PubMed

Front Mol Biosci. 2025 Apr 7;12:1549223. doi: 10.3389/fmolb.2025.1549223. eCollection 2025.ABSTRACTOBJECTIVE: Cholangiocarcinoma (CCA) is a highly aggressive malignancy, and early diagnosis remains challenging. Metabolic biomarkers are increasingly recognized as promising tools for the early detection of cancer. However, a comprehensive exploration of metabolic alterations in CCA, especially from a global metabolic perspective, has yet to be fully realized. To identify reliable metabolic markers for the early diagnosis of CCA and to explore its potential pathogenesis through an in-depth analysis of global metabolism.METHODS: Serum samples from 30 CCA patients and 31 healthy individuals were analyzed using an unbiased UPLC-Q-TOF-MS based metabolomics approach. Principal component analysis (PCA) and orthogonal projections to latent structures discriminant analysis (OPLS-DA) were applied to identify potential biomarkers. High-resolution MS/MS and available standards were used to further confirm the identified metabolites. A systematic metabolic pathway analysis was conducted to interpret the biological roles of these biomarkers and explore their relevance to CCA progression.RESULTS: A total of 25 marker metabolites were identified, including lysophosphatidylcholines (LysoPCs), phosphatidylcholines (PCs), organic acids, sphinganine, and ketoleucine. These metabolites effectively distinguished CCA patients from healthy controls, with an AUC of 0.995 for increased biomarkers and 0.992 for decreased biomarkers in positive mode. In negative mode, the AUC for increased and decreased biomarkers was 0.899 and 0.976, respectively. The metabolic pathway analysis revealed critical biological functions linked to these biomarkers, offering insights into the molecular mechanisms underlying CCA initiation and progression.CONCLUSION: This study identifies novel metabolic biomarkers for the early diagnosis of CCA and provides a deeper understanding of the metabolic alterations associated with the disease. These findings could contribute to the development of diagnostic strategies and therapeutic interventions for CCA.PMID:40260405 | PMC:PMC12009706 | DOI:10.3389/fmolb.2025.1549223

Front Mol Biosci. 2025 Apr 7;12:1426949. doi: 10.3389/fmolb.2025.1426949. eCollection 2025.ABSTRACTINTRODUCTION: Prostate cancer (PC) diagnosis relies on histopathological examination of prostate biopsies, which is restricted by insufficient sampling of all tumors present. Including samples from non-PC but tumor instructed normal tissues (TINT) may increase the diagnostic power by displaying the adaptive responses in benign tissues near tumors.METHODS: Here, we applied high-resolution magic angle spinning nuclear magnetic resonance (HR MAS NMR) to identify metabolomic biomarkers of possible diagnostic value in benign prostate tissues near low/high-grade tumors.RESULTS: Benign samples near high-grade tumors (B ISUP 3 + 4) exhibited altered metabolic profiles compared to those close to low-grade tumors (B ISUP 1 + 2). The levels of six metabolites differentiated between the two groups; myo-inositol, lysine, serine and combined signal of lysine/leucine/arginine were increased in benign samples near high-grade tumors (B ISUP 3 + 4) compared to near low-grade tumors (B ISUP 1 + 2), while levels of ethanolamine and lactate were decreased. Additionally, we revealed metabolic differences in non-cancer tissues as a function of their distance to the nearest tumor. Eight metabolites (glutathione, glutamate, combined signal of glutamate/glutamine - glx, glycerol, inosine, ethanolamine, serine and arginine) differentiated between benign tissue located close to the tumor (d ≤ 5 mm) compared to those far away (d ≥ 1 cm).CONCLUSION: Our HR MAS NMR-based approach identified metabolic signatures in prostate biopsies that reflect the response of benign tissues to the presence of nearby located tumors in the same prostate and confirmed the power of the TINT concept for improved PC diagnostics and understanding of tumor-tissue interactions.PMID:40260402 | PMC:PMC12009692 | DOI:10.3389/fmolb.2025.1426949

Front Pharmacol. 2025 Apr 7;16:1534748. doi: 10.3389/fphar.2025.1534748. eCollection 2025.ABSTRACTINTRODUCTION: Tiebangchui (TBC, Tibetan name: བང་ང་ནག་པ།), the dried tuberous root of Aconitum pendulum Busch. and Aconitum flavaum Hand.-Mazz., is a prevalent used Tibetan medicine, recognized for its significant therapeutic effects despite its high toxicity. It is commonly employed in treating the diseases categorized as "Long" (རླུང་ནད།), cold, "Huang-shui" (སེར་ཆུ་ནད།), leprosy, and mania in Tibetan medicine. Notably, it is utilized in the treatment of rheumatoid arthritis, which is classified under the "Huang-shui" disease category according to Tibetan medical theory. Given its considerable toxicity, various processing techniques aimed at reducing the harmful effects of TBC are essential for its safe application in clinical settings. Hezi-decoction-processed method is a distinctive and effective traditional processing method of Tibetan medicine, but the overall variability of chemical constituents in the Hezi-decoction-processed TBC is still unclear. This investigation sought to examine a variety of diterpenoid alkaloids and tanning constituents, identify potential metabolic markers for differentiating the unprocessed TBC and Hezi-decoction-processed TBC at varying processing times, and determine the optimal processing time for reducing toxicity and maintaining efficacy.METHODS: A combination of metabolomic techniques was developed, integrating ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) with desorption electrospray ionisation mass spectrometry imaging (DESI-MSI) coupled with quantitative analytical techniques. This was done with the objective of monitoring the dynamic alterations in chemical constituents in TBC during the processing time. Metabolic markers were observed via DESI-MSI, and three alkaloids and five tannin acids were quantified through the use of UPLC and HPLC.RESULTS: Fifty-one compounds were identified in unprocessed TBC and processed samples, of which 31 were discernible from unprocessed TBC. A total of 22 metabolic markers, such as aconine, aconitine, benzoylaconine, chebulic acid, gallic acid, and corilagin, can proficiently distinguish between raw and processed TBC with different processing times. And the results of content determination of three alkaloids and five tannins showed that they were stabilized at 72 h. The monoester-diterpenoid alkaloids (MDAs) and diester-diterpenoid alkaloids (DDAs) levels were 0.0149% and 0.0852% in 72 h, respectively. The contents of gallic acid, corilagin, 1,2,3,4,6-O-pentagalloylglucose, chebulinic acid, and ellagic acid were 8.9706, 9.3444, 1.2438, 5.7582, and 3.1160 mg/g, respectively. The distribution and accumulation of metabolic markers during processing were investigated by DESI-MS. The results of DESI-MSI were consistent with those of content determination experiments. Combined with the multivariate statistical analysis, content determination of three alkaloids and five tannin acids and DESI-MSI, 72 h is demonstrated to be the appropriate time for toxicity attenuation and efficacy reservation of TBC.DISCUSSION: The implementation of this technique could contribute to the identification of markers in Hezi decoction-processed TBC and the establishment of effective quality control and evaluation procedures to ensure the safety of TBC. The proposed method has the potential to elucidate the processing mechanism of Aconitum medicines and other toxic traditional Chinese medicines, given its wide applicability.PMID:40260374 | PMC:PMC12009863 | DOI:10.3389/fphar.2025.1534748

Front Endocrinol (Lausanne). 2025 Apr 7;16:1504614. doi: 10.3389/fendo.2025.1504614. eCollection 2025.ABSTRACTINTRODUCTION: Maintaining polyamines homeostasis is essential for cardiovascular health, whereas elevated uric acid levels are recognized as a significant risk factor for the onset and progression of cardiovascular diseases. However, the interaction between uric acid and the regulation of polyamine homeostasis has not been extensively investigated. The objective of this study was to investigate the influence of uric acid on cardiac polyamines regulation and elucidate the role of polyamines in uric acid induced cardiomyocytic injury.METHODS: The in vitro experiments utilized H9C2 cardiomyocytes, the hyperuricemic mouse model was established via potassium oxonate and hypoxanthine. Techniques included energy metabolomics, HPLC for polyamine quantification, qPCR, ELISA, immunofluorescence, and mitochondrial membrane potential assessment using JC-1 staining, MTT cell viability analysis.RESULTS: Uric acid treatment can alter ornithine metabolism in cardiomyocytes, revealed a potential of shifting it from the traditional ornithine cycle towards the polyamine cycle. Both ODC1 and SAT1 protein levels were up-regulated in hyperuricemic mice indicated a dysorder of polyamines homostasis. A downregulation tendency of spermidine and spermine levels were observed in cardiomyocytes under uric acid treatment. Notably, exogenous supplementation with spermidine or spermine effectively mitigated the uric acid-induced decline in cardiomyocyte viability and mitochondrial membrane potential.DISCUSSION: Uric acid disrupts polyamine homeostasis, leading to mitochondrial dysfunction and cardiomyocyte damage. Exogenous polyamine supplementation demonstrates therapeutic potential by preserving mitochondrial integrity. These findings unveil a potential mechanism underlying uric acid-induced cardiac injury and propose polyamine replenishment as a viable intervention strategy for hyperuricemia-related cardiovascular complications.PMID:40260285 | PMC:PMC12009720 | DOI:10.3389/fendo.2025.1504614

Front Cell Infect Microbiol. 2025 Apr 7;15:1550908. doi: 10.3389/fcimb.2025.1550908. eCollection 2025.ABSTRACTJiawei Ermiao Granule (JWEMG) is a traditional Chinese herbal formulation widely used in China for the treatment of human papilloma virus (HPV) infections. However, the mechanisms underlying their efficacy in clearing HPV infections remain unclear. This study aimed to elucidate the mechanisms by which JWEMG clears persistent HPV infections from a metabolomics perspective using modern analytical techniques. Untargeted and targeted metabolomics analyses were performed on vaginal lavage samples from 33 patients using liquid chromatograph mass spectrometer (LC-MS) and hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS). Untargeted metabolomics identified 47 potential biomarkers through volcano plot analysis, among which 30 exhibited a reversal trend following JWEMG intervention. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that JWEMG may exert therapeutic effects on patients with persistent HPV infections via pathways related to starch and sucrose metabolism, galactose metabolism, fructose and mannose metabolism, and amino sugar and nucleotide sugar metabolism. Targeted metabolomics revealed a significant increase in tyrosine levels in the vaginal/cervical microenvironment following JWEMG treatment. By integrating targeted and untargeted metabolomics, this study provides a comprehensive exploration of the holistic effects of JWEMG on HPV-infected patients, addressing the challenges of scientifically explaining the pharmacological mechanisms of multi-component, multi-target traditional Chinese medicines.PMID:40260114 | PMC:PMC12009767 | DOI:10.3389/fcimb.2025.1550908

Front Cell Neurosci. 2025 Apr 7;19:1541347. doi: 10.3389/fncel.2025.1541347. eCollection 2025.ABSTRACTINTRODUCTION: Age-related hearing loss (ARHL) is linked to dementia, with mitochondrial dysfunction playing a key role in its progression. Deficient mitochondrial tRNA modifications impair protein synthesis and energy metabolism, accelerating ARHL. Mitochonic acid 5 (MA-5) has shown promise as a therapeutic candidate by improving mitochondrial function, reducing oxidative stress, and stabilizing membrane potential.METHODS: In this study, we investigated the effects of MA-5 on ARHL in cyclin-dependent kinase 5 regulatory subunit-associated protein 1 (Cdk5rap1) knockout (KO) mice, which exhibit early-onset ARHL due to abnormalities in mitochondrial transfer RNA (mt-tRNA) modifications.RESULTS: MA-5 treatment effectively attenuated ARHL progression in Cdk5rap1-KO mice by improving auditory brainstem response thresholds and distortion product otoacoustic emissions. It also reduced spiral ganglion and outer hair cell loss, while preserving the cochlear structural integrity by preventing mitochondrial degeneration in spiral ligament fibrocytes. Mechanistically, MA-5 upregulated the expression of silent information regulator sirtuin 1 and promoted the nuclear translocation of yes-associated protein, both of which are involved in regulating mitochondrial function and cellular senescence. Metabolomics analysis further demonstrated that MA-5 restored mitochondrial metabolism, reduced lactate accumulation, and maintained mitochondrial integrity.CONCLUSION: These findings suggest that MA-5 is a viable treatment option for ARHL and other age-related disorders associated with mitochondrial dysfunction.PMID:40260078 | PMC:PMC12009901 | DOI:10.3389/fncel.2025.1541347

Food Funct. 2025 Apr 22. doi: 10.1039/d5fo00232j. Online ahead of print.ABSTRACTSoluble sugars are indeed key factors in the formation of tea sweetness quality. However, the specific impact they exert on tea sweetness has not been clearly elucidated. Consequently, in this study, one bud and two leaves of the same tea variety were utilized to produce six types of tea for sensory evaluation, electronic tongue analysis, and targeted sugar metabolomics analysis, aiming to systematically assess the influence of soluble sugars on the sweetness contribution in different teas. The results obtained from sensory evaluation and the electronic tongue indicate that the sweetness order of various teas is green tea (GT) > yellow tea (YT) > dark tea (DT) > oolong tea (OT) > black tea (BT) > white tea (WT). Through metabolomics, 26 crucial differential metabolites were identified, among which sucrose, inositol, D-fructose, glucose, and D-arabinitol constitute the main sugar components that distinguish the sweetness characteristics of the six types of tea. This study offers a comprehensive and detailed overview of the effects of commonly employed processing methods on the sweetness quality of tea as well as its metabolic properties. It thereby lays a solid theoretical foundation for optimizing processing techniques to enhance the sweetness quality of tea and to better serve tea production practices.PMID:40259751 | DOI:10.1039/d5fo00232j

Environ Toxicol. 2025 Apr 21. doi: 10.1002/tox.24525. Online ahead of print.ABSTRACTY. Xia, L. Duan, X.L. Zhang, Y.J. Niu, and X. Ling, "Integrated Analysis of Gut Microbiota and Metabolomic Profiling in Colorectal Cancer Metastasis," Environmental Toxicology 39, no. 10 (2024): 4467-4478, https://doi.org/10.1002/tox.24228. The above article, published online on 14 March 2024 in Wiley Online Library (http://onlinelibrary.wiley.com/), has been retracted by agreement between the journal Editor-in-Chief, Christyn Bailey; and Wiley Periodicals LLC. Following an investigation by the publisher, the parties have concluded that this article was accepted solely on the basis of a compromised peer review process. Therefore, the article must be retracted.PMID:40259709 | DOI:10.1002/tox.24525

J Cheminform. 2025 Apr 21;17(1):56. doi: 10.1186/s13321-025-00994-6.ABSTRACTMetabolites serve as crucial biomarkers for assessing disease progression and understanding underlying pathogenic mechanisms. However, when the metabolic pathway category of metabolites is unknown, researchers face challenges in conducting metabolomic analyses. Due to the complexity of wet laboratory experimentation for pathway identification, there is a growing demand for predictive methods. Various computational approaches, including machine learning and graph neural networks, have been proposed; however, interpretability remains a challenge. We have developed a neural network framework called MotifMol3D, which is designed for predicting molecular metabolic pathway categories. This framework introduces motif information to mine local features of small-sample molecules, combining with graph neural network and 3D information to complete the prediction task. Using a dataset of 5,698 molecules that participate in 11 metabolic pathway categories in the KEGG database, MotifMol3D outperformed state-of-the-art methods in precision, recall, and F1 score. In addition, ablation study and motif analysis have demonstrated the effectiveness and usefulness of the model. Motif analysis, in particular, has shown motif information can actually characterize the main features of specific pathway molecules to a certain extent and enhance the interpretability of the model. An external validation further corroborates this observation. MotifMol3D is an open-source tool that is available at https://github.com/Irena-Zhang/MotifMol3D.git .Scientific contribution MotifMol3D integrates motif information, graph neural networks, and 3D structural data to enhance feature extraction for small-sample molecules, improving the precision and interpretability of metabolic pathway predictions. The model outperforms state-of-the-art approaches in precision, recall, and F1 score. This work reveals how motif information characterizes pathway-specific molecules, offering novel insights into molecular properties within metabolic pathways.PMID:40259421 | DOI:10.1186/s13321-025-00994-6

Microb Cell Fact. 2025 Apr 21;24(1):90. doi: 10.1186/s12934-025-02711-2.ABSTRACTRice blast, a disease caused by Magnaporthe oryzae, significantly threatens global rice production. To improve the anti-M. oryzae activity of Streptomyces bikiniensis HD-087 metabolites, the effects of inducer, Magnaporthe oryzae acellular filtrate, on secondary metabolism of S. bikiniensis HD-087 were studied. The results showed that M. oryzae cell-free filtrate cultured for 96 h served as the most effective inducer, significantly enhancing the anti-M. oryzae activity of metabolites of S. bikiniensis HD-087 and increasing the diameter of the inhibitory zone by 2.96 mm. The inhibition rates of M. oryzae colony diameter and spore germination in the induced group were 12.39% and 39.6% higher than those in the non-induced group, respectively. Metabolomic profiling of strain HD-087 highlighted substantial differences between the induced and non-induced groups. At 48 h of fermentation, a total of 705 distinct metabolites were identified, while at 96 h this number decreased to 321. Moreover, induction markedly altered primary pathways such as the tricarboxylic acid cycle, amino acid biosynthesis, and fatty acid metabolism in S. bikiniensis HD-087. qPCR analysis showed that nrps genes and pks genes in the induced group were significantly up-regulated by 9.92 ± 0.51 and 2.71 ± 0.17 times, respectively, and biotin carboxylase activity was also increased 26.63%. These results provide a theoretical basis for using inducers to enhance the antimicrobial ability of Streptomyces.PMID:40259378 | DOI:10.1186/s12934-025-02711-2

Microb Cell Fact. 2025 Apr 21;24(1):89. doi: 10.1186/s12934-025-02718-9.ABSTRACTBACKGROUND: Members of the fungal genus Trichoderma are well-known for their mycoparasitic and plant protecting activities, rendering them important biocontrol agents. One of the most significant specialized metabolites (SMs) produced by various Trichoderma species is the unsaturated lactone 6-pentyl-alpha-pyrone (6-PP). Although first identified more than 50 years ago and having pronounced antifungal and plant growth-promoting properties, the biosynthetic pathway of 6-PP still remains unresolved.RESULTS: Here, we demonstrate that 6-PP is biosynthesized via the polyketide biosynthesis pathway. We identified Pks1, an iterative type I polyketide synthase, as crucial for its biosynthesis in Trichoderma atroviride, a species recognized for its prominent 6-PP production abilities. Phylogenetic and comparative genomic analyses revealed that the pks1 gene is part of a biosynthetic gene cluster conserved in those Trichoderma species that are known to produce 6-PP. Deletion of pks1 caused a complete loss of 6-PP production in T. atroviride and a significant reduction in antifungal activity against Botrytis cinerea and Rhizoctonia solani. Surprisingly, the absence of pks1 led to enhanced lateral root formation in Arabidopsis thaliana during interaction with T. atroviride. Transcriptomic analysis revealed co-regulation of pks1 with adjacent genes, including candidates coding for a C3H1-type zinc finger protein and lytic polysaccharide monooxygenase, suggesting coordination between 6-PP biosynthesis and environmental response mechanisms.CONCLUSION: Our findings establish pks1 as an essential gene for 6-PP biosynthesis in T. atroviride, providing novel insights into the production of one of the most significant compounds of this mycoparasite. These findings may pave the way for the development of improved biocontrol agents and the application of 6-PP as potent biopesticide contributing to an eco-friendly and sustainable way of plant disease management.PMID:40259335 | DOI:10.1186/s12934-025-02718-9

BMC Musculoskelet Disord. 2025 Apr 21;26(1):392. doi: 10.1186/s12891-025-08642-8.ABSTRACTBACKGROUND: Osteoarthritis is a common degenerative joint disease marked by cartilage degeneration and inflammation. This study investigates the therapeutic potential of adipose-derived stromal cells (ASCs) and their secretome in a rat model of osteoarthritis.METHODS: ASCs were extracted from human adipose tissue, cultured, and primed with human platelet lysate. The secretome was collected after 48 h of serum-free culture. Osteoarthritis was induced in rats using monosodium iodoacetate, and after 14 days, they were treated with saline solution, ASCs, or secretome. Over five weeks, body weight and histopathological changes were monitored.RESULTS: No clinical complications arose post-treatment, and all rats gained weight similarly. ASC treatment increased histopathological changes associated with osteoarthritis, including severe cartilage necrosis and bone remodeling. Conversely, the secretome treatment resulted in mild to moderate cartilage degeneration, similar to that observed in the control group. These findings suggest that ASCs may contribute to disease progression in this model, while the secretome did not show significant effects on cartilage histology compared to the control group. Further studies are needed to determine whether optimizing the secretome composition or dosing could enhance its therapeutic potential.CONCLUSIONS: This study highlights the complexity of ASC interactions with the immune system, while secretome may be a well-tolerated treatment, further studies are needed to determine its potential therapeutic benefits.PMID:40259333 | DOI:10.1186/s12891-025-08642-8

BMC Plant Biol. 2025 Apr 21;25(1):505. doi: 10.1186/s12870-025-06505-x.ABSTRACTBACKGROUND: Plants in arid environments can regulate the generation of specialized metabolites to enhance their adaptability. Roots serve as the first defense line, responding directly to drought situations; however, the knowledge regarding the molecular mechanisms of metabolite changes to drought in maize roots remain largely limited. Here, we employed RNA-seq and UPLC-MS/MS methods to examine changes in the root metabolome and transcriptome of maize seedlings subjected to moderate drought (MD) and severe drought (SD) conditions by controlling water supply.RESULTS: Compared to the untreated control group, 460 differentially accumulated metabolites were detected in roots under MD and SD conditions. Among these metabolites, lignin compounds emerged as the primary response to drought. Most lignin metabolites, including caffealdehyde, sinapyl alcohol, coniferaldehyde, p-coumaryl alcohol, and p-coumaric acid, showed a significant increase under MD but decreased under SD. Transcriptional profiling identified 903 and 5306 differential genes in roots treated with MD and SD, respectively. The majority of these genes were associated with lignin biosynthesis, hormone synthesis and signal transduction, and defense response processes. These metabolites and genes play crucial roles in lignin biosynthesis, antioxidant capacity, hormone balance, and root growth, particularly under MD conditions, which aligns with the results from morpho-physiological studies. Further, a conjoint omics analysis highlighted the significant regulatory roles of hormone-associated genes in lignin formation.CONCLUSION: Our results suggest that the co-regulation of the lignin biosynthesis pathway and hormone signals significantly enhances root performance, helping maize maintain growth under MD conditions. This study leads to a better understanding of the regulatory mechanisms involved in maize root adaptation to drought environments.PMID:40259225 | DOI:10.1186/s12870-025-06505-x

Sci Rep. 2025 Apr 21;15(1):13800. doi: 10.1038/s41598-025-98814-2.ABSTRACTBisphenol AF (BPAF), a fluorinated alternative to the plasticizer bisphenol A (BPA), is found in both the environment and the human body. Fructose is one of the sweeteners that has been widely used in recent years. Prior research has verified that the combined exposure to fructose and BPA considerably worsened the impact on glycolipid metabolism. However, it is currently unclear whether BPAF have a combination effect on health with fructose. Serum glucose and insulin, liver biochemistry, histology of the liver and adipose tissue, serum profiles of amino acids, vitamins, bile acids, steroid hormones, catecholamines, and adipocytokines like leptin, omentin-1, adiponectin, asprosin, and adipocyte fatty acid binding protein (A-FABP) of male mice were all investigated in this study following a week of combined exposure to two doses of BPAF (lower dose: 0.25, and higher dose: 25 μg/kg daily). The results showed that simultaneous exposure to lower doses of BPAF and fructose considerably increased blood insulin and liver coefficient, total bilirubin, direct bilirubin, and glucose while significantly decreasing body weight, food intake, liver creatinine, and serum leptin, asprosin, and A-FABP. According to histology analysis, adipocyte enlargement may result from lower dose BPAF and fructose combined exposure, while bile duct dilatation may result from both lower and higher doses of BPAF combined with fructose. Concurrently, the combination of lower doses of BPAF and fructose increased the release of adrenocortical hormones and catecholamines, worsened metabolic disorders in amino acids such as histidine, arginine and proline, branched chain amino acid (isoleucine), and aromatic amino acids (tryptophan and phenylalanine), and aggravated the depletion of vitamin B12 and A. Interestingly, following the combined exposure to BPAF and fructose, bile acids including taurocholic acid, deoxycholic acid, cholic acid, and taurine ursodeoxycholic acid rose in a dose-dependent manner. According to these results, exposure to fructose and BPAF together may have a more detrimental effect on metabolism than either substance alone. Further research should be conducted to verify the impact of joint exposure to BPAF and fructose on human.PMID:40259005 | DOI:10.1038/s41598-025-98814-2

Sci Rep. 2025 Apr 21;15(1):13671. doi: 10.1038/s41598-025-97463-9.ABSTRACTColorectal cancer (CRC) is one of the most common cancers; however, accurately predicting prognosis based on existing molecular subtypes remains challenging. The XELOX regimen, which combines oxaliplatin and capecitabine, is the cornerstone of chemotherapy for CRC treatment. However, there is a notable lack of reliable predictive models for determining the sensitivity of this treatment. This study aimed to establish a novel classification system for CRC and develop a predictive model for XELOX chemotherapeutic sensitivity using serum metabolomics. We recruited 89 patients with CRC and 89 age- and sex-matched healthy controls for untargeted metabolomic studies to identify tumor-specific serum metabolites. The patients were grouped into distinct metabolic subtypes using unsupervised clustering. A serum metabolite combination predictive of the efficacy of XELOX was established using Cox regression analysis in 34 patients with stage III CRC. Using unsupervised clustering based on the serum metabolites, three distinct clusters were identified. Notably, Cluster 3, which was characterized by uniform lipid and amino acid levels, demonstrated the best prognosis. Our analysis revealed that D-glucose 6-phosphate, presqualene diphosphate, and leukotriene B4 levels were negatively correlated with XELOX sensitivity, whereas 15-HETE and N-acetyl-l-methionine levels were positively correlated. Based on these findings, we constructed a predictive model validated in an independent cohort of 34 patients with stage III CRC. In summary, this study identified a novel classification of CRC based on serum metabolites and developed a potential prognostic model for XELOX chemotherapeutic efficacy, which may have direct effects on the treatment and prognosis of CRC.PMID:40258977 | DOI:10.1038/s41598-025-97463-9

Sci Rep. 2025 Apr 21;15(1):13701. doi: 10.1038/s41598-025-98409-x.ABSTRACTChrysosplenetin, a polymethoxy flavonol purified in our laboratory from the waste products generated during the industrial extraction of artemisinin, has been previously demonstrated to be a potential inhibitor of artemisinin resistance. Based on NMR-untargeted metabolomics, one of its hypothesized mechanisms of action is associated with the regulation of amino acid metabolism. In this study, we further quantified the key amino acids using LC-MS/MS targeted metabolomics and screened out the perturbed metabolic pathway network, which was characterized by tissue-specific differences. As a result, among the commonly and uniquely altered metabolites, increased levels of phenylalanine, tryptophan, and isoleucine were detected in the serum and various organs of the resistant groups. Interestingly, while the individual use of chrysosplenetin or artemisinin elevated the contents of these amino acids, their combination led to a significant down-regulation of these amino acids in the serum and intestines. Therefore, chrysosplenetin has the potential to act as a restorer of amino acid metabolism homeostasis, which is associated with artemisinin resistance in Plasmodium berghei K173.PMID:40258976 | DOI:10.1038/s41598-025-98409-x

Sci Rep. 2025 Apr 22;15(1):13814. doi: 10.1038/s41598-025-98781-8.ABSTRACTMetabolites, particularly those derived from gut microbiota, play crucial roles in modulating immune responses, but the impact of most metabolites on immune cells remains unexplored. To systematically investigate the effect of metabolites on immune cells, we treated peripheral blood mononuclear cells (PBMCs) with 364 endogenous and gut microbiota metabolites and analyzed their impact on the PBMC transcriptome using RNA sequencing (RNA-seq). Clustering analysis revealed three distinct metabolite groups (Cluster 0, 1, 2), each exerting unique immunomodulatory effects. Cluster 1 metabolites, enhanced inflammatory pathways (e.g., cytokine signaling, neutrophil migration) and suppressed ferroptosis, potentially prolonging immune cell activity. In contrast, Cluster 0 metabolites promoted antigen presentation and extracellular matrix repair, while Cluster 2 metabolites upregulated autophagy-related pathways (e.g., GTPase signaling, ubiquitin-protein regulation), suggesting anti-inflammatory and tissue-homeostatic functions. Immune deconvolution highlighted Cluster 1-driven monocyte-to-M0 macrophage differentiation and elevated activated dendritic/mast cells, aligning with pro-inflammatory outcomes. Metabolites in Clusters 0/2 were enriched in the TCA cycle and alanine/aspartate metabolism, whereas Cluster 1 metabolites correlated with beta-alanine and branched-chain amino acid pathways. Gut microbiota analysis identified 23 species overrepresented in Cluster 1, linking dysbiosis to inflammatory metabolite profiles. Together, this high-throughput atlas elucidates how bloodborne metabolites shape PBMC function, offering insights into metabolic-immune crosstalk and potential therapeutic targets for inflammatory and autoimmune disorders.PMID:40258971 | DOI:10.1038/s41598-025-98781-8

Nat Cell Biol. 2025 Apr 21. doi: 10.1038/s41556-025-01650-9. Online ahead of print.ABSTRACTNutrient stress represents an important barrier for anti-tumour immunity, and tumour interstitial fluid often contains metabolites that hinder immune function. However, it is difficult to isolate the effects of tumour nutrient stress from other suppressive factors. Thus, we used a chemically defined cell culture medium based on the metabolomic profile of tumour interstitial fluid: tumour interstitial fluid medium (TIFM). Culture of CD8+ T cells in TIFM limited cell expansion and impaired CD8+ T cell effector functions upon restimulation, suggesting that tumour nutrient stress alone is sufficient to drive T cell dysfunction. We identified phosphoethanolamine (pEtn), a phospholipid intermediate, as a driver of T cell dysfunction. pEtn dampened T cell receptor signalling by depleting T cells of diacylglycerol required for T cell receptor signal transduction. The reduction of pEtn accumulation in tumours improved intratumoural T cell function and tumour control, suggesting that pEtn accumulation plays a dominant role in immunosuppression in the tumour microenvironment.PMID:40258951 | DOI:10.1038/s41556-025-01650-9

Sci Rep. 2025 Apr 21;15(1):10980. doi: 10.1038/s41598-025-95403-1.ABSTRACTSleep disorders have become a global social problem that increases the risk of developing mental illnesses and metabolic diseases. We aimed to identify biomarkers with which to non-invasively and objectively evaluate chronic sleep disorders. We used capillary electrophoresis-Fourier transform mass spectrometry (CE-FTMS) to analyze metabolomes in saliva collected from 50 persons each with good (≤ 2) and poor (≥ 6) sleep quality scored according to the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J) self-report questionnaire. The levels of five metabolites including glycerol and hippuric acid and eight including 2-hydroxybutyric acid (2HB), were respectively decreased and increased in participants with poor sleep quality. We established a random forest model consisting of six metabolites, including glycerol and hippuric acid, with a prediction accuracy of 0.866. Correlations between metabolites and sleep satisfaction were assessed using the Oguri-Shirakawa-Azumi sleep inventory, middle-age and aged version (OSA-MA) questionnaire. The results showed that 2'-deoxyguanosine, N1-acetylspermine, and 2,4-dihydroxybenzoic acid correlated positively, whereas glucosamine 6-phosphate and trimethylamine N-oxide correlated negatively with sleep quality. These findings suggested that changes in salivary metabolites reflect pathophysiological mechanisms of chronic sleep disorders, and that saliva samples could serve as non-invasive and objective diagnostic targets for predicting habitual sleep quality.PMID:40258870 | DOI:10.1038/s41598-025-95403-1

Sci Rep. 2025 Apr 21;15(1):13748. doi: 10.1038/s41598-025-94701-y.ABSTRACTSepsis after trauma and trauma-induced SIRS have similar symptoms, making their differentiation challenging. Therefore, biomarkers are needed to differentiate between sepsis after trauma and trauma-induced SIRS. We hypothesized that sepsis following trauma induces distinct alterations in blood metabolism compared to trauma-induced SIRS and sought to identify metabolite biomarkers in blood that could differentiate between the two. In this retrospective study, the existing blood metabolomics data from 60 patients without trauma-induced SIRS, 40 patients with trauma-induced SIRS, and 50 non-trauma control cases were analyzed. Among 40 traumatic patients with SIRS, 16 developed sepsis (SDS group), 24 did not develop sepsis (SDDS group) within the subsequent two-week period after trauma. A pairwise comparison between SDS group and SDDS group was used to screen the differential metabolites as biomarkers distinguishing sepsis after trauma from trauma-induced SIRS. Using partial least‑squares discriminant analysis, we demonstrated that SDS group was metabolically distinct from the SDDS group. A total of 37 differential metabolites were found between SDS group and SDDS group. We selected 5 most significantly different metabolites between SDS and SDDS groups as biomarkers to discriminate sepsis after trauma from trauma-induced SIRS, which were 7-alpha-carboxy-17-alpha-carboxyethylandrostan lactone phenyl ester, docosatrienoic acid, SM 8:1;2O/26:1, SM 34:2;2O, and N1-[1-(3-isopropenylphenyl)-1-methylethyl]-3-oxobutanamide. Our study has identified the potential of these biomarkers for differentiating sepsis after trauma from trauma-induced SIRS. This not only provides a new approach for the early diagnosis of sepsis after trauma but also lays a solid foundation for further research based on targeted metabolomics, which may lead to the development of more effective treatment strategies in the future.PMID:40258847 | DOI:10.1038/s41598-025-94701-y