PubMed

bioRxiv [Preprint]. 2025 Apr 1:2025.03.27.645621. doi: 10.1101/2025.03.27.645621.ABSTRACTD-2-hydroxyglutarate (D-2HG) is a potent oncometabolite capable of disrupting chromatin architecture, altering metabolism, and promoting cellular dedifferentiation. As a result, ectopic D-2HG accumulation induces neurometabolic disorders and promotes progression of multiple cancers. However, the disease-associated effects of ectopic D-2HG accumulation are dependent on genetic context. Specifically, neomorphic mutations in the mammalian genes Isocitrate dehydrogenase 1 ( IDH1 ) and IDH2 result in the production of enzymes that inappropriately generate D-2HG from α-ketoglutarate (αKG). Within this genetic background, D-2HG acts as an oncometabolite and is associated with multiple cancers, including several diffuse gliomas. In contrast, loss-of-function mutations in the gene D-2-hydroxyglutarate dehydrogenase (D2hgdh) render cells unable to degrade D-2HG, resulting in excessive buildup of this molecule. D2hgdh mutations, however, are not generally associated with elevated cancer risk. This discrepancy raises the question as to why ectopic D-2HG accumulation in humans induces context-dependent disease outcomes. To enable such genetic studies in vivo , we generated two novel loss-of-function mutations in the Drosophila melanogaster gene D2hgdh and validated that these alleles result in ectopic D-2HG. Moreover, we observed that D2hgdh mutations induce developmental and metabolomic phenotypes indicative of elevated D-2HG accumulation. Overall, our efforts provide the Drosophila community with new mutant strains that can be used to study D-2HG function in human disease models as well as in the context of normal growth, metabolism, and physiology.PMID:40236175 | PMC:PMC11996423 | DOI:10.1101/2025.03.27.645621

bioRxiv [Preprint]. 2025 Apr 3:2025.04.01.646677. doi: 10.1101/2025.04.01.646677.ABSTRACTMounting evidence implicates inflammation as a key factor in Alzheimer's disease (AD) development. We previously identified pro-inflammatory soluble epoxide hydrolase (sEH) metabolites to be elevated in plasma and CSF of AD patients and to be associated with lower cognition in non-AD subjects. Soluble epoxide hydrolase is a key enzyme converting anti-inflammatory epoxy fatty acids to pro-inflammatory diols, reported to be elevated in multiple cardiometabolic disorders. Here we analyzed over 700 fasting plasma samples from the baseline of Alzheimer's Disease Neuroimaging Initiative (ADNI) 2/GO study. We applied targeted mass spectrometry method to provide absolute quantifications of over 150 metabolites from oxylipin and endocannabinoids pathway, interrogating the role for inflammation/immune dysregulation and the key enzyme soluble epoxide hydrolase in AD. We provide further insights into the regulation of this pathway in different disease stages, APOE genotypes and between sexes. Additionally, we investigated in mild cognitive impaired (MCI) patients, metabolic signatures that inform about resilience to progression and conversion to AD. Key findings include I) confirmed disruption in this key central pathway of inflammation and pointed to dysregulation of sEH in AD with sex and disease stage differences; II) identified markers of disease progression and cognitive resilience using sex and ApoE genotype stratified analysis highlighting an important role for bile acids, lipid peroxidation and stress response hormone cortisol. In conclusion, we provide molecular insights into a central pathway of inflammation and links to cognitive dysfunction, suggesting novel therapeutic approaches that are based on targeting inflammation tailored for subgroups of individuals based on their sex, APOE genotype and their metabolic profile.PMID:40236050 | PMC:PMC11996541 | DOI:10.1101/2025.04.01.646677

bioRxiv [Preprint]. 2025 Apr 2:2025.03.28.645975. doi: 10.1101/2025.03.28.645975.ABSTRACTImmune checkpoint blockade (ICB) has transformed cancer treatment, but success rates remain low in most cancers. Recent research suggest that dietary fiber enhances ICB response in melanoma patients and murine preclinical models through microbiome-dependent mechanisms. Yet, the robustness of this effect across cancer types and dietary contexts remains unclear. Specifically, prior literature compared grain-based chow (high fiber) to low-fiber purified diet, but these diets differ also on other dimensions including phytochemicals. Here we investigated, in mice fed grain-based chow or purified diets with differing quantities of isolated fibers (cellulose and inulin), metabolite levels and ICB activity in multiple tumor models. The blood and fecal metabolome were relatively similar between mice fed high- and low-fiber purified diets, but differed massively between mice fed purified diets or chow, identifying the factor as diet type, independent of fiber. Tumor growth studies in three implantable and two spontaneous genetically engineered tumor models revealed that fiber has a weaker impact on ICB (anti-PD-1) efficacy than previously reported. In some models, dietary modulation impacted ICB activity, but not in a consistent direction across models. In none of the models did we observe the pattern expected if fiber controlled ICB efficacy: strong efficacy in both chow and high-fiber purified diet but low efficacy in low-fiber purified diet. Thus, dietary fiber appears to have limited or inconsistent effect on ICB efficacy in mouse models, and other dietary factors that correlate with fiber intake may underlie the clinical correlations between fiber consumption and immunotherapy outcomes.PMID:40235983 | PMC:PMC11996298 | DOI:10.1101/2025.03.28.645975

bioRxiv [Preprint]. 2025 Apr 1:2025.03.31.646497. doi: 10.1101/2025.03.31.646497.ABSTRACTBACKGROUND: While operative and perioperative care continues to improve for single ventricle congenital heart disease (SV), long-term morbidities and mortality remain high. Importantly, phosphodiesterase-5 inhibitor therapies (PDE5i) are increasingly used, however, little is known regarding the direct myocardial effects of PDE5i therapy in the SV population.OBJECTIVES: Our group has previously demonstrated that the failing SV myocardium is characterized by increased PDE5 activity and impaired mitochondrial bioenergetics. Here we sought to determine whether serum circulating factors contribute to pathological metabolic remodeling in SV, and whether PDE5i therapy abrogates these changes.METHODS: Using an established in vitro model whereby primary cardiomyocytes are treated with patient sera +/- PDE5i, we assessed the impact of circulating factors on cardiomyocyte metabolism. Mass spectrometry-based lipidomics and metabolomics were performed to identify phospholipid and metabolite changes. Mitochondrial bioenergetics were assessed using the Seahorse Bioanalyzer and a stable isotope based mitochondrial enzyme activity assay. Relative mitochondrial copy number was quantified using RT-qPCR.RESULTS: Our data suggest that serum circulating factors contribute to fundamental changes in cardiomyocyte bioenergetics, including impaired mitochondrial function associated with decreased cardiolipin and other phospholipid species, increased reactive oxygen species (ROS) generation, and altered metabolite milieu. Treatment with PDE5i therapy was sufficient to abrogate a number of these metabolic changes, including a rescue of phosphatidylglycerol levels, a reduction in ROS, improved energy production, and normalization of several key metabolic intermediates.CONCLUSIONS: Together, these data suggest PDE5i therapy has direct cardiomyocyte effects and contributes to beneficial cardiomyocyte metabolic remodeling in SV failure.PMID:40235974 | PMC:PMC11996461 | DOI:10.1101/2025.03.31.646497

Biofilm. 2025 Mar 26;9:100276. doi: 10.1016/j.bioflm.2025.100276. eCollection 2025 Jun.ABSTRACTBacterial cellulose (BC), a promising versatile biopolymer produced by bacteria, has an immense potential in various industries. However, large-scale application is hindered by high production costs and low yields. This study introduces an innovative approach combining a prolonged static culturing with intermittent harvesting. This novel strategy resulted in a significant increase in BC productivity, achieving up to a threefold rise in biomass within the first 35 days. Prolonged growth and continuous harvesting not only enhanced productivity but also led to a mutant strain M2 with higher yields and distinct BC architecture. Mechanical and structural analyses revealed that sequential harvest correlated with increasing crystallinity, altered crystallite sizes, and improved stiffness of the dry material during initial cycles, potentially reflecting bacteria adaptation to resources limitations. Genomic analysis identified key mutations in the M2 strain, including one in the RelA/SpoT enzyme, suggesting a reduced stringent response that promotes growth under nutrient-limiting conditions. Untargeted metabolomic profiling revealed deregulation of several metabolites, including a significant difference in fatty acid metabolites that could potentially influence membrane fluidity and BC secretion. Such metabolic and structural adaptations enhance BC production efficiency and material properties. These findings highlight the potential of intermittent harvesting for sustainable BC production and the role of bacterial adaptation in tuning BC properties. Further research will optimize this strategy and expand its applications in developing tailored biomaterials for diverse industries.PMID:40235734 | PMC:PMC11999647 | DOI:10.1016/j.bioflm.2025.100276

Front Cell Dev Biol. 2025 Mar 28;13:1530996. doi: 10.3389/fcell.2025.1530996. eCollection 2025.ABSTRACTBACKGROUNDS: There is growing evidence that autoimmune illnesses are associated with the metabolome and microbiota. Because Behçet's disease (BD) is not often diagnosed as a systemic disorder, the aim of this research was to investigate changes in gut flora and metabolites in BD patients.METHODS: We used 16S rRNA gut microbiota gene sequencing and UPLC-QTOF-MS analysis to gather stool and serum samples from 12 age-matched healthy controls and 17 BD patients. The correlation between changes in gut microbiota and metabolites was then further analyzed.RESULTS: In contrast to healthy controls, our investigation revealed significant changes in the makeup of gut flora in BD patients. In particular, we observed that in the BD group, there was a large drop in clostridia but a noticeable rise in γ-proteobacteria and betaproteobacteria. The serum metabolomics profiles of BD patients and healthy controls may be reliably differentiated using unsupervised principal component analysis (PCA). Several metabolites, including L-phenylalaine, tricarballylic acid, beta-leucine, ketoleucine, ascorbic acid, l-glutamic acid, l-malic acid, d-glucopyranuronic acid, and methyl acetoacetate, were found to have differential expression between BD patients and healthy controls. All of these metabolites were significantly lower in the BD group. Furthermore, we discovered strong associations between the detected metabolites such as tricarballylic acid, L-malic acid, D-glucopyranuronic acid with certain microbial families, such Prevotellaceae and Alcaligenaceae.CONCLUSION: Patients with BD were found to have significant changes in the makeup of their gut flora and metabolites.PMID:40235731 | PMC:PMC11997388 | DOI:10.3389/fcell.2025.1530996

Comput Struct Biotechnol J. 2025 Mar 29;27:1359-1369. doi: 10.1016/j.csbj.2025.03.045. eCollection 2025.ABSTRACTThis study investigates the potential of 1H NMR spectroscopy for predicting key chemical and sensory attributes in olive oil. By integrating NMR data with traditional chemical analyses and sensory evaluation, we developed multivariate models to evaluate the predictive power of NMR spectra coupled with machine learning algorithms for 50 distinct olive oil quality parameters, including physicochemical properties, fatty acid composition, total polyphenols, tocopherols, and sensory attributes. We applied Random Forest regression models to correlate NMR spectra with these parameters, achieving promising results, particularly for predicting major fatty acids, total polyphenols, and tocopherols. We have also found the collected data to be highly effective in classifying olive cultivars and the years of harvest. Our findings highlight the potential of NMR spectroscopy as a rapid, non-destructive, and environmentally friendly tool for olive oil quality assessment. This study introduces a novel approach that combines machine learning with 1H NMR spectral analysis to correlate analytical data for predicting essential qualitative parameters in olive oil. By leveraging 1H NMR spectra as predictive proxies, this methodology offers a promising alternative to traditional assessment techniques, enabling rapid determination of several parameters related to chemical composition, sensory attributes, and geographical origin of olive oil samples.PMID:40235639 | PMC:PMC11999361 | DOI:10.1016/j.csbj.2025.03.045

New Phytol. 2025 Apr 16. doi: 10.1111/nph.70103. Online ahead of print.ABSTRACTMetal metabolism in plant-galler interactions is largely unknown. We hypothesise that the mites manipulate metal distribution by sequestration of excessive levels and differential regulation of metalloproteins to support the main functions of gall-nutrition, protection and microenvironment. Using the Tilia cordata-eriophyid mites system, we aimed to reveal the role of metals in galls by investigating their distribution, speciation, gene expression and metabolome profiling. Complementary spectroscopy techniques (μXRF and μXANES tomographies, electron paramagnetic resonance), histochemical, metabolomic and transcriptomic analyses were employed. Mn was the most abundant micronutrient in the galls. Differential cell-specific Mn accumulation (idioblasts vs nutritive tissue) and speciation are essential for its homeostasis. Mn(II)-aquo complex, co-localised with Ca, sequestered in idioblasts, while Mn bound to stronger ligands including enzymes accumulated in the nutritive tissue. Zn, Cu and Fe predominately accumulated in the nutritive tissue to support intensive metabolic processes such as secondary and lipid metabolism, protein N-glycosylation and redox regulation. The slower rate of redox-sensitive spin probes' decay in the galls indicated a lower amount of antioxidants than in the leaf. We reveal essential functions of micronutrients in the galls, supporting the developmental and chemical changes in the host plant, and the nutrition of the galler.PMID:40235337 | DOI:10.1111/nph.70103

Brain Pathol. 2025 Apr 15:e70011. doi: 10.1111/bpa.70011. Online ahead of print.ABSTRACTDuring Parkinson's disease (PD), loss of brainstem-based pedunculopontine nucleus' (PPN) cholinergic neurons induces progressive postural-gait disability (PGD). PPN-deep brain stimulation inconsistently alleviates PGD, due to stereotactic targeting inaccuracies resulting from insufficiently detailed human PPN anatomical descriptions. Relatedly, rodent studies show rostro-caudal clustering of PPN-cholinergic neurons, reflecting functional sub-territories. We applied unbiased cerebro-bilateral 3-dimensional (3-D) stereology to post-mortem PPNs from PD versus neurological-control cases, to estimate total numbers of cholinergic neurons and describe their rostro-caudal distribution. Given ambiguous descriptions of the PPN's confines, we utilized two complimentary definitions of the PPN's anatomical boundaries. The first was based on the structure's gross anatomy, by considering the nucleus as a recognizable "channel" enclosed by distinct white matter fiber tracts (WMFT) encompassing the medial lemniscus, central tegmental tract and decussation of the superior cerebellar peduncle. Second, the PPN was recognized by its histological architecture, as a dense collection of cholinergic neurons (the "Ch5" group) that were immunoreactive for choline acetyltransferase (ChAT), the enzyme responsible for biosynthesis of the neurotransmitter acetylcholine. Many such ChAT-immunoreactive neurons were dispersed within the traversing tracks and hence the PPN's Ch5-based outlining method permitted their stereological capture while also allowing distinction between the PPN's two subnuclei, namely the pars compacta (PPNc) and pars dissipata (PPNd), based on subnuclei-specific cholinergic cytoarchitectural organization. We further reconstructed template data as 3-D renders, revealing gross morphological differences between control and PD-affected PPNs. PD brains revealed significant PPN cholinergic neuronal loss, particularly affecting the PPNd. Control cases showed bimodal clustering of cholinergic neurons, prominently affecting left-sided PPNs. Most PD cases revealed more severe cholinergic neuronal loss in right-sided PPNs, potentially driving symptom lateralization. Our study provides a comprehensive cholinergic cytoarchitectural atlas of the human PPN in health versus during PD.PMID:40235161 | DOI:10.1111/bpa.70011

Clin Transl Med. 2025 Apr;15(4):e70292. doi: 10.1002/ctm2.70292.NO ABSTRACTPMID:40235096 | DOI:10.1002/ctm2.70292

Stem Cell Res Ther. 2025 Apr 15;16(1):179. doi: 10.1186/s13287-025-04308-3.ABSTRACTBACKGROUND: When a tooth suffers severe injuries, dental pulp stem cells migrate and differentiate into odontoblast-like cells to form restorative dentin. Kruppel-like factor 6 (KLF6) activates the odontoblast differentiation of dental papilla cells during tooth development. However, the mechanisms by which KLF6 regulates the function of odontoblast-like cells differentiated from human dental pulp stem cells (hDPSCs) remain unknown.METHODS: KLF6 was over-expressed or silenced by lentivirus transfection. Transcriptome sequencing and metabolomics were performed to reveal main changes in KLF6 high expressed hDPSCs. Mitochondrial morphology was observed by confocal microscope and cryo-transmission electron microscopy. Metabolic assays and metabolic flux were used to determine changes in cellular metabolic characteristics. Glutamine, glutamate, α-KG, and citrate concentrations were detected in cultured cells. Citrate and Ca concentration were detected in ECM. Adeno-associated virus were used to silence KLF6 in mice. A mouse dental injury model was established to investigate the role of KLF6 and glutamine metabolism in dentin repair in vivo.RESULTS: RNA sequencing and metabolomics showed a remarkable influence on glutamine metabolism, mitochondrial respiration, and the TCA cycle by KLF6 overexpression. Metabolic assays and mitochondrial morphology observation found KLF6 promoted glutamine metabolism and mitochondrial function, and glutamine metabolism and mitochondrial respiration are enhanced during odontogenic differentiation of hDPSCs. Deprivation of glutamine inhibited mineralization of hDPSCs and restrained deposition of citrate and Ca in ECM. Increased glutamine entry into the tricarboxylic acid (TCA) cycle was both observed in differentiated hDPSCs and KLF6 overexpressed hDPSCs. ChIP-qPCR experiments revealed that KLF6 can directly bind to the promoter sequences of GLS1 and GDH. Supplementation of α-KG rescued suppression of odontogenic differentiation and mineralization induced by KLF6 knockdown. Inhibition of glutamine metabolism and knockdown of KLF6 attenuated tertiary dentin formation in vivo.CONCLUSIONS: Our study shows that KLF6 mediates biomineralization in the newly generated functional odontoblast-like cells differentiated from hDPSCs by altering cell metabolism preferences. KLF6 facilitated glutamine influx into the TCA cycle, leading to increased deposition of citrate in the ECM.These findings may inspire the development of novel strategies for reparative dentin formation.PMID:40234972 | DOI:10.1186/s13287-025-04308-3

Biomed Eng Online. 2025 Apr 15;24(1):43. doi: 10.1186/s12938-025-01378-5.ABSTRACTOBJECTIVES: Chronic obstructive pulmonary disease (COPD) frequently coexists with metabolic syndrome (MS), compounding its impact on patients' health and quality of life. This study aimed to elucidate the immune and metabolic response characteristics in COPD patients with and without MS.METHODS: A total of 11,315 COPD patients admitted to the Department of Respiratory and Critical Care Medicine at the Third People's Hospital of Chengdu between January 1, 2013, and May 1, 2023, were selected. Multivariate logistic regression was conducted to identify the risk factors for acute exacerbation of chronic obstructive pulmonary disease. Moreover, from this cohort, 30 patients (18 with COPD and 12 with COPD-MS) were recruited for a further study to investigate the underlying mechanisms of COPD and COPD-MS. Blood samples were collected from these participants to perform transcriptomic and metabolomic analyses, aiming to explore the differences in immune responses and metabolic alterations between the two groups.RESULTS: Our findings indicate a significant enhancement of neutrophil-mediated immune responses in COPD-MS patients. Transcriptomic analysis revealed 327 differentially expressed genes (DEGs) significantly involved in neutrophil-mediated immunity. Key metabolic pathways were disrupted, with 39 differential metabolites identified. Notably, metabolites, such as L-homoarginine and diethanolamine, which were elevated in COPD-MS patients, showed strong correlations with DEGs involved in neutrophil pathways and immune checkpoint regulation. The study also found decreased levels of IL4 and IL5RA in COPD-MS patients, suggesting a shift from Th2 to Th1 inflammatory responses, potentially contributing to glucocorticoid resistance.CONCLUSIONS: COPD patients with metabolic syndrome exhibit a heightened neutrophil-mediated inflammatory response and significant metabolic disturbances, which underscores the need for precise therapeutic strategies targeting both metabolic and inflammatory pathways to improve patient outcomes and manage COPD-MS complexities effectively.PMID:40234868 | DOI:10.1186/s12938-025-01378-5

BMC Genomics. 2025 Apr 15;26(1):378. doi: 10.1186/s12864-025-11542-9.ABSTRACTBACKGROUND: The medicinal mushroom Sanghuangporus is renowned in East Asia for its potent therapeutic properties, attributed in part to its bioactive sesquiterpenoids. However, despite their recognized medicinal potential, the biosynthetic pathways and specific enzymes responsible for sesquiterpenoid production in Sanghuangporus remain unexplored, limiting opportunities to optimize their medicinal applications.RESULTS: Sesquiterpenoids from four Sanghuangporus species were extracted through targeted isolation using mass spectrometry (MS)-based metabolomics, resulting in the discovery of six known abscisic acid-related compounds and one new compound, whose structure was determined through spectroscopic and computational analysis. We employed a natural product genome mining approach to identify a putative biosynthetic gene cluster (BGC) containing a sesquiterpene synthase gene, ancA, associated with the detected compounds. Biosynthetic pathways for these compounds were proposed based on an integrative approach combining BGC analysis and MS2 fragment-based dereplication. Further analyses revealed that the gene content and synteny of the ancA BGC are relatively well-conserved across Sanghuangporus species but less so outside the genus.CONCLUSIONS: A sesquiterpene synthase gene, its associated BGC, and the biosynthetic pathway for a group of detected abscisic acid-related sesquiterpenoids in Sanghuangporus were predicted through genomic and metabolic data analyses. This study addresses a critical gap in understanding the genetic basis of sesquiterpenoid production in Sanghuangporus and offers insights for future research on engineering metabolic pathways to enhance sesquiterpenoid production for medicinal use.PMID:40234762 | DOI:10.1186/s12864-025-11542-9

BMC Genomics. 2025 Apr 15;26(1):375. doi: 10.1186/s12864-025-11586-x.ABSTRACTBACKGROUND: Strong tolerance to seed aging is an important agricultural trait for sweet corn production. Previous studies have primarily focused on the QTLs for the seed vigor. However, there were few researches involving in the metabolome and transcriptome of artificial aging seeds.RESULTS: Using two inbred lines with significant differences in seed artificial aging tolerance, RNA sequencing and non-targeted metabolomic analysis were employed to extensively evaluate transcripts and metabolites in seeds that underwent artificial aging. Fourteen common transcripts and 16 common metabolites with sustained differential expression were identified in the two lines, suggesting their potential necessity in seed response to artificial aging. Enrichment analysis of differentially expressed genes (DEGs) in the transcriptome at different stages revealed significant enrichment KEGG pathways, "Oxidative phosphorylation" was the common pathway in the 0d vs 3d comparison for K107 and L155. The identical enriched KEGG pathways were observed in the 3d vs 6d comparison for K107 and 0d vs 6d comparison for L155, indicating a slower transcriptomic response in the aging-tolerance line. DEGs at 0 days between the two lines had been enriched in the "Terpenoid backbone biosynthesis" and "Ribosome" pathways, while at 6 days, the enrichment pathway were "Sulfur metabolism", "Linoleic acid metabolism", and "Plant hormone signal transduction". A total of 312 differentially expressed metabolites (DEMs) were found at 0, 3 and 6 days after seed aging treatment, and they shared enriched metabolic pathway of "ABC transporters". The KEGG enrichment of DEGs and DEMs shared the common pathway, namely "Linoleic acid metabolism". Among these, the most abundant metabolites were Glutathione, Adenosine, Trehalose, and 10E,12Z-Octadecadienoic acid. Focusing on the ascorbate-glutathione pathway revealed that the difference in ROS production and the ROS scavenging capability mediated by glutathione S-transferase (GST) genes were important factors contributing to the differing seed aging tolerance in the two lines.CONCLUSION: In summary, these results contribute to a deeper understanding of the overall mechanisms underlying artificial aging tolerance in sweet corn seeds. The findings of this study are expected to provide valuable insights for the storage of sweet corn seeds.PMID:40234743 | DOI:10.1186/s12864-025-11586-x

Sci Rep. 2025 Apr 15;15(1):12889. doi: 10.1038/s41598-025-98016-w.ABSTRACTInfections caused by the Gram-negative bacterium Helicobacter pylori (H. pylori) can lead to gastritis, gastric or duodenal ulcers, and even gastric cancer in humans. Investigating quantitative changes in soluble biomarkers associated with H. pylori infection offers a promising method for monitoring the progression of the infection, inflammatory response and potentially systemic consequences. This study aimed to identify, using an experimental model of H. pylori infection in guinea pigs, the specific metabolomic biomarkers in the serum of H. pylori-infected (32) versus uninfected (32) animals. The H. pylori status was confirmed through histological, molecular, and serological examinations. Metabolomic profiling was conducted using UPLC-QTOF/MS methods. The metabolomic biomarkers significantly associated with H. pylori infection were selected based on volcano plots and traditional univariate receiver operating characteristics (ROC). This study identified 12 unique metabolites significantly differentiating H. pylori-infected guinea pigs from uninfected ones. In summary, the metabolomic profiling of serum samples, in combination with ROC characteristics of the data, enhances the monitoring of H. pylori infection and related inflammatory responses in guinea pigs experimentally infected with these bacteria, with potential applications in humans for prediction the infection course and its systemic effects.PMID:40234702 | DOI:10.1038/s41598-025-98016-w

Cell Death Differ. 2025 Apr 15. doi: 10.1038/s41418-025-01503-w. Online ahead of print.ABSTRACTGlioblastoma (GBM) employs various strategies to resist therapy, resulting in poor patient survival. A key aspect of its survival mechanisms lies in metabolic regulation, maintaining rapid growth and evading cell death. Recent studies revealed the connection between therapy resistance and ferroptosis, a lipid peroxidation-dependent cell death mechanism triggered by metabolic dysfunction. Our aim was to identify novel regulators of therapy resistance in GBM cells. We conducted a comprehensive analysis combining RNA-sequencing data from a panel of human GBM cell models and TCGA GBM patient datasets. We focused on the top-12 differentially expressed gene candidates associated with poor survival in GBM patients and performed an RNA interference-mediated screen to uncover the radiochemosensitizing potential of these molecules and their impact on metabolic activity, DNA damage, autophagy, and apoptosis. We identified exostosin glycosyltransferase 2 (EXT2), an enzyme previously described in heparan sulfate biosynthesis, as the most promising candidate. EXT2 depletion elicited reduced cell viability and proliferation as well as radiochemosensitization in various GBM cell models. Mechanistically, we explored EXT2 function by conducting untargeted and targeted metabolomics and detected that EXT2-depleted GBM cells exhibit a differential abundance of metabolites belonging to S-adenosylmethionine (SAM) metabolism. Considering these metabolic changes, we determined lipid peroxidation and found that the diminished antioxidant capacity resulting from decreased levels of metabolites in the transsulfuration pathway induces ferroptosis. Moreover, modifications of specific SAM and transsulfuration metabolism associated enzymes revealed a prosurvival and ferroptosis-reducing function when EXT2 is depleted. Collectively, our results uncover a novel role of EXT2 in GBM cell survival and response to X-ray radiation, which is controlled by modulation of ferroptosis. These findings expand our understanding of how GBM cells respond to radio(chemo)therapy and may contribute to the development of new therapeutic approaches.PMID:40234611 | DOI:10.1038/s41418-025-01503-w

Sci Rep. 2025 Apr 15;15(1):12905. doi: 10.1038/s41598-025-96010-w.ABSTRACTType 2 diabetes mellitus (T2DM) is closely associated with an increased risk and adverse event of acute coronary syndrome (ACS). The present study aims to investigate the association between differential urinary metabolites and major adverse cardiovascular events (MACEs) in patients with ACS co-morbid T2DM with preserved renal function, and to explore the potential value of the metabolites as prognostic biomarkers in this population. Ultra-high performance liquid chromatography-mass spectrometry (UHPLC/MS) was used to analyze urine samples from ACS co-morbid T2DM. Spearman's correlation was used to examine the association between differential metabolites and serum fasting blood glucose (FBG), glycated hemoglobin (HbA1c), Syntax score I, and MACE. The Cox proportional hazards models and Kaplan-Meier survival curves were used to identify MACE risk factors. A total of 101 differential urinary metabolites were identified, of which seven showed a correlation with FBG, HbA1c, Syntax score I and MACE. In particular, myo-inositol and (E)-Monocrotophos emerged as significant indicators of poor prognosis in ACS co-morbid with T2DM. Urinary metabolomic alteration is closely associated with clinical manifestation of ACS co-morbid T2DM. Urinary myo-inositol and (E)-Monocrotophos may be considered as prognostic biomarkers of ACS co-morbid T2DM.PMID:40234531 | DOI:10.1038/s41598-025-96010-w

Sci Rep. 2025 Apr 15;15(1):13007. doi: 10.1038/s41598-025-96877-9.ABSTRACTEwing Sarcoma (EwS) is a rare pediatric malignancy characterized by a unique t(11:22) (q24;q12) translocation resulting in the pathognomonic EWSR1::FLI1 fusion. Recent reports indicate that the EWSR1::FLI1 oncofusion drives aberrant expression of numerous transcripts, including Lipoxygenase Homology Domains 1 (LOXHD1). Given its highly restricted protein expression pattern and role in EwS tumorigenesis and metastasis, LOXHD1 may serve as a novel immunotherapeutic target in this malignancy. LOXHD1 immunogenic epitopes restricted to HLA-A*02:01 allowed for the isolation of a high avidity αβTCR. LOXHD1-specific TCR engineered CD8+ T cells conferred cytotoxic activity against a panel of HLA-A*02:01+ EwS tumor cell lines and adoptive transfer led to tumor eradication in a mouse xenograft model of EwS. This study nominates LOXHD1 as an oncofusion regulated, non-mutated tumor associated antigen (TAA) with expression limited to inner hair cells of the cochlea, adult testis, and EwS.PMID:40234527 | DOI:10.1038/s41598-025-96877-9

Sci Rep. 2025 Apr 15;15(1):13012. doi: 10.1038/s41598-025-93882-w.ABSTRACTAge-related macular degeneration (AMD) is associated with chronic inflammation of the retinal pigment epithelium (RPE) and elevated cytokines including TNFα, TGF-β, IL-6, and IL-1β. As a metabolic intermediary supporting aerobic glycolysis in the adjacent photoreceptors, the RPE's metabolic responses to inflammation and the optimal methods to study cytokine-driven metabolic programming remain unclear. We performed a rigorous comparison of ARPE-19 cells and rat eyecup metabolomes, revealing key distinctions. Rat eyecups exhibit higher levels of lactate and palmitate but depleted glutathione and high-energy nucleotides. Conversely, ARPE-19 cells are enriched with high-energy currency metabolites and the membrane phospholipid precursors phosphocholine and inositol. Both models showed contrasting responses to individual cytokines: ARPE-19 cells were more sensitive to TNFα, while eyecups responded more strongly to TGF-β2. Notably, a combined cytokine cocktail elicited stronger metabolic effects on ARPE-19 cells, more potently impacting both metabolite abundance (41 vs. 29) and glucose carbon flux (29 vs. 5), and influencing key RPE metabolites such as alanine, glycine, aspartate, proline, citrate, α-ketoglutarate, and palmitate. Overall, these findings position ARPE-19 cells as a more responsive platform for studying inflammatory cytokine effects on RPE metabolism and reveal critical RPE metabolites which may be linked with AMD pathogenesis.PMID:40234500 | DOI:10.1038/s41598-025-93882-w

Sci Rep. 2025 Apr 15;15(1):11341. doi: 10.1038/s41598-025-91631-7.ABSTRACTNatural rubber (NR) is an important material with excellent physical properties. Unlike synthetic rubber from petroleum, NR contains non-rubber components such as proteins, lipids, and metal ions. The non-rubber components are known to affect the properties of NR. In this study, latex samples of Hevea brasiliensis were collected for nine months and their metabolites were comprehensively analyzed by mass spectrometry. NR was made from the same latex samples used for the mass spectrometry, and their vulcanization, tensile and thermal-aging properties were assessed. By using this approach of integrating metabolite and property data, we aim to clarify the influence of metabolites on the physical properties of NR. These results suggest that the metabolite composition in the latex and the NR properties changed seasonally. Correlation analysis between the metabolites and the properties of NR indicated that different metabolites affected different properties. A regression model of NR properties using metabolites as the explanatory variables suggests that about five metabolites need to be considered when examining the relationship between properties and metabolites. This method, which combines comprehensive analysis and characterization of NR, contributes to studies aimed at elucidating how the superior properties of NR are brought about.PMID:40234483 | DOI:10.1038/s41598-025-91631-7