neurocognitive dysfunction.PMID:42720516 | DOI:10.1002/cns.71134