PubMed

Se Pu. 2025 Mar;43(3):207-219. doi: 10.3724/SP.J.1123.2024.04003.ABSTRACTGlutamine synthetase (GS), the only enzyme responsible for de novo glutamine synthesis, plays a significant role in cancer progression. As an example of the consequences of GS mutations, the R324C variant causes congenital glutamine deficiency, which results in brain abnormalities and neonatal death. However, the influence of GS-deficient mutations on cancer cells remains relatively unexplored. In this study, we investigated the effects of GS and GS-deficient mutations, including R324C and previously unreported K241R, which serve as models for GS inactivation. This study provided intriguing insights into the intricate relationship between GS mutations and cancer cell metabolism. Our findings strongly support recent studies that suggest GS deletion leads to the suppression of diverse signaling cascades associated with glutamine metabolism under glutamine-stripping conditions. The affected processes include DNA synthesis, the citric acid cycle, and reactive oxygen species (ROS) detoxification. This suppression originates from the inherent inability of cells to autonomously synthesize glutamine under glutamine-depleted conditions. As a key source of reduced nitrogen, glutamine is crucial for the formation of purine and pyrimidine bases, which are essential building blocks for DNA synthesis. Furthermore, the citric acid cycle is inhibited by the absence of negatively charged glutamate within the mitochondrial matrix, particularly when glutamine is scarce. This deficiency decreases the flux of α-ketoglutarate (α-KG), a principal driver of the citric acid cycle. Intermediate metabolites of the citric acid cycle directly or indirectly contribute to the generation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a core component of redox homeostasis. Using the GS_R324C and GS_K241R mutants, we conducted an integrative transcriptomics and metabolomics analysis. The GS mutants with reduced activity activated multiple amino acid biosynthesis pathways, including arginine-proline, glycine-serine-threonine, and alanine-aspartate-glutamate metabolism. This intriguing behavior led us to hypothesize that despite hindrance of the citric acid cycle, abundant intracellular glutamate is redirected through alternative processes, including transamination. Simultaneously, key metabolic enzymes in the amino acid synthesis pathways, such as glutamic-oxaloacetic transaminase 1 (GOT1), glutamic-pyruvic transaminase 2 (GPT2), pyrroline-5-carboxylate reductase 1 (PYCR1), and phosphoserine aminotransferase 1 (PSAT1), exhibited increased mRNA levels. Additionally, GS deficiency appeared to upregulate the expression of glutamine transporters SLC38A2 and SLC1A5. Thus, restricting extracellular amino acids, such as glutamine, induces a stress response while promoting transcription or translation by a select group of genes, thereby facilitating cellular adaptation. However, similar to GS_WT, both GS_R324C and GS_K241R were modulated by glutamine treatment. Among GS-activity-dependent behaviors, the increased expression of numerous aminoacyl-tRNA synthetases (ARSs), which are critical for aminoacyl-tRNA biosynthesis, remains poorly understood. Most ARS-encoding genes are transcriptionally induced by activating transcription factor 4 (ATF4), the expression of which increases under oxidative stress, endoplasmic reticulum stress, hypoxia, and amino acid limitation. In GS-deficient cells, the increased expression of ATF4 was accompanied by pronounced stress caused by glutamine starvation. Thus, ARS upregulation may predominantly arise from increased ATF4 expression in GS-deficient cells. Additionally, transcriptomic analysis revealed the differential expression of specific genes, regardless of GS activity, suggesting that GS is involved in various processes other than glutamine synthesis, including angiogenesis. Although our omics study was limited to H1299 cells, in subsequent experiments, we validated our findings using additional cell lines, including Hepa1-6 and LN-229. To attain a more comprehensive understanding of the impact of the newly identified GS_K241R mutant, our investigation should be extended to various cell types and mouse models. In summary, we identified and investigated GS-deficient mutations in cancer cells and conducted an integrative transcriptomics-metabolomics analysis with comparisons to wild-type GS. This comprehensive approach provided crucial insights into the intricate pathways modulated by GS activity. Our findings advance the understanding of how GS functions in the context of reprogrammed cellular metabolism, particularly during glutamine deprivation. The altered metabolism triggered by elevated glutamate levels arising from GS mutations highlights the remarkable plasticity of cancer cell metabolism. Notably, considering the increasing research focus on GS as a potential therapeutic target in various cancer types, the findings of this study could provide innovative perspectives for drug development and the formulation of clinical treatment strategies.PMID:40045642 | DOI:10.3724/SP.J.1123.2024.04003

Anim Biosci. 2025 Feb 27. doi: 10.5713/ab.24.0628. Online ahead of print.ABSTRACTOBJECTIVE: The aim of this study is to investigate the dynamic changes of plasma bile acids (BA) and their associations with physiological metabolisms and fecal microbiome in transitional dairy cows.METHODS: Twenty multiparous dairy cows were selected, the blood and fecal samples were collected at d -21, -7, +7, and +21 relative to calving. The targeted metabolome and 16s rDNA gene sequencing were applied to detect BA profiles and fecal microbial composition, respectively.RESULTS: Totally, 32 BA species including 9 primary BAs (PBA) and 23 secondary BAs (SBA) were identified. Most of the PBAs (7 out to 9) and SBAs (15 out to 23) exhibited significant increases postpartum compared to prepartum. Notably, ursodeoxycholic acid, taurocholic acid and 7-ketodeoxycholic acid showed higher importance. Correlation analysis showed the BAs concentrations positively correlated with the concentrations of aspartate aminotransferase, total antioxidant capacity, and glutathione peroxidase, but negatively correlated with the concentrations of triglyceride significantly. A decline in bacterial alpha diversity in postpartum and significantly different β-diversity were observed. Additionally, 30 significant different genera were identified over the transition period. Among these, six and eleven biomarkers such as Alistipes and Ruminococcaceae_UCG_014 were identified at +7d and +21d, respectively. Furthermore, the abundances of choloylglycine hydrolase and 7-alpha-hydroxysteroid dehydrogenase involved in SBA biosynthesis were significantly higher postpartum as determined by PICRUSt2 analysis over the transition period.CONCLUSION: These findings underscore a significant surge in the demand for BAs for postpartum dairy cows and highlight the potential impact of BAs on bovine health. By shedding light on these metabolic dynamics, our study offers valuable insights into strategies for optimizing the nutrition and well-being of perinatal dairy cows.PMID:40045625 | DOI:10.5713/ab.24.0628

Aging Cell. 2025 Mar 5:e70037. doi: 10.1111/acel.70037. Online ahead of print.ABSTRACTNicotinamide adenine dinucleotide kinase (NADK) is essential to the generation of nicotinamide adenine dinucleotide phosphate (NADP(H)), an important metabolic coupling factor involved in glucose-stimulated insulin secretion. In the present study, we showed that the expression of Nadk and Nadk2 transcripts and NADP(H) content were lower in islets of 80-week-old (aged) mice than those of 8-week-old (young) mice. This was associated with diminished oral glucose tolerance of old mice and the glucose-stimulated insulin secretion (GSIS) response of islets. Knockdown (KD) of Nadk or Nadk2 gene expression in NIT-1 cells impaired glucose-stimulated insulin secretion. Metabolomic analysis revealed that Nadk KD specifically affected purine metabolism in glucose-stimulated cells. The levels of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) were higher in KD cells than in the non-targeting control (NTC) cells. Phosphorylation of AMP-activated protein kinase (AMPK) was elevated in glucose-treated KD cells compared to that of NTC cells. Increased AICAR level and AMPKα phosphorylation were observed in the glucose-stimulated islets of the aged mice. Genetic and pharmacological inhibition of AMPK promoted glucose-stimulated insulin release by KD cells and the aged mouse islets. It is likely that NADK is modulatory to AMPK activation in pancreatic β-cells and to their GSIS response. Enhanced AICAR formation in KD cells was accompanied by significantly increased conversion from inosine monophosphate (IMP) in a tetrahydrofolate (THF)-dependent manner. Folate supplementation augmented the GSIS response of KD cells and aged mouse islets. Taken together, these findings suggest that the aging-associated decline in NADK expression may underlie the reduced insulin secretory capacity of pancreatic β-cells.PMID:40045495 | DOI:10.1111/acel.70037

Gut Microbes. 2025 Dec;17(1):2474143. doi: 10.1080/19490976.2025.2474143. Epub 2025 Mar 5.ABSTRACTThe interplay between bile acids (BAs) and metabolic diseases has gained importance in recent years, with a variety of studies investigating their relationship with diverging results. Therefore, in the present study we performed a detailed analysis of BA metabolism in 492 subjects with different metabolic phenotypes. Besides microbiomics and metabolomics this investigation included in silico analysis of community metabolism to examine metabolic interchange between different microbes as well as microbes and the human host. Our findings revealed distinct changes in the BA profiles of patients with diabetes and prediabetes, whereas obesity alone had no influence on circulating BAs. Impaired glycemic control led to increased circulating BAs, a shift toward more secondary BAs, and an increase in the ratio of glycine to taurine-conjugated BAs. Additional analyses revealed that the ratio of glycine to taurine conjugation demonstrated variations between the single BAs, cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA), regardless of the metabolic status, with CA having a higher fraction of taurine conjugation. Furthermore, we found that microbiome alterations are associated with BAs, independent of diabetes or obesity. Analysis of microbial community metabolism revealed differential relative pathway abundance in relation to diabetes, particularly those related to membrane and polyamine synthesis. Increased bacterial cross-feeding of polyamines, galactose, and D-arabinose also coincided with an increase in BA. Notably, our serum metabolome analysis mirrored several of the previously in silico predicted exchanged metabolites, especially amino acid metabolism. Therefore, targeting BA metabolism may be a future approach for the treatment of metabolic diseases, especially prediabetes and type 2 diabetes.PMID:40045464 | DOI:10.1080/19490976.2025.2474143

BMC Cancer. 2025 Mar 5;25(1):402. doi: 10.1186/s12885-025-13820-x.ABSTRACTBACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is among the most aggressive malignancies, underscoring the need for early diagnosis to improve patient outcomes. Tumor-derived exosomes, which can be non-invasively obtained and reflect the metabolic state of tumors in real-time, are under increasing investigation for their diagnostic potential. Herein we analyzed metabolite differences in exosomes, serum, and tissues from patients with HNSCC to identify potential diagnostic biomarkers of clinical relevance.METHODS: Non-targeted metabolomics based on liquid chromatography-mass spectrometry was employed to quantify metabolites in exosome, serum, and tissue samples from 11 patients with HNSCC and six patients without cancer. The metabolic profiles of HNSCC were analyzed through univariate and multivariate statistical methods, differential metabolite analysis, and pathway enrichment analysis.RESULTS: We identified three differential metabolites in exosomes, 45 in serum, and 33 in tissues. Notably, patients with HNSCC exhibited significant disruptions in protein and amino acid metabolism. Spermine was exclusively detected in exosomes and tissues from patients with HNSCC. We hypothesize that spermine is extracellularly secreted by malignant cells via exosomes and subsequently enters the bloodstream. Moreover, spermine synthase was highly expressed in HNSCC tissues. Knocking down spermine synthase markedly impaired HNSCC cell proliferation and migration.CONCLUSIONS: This study provides a preliminarily characterization of the metabolic profile of HNSCC and highlights spermine and its synthetic pathways as potential diagnostic and therapeutic targets. Future studies are warranted to elucidate the mechanism of action of spermine in HNSCC and explore its utility in early diagnosis and therapeutic development.PMID:40045286 | DOI:10.1186/s12885-025-13820-x

Nat Metab. 2025 Mar 5. doi: 10.1038/s42255-025-01245-6. Online ahead of print.ABSTRACTPreclinical studies have shown that asparagine deprivation enhances T cell antitumour responses. Here we apply compassionate use of L-asparaginase, usually employed to treat blood malignancies, on patients with recurrent metastatic nasopharyngeal carcinoma. The use of L-asparaginase notably enhances immune-checkpoint blockade therapy in patients by strengthening CD8+T cell fitness. Our study shows that this combination is a promising avenue for clinical application and provides further mechanistic insight into how asparagine restriction rewires T cell metabolism.PMID:40045118 | DOI:10.1038/s42255-025-01245-6

Planta. 2025 Mar 5;261(4):79. doi: 10.1007/s00425-025-04646-9.ABSTRACTOmics approaches provide comprehensive insights into plant arsenic stress responses, setting the stage for engineering arsenic-tolerant crops. Understanding arsenic (As) toxicity in plants is crucial for environmental and agricultural sustainability, considering the implications of As in impacting soil productivity and environmental health. Although some articles already examined the detailed molecular mechanisms behind As toxicity and tolerance, a comprehensive review of recent omics advancements in studying plant responses to As exposure is needed. The present review highlights the valuable contribution of omics approaches (genomics, transcriptomics, proteomics, and metabolomics) to characterize the intricate response to As overall, which could empower As-tolerant plant development. Genomic techniques, such as QTL mapping, GWAS, RAPD, and SSH, hold the potential to provide valuable insights into the genetic diversity and expression patterns associated with the plant response to As stress, highlighting also the power of new advanced technology such as CRISPR-Cas9. Transcriptomics approaches (e.g., microarrays and RNA sequencing) revealed gene expression patterns in plants under As stress, emphasizing the role of sulfur metabolism in As tolerance. Proteomics, using 2-DE combined with MALDI-ToF MS or ESI-MS/MS, offers insights into the stress-inducible proteins and their involvement in As toxicity mitigation, while iTRAQ-based proteomics enabled an understanding of cultivar-specific responses under high As concentration. Metabolomics, with LC-MS, GC-MS, (U)HPLC, and NMR, elucidated small molecule alterations and complex metabolic activities occurring under As plant exposure. Compendium of data and evidence-related tools offers a foundation for advancing As-tolerant plant development and promoting environmental and agricultural resilience.PMID:40044842 | DOI:10.1007/s00425-025-04646-9

Sci Rep. 2025 Mar 5;15(1):7763. doi: 10.1038/s41598-025-91039-3.ABSTRACTSeed dormancy is a common physiological phenomenon during storage which has a great impact on timely germination of seeds. An in-depth analysis of the physiological and molecular mechanisms of perilla seed dormancy release is of great significance for cultivating high-vigor perilla varieties. We used gibberellin A3-soaked seeds (GA), natural dormancy-release seeds (CK) and water-soaked seeds (WA) to study the changes in the transcriptome and metabolome of dormancy release. The germination test revealed that the optimum concentration of gibberellin A3 for releasing dormancy from perilla seeds was 200 mg/L. The results revealed that plant hormone signal transduction, starch and sucrose metabolism and citric acid cycle were significantly enriched metabolic pathways closely related to seed dormancy release. Perilla seeds release their dormancy by enhancing the expression of GID1, PIF3, SnRK2, IAA, ARR-A, GH3, MKK4_5, otsB, GN1_2_3, glgC, WAXY, inhibiting the expression of DELLA, PP2C, glga, bglX, and GN4, and regulating the content of gibberellin A4, abscisic acid, auxin, sucrose, maltose, trehalose, and α-D-glucose 1-phosphate. Auxin plays an important role in breaking perilla seed dormancy and promoting seed germination. The energy required for breaking seed dormancy and germination of perilla seeds is mainly provided through sucrose metabolism. Citric acid cycle (TCA cycle) is the main energy supply transformation pathway for seed germination.PMID:40044827 | DOI:10.1038/s41598-025-91039-3

Nat Commun. 2025 Mar 5;16(1):2213. doi: 10.1038/s41467-025-57675-z.NO ABSTRACTPMID:40044695 | DOI:10.1038/s41467-025-57675-z

Nat Commun. 2025 Mar 5;16(1):2215. doi: 10.1038/s41467-025-57674-0.NO ABSTRACTPMID:40044665 | DOI:10.1038/s41467-025-57674-0

Cell Prolif. 2025 Mar 5:e70014. doi: 10.1111/cpr.70014. Online ahead of print.ABSTRACTMaternal age has been reported to impair oocyte quality. However, the molecular mechanisms underlying the age-related decrease in oocyte competence remain poorly understood. Cumulus cells establish direct contact with the oocyte through gap junctions, facilitating the provision of crucial nutrients necessary for oocyte development. In this study, we obtained the proteomic and metabolomic profiles of cumulus cells from both young and old mice. We found that fatty acid beta-oxidation and nucleotide metabolism, markedly active in aged cumulus cells, may serve as a compensatory mechanism for energy provision. Tryptophan undergoes two principal metabolic pathways, including the serotonin (5-HT) synthesis and kynurenine catabolism. Notably, we discovered that kynurenine catabolism is reduced in aged cumulus cells compared to young cells, whereas 5-HT synthesis exhibited a significant decrease. Furthermore, the supplement of 5-HT during cumulus-oocyte complexes (COCs) culture significantly ameliorated the metabolic dysfunction and meiotic defects in old oocytes. In sum, our data provide a comprehensive multiple omics resource, offering potential insights for improving oocyte quality and promoting fertility in aged females.PMID:40044606 | DOI:10.1111/cpr.70014

J Affect Disord. 2025 Mar 3:S0165-0327(25)00325-8. doi: 10.1016/j.jad.2025.02.109. Online ahead of print.ABSTRACTBACKGROUND: Major depressive disorder (MDD) involves molecular alterations and pathway dysregulation. Metabolic interconnections are crucial for normal functioning, yet current analysis focuses on individual pathways or biomarkers, overlooking intricate metabolic biomarker interactions.METHODS: Plasma metabolomic data from 182,053 UK Biobank participants [9425 MDD, and 172,628 healthy controls (HC)] were used to construct metabolic correlation networks through bootstrap inference analysis (bootstrap step size: 1000, 3000, 5000, 7000, 9000; n = 1000 times/size). Differential core metabolic network signatures between MDD and HC were identified by machine learning, followed by metabolic pathway analysis. Various deep learning and machine learning models were employed to differentiate MDD from HC groups using the identified network features and baseline characteristics.RESULTS: The MDD metabolic network showed marked reorganization, with a sparser and more streamlined network structure compared to controls (p < 0.05 for both Vnet-edge and Vnet-node). Analysis of the core network in MDD revealed four key altered pathways, with linoleic acid metabolism being the most influential (p < 0.01, impact = 0.29). An extreme gradient boosting model combining network signatures and baseline features achieved 73 % accuracy, and an AUROC of 0.82 in differentiating MDD from HC groups.CONCLUSIONS: This large-scale, metabolomic connectome analysis revealed consistent dysregulated metabolic network features in MDD, providing a robust and distinguishable framework compared to controls. The MDD network exhibits distinct connectivity patterns, particularly within linoleic acid metabolism. Integrating metabolomics as networks, rather than isolated markers, offers a promising approach for elucidating MDD pathophysiology and identifying diagnostic biomarkers.PMID:40044084 | DOI:10.1016/j.jad.2025.02.109

Metab Eng. 2025 Mar 3:S1096-7176(25)00030-8. doi: 10.1016/j.ymben.2025.02.014. Online ahead of print.ABSTRACTThe oleaginous yeast R. toruloides has been exploited for many bioproducts, including several terpenes, owing to its oleaginous nature and biomass inhibitor tolerance. Here, we built upon previous (E)-⍺-bisabolene work by iteratively stacking the complete mevalonate pathway from Saccharomyces cerevisiae onto a multicopy bisabolene synthase parent strain. Metabolomics and proteomics verified heterologous pathway expression and identified metabolic bottlenecks at three intermediate steps, with candidate feedback-resistant mevalonate kinases screening improving titers 15%. Subtle differences in codon optimization, and preliminary attenuation of completing flux toward lipids resulted in 6-fold, 7-fold higher titers relative to controls, respectively. Media optimization led to modest improvements, with zinc identified as the most promising at 10% titer improvement. Ultimately, high-performance strains were cultivated with corn-stover biomass hydrolysate in microtiter plates at 300 g/L total sugar, achieving 20.8 g/L bisabolene, the highest reported titer in the literature. A 2 L glucose minimal medium bioreactor achieved 19.3 g/L bisabolene and a literature-high productivity of 0.11 g/L/h.PMID:40044027 | DOI:10.1016/j.ymben.2025.02.014

Int J Biol Macromol. 2025 Mar 3:141715. doi: 10.1016/j.ijbiomac.2025.141715. Online ahead of print.ABSTRACTOBJECTIVE: Radix Hedysari Polysaccharides (RHP) are the principal bioactive constituents of the traditional Chinese medicinal herb Radix Hedysari. This study aims to evaluate the neuroprotective effects of RHP in both cellular and animal models of Alzheimer's disease (AD) and to elucidate the underlying molecular mechanisms.METHODS: HT22 cells subjected to Aβ25-35-induced cytotoxicity were pretreated with RHP, followed by assessments of reactive oxygen species (ROS) generation, mitochondrial superoxide (mSOX) levels, and mitochondrial membrane potential (ΔΨm). Senescence-accelerated mouse-prone 8 (SAMP8) mice were orally administered RHP for 12 weeks. Behavioral assays were conducted to assess cognitive function, while metabolomic and proteomic analyses were performed to examine serum metabolic alterations and hippocampal protein expression profiles. Additionally, neuronal autophagy and gut barrier integrity were evaluated using immunohistochemistry, transmission electron microscopy, and biomarker quantification.RESULTS: RHP treatment significantly attenuated Aβ25-35-induced oxidative stress in HT22 cells by reducing ROS and mSOX production while preserving ΔΨm. In SAMP8 mice, RHP improved cognitive performance, preserved hippocampal mitochondrial ultrastructure, and enhanced neuronal autophagic activity. Moreover, RHP modulated serum metabolic pathways and alleviated gut barrier dysfunction, suggesting a role in gut-brain axis regulation.CONCLUSION: RHP ameliorates cognitive impairment in SAMP8 mice, potentially through its modulation of systemic metabolism, mitigation of neuronal mitochondrial damage, and restoration of gut barrier integrity. These findings highlight the therapeutic potential of RHP in AD intervention and warrant further investigation into its mechanistic underpinnings.PMID:40044002 | DOI:10.1016/j.ijbiomac.2025.141715

Int J Biol Macromol. 2025 Mar 3:141667. doi: 10.1016/j.ijbiomac.2025.141667. Online ahead of print.ABSTRACTIn this study, a composite film (CF) made of polyvinyl alcohol, pullulan, and ZnO nanoparticles was prepared by solution casting. The CF were applied to the postharvest preservation of Allium mongolicum Regel. Widely targeted metabolomics analysis of A. mongolicum Regel by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to investigate the mechanism of action of active substances in A. mongolicum Regel during CF-treated storage process. Analysis of the results showed that 1534 metabolites were present in CF-treated A. mongolicum Regel, of which 175 metabolites were significantly different. KEGG analysis showed that the differential metabolites were mainly involved in metabolic pathways, secondary metabolite biosynthesis, including the biosynthetic metabolism of compounds such as flavonoids and phenolic acids and alkaloids. The changes in these secondary metabolites further affected key metabolic pathways such as flavonoid biosynthesis, phenylalanine metabolism, carbon fixation in photosynthesis and glycolysis. These results help to explain the preservation mechanism of A. mongolicum Regel during the storage period and provide an important theoretical basis for the preservation of A. mongolicum Regel composite film packaging in the future.PMID:40043986 | DOI:10.1016/j.ijbiomac.2025.141667

Int J Biol Macromol. 2025 Mar 3:141714. doi: 10.1016/j.ijbiomac.2025.141714. Online ahead of print.ABSTRACTAuricularia auricula is abundant in polysaccharides that received increasing attention due to their variety biological activities and prebiotic potential. In order to explore the role of A. auricula polysaccharides (AAP) in regulating human gut microbiota and metabolic health, this study employed metagenomic and metabolomic analyses to examine the impact of AAP on the gut microbiota via in vitro fecal fermentation experiments. After in vitro fermentation, the data indicated that gut microbiota utilized AAP to produce rich short-chain fatty acids (SCFAs) including acetic acid, propionic acid, butyric acid and modulate gut microbiota structure, such as increasing the proportion of Bacteroidetes to Firmicutes, elevating the abundance of beneficial bacteria, including Bacteroides, especially the Parabacteroides, and inhibiting the abundance of harmful bacteria such as Bilophila, Morganella, and Escherichia-Shigella. Furthermore, the metabolomic analysis indicated that AAP utilization by gut microbes substantially alters the metabolic profile, in which 26 potential biological biomarkers were found and affects tryptophan, bile acids, purines, and butyric acid pathways to promote host health. In conclusion, this research indicated that AAP has a prebiotic potential, which can regulate the gut microbiota and promote host health. Moreover, this study provided scientific evidence for using AAP as a functional food with prebiotic effect.PMID:40043973 | DOI:10.1016/j.ijbiomac.2025.141714

Environ Pollut. 2025 Mar 3:125968. doi: 10.1016/j.envpol.2025.125968. Online ahead of print.ABSTRACTPer- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment, bioaccumulate, and may have toxic effects. This study used non-native cane toads (Rhinella marina) to examine PFAS and metal accumulation and impacts in large terrestrial amphibians from urban and peri-urban areas. We quantified 38 PFAS compounds and 36 environmental and legacy metal(loid)s in 52 adult cane toad livers collected from six locations around Southeast Queensland, Australia, along a known PFAS gradient. Associations among PFAS, metal(loid) concentrations, and whole-organism metrics were assessed. An omics-led approach assessed biochemical responses in liver, muscle, fat and gonad/egg tissues associated with these PFAS concentrations. Liver PFAS concentrations ranged from 0.5 to 82.1 μg/kg ww, with one male outlier at 452 μg/kg ww (mean: 18 ± 21 SD μg/kg ww, excluding outlier). PFOS was the most dominant PFAS (60 ± 26 SD% of total), followed by PFDoDA (13 ± 9 SD%). The liver metal(loid)s with statistically significant variation among locations and sex were Al, As, Ca, Cu, Mn, Ni, Se, Sn, Sr and V. Total PFAS had no associations with whole-organism metrics, and body condition and relative femur length showed a weak interaction effect between PFAS and Ni. Metabolic profiling revealed sex-specific differences linked to total PFAS, with females showing a broader metabolic perturbation. The strongest metabolic signals were in glycerolipid metabolism, ether lipid metabolism, and fatty acid biosynthesis, though these effects were statistically weak. PFAS and metal(loid) levels were low compared to those previously recorded in tertiary consumers and aquatic vertebrates from contaminated areas. Despite minor metabolomic changes, the overall health impact was minimal. These findings contribute to the development of tissue PFAS guideline values for wild amphibians, but further studies on higher PFAS levels of accumulation and responses of additional amphibian species are needed.PMID:40043876 | DOI:10.1016/j.envpol.2025.125968

Environ Pollut. 2025 Mar 3:125966. doi: 10.1016/j.envpol.2025.125966. Online ahead of print.ABSTRACTTriclosan (TCS), a typical endocrine disruptor, is widely used as an antibacterial agent in consumer goods. However, there are few studies on the effects of long-term low-dose TCS exposure on ovarian function in F1 female mice. In this paper, F1 female mice were exposed to TCS (0-3000 μg/kg/day) from intrauterine to postnatal day (PND) 91 to investigate its effects on the ovary. The results revealed that the number of total follicles was decreased, while atretic follicles was increased after TCS exposure. At the hormonal level, the secretion of estradiol was reduced, while follicle-stimulating hormone and luteinizing hormone were increased after TCS exposure. Observation of vaginal smear showed that TCS disrupted the estrous cycle of F1 female mice, especially at the dose of 3000 μg/kg/day. Moreover, TCS promoted cell apoptosis by activating the p38-MAPK signaling pathway and oxidative stress in vitro. In addition, analysis of the fecal microbiome and serum metabolomics revealed that exposure to TCS may cause gut microbiota disruption and metabolic abnormalities in F1 female mice. In conclusion, long-term low-dose TCS exposure may induce primary ovarian insufficiency phenotype in F1 female mice via inducing cell apoptosis and disrupting gut microbiota and metabolism.PMID:40043874 | DOI:10.1016/j.envpol.2025.125966

J Dairy Sci. 2025 Mar 3:S0022-0302(25)00132-8. doi: 10.3168/jds.2025-26273. Online ahead of print.ABSTRACTThe fecal metabolome comprises metabolites that are excreted or not absorbed by the animal. This study examined the changes in the fecal metabolome of dairy cows from the end of one lactation period, through the dry period, and into the subsequent lactation. Twelve Holstein cows (BW = 745 ± 71 kg, BCS = 3.43 ± 0.66) were housed in a tie-stall barn from 7 wk before to 15 wk after parturition, with dry-off occurring approximately 6 wk before the expected calving date (mean dry-off time = 42 d). Fecal samples were taken at wk -7, -5, -1, +1, +5, +10, +15 relative to calving. Targeted metabolomics identified a total of 93 metabolites, including AA, biogenic amines, bile acids (BA), and acylcarnitines (AcylCN) and some phospholipids. Principal component analysis (PCA) revealed clear metabolic shifts that showed a clear separation between the samples from the dry period and the samples from the end, early and middle of lactation, indicating significant changes in the metabolic profiles in the feces. The transition from the dry period (wk -5, -1 relative to calving) to lactation (wk +1, +5, +10, +15, -7 relative to calving) is characterized by an increase in fecal AA and metabolites, such as Glu, Met, β-alanine, and methionine sulfoxide, reflecting a shift in nitrogen metabolism to support increased protein metabolism for milk production. Higher concentrations of polyamines, such as spermidine and putrescine, were observed postpartum, indicating increased cell growth and improved tissue regeneration. Elevated gamma-aminobutyric acid (GABA) levels during lactation indicate increased microbial activity driven by a nutrient-rich diet. Results showed significant adjustments in bile acid profiles as cows transitioned into lactation. Deoxycholic acid (DCA) remained the predominant BA in feces, reflecting ongoing microbial transformation, while glycine- and taurine-conjugated BA increased postpartum, suggesting improved enterohepatic circulation and lipid absorption. Fecal acylcarnitines showed dynamic shifts with elevated levels during late gestation, a decrease in the dry period, and an increase postpartum, indicating increased fatty acid oxidation to meet energy demands. Results showed that phosphatidylcholines decreased prepartum but increased after calving. This indicates shifts in lipid metabolism reflecting energy requirements in lactation and suggests that fecal lipid composition is an indicator of metabolic adaptations in dairy cows. In particular, PCA revealed cosiderable overlap in the fecal metabolite profiles of multiparous and primiparous cows, indicating similar metabolic profiles. This was also confirmed by volcano plots, which showed no significant differences in fecal metabolism between the 2 groups across different weeks relative to calving (wk -7, -5, -1, +1, +5, +10, +15). Overall, these results emphasize the complex interactions between dietary factors, liver and gastrointestinal function, and the gut microbiome in shaping the fecal metabolite profile of dairy cows. These results underscore the value of this data set in advancing the application of fecal metabolome profiling to investigate metabolic changes during critical transitions in the lactation cycle of dairy cows.PMID:40043758 | DOI:10.3168/jds.2025-26273

Cell Host Microbe. 2025 Feb 26:S1931-3128(25)00056-3. doi: 10.1016/j.chom.2025.02.008. Online ahead of print.ABSTRACTIntestinal protists are detected by the host innate immune system through mechanisms that remain poorly understood. Here, we demonstrate that Tritrichomonas protozoa induce thickening of the colonic mucus in an NLRP6-, ASC-, and caspase-11-dependent manner, consistent with the activation of sentinel goblet cells. Mucus growth is recapitulated with cecal extracts from Tritrichomonas-infected mice but not purified protozoa, suggesting that NLRP6 may detect infection-induced microbial dysbiosis. In agreement, Tritrichomonas infection causes a shift in the microbiota with the expansion of Bacteroides and Prevotella, and untargeted metabolomics reveals a dramatic increase in several classes of metabolites, including sphingolipids. Finally, using a combination of gnotobiotic mice and ex vivo mucus analysis, we demonstrate that wild-type, but not sphingolipid-deficient, B. thetaiotaomicron is sufficient to induce NLRP6-dependent sentinel goblet cell function, with the greatest effect observed in female mice. Thus, we propose that NLRP6 is a sensor of intestinal protozoa infection through monitoring microbial sphingolipids.PMID:40043701 | DOI:10.1016/j.chom.2025.02.008