PubMed

Acta Pharm Sin B. 2025 Mar;15(3):1359-1382. doi: 10.1016/j.apsb.2025.01.006. Epub 2025 Jan 19.ABSTRACTEnvironmental toxicants have been linked to aging and age-related diseases. The emerging evidence has shown that the enhancement of detoxification gene expression is a common transcriptome marker of long-lived mice, Drosophila melanogaster, and Caenorhabditis elegans. Meanwhile, the resistance to toxicants was increased in long-lived animals. Here, we show that farnesoid X receptor (FXR) agonist obeticholic acid (OCA), a marketed drug for the treatment of cholestasis, may extend the lifespan and healthspan both in C. elegans and chemical-induced early senescent mice. Furthermore, OCA increased the resistance of worms to toxicants and activated the expression of detoxification genes in both mice and C. elegans. The longevity effects of OCA were attenuated in Fxr -/- mice and Fxr homologous nhr-8 and daf-12 mutant C. elegans. In addition, metabolome analysis revealed that OCA increased the endogenous agonist levels of the pregnane X receptor (PXR), a major nuclear receptor for detoxification regulation, in the liver of mice. Together, our findings suggest that OCA has the potential to lengthen lifespan and healthspan by activating nuclear receptor-mediated detoxification functions, thus, targeting FXR may offer to promote longevity.PMID:40370561 | PMC:PMC12069902 | DOI:10.1016/j.apsb.2025.01.006

Acta Pharm Sin B. 2025 Mar;15(3):1383-1396. doi: 10.1016/j.apsb.2025.01.017. Epub 2025 Jan 28.ABSTRACTDespite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.PMID:40370557 | PMC:PMC12069247 | DOI:10.1016/j.apsb.2025.01.017

Acta Pharm Sin B. 2025 Mar;15(3):1430-1446. doi: 10.1016/j.apsb.2025.01.024. Epub 2025 Feb 10.ABSTRACTThe liver regenerative capacity is crucial for patients with end-stage liver disease following partial hepatectomy (PHx). The specific bacteria and mechanisms regulating liver regeneration post-PHx remain unclear. This study demonstrated dynamic changes in the abundance of Parabacteroides distasonis (P. distasonis) post-PHx, correlating with hepatocyte proliferation. Treatment with live P. distasonis significantly promoted hepatocyte proliferation and liver regeneration after PHx. Targeted metabolomics revealed a significant positive correlation between P. distasonis and β-hydroxybutyric acid (BHB), as well as hyodeoxycholic acid and 3-hydroxyphenylacetic acid in the gut after PHx. Notably, treatment with BHB, but not hyodeoxycholic acid or 3-hydroxyphenylacetic acid, significantly promoted hepatocyte proliferation and liver regeneration in mice after PHx. Moreover, STAT3 inhibitor Stattic attenuated the promotive effects of BHB on cell proliferation and liver regeneration both in vitro and in vivo. Mechanistically, P. distasonis upregulated the expression of fatty acid oxidation-related proteins, and increased BHB levels in the liver, and then BHB activated the STAT3 signaling pathway to promote liver regeneration. This study, for the first time, identifies the involvement of P. distasonis and its associated metabolite BHB in promoting liver regeneration after PHx, providing new insights for considering P. distasonis and BHB as potential strategies for promoting hepatic regeneration.PMID:40370533 | PMC:PMC12069244 | DOI:10.1016/j.apsb.2025.01.024

Front Mol Biosci. 2025 Apr 30;12:1595602. doi: 10.3389/fmolb.2025.1595602. eCollection 2025.ABSTRACTThe increasing prevalence of depression profoundly affects female ovarian health. Although Cuscutae Semen (CS) is acknowledged for treating reproductive disorders, its pharmacological mechanisms in depression-induced ovarian dysfunction remain insufficiently explored. This study investigated CS's effects in a chronic unpredictable mild stress (CUMS) mouse model of depression. Mice were divided into control, CUMS model, CS treatment and estradiol treatment group. Behavioral and biochemical analyses assessed depressive-like behaviors and hormone levels. Untargeted metabolomics utilizing ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was applied to identify differential metabolites of CS in the treatment of depression-induced ovarian dysfunction. These findings were confirmed through real-time quantitative polymerase chain reaction assays. Based on the outcomes from behavioral and biochemical assays, CS effectively ameliorated the chronic unpredictable mild stress-induced reproductive ailment in mice. Ten differential metabolites were identified, highlighting the impact of CUMS and CS's ameliorative effects. Pathways linked to arachidonic acid metabolism, glycerophospholipid metabolism, linoleic acid metabolism, and steroid hormone biosynthesis were involved. Seven target genes further validated the metabolomic analysis. This study provides strong evidence of CS's therapeutic potential in alleviating depression-induced ovarian dysfunction, shedding light on its pharmacological mechanisms and supporting its use as a functional medical food.PMID:40370520 | PMC:PMC12074923 | DOI:10.3389/fmolb.2025.1595602

Patient Prefer Adherence. 2025 May 9;19:1385-1395. doi: 10.2147/PPA.S514170. eCollection 2025.ABSTRACTPURPOSE: The emerging clinical implications of medical foods and dietary supplements in cancer patients have been recognized. This study aimed to evaluate the perception and usage of these products in cancer patients undergoing chemotherapy.PATIENTS AND METHODS: Cross-sectional descriptive research was conducted by face-to-face interviews between October 2017 and February 2018. The participants provided written informed consent before data collection.RESULTS: This study included 201 patients (mean age 55.9 years) with gastrointestinal, breast, gynecological, and respiratory tract cancers, primarily receiving antimetabolite or platinum-based regimens. Awareness of medical foods and dietary supplements was high, at 97% and 98%, respectively. Most patients (91.5% for medical foods, 80.1% for dietary supplements) believed these products could be used safely without side effects, and over 70% thought they could be used concurrently with chemotherapy. More than half of the patients reported receiving supplement information from friends or relatives, while 65.2% stated that healthcare providers did not ask about their uses. Notably, 69.7% and 51.2% of patients reported current use of medical foods and dietary supplements, respectively, but 61.7% did not disclose this to their healthcare providers primarily since they were not asked.CONCLUSION: These findings highlight the need for healthcare professionals to actively address the use of medical foods and dietary supplements with cancer patients. Enhanced communication and guidance could ensure safe and effective integration of these products into supportive cancer care.PMID:40370472 | PMC:PMC12075470 | DOI:10.2147/PPA.S514170

Technol Health Care. 2025 May 15:9287329251339074. doi: 10.1177/09287329251339074. Online ahead of print.ABSTRACTBackgroundAortic aneurysms (AA), including thoracic (TAA) and abdominal (AAA) types, are life-threatening conditions with complex and poorly understood mechanisms. Metabolic alterations, particularly in amino acid and energy metabolism, have been linked to AA, but their roles remain unclear due to limited and confounded observational evidence.ObjectiveThis research aimed to comprehensively investigate the potential causal links between serum metabolites and the development of thoracic (TAA) and abdominal (AAA) aortic aneurysms.MethodsWe analyzed serum metabolites from the Metabolomics data, using datasets of 353,049 individuals for TAA (3510 cases) and 353,087 individuals for AAA (3548 cases). Mendelian randomization (MR) techniques, including MR-Egger regression and inverse-variance weighting (IVW), assessed causality, with heterogeneity tested using Cochran's Q and I2 statistics, and pleiotropy via the MR-Egger intercept. Sensitivity was further checked through leave-one-out analysis. SNP annotations identified genes linked to TAA and AAA, and metabolic pathways were also analyzed.ResultsNine metabolites were causally linked to TAA, with three as risk factors, while 18 metabolites were associated with AAA, including eight risk factors. 3-dehydrocarnitine showed contrasting effects, acting as a risk factor for TAA (OR = 2.704; P = 0.031) and a protective factor for AAA (OR = 0.303; P = 0.025). Pathway analysis revealed TAA-related pathways such as "Pyruvaldehyde degradation" and "Arginine biosynthesis," while AAA was linked to "Phenylalanine metabolism" and "Valine, leucine, and isoleucine biosynthesis." No horizontal pleiotropy was detected, and results were robust.ConclusionsIdentified metabolites and pathways may serve as potential biomarkers and therapeutic targets for the clinical assessment and prevention of TAA and AAA.PMID:40370076 | DOI:10.1177/09287329251339074

Biofouling. 2025 May 14:1-14. doi: 10.1080/08927014.2025.2502936. Online ahead of print.ABSTRACTBurkholderia pseudomallei biofilms are resistant to antibiotics and immune responses, leading to persistent infections. This study aimed to investigate the metabolic profiles of B. pseudomallei in biofilms and the extracellular polymeric substances (EPS) produced during grown in LB or MVBM medium using Nuclear Magnetic Resonance (NMR) spectroscopy to identify key metabolites. The results revealed similar biofilm metabolites in both media. However, betaine was detected in LB, but not in the case of MVBM. Acetate was significantly higher in MVBM compared to that of LB. Pathway analysis revealed that betaine-producing B. pseudomallei biofilm in LB was associated with metabolism of glycine, serine, and threonine, while acetate in MVBM was associated with metabolism of taurine and hypotaurine, phosphonate and phosphinate, and glycolysis/gluconeogenesis. The NMR analysis of EPS disclosed shared metabolites including dimethylsulfide, 1-methyluric acid and oxypurinol. This study provides the first extensive investigation into B. pseudomallei biofilm and EPS metabolites, identifying pathways that offer potential targets for combating B. pseudomallei biofilm-associated infections.PMID:40369969 | DOI:10.1080/08927014.2025.2502936

Anim Biosci. 2025 May 12. doi: 10.5713/ab.25.0038. Online ahead of print.ABSTRACTOBJECTIVE: This study aimed to investigate the metabolic changes and immune responses in Jersey dairy cows under heat stress (HS). The focus was on understanding HS-induced alterations in metabolism and immunity compared to HS-free cows.METHODS: Proton nuclear magnetic resonance spectroscopy-based metabolomics was performed on rumen fluid, serum, and milk samples which were collected through single sampling from HS-free (n = 9) and HS-exposed (n = 8) Jersey cows. Immune cell proportions and functions in peripheral blood mononuclear cells were analyzed to identify heat-sensitive immunological changes. Correlation analysis was conducted to link immune indicators with serum metabolites.RESULTS: Metabolomics revealed potential HS biomarkers in biofluids: nicotinate and phenylacetate in rumen fluid; isopropanol in serum; and glycine and trehalose in milk. HS increased B cell and CD4+ T cell populations, as well as Th17 cells and IL-17A expression in PBMCs. Twenty-three metabolites correlated strongly with five immune indicators, with nine metabolites exhibiting a positive correlation and fourteen a negative correlation.CONCLUSION: Heat stress alters the both metabolism and immune cell function in Jersey dairy cows. These findings provide key information for the development of diagnostic methods for heat stress and nutritional intervention strategies to mitigate heat stress for dairy cows.PMID:40369753 | DOI:10.5713/ab.25.0038

Gigascience. 2025 Jan 6;14:giaf035. doi: 10.1093/gigascience/giaf035.ABSTRACTBACKGROUND: Truly understanding the cancer biology of heterogeneous tumors in precision medicine requires capturing the complexities of multiple omics levels and the spatial heterogeneity of cancer tissue. Techniques like mass spectrometry imaging (MSI) and spatial transcriptomics (ST) achieve this by spatially detecting metabolites and RNA but are often applied to serial sections. To fully leverage the advantage of such multi-omics data, the individual measurements need to be integrated into 1 dataset.RESULTS: We present the Multi-Omics Imaging Integration Toolset (MIIT), a Python framework for integrating spatially resolved multi-omics data. A key component of MIIT's integration is the registration of serial sections for which we developed a nonrigid registration algorithm, GreedyFHist. We validated GreedyFHist on 244 images from fresh-frozen serial sections, achieving state-of-the-art performance. As a proof of concept, we used MIIT to integrate ST and MSI data from prostate tissue samples and assessed the correlation of a gene signature for citrate-spermine secretion derived from ST with metabolic measurements from MSI.CONCLUSION: MIIT is a highly accurate, customizable, open-source framework for integrating spatial omics technologies performed on different serial sections.PMID:40366868 | DOI:10.1093/gigascience/giaf035

Microbiome. 2025 May 14;13(1):120. doi: 10.1186/s40168-025-02106-w.ABSTRACTBACKGROUND: The supramolecular structure and composition of milk fat globules in breast milk is complex. Lipid droplets in formula milk are typically smaller compared to human milk and differ in their lipid and protein composition. These droplets play an important role in gut and immune maturation, and their components possess antimicrobial and antiviral properties. Here, the influence of a concept infant formula (IF) containing large milk phospholipid-coated lipid droplets on the maturation of the infant microbiota, metabolome, and weight gain in the first year of life was investigated.RESULTS: Formula-fed infants were randomized to receive either a standard IF (Control) or a Test formula containing large milk phospholipid-coated lipid droplets (Test) until 17 weeks of age. A breast-fed Reference group was also investigated. At 3 months of age, several taxa identified as opportunistic pathogens (e.g., Enterobacter, Klebsiella, Enterococcus, Streptococcus) were less abundant in the Test stools compared to Control, while an enrichment of the butyrate-producing Ruminococcaceae and Lachnospiraceae was observed. These findings indicate that the Test formula resulted in gut microbiota maturation trajectories more comparable to healthy breast-fed infants. This was accompanied by variation in several fecal and plasma metabolites at 3 months of age related to gut microbial metabolism including bile acids, hippurate, phenylacetylglycine, trimethylamine, and various lipids and fatty acids. At 12 months, measures of subcutaneous fat and body mass index (BMI) were significantly higher in infants receiving standard IF compared to those receiving breast milk. However, this weight gain and adiposity was attenuated in the Test group infants.CONCLUSIONS: The presence of large phospholipid-coated lipid droplets in formula milk positively influenced the development of the infants' gut microbiota, their metabolomic profiles, and their body composition to more closely resemble breast-fed infants compared to standard IF. These droplets may further enhance the restriction of pathogenic bacteria seen with standard infant formula and suggest a potential impact on infant metabolic programming that may contribute to physiological development. Video Abstract.PMID:40369689 | DOI:10.1186/s40168-025-02106-w

Anim Microbiome. 2025 May 14;7(1):49. doi: 10.1186/s42523-025-00417-9.ABSTRACTBACKGROUND: In recent years, rising temperatures due to climate change have become significant stressors in aquatic environments, impacting disease incidence, growth, and gut microbiota in fish. Cold-water species, such as the olive flounder (Paralichthys olivaceus), are particularly vulnerable to increasing water temperatures. Despite its economic importance as a species farmed in East Asia, research on temperature-dependent shifts in the gut microbiota and metabolome of olive flounder remains limited. This study investigates the effects of water temperature on the gut microbiota and metabolome of olive flounder using full-length 16 S rRNA sequencing with Oxford Nanopore Technologies and metabolomics analysis with high-resolution liquid chromatography-mass spectrometry (LC-MS). The analysis compares individuals exposed to three water temperatures (18 °C, 22 °C, and 26 °C).RESULTS: Temperature significantly influenced the composition of gut microbiota, with an increase in Gammaproteobacteria abundance at higher temperatures. Potential pathogens such as Vibrio and Photobacterium increased from 22 °C to 26 °C, while Pseudomonas declined, suggesting an elevated risk of pathogen infection at 26 °C. Functional predictions revealed that gut bacteria regulated host metabolism, particularly carbohydrate, amino acid, and lipid pathways. Metabolomic analysis showed reduced levels of polyunsaturated fatty acids (PUFAs) and phosphatidylcholine (PC)-related metabolites at higher temperatures. Notably, the umami flavor-related compound aspartic acid decreased, while the bitter flavor-related compound phenylalanine increased. Correlation analysis identified significant associations between bacterial genera, such as Comamonas,Pseudomonas,Sphingomonas, and Stentotrophomonas (positive correlation), and Legionella and Phaeobacter (negative correlation), with shifts in PUFAs and PC metabolites.CONCLUSIONS: This study demonstrates that environmental temperature significantly affects the gut microbiota and muscle metabolites of olive flounder. Higher temperatures diversified gut bacterial communities and altered metabolite profiles, with reductions in PUFAs and PC-related compounds linked to specific bacterial genera. These findings highlight the potential of these bacterial genera as biomarkers or probiotics for improving aquaculture practices and environmental adaptation strategies. By establishing a strong correlation between gut microbiota and muscle metabolites, this research provides insights that could contribute to sustainable flounder farming and enhance resilience to climate change.PMID:40369686 | DOI:10.1186/s42523-025-00417-9

BMC Plant Biol. 2025 May 14;25(1):635. doi: 10.1186/s12870-025-06636-1.ABSTRACTBACKGROUND: Human bacterial pathogens such as Salmonella enterica and Escherichia coli can colonize the apoplast of leafy greens, where they may evade standard sanitization measures and persist until produce consumption. Bacterial survival in this niche is influenced by plant immune responses that may vary according to bacterial species and plant genotypes. The variability in immune responses has been associated with differences in pathogen persistence capacity within the phyllosphere. In addition, emerging evidence suggests that preexisting and inducible plant metabolites contribute to either restricting or facilitating colonization of human pathogens in plant tissues. Identifying the molecular mechanisms underlying these interactions is crucial for developing strategies to mitigate contamination in fresh produce.RESULTS: We characterized whole-leaf transcriptome and apoplast metabolome profiles of three lettuce cultivars upon exposure to the human pathogenic bacteria S. enterica ser. Typhimurium 14028s and E. coli O157:H7. The lettuce genotypes Lollo Rossa and Green Towers exhibited stronger transcriptional modulation, primarily associated with defense-related processes and showed reduced bacterial survival in their apoplast. Surprisingly, Green Towers did not generate callose deposition or reactive oxygen species burst responses at levels comparable to that of Lollo Rossa, suggesting it has distinct modifications in the apoplastic conditions that restrict pathogen persistence. Apoplastic metabolomic profiling revealed specific compounds alterations in Green Towers linked to bacterial survival, indicating their potential role in this genotype's defense mechanism. In contrast, the lettuce cultivar Red Tide exhibited minimal transcriptional and metabolic modulation, lack of robust defense activation, which was accompanied by apoplastic bacterial survival.CONCLUSIONS: This study provides evidence that lettuce cultivars exhibit distinct molecular responses that may influence the persistence of human bacterial pathogens in the leaf apoplast. The results indicate that both immune response activation and metabolite composition may contribute to restrict apoplastic bacterial persistence or growth. These findings offer novel insights into the genetic and biochemical factors shaping lettuce-pathogen interactions, which might inform breeding programs and agronomic practices aimed at enhancing food safety.PMID:40369434 | DOI:10.1186/s12870-025-06636-1

Neurosci Bull. 2025 May 14. doi: 10.1007/s12264-025-01398-0. Online ahead of print.ABSTRACTChemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.PMID:40369268 | DOI:10.1007/s12264-025-01398-0

Commun Chem. 2025 May 14;8(1):147. doi: 10.1038/s42004-025-01521-2.ABSTRACTThe development of analytical technology that allows investigation of the diversity of cells that form biological tissues based on molecular information is important to elucidate the heterogeneity of cells and pathological mechanisms. Here, we present a proof-of-concept demonstration of single-cell mass spectrometry imaging (SC-MSI) via tapping-mode scanning probe electrospray ionization (t-SPESI), which is an atmospheric-pressure sampling ionization technique. We developed a novel t-SPESI unit that can be used in combination with an inverted fluorescence microscope and basic technologies to extract components from microregions of cells and measure ions with high sensitivity. We performed multimodal (fluorescence, lipid ion, and topographic) imaging of two types of HeLa cells labeled with fluorescent dyes and chemically fixed and showed the potential for subcellular-scale analysis of both cell structure and chemical composition. Furthermore, we evaluated the lipid species by comparing the SC-MSI results with those of supercritical fluid chromatography tandem mass spectrometry. The technical advancement presented here is effective for distinguishing cell types based on the signal intensity of lipid ions in single cells and investigating differences in the subcellular localization of lipids in different types of cells.PMID:40369247 | DOI:10.1038/s42004-025-01521-2

Pediatr Res. 2025 May 15. doi: 10.1038/s41390-025-04074-1. Online ahead of print.ABSTRACTBACKGROUND: Intrinsic resistance reduces the effectiveness of many anticancer therapies. Anlotinib, a small-molecule multi-targeted tyrosine kinase inhibitor, has shown potential in treating hepatoblastoma. This study investigates the role of γ-aminobutyric acid (GABA) in anlotinib resistance using in vivo and in vitro models.METHODS: HuH-6 hepatoblastoma cells were implanted into nude mice to assess the effects of anlotinib on tumor growth. Neurotransmitter-targeted metabolomics was performed to analyze neurotransmitter metabolism in xenograft tumor tissues. In vitro, HuH-6 and HepG2 cells were treated with anlotinib to evaluate changes in GABA synthesis, degradation, and associated protein expression.RESULTS: Anlotinib significantly inhibited HuH-6 tumor growth but was less effective than cisplatin. Neurotransmitter-targeted metabolomics showed tumors treated with anlotinib exhibited increased GABA levels. Anlotinib treatment also upregulated the protein expression of GAD1, a key enzyme in GABA synthesis. In vitro, anlotinib treatment enhanced GABA release and GAD1 expression in hepatoblastoma cells. Exogenous GABA stimulation promoted cell proliferation in vitro and tumor growth in vivo. Notably, GAD1 knockdown enhanced anlotinib's inhibitory effects on hepatoblastoma in vitro and in vivo.CONCLUSION: Anlotinib induces intrinsic resistance in hepatoblastoma by upregulating GAD1 and increasing GABA accumulation. Targeting GAD1 may enhance anlotinib's therapeutic efficacy and help overcome resistance.IMPACT: Anlotinib upregulates GAD1 to enhance GABA synthesis, driving intrinsic resistance in hepatoblastoma by activating tumor-promoting GABA signaling in the tumor microenvironment. First identification of the GAD1/GABA axis as a critical mediator of anlotinib resistance, expanding understanding of neurotransmitter-driven drug tolerance in pediatric cancers. GAD1 knockdown synergizes with anlotinib to overcome resistance, establishing a combinatorial strategy to enhance antitumor efficacy in preclinical models. Proposes targeting GABA metabolism to optimize anlotinib-based therapies, addressing unmet needs in refractory hepatoblastoma treatment.PMID:40369243 | DOI:10.1038/s41390-025-04074-1

Cell Mol Immunol. 2025 May 14. doi: 10.1038/s41423-025-01294-7. Online ahead of print.ABSTRACTProtein malonylation represents a recently identified posttranslational modification whose role in CD8+ T cell differentiation and functionality remains incompletely understood. In this study, we demonstrate that enhancing protein malonylation through sodium malonate (SM) treatment promotes CD8+ T cell memory formation in response to bacterial infection, subsequently potentiating recall responses. Comparative metabolomic analysis between SM-treated and control CD8+ T cells revealed significant metabolic alterations associated with protein malonylation. We present the first comprehensive proteomic analysis of lysine malonylation in murine CD8+ T cells, identifying 77 malonylation sites across 64 proteins involved in diverse cellular processes, particularly metabolic pathways. Malonylation of STAT6 was confirmed via the use of a specific chemical probe. Notably, we established that malonylation at the lysine 374 site of STAT6 results in increased TCF1 expression, due to alleviated transcriptional repression of TCF1 by STAT6. Collectively, our findings provide compelling evidence that protein malonylation plays a significant role in regulating CD8+ T cell memory formation.PMID:40369188 | DOI:10.1038/s41423-025-01294-7

Pediatr Nephrol. 2025 May 14. doi: 10.1007/s00467-025-06782-6. Online ahead of print.ABSTRACTBACKGROUND: Urinary tract infection (UTI) is a common bacterial infection in the pediatric population. Febrile urinary tract infection (fUTI) can lead to severe complications such as urosepsis as well as kidney scarring, chronic kidney disease, and systemic hypertension. Recent research supports the hypothesis that dysbiosis of the microbiome may play a role in the pathogenesis and development of fUTI in infants. Our main aim was to compare the shift in gut microbiota composition between children with the first fUTI and controls.METHODS: We conducted an observational study with 17 children with the first fUTI compared to 18 healthy controls. We performed analysis of the gastrointestinal microbiome and measurements of metabolites in stool and urine.RESULTS: In the gut microbiome, we found significant differences with lower α-diversity the Shannon index) and significantly lower relative abundance of probiogenic bacteria (short-chain fatty acids (SCFA)) in children with the first episode of fUTI before the start of antibiotic therapy. Furthermore, our findings confirm that the length of breastfeeding has significant influence on gut microbiota composition, reducing pathogenic bacteria and enhancing beneficial taxa. Shannon diversity, duration of breastfeeding, and specific taxa, particularly Faecalibacterium and Escherichia, emerged as strong predictors linked to the development of fUTI.CONCLUSIONS: This study demonstrates that gut microbiome changes are associated with the onset of fUTI in children. Machine learning models identified Shannon index, specific bacterial taxa, and breastfeeding as strong predictors of fUTI. The study highlighted the potential role of the gut microbiome in preventing fUTI.PMID:40369126 | DOI:10.1007/s00467-025-06782-6

Sci Rep. 2025 May 14;15(1):16789. doi: 10.1038/s41598-025-01329-z.ABSTRACTThe Global Burden of Disease Study 2021 reports that stroke remains a leading cause of death, with ischemic stroke (IS) presenting significant challenges in screening, prevention, and treatment. We explored the causal effects of 1,400 plasma metabolites on IS outcomes using a two-sample Mendelian randomization (MR) framework. We assessed causal relationships between IS and 11 common clinical risk factors and further examined these relationships for metabolites. Mediation analysis identified mechanisms for metabolites affecting both IS and its risk factors. Finally, a phenome-wide association study (PheWAS) MR analysis evaluated the side effects and additional indications of IS-associated metabolites across 3,948 phenotypes from the UKBB GWAS. Nineteen metabolites showed a causal relationship with IS. MR analysis confirmed body mass index (BMI), high-density lipoprotein (HDL), systolic blood pressure (SBP), diastolic blood pressure (DBP), and type 2 diabetes (T2D) as risk factors for IS. Among 136 metabolites associated with at least one IS risk factor, 132 were linked to risk factors but not directly to IS. BMI, DBP, and coffee intake mediated the causal relationship between IS and the levels of 1-stearoyl-GPG (18:0), 1-oleoyl-2-linoleoyl-GPE (18:1/18:2), Octadecadienedioate (C18:2-DC), and X-24,951. Phe-MR analysis indicated that these metabolites were protective and affected other indications similarly to IS. Our findings reveal causal pathways and identify four potential biomarkers for IS, providing new insights for its screening, prevention, and treatment.PMID:40369036 | DOI:10.1038/s41598-025-01329-z

Sci Rep. 2025 May 14;15(1):16784. doi: 10.1038/s41598-025-01691-y.ABSTRACTOil palm plantations face serious challenges from Ganoderma boninense, a pathogen that causes basal stem rot (BSR), leading to significant productivity losses, with an estimated economic impact of 68.73%. Ganoderma spreads through direct root contact and airborne spores, affecting plantations across Indonesia, Malaysia, and other countries. Understanding the mechanisms of oil palm resistance to Ganoderma is crucial for developing effective strategies. Metabolomic profiling, ¹H NMR spectroscopy, offers a promising tool for identifying and quantifying metabolic changes associated with Ganoderma resistance. This study, ¹H NMR was employed to analyze root tissues of resistant, susceptible, and control oil palm seedlings exposed to Ganoderma. The results indicated that PCA effectively differentiated resistant palms from susceptible ones, while PLS-DA identified 14 significant metabolites. Further analysis using OPLS-DA and ROC revealed that ascorbic acid, D-gluconic acid, D-fructose, and 2-oxoisovalerate could serve as potential biomarkers for screening resistant palms. The metabolites identified in this study hold considerable promise for supporting breeding programs to develop oil palm varieties with enhanced resistance to BSR.PMID:40369018 | DOI:10.1038/s41598-025-01691-y

Sci Rep. 2025 May 14;15(1):16698. doi: 10.1038/s41598-025-01348-w.ABSTRACTThis study evaluated the antibacterial and anticancer properties of S. mauritianum fruit components through LC-QTOF-MS/MS metabolomic profiling. The samples were extracted, and the antibacterial activity was conducted using a standard Resazurin microtiter assay. The minimum inhibitory concentrations (MICs) of the crude extracts were evaluated against reference pathogenic bacterial isolates. The anticancer activity of the extracts was tested against U-87 MG glioblastoma and A549 lung carcinoma cells (ATCC cancer cell lines). The real-time toxicity assay and comprehensive metabolomic profiling were evaluated for the crude extracts. Results revealed that the ripe fruit coat exhibited the richest chemical diversity, with 15 unique metabolites, while the unripe fruit had 5. Detailed classification of the identified metabolites showed that alkaloids accounted for 33.3%, followed by terpenoids (21.2%). The extracts of the fruit components had significant antibacterial activity against the referenced pathogens of public health importance. Extracts from the ripe fruit coat demonstrated significant cytotoxicity on U-87 MG glioblastoma cell viability, suggesting potential anticancer activity, while the effect on A549 lung carcinoma cells showed high viability across all treatments. The real-time cytotoxicity assays further highlighted the dose-dependent inhibition of glioblastoma cells by crude extracts from the ripe fruit coat, emphasizing its therapeutic potential.PMID:40368974 | DOI:10.1038/s41598-025-01348-w