PubMed

bioRxiv [Preprint]. 2024 Dec 18:2024.12.17.629031. doi: 10.1101/2024.12.17.629031.ABSTRACTGuanosine triphosphate (GTP) is essential for macromolecular biosynthesis, and its intracellular levels are tightly regulated in bacteria. Loss of the alarmone (p)ppGpp disrupts GTP regulation in Bacillus subtilis , causing cell death in the presence of exogenous guanosine and underscoring the critical importance of GTP homeostasis. To investigate the basis of guanosine toxicity, we performed a genetic selection for spontaneous mutations that suppress this effect, uncovering an unexpected link between GTP synthesis and glycolysis. In particular, we identified suppressor mutations in pyk , which encodes pyruvate kinase, a glycolytic enzyme. Metabolomic analysis revealed that inactivating pyruvate kinase prevents guanosine toxicity by reducing GTP levels. Although traditionally associated with ATP generation via substrate-level phosphorylation, B. subtilis pyruvate kinase in vitro was found to produce GTP and UTP approximately ten and three times more efficiently than ATP, respectively. This efficient GTP/UTP synthesis extends to Enterococcus faecalis and Listeria monocytogenes , challenging the conventional understanding of pyruvate kinase's primary role in ATP production. These findings support a model in which glycolysis directly contributes to GTP synthesis, fueling energy-demanding processes such as protein translation. Finally, we observed a synergistic essentiality of the Δ ndk Δ pyk double mutant specifically on glucose, indicating that pyruvate kinase and nucleoside diphosphate kinase are the major contributors of NTP production and complement each other during glycolysis. Our work highlights the critical role of nucleotide selectivity in pyruvate kinase and its broader implications in cellular physiology.IMPORTANCE: In this study, we reveal pyruvate kinase, a key glycolytic enzyme, primarily generates GTP from GDP in Bacillus subtilis , relatively to other trinucleotides such as ATP. This finding, uncovered through genetic selection for mutants that suppress toxic GTP overaccumulation, challenges the conventional understanding that pyruvate kinase predominantly produces ATP via substrate-level phosphorylation. The substantial role of GTP production by pyruvate kinase suggests a model where glycolysis rapidly and directly supplies GTP as the energy currency to power high GTP-demanding processes such as protein synthesis. Our results underscore the importance of nucleotide selectivity (ATP vs. GTP vs UTP) in shaping the physiological state and fate of the cell, prompting further exploration into the mechanisms and broader implications of this selective nucleotide synthesis.PMID:39763737 | PMC:PMC11702619 | DOI:10.1101/2024.12.17.629031

Front Immunol. 2024 Dec 23;15:1514977. doi: 10.3389/fimmu.2024.1514977. eCollection 2024.ABSTRACTIn recent years, tumors have emerged as a major global health threat. An increasing number of studies indicate that the production, development, metastasis, and elimination of tumor cells are closely related to the tumor microenvironment (TME). Advances in artificial intelligence (AI) algorithms, particularly in large language models, have rapidly propelled research in the medical field. This review focuses on the current state and strategies of applying AI algorithms to tumor metabolism studies and explores expression differences between tumor cells and normal cells. The analysis is conducted from the perspectives of metabolomics and interactions within the TME, further examining the roles of various cytokines. This review describes the potential approaches through which AI algorithms can facilitate tumor metabolic studies, which offers a valuable perspective for a deeper understanding of the pathological mechanisms of tumors.PMID:39763649 | PMC:PMC11701166 | DOI:10.3389/fimmu.2024.1514977

Front Oncol. 2024 Dec 23;14:1486310. doi: 10.3389/fonc.2024.1486310. eCollection 2024.ABSTRACTArtificial intelligence (AI) has significantly impacted various fields, including oncology. This comprehensive review examines the current applications and future prospects of AI in lung cancer research and treatment. We critically analyze the latest AI technologies and their applications across multiple domains, including genomics, transcriptomics, proteomics, metabolomics, immunomics, microbiomics, radiomics, and pathomics in lung cancer research. The review elucidates AI's transformative role in enhancing early detection, personalizing treatment strategies, and accelerating therapeutic innovations. We explore AI's impact on precision medicine in lung cancer, encompassing early diagnosis, treatment planning, monitoring, and drug discovery. The potential of AI in analyzing complex datasets, including genetic profiles, imaging data, and clinical records, is discussed, highlighting its capacity to provide more accurate diagnoses and tailored treatment plans. Additionally, we examine AI's potential in predicting patient responses to immunotherapy and forecasting survival rates, particularly in non-small cell lung cancer (NSCLC). The review addresses technical challenges facing AI implementation in lung cancer care, including data quality and quantity issues, model interpretability, and ethical considerations, while discussing potential solutions and emphasizing the importance of rigorous validation. By providing a comprehensive analysis for researchers and clinicians, this review underscores AI's indispensable role in combating lung cancer and its potential to usher in a new era of medical breakthroughs, ultimately aiming to improve patient outcomes and quality of life.PMID:39763611 | PMC:PMC11700796 | DOI:10.3389/fonc.2024.1486310

J Oral Microbiol. 2024 Dec 24;17(1):2442420. doi: 10.1080/20002297.2024.2442420. eCollection 2025.ABSTRACTBACKGROUND: Type 2 diabetes mellitus (T2DM) development is closely linked to microbiota, influenced by geography, ethnicity, gender, and age. While the relationship between oral microbiota and T2DM has been explored, specific microbiota associated with T2DM in the Dai and Han populations remains unclear. This study aims to compare oral microbiota differences and identify keystone species between these populations, both with and without T2DM.METHODS: We recruited 28 han participants (6 healthy children, 10 healthy adults, 12 adults with T2DM) and 34 Dai participants (11 healthy children, 10 healthy adults, 13 adults with T2DM). Blood samples were collected for biochemical analysis, and saliva samples underwent DNA extraction and 16S rRNA sequencing.RESULTS: Age significantly influenced oral microbiota differences between the Dai and Han populations, overshadowing the effects of diabetes. In the Dai population with T2DM, notable increases in Alistipes putredinis, Lactobacillus spp., Faecalibacterium prausnitzii, and Akkermansia muciniphila were observed compared to the Han population. Keystone genera differed, with Fusibacter central to the Dai population's microbial network, while the Han network was more scattered.CONCLUSION: This is the first comparative analysis of oral microbiota in the Dai and Han populations with T2DM, highlighting age and ethnicity's influence on microbial composition.PMID:39763576 | PMC:PMC11703080 | DOI:10.1080/20002297.2024.2442420

medRxiv [Preprint]. 2024 Dec 16:2024.12.16.24317793. doi: 10.1101/2024.12.16.24317793.ABSTRACTIncreasing evidence suggests the involvement of metabolic alterations in neurological disorders, including Alzheimer's disease (AD), and highlights the significance of the peripheral metabolome, influenced by genetic factors and modifiable environmental exposures, for brain health. In this study, we examined 1,387 metabolites in plasma samples from 1,082 dementia-free middle-aged participants of the population-based Rotterdam Study. We assessed the relation of metabolites with general cognition (G-factor) and magnetic resonance imaging (MRI) markers using linear regression and estimated the variance of these metabolites explained by genes, gut microbiome, lifestyle factors, common clinical comorbidities, and medication using gradient boosting decision tree analysis. Twenty-one metabolites and one metabolite were significantly associated with total brain volume and total white matter lesions, respectively. Fourteen metabolites showed significant associations with G-factor, with ergothioneine exhibiting the largest effect (adjusted mean difference = 0.122, P = 4.65x10 -7 ). Associations for nine of the 14 metabolites were replicated in an independent, older cohort. The metabolite signature of incident AD in the replication cohort resembled that of cognition in the discovery cohort, emphasizing the potential relevance of the identified metabolites to disease pathogenesis. Lifestyle, clinical variables, and medication were most important in determining these metabolites' blood levels, with lifestyle, explaining up to 28.6% of the variance. Smoking was associated with ten metabolites linked to G-factor, while diabetes and antidiabetic medication were associated with 13 metabolites linked to MRI markers, including N-lactoyltyrosine. Antacid medication strongly affected ergothioneine levels. Mediation analysis revealed that lower ergothioneine levels may partially mediate negative effects of antacids on cognition (31.5%). Gut microbial factors were more important for the blood levels of metabolites that were more strongly associated with cognition and incident AD in the older replication cohort (beta-cryptoxanthin, imidazole propionate), suggesting they may be involved later in the disease process. The detailed results on how multiple modifiable factors affect blood levels of cognition- and brain imaging-related metabolites in dementia-free participants may help identify new AD prevention strategies.PMID:39763567 | PMC:PMC11702749 | DOI:10.1101/2024.12.16.24317793

J Cereb Blood Flow Metab. 2025 Jan 7:271678X241310729. doi: 10.1177/0271678X241310729. Online ahead of print.ABSTRACTHuman primary (hpBMEC) and induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial-like cells (hiBMEC) are interchangeably used in blood-brain barrier models to study neurological diseases and drug delivery. Both hpBMEC and hiBMEC use glutamine as a source of carbon and nitrogen to produce metabolites and build proteins essential to cell function and communication. We used metabolomic, transcriptomic, and computational methods to examine how hpBMEC and hiBMEC metabolize glutamine, which may impact their utility in modeling the blood-brain barrier. We found that glutamine metabolism was systemically different between the two cell types. hpBMEC had a higher metabolic rate and produced more glutamate and GABA, while hiBMEC rerouted glutamine to produce more glutathione, fatty acids, and asparagine. Higher glutathione production in hiBMEC correlated with higher oxidative stress compared to hpBMEC. α-ketoglutarate (α-KG) supplementation increased glutamate secretion from hiBMEC to match that of hpBMEC; however, α-KG also decreased hiBMEC glycolytic rate. These fundamental metabolic differences between BMEC types may impact in vitro blood-brain barrier model function, particularly communication between BMEC and surrounding cells, and emphasize the importance of evaluating the metabolic impacts of iPSC-derived cells in disease models.PMID:39763385 | DOI:10.1177/0271678X241310729

Plant Dis. 2025 Jan 6. doi: 10.1094/PDIS-09-24-2049-SC. Online ahead of print.ABSTRACTCrown rust caused by the basidiomycete fungus Puccinia coronata f. sp. avenae (Pca) results in significant crop losses worldwide. Genetic solutions to protect against this disease require disease resistance gene discovery and introduction of resistance genes into elite germplasm by breeders. To inform disease resistance breeding activities, it is paramount to monitor changes of virulence in the Pca population and link those to genotypes of the pathogen. In 2023, a collection of 37 Pca isolates from diverse regions in Australia were gathered and their infection types across a commonly used set of oat differential lines determined to assign virulence pathotypes. We compared those virulence phenotypes to data collected in previous collections. While some of the virulence phenotypes had been reported in 2022, our analysis detected new virulence or an increase in frequency for virulence on some resistance genes. Notably, some of the frequency increases in virulence were recorded in Western Australia (WA), a region of interest due to its role in oat production for milling.PMID:39763272 | DOI:10.1094/PDIS-09-24-2049-SC

Sci Prog. 2025 Jan-Mar;108(1):368504241304205. doi: 10.1177/00368504241304205.ABSTRACTOBJECTIVE: The expansion of human activities in northern Colombia has increased human-snake encounters, particularly with venomous Porthidium lansbergii lansbergii. Given the limited knowledge of systemic envenomation effects and previous studies focusing only on early murine symptoms, this investigation aimed to describe the time-course physiopathology of P. lansbergii lansbergii envenomation following intramuscular injection in vivo.METHODS: Venom was inoculated in the gastrocnemius muscles of Swiss Webster mice, and blood, urine, and tissue samples were taken at different times to evaluate lethality and biochemical markers of renal function and oxidative stress.RESULTS: This study reports the first intramuscular LD50 for P. lansbergii lansbergii venom at 24.83 mg/Kg. Administering 80% of this LD50 induced early signs of renal injury, evidenced by urinary biomarkers over 24 h. The antioxidant activity was found at low levels in kidney tissue throughout the evaluated time post-envenomation. Malondialdehyde activity increased at the earliest point, while proinflammatory activity increased later. Urine metabolomics revealed elevated taurine and allantoin in the envenomed groups.DISCUSSION: Compensatory mechanisms in response to oxidative stress and tissue damage induced by the venom were evident in the envenomed mice over the evaluated time. However, histological analysis revealed evidence of pro-inflammatory processes occurring only at early times. Metabolomic analyses of urine samples identified taurine as a potential early biomarker of elevated oxidative stress and protein and creatinine levels.CONCLUSIONS: P. lansbergii lansbergii venom induces alterations in murine renal tissue, affecting urinary biomarkers of kidney function within hours post-envenomation. Delayed proinflammatory effects may suggest an antioxidant imbalance in the envenomed mice, with unknown long-term effects. Further research on the role of oxidative stress and inflammation in renal structure and function following envenomation is necessary, emphasizing the need for prompt clinical management.PMID:39763189 | DOI:10.1177/00368504241304205

Breast Cancer Res. 2025 Jan 6;27(1):2. doi: 10.1186/s13058-024-01956-w.ABSTRACTBACKGROUND: Neoadjuvant chemotherapy (NACT) is the standard-of-care treatment for patients with locally advanced breast cancer (LABC), providing crucial benefits in tumor downstaging. Clinical parameters, such as molecular subtypes, influence the therapeutic impact of NACT. Moreover, severe adverse events delay the treatment process and reduce the effectiveness of therapy. Although metabolic changes during cancer treatment are crucial determinant factors in therapeutic responses and toxicities, related clinical research remains limited.METHODS: One hundred paired blood samples were collected from 50 patients with LABC before and after a complete NACT treatment cycle. Untargeted metabolomics was used by liquid chromatography-mass spectrometry (LC-MS) to investigate the relationship between dynamically changing metabolites in serum and the responses and toxicities of NACT.RESULTS: Firstly, we observed significant alterations in serum metabolite levels pre- and post-NACT, with a predominant enrichment in the sphingolipid and amino acid metabolism pathways. Second, pre-treatment serum metabolites successfully predicted the therapeutic response and hematotoxicities during NACT. In particular, molecular subtype variations in favorable treatment responses are linked to acyl carnitine levels. Finally, we discovered that the therapeutic effects of NACT could be attributed to essential amino acid metabolism.CONCLUSION: This study elucidated the dynamic changes in metabolism during NACT treatment, providing a possibility for developing responsive metabolic signatures for personalized NACT treatment.PMID:39762945 | DOI:10.1186/s13058-024-01956-w

BMC Genomics. 2025 Jan 6;26(1):10. doi: 10.1186/s12864-024-11067-7.ABSTRACTBACKGROUND: Trimethylamine N-oxide (TMAO) is a metabolite produced by gut microbiota, and its potential impact on lipid metabolism in mammals has garnered widespread attention in the scientific community. Bovine fatty liver disease, a metabolic disorder that severely affects the health and productivity of dairy cows, poses a significant economic burden on the global dairy industry. However, the specific role and pathogenesis of TMAO in bovine fatty liver disease remain unclear, limiting our understanding and treatment of the condition. This study aims to construct a bovine fatty liver cell model using an integrated approach that combines transcriptomic, proteomic, and metabolomic data. The objective is to investigate the impact of TMAO on lipid metabolism at the molecular level and explore its potential regulatory mechanisms.RESULTS: We established an in vitro bovine fatty liver cell model and conducted a comprehensive analysis of cells treated with TMAO using high-throughput omics sequencing technologies. Bioinformatics methods were employed to delve into the regulatory effects on lipid metabolism, and several key genes were validated through RT-qPCR. Treatment with TMAO significantly affected 4790 genes, 397 proteins, and 137 metabolites. KEGG enrichment analysis revealed that the significantly altered molecules were primarily involved in pathways related to the pathology of fatty liver disease, such as metabolic pathways, insulin resistance, hepatitis B, and the AMPK signaling pathway. Moreover, through joint analysis, we further uncovered that the interaction between TMAO-mediated AMPK signaling and oxidative phosphorylation pathways might be a key mechanism promoting lipid accumulation in the liver.CONCLUSIONS: Our study provides new insights into the role of TMAO in the pathogenesis of bovine fatty liver disease and offers a scientific basis for developing more effective treatment strategies.PMID:39762777 | DOI:10.1186/s12864-024-11067-7

Sci Rep. 2025 Jan 6;15(1):937. doi: 10.1038/s41598-024-84028-5.ABSTRACTScorpion is a commonly used drug in traditional Chinese medicine for treating epilepsy, although the exact mechanisms are not yet fully understood. This study aimed to compare the treatment effects of Scorpion water extract (SWE) and Scorpion ethanol extract (SEE) on mice with pentetrazole-induced epilepsy and investigate the possible mechanisms through metabolomics methods. A pentetrazole-induced epileptic mice model was used to assess the corrective effects of SWE and SEE. Untargeted metabolomics, utilizing UPLC-Q-TOF/MS, was employed to analyze the metabolic profiles of mice and identify metabolic changes following scorpion treatment. The results revealed that only SWE showed therapeutic effects in epileptic mice. Metabolomics analysis demonstrated significant alterations in metabolic signatures between the pentetrazole-induced epileptic mice and SWE groups. By utilizing orthogonal partial least squares discrimination analysis, 44 and 108 potential biomarkers in mouse serum were identified in positive and negative ion modes, respectively. Differential metabolites related to epilepsy were then used to pinpoint relevant pathways in epileptic mice, such as linoleic acid metabolism, biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, and ether lipid metabolism. In conclusion, this study highlights the corrective effects of Scorpion on epileptic mice and provides insight into the underlying metabolic pathways involved in its efficacy.PMID:39762379 | DOI:10.1038/s41598-024-84028-5

BMJ Open. 2025 Jan 6;15(1):e095392. doi: 10.1136/bmjopen-2024-095392.ABSTRACTINTRODUCTION: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD). The strong association between gut and liver inflammation has driven several pathogenic hypotheses to which the intestinal microbiome is proposed to contribute. Pilot studies of faecal microbiota transplantation (FMT) in PSC and IBD are demonstrated to be safe and associated with increased gut bacterial diversity. However, the longevity of such changes and the impact on markers of disease activity and disease progression have not been studied. The aim of this clinical trial is to determine the effects of repeated FMT as a treatment for PSC-IBD.METHODS AND ANALYSIS: FAecal micRobiota transplantation in primary sclerosinG chOlangitis (FARGO) is a phase IIa randomised placebo-controlled trial to assess the efficacy and safety of repeated colonic administration of FMT in patients with non-cirrhotic PSC-IBD. Fifty-eight patients will be recruited from six sites across England and randomised in a 1:1 ratio between active FMT or FMT placebo arms. FMT will be manufactured by the University of Birmingham Microbiome Treatment Centre, using stool collected from rigorously screened healthy donors. A total of 8 weekly treatments will be delivered; the first through colonoscopic administration (week 1) and the remaining seven via once-weekly enema (up to week 8). Participants will then be followed on a 12-weekly basis until week 48 from the first treatment visit. The primary efficacy outcome will be to determine the effect of FMT on serum alkaline phosphatase values over time (end of study at 48 weeks). Key secondary outcomes will be to evaluate the impact of FMT on other liver biochemical parameters, PSC risk scores, circulating and imaging markers of liver fibrosis, health-related quality of life measures, IBD activity and the incidence of PSC-related clinical events. Key translational objectives will be to identify mucosal metagenomic, metatranscriptomic, metabolomic and immunological pathways associated with the administration of FMT.ETHICS AND DISSEMINATION: The protocol was approved by the South Central-Hampshire B Research Ethics Committee (REC 23/SC/0147). Participants will be required to provide written informed consent. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications.TRIAL REGISTRATION NUMBER: The trial was registered at ClinicalTrials.gov on 23 February 2024 (NCT06286709). Weblink: Study Details | FAecal Microbiota Transplantation in primaRy sclerosinG chOlangitis | ClinicalTrials.gov.PMID:39762111 | DOI:10.1136/bmjopen-2024-095392

Crit Rev Oncol Hematol. 2025 Jan 4:104608. doi: 10.1016/j.critrevonc.2024.104608. Online ahead of print.ABSTRACTLung cancer is the leading cause of cancer-related mortality worldwide, highlighting the urgent need for more accurate and minimally invasive diagnostic tools to improve early detection and patient outcomes. While low-dose computed tomography (LDCT) is effective for screening in high-risk individuals, its high false-positive rate necessitates more precise diagnostic strategies. Liquid biopsy, particularly ctDNA methylation analysis, represents a promising alternative for non-invasive classification of indeterminate pulmonary nodules (IPNs). This review highlights the progress and clinical potential of liquid biopsy technologies, including traditional proteins markers, cfDNA, exosomes, metabolomics, circulating tumor cells (CTCs) and platelets, in lung cancer diagnosis. We discuss the integration of ctDNA methylation analysis with traditional imaging and clinical data to enhance the early detection of IPNs, as well as potential solutions to address the challenges of low biomarker concentration and background noise. By advancing precision diagnostics, liquid biopsy technologies could transform lung cancer management, improve survival rates, and reduce the disease burden.PMID:39761937 | DOI:10.1016/j.critrevonc.2024.104608

Int J Biol Macromol. 2025 Jan 4:139533. doi: 10.1016/j.ijbiomac.2025.139533. Online ahead of print.ABSTRACTMyostatin (MSTN) is a protein that plays a crucial role in regulating skeletal muscle development. Despite the known benefits of MSTN mutant cattle for increasing beef production, their potential impact on CH4 emissions has not been quantified. The study comparing wild-type (WT) cattle to MSTN-knockout (MSTN-KO) cattle revealed that CH4 production was lower. Macrogenomic analysis revealed a significant decrease in rumen archaea, with reduced Richness indices (P = 0.036). The MSTN-KO cattle also showed altered archaea distribution and composition at different taxonomic levels. LEfSe results showed changes in 21 methanogenic archaea clades, with obligately hydrogen (H2)-dependent methylotrophs Candidatus Methanoplasma termitum species belonging to Methanomassiliicoccales order demonstrating the most significant decrease. Rumen metabolites revealed a decrease in the ratio of acetate to propionate, indicating a shift in rumen fermentation pattern towards propionate fermentation. Additionally, the changing trend of methanogenic archaea is consistent with the evolution of methanogens, and this is correlated with the higher levels of linoleic acid in the rumen of MSTN-KO cattle. Linoleic acid affects the utilization of H2 by methanogenic archaea, leading to a reduction in obligately H2-dependent methylotrophs. Our study suggests that MSTN-KO cattle have potential as an economically and ecologically benign breed for reducing methane emissions.PMID:39761884 | DOI:10.1016/j.ijbiomac.2025.139533

Int J Biol Macromol. 2025 Jan 4:139514. doi: 10.1016/j.ijbiomac.2025.139514. Online ahead of print.ABSTRACTNumerous studies indicate that Schisandra chinensis (Turcz.) Baill (SC) has anti-type 2 diabetes mellitus (T2DM) effects, and its processed products are commonly used in clinical practice. However, limited reports exist on the mechanisms of polysaccharides from its vinegar products and their role in T2DM. We purified a novel polysaccharide from vinegar-processed Schisandra chinensis (VSC) and used intestinal microbiota 16S rRNA analysis and metabolomics to study changes in T2DM mice after vinegar-processed Schisandra chinensis polysaccharide (VSP) intervention, aiming to elucidate how VSP alleviates T2DM. VSP has shown significant therapeutic effects in T2DM mice, which can regulate the imbalance of glucose and lipid metabolism, alleviate pancreatic and liver damage, restore the integrity of the intestinal barrier, and inhibit the inflammatory response. Serum metabolomics and microbiological analysis showed that VSP could significantly regulate 104 endogenous metabolites and rectify gut microbiota disorders in T2DM mice. Additionally, VSP enhanced the levels of short-chain fatty acids (SCFAs) and the expression of GPR41/43 in the colon of T2DM mice. Correlation analysis revealed significant correlations among specific gut microbiota, serum metabolites, and fecal SCFAs. Overall, these findings will provide a basis for further VSP development.PMID:39761882 | DOI:10.1016/j.ijbiomac.2025.139514

J Adv Res. 2025 Jan 4:S2090-1232(25)00003-7. doi: 10.1016/j.jare.2025.01.003. Online ahead of print.ABSTRACTINTRODUCTION: Hyperglycemia and hyperlipidemia are the hallmarks of type 2 diabetes mellitus (T2DM). T2DM is a systemic metabolic disease caused by insulin resistance and malfunctioning pancreatic β-cells. Although ginseng (the roots of Panax ginseng C.A. Meyer) can be used to treat T2DM, the underlying mechanism is unclear.OBJECTIVES: To assess the role and mechanism of, γ-aminobutyric acid-fructosyl-glucose (GABAFG), a maillard reaction product of ginseng, in T2DM treatment.METHODS: The metabolism of GABAFG in serum and tissues was analyzed via ultra-high performance liquid chromatography-Q exactive-mass spectrometry (UHPLC-QE-MS). The molecular mechanisms of GABAFG in pancreatic β-cells (in vivo and in vitro) were investigated via Western blotting, qPCR and immunofluorescence. In addition, the results were validated via high-throughput sequencing and serum metabolomics.RESULTS: GABAFG alleviated the elevation of blood glucose and blood lipids in HFD/STZ-induced T2DM mice. Also, GABAFG reduced the insulin resistance-associated IRS-1 signaling axis in pancreatic β-cells in vitro. Mechanistically, GABAFG targeted the nuclear translocation of TFEB inhibited apoptosis of pancreatic β-cells by enhancing autophagolysosome function. In addition, GABAFG remodeled the gut microbiota. Specifically, GABAFG increased Akkermansia, decreased Romboutsia abundance, and decreased serum glycerophospholipid metabolism, thus alleviating T2DM-induced dyslipidemia.CONCLUSION: This is the first study to assess the pharmacological effects of ginseng-derived GABAFG in T2DM. Therefore, this study provides a new theoretical basis for understanding ginseng effect in metabolic diseases.PMID:39761869 | DOI:10.1016/j.jare.2025.01.003

J Ethnopharmacol. 2025 Jan 4:119327. doi: 10.1016/j.jep.2025.119327. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Ardisia is a large genus of Primulaceae, 734 accepted species worldwide, and most species are used as ethnomedicines for the treatment of bruises, rheumatism, tuberculosis, and various inflammatory diseases. According to our previous ethnobotanical survey, Ardisia gigantifolia Stapf, Ardisia hanceana Mez (Da-luo-san), and Ardisia crenata Sims (Xiao-luo-san) are commonly used in folk medicine for the treatment of rheumatism. Among them, A. hanceana and A. crenata in folklore has "Use Da-luo-san and Xiao-luo-san together for better rheumatism treatment". These three plants can be referred to as the characteristic herbs of Ardisia.AIM OF THE STUDY: To characterize the metabolites of three plants of Ardisia, clarify the metabolites differences, validate the traditional folk applications, and identify potential biomarkers.MATERIALS AND METHODS: UPLC-QTOF-MS and UPLC-QTRAP-MS metabolomics analysis techniques were utilized to reveal the metabolites of three plants of Ardisia. Combined with multivariate statistical analysis, differentially accumulated metabolites (DAMs) and biomarkers were screened. The inhibition of NO production was measured, and the p_value was determined using one-way ANOVA with Fisher's LSD test, to validate folk traditional application.RESULTS: A total of 328 metabolites were identified from the three plants' roots using UPLC-QTOF-MS, and 86 DAMs were screened by OPLS-DA. Among them, flavonoids are the main DAMs, especially between Zou-ma-tai group (A. gigantifolia) and the Luo-san group (A. hanceana and A. crenata). UPLC-QTRAP-MS was used to quantify the three DAMs, and it was found that the contents of (+/-)-catechin and gallic acid were higher in the Luo-san group. To verify the traditional application of the three plants, it was found that the activity of the three plants was better at 0.2 mg/mL, and the activity of the Luo-san group was significantly stronger than that of the Zou-ma-tai (p < 0.001). Further, 16 potential anti-inflammatory active biomarkers were screened by the two groups, and the relative contents of flavonoids was significantly higher in the Luo-san group, which was inferred to be a possible key active ingredient in the Luo-san group for the treatment of rheumatic diseases. Further network pharmacological methods verified that these flavonoid components may exert their therapeutic effects on rheumatic diseases by modulating multiple signaling pathways such as TNF, 1L-17, NF-κB, and T-cell receptor through key targets such as PTGS2, ESR1, ALOX5, CA2, XDH, and AKR1B1.CONCLUSION: This study identified the main active metabolites of the three plants of Ardisia, verified the local folklore that "Use Da-luo-san and Xiao-luo-san together for better rheumatism treatment", and spread the folk traditional knowledge. It is indicated that the Luo-san group have important potential medicinal value and development prospects. It further provides a scientific basis for the conservation and utilization of Ardisia resources as well as sustainable development.PMID:39761835 | DOI:10.1016/j.jep.2025.119327

Environ Pollut. 2025 Jan 4:125646. doi: 10.1016/j.envpol.2025.125646. Online ahead of print.ABSTRACTThe biological pathways connecting ambient fine particulate matter (PM2.5)-induced initial adverse effects to the development of atherosclerotic cardiovascular diseases are not fully understood. We hypothesize that lysoglycerophospholipids (LysoGPLs) are pivotal mediators of atherosclerosis induced by exposure to PM2.5. This study investigated the changes of LysoGPLs in response to PM2.5 exposure and the mediation role of LysoGPLs in the pro-atherosclerotic effects of PM2.5 exposure. In this longitudinal panel study, 110 adults aged 50-65 years from Beijing, China, were followed between 2013 and 2015. Targeted metabolomics analyses were utilized to quantify 18 LysoGPLs from five subclasses in 579 plasma samples. Daily PM2.5 mass concentration was monitored at a station. We used linear mixed-effect models to estimate the responses of LysoGPLs to PM2.5 exposure. Subsequently, mediation analyses were conducted to investigate the mediating role of LysoGPLs in PM2.5-associated changes in non-high density lipoprotein-cholesterol (Non-HDL-C), a biomarker for pro-atherosclerotic apolipoprotein B-containing lipoproteins, and various inflammatory biomarkers, including interleukin (IL)-8, monocyte chemoattractant protein-1 (MCP-1), soluble CD40 ligand, and interferon (IFN)-γ. Short- to medium-term (1-30 days) PM2.5 exposure was associated with significant increases in six lysophosphatidic acids (LPAs), three lysoalkylphosphatidylcholines [LPC(O)s], and three lysophosphatidylglycerols (LPGs), as well as decreases in two LPAs and one lysophosphatidylserine (LysoPS), with maximus changes of 0.5-2.1%, 0.8-2.1%, 1.9-3.0%, -1.4--3.7%, and -8.0%, respectively. Furthermore, the elevated levels of LPA 18:1/18:2, LPC(O) 18:0/18:1, and LPG 16:0/16:1/18:0 significantly mediated the PM2.5-associated increase in Non-HDL-C (18-49%), IL-8 (9-24%), MCP-1 (12-26%), and IFN-γ (4-12%) over 30 days. In conclusion, short- to medium-term PM2.5 exposure was associated with altered metabolism of LysoGPLs, which mediated the PM2.5-associated pro-atherosclerotic response.PMID:39761719 | DOI:10.1016/j.envpol.2025.125646

Plant Physiol. 2025 Jan 6:kiaf005. doi: 10.1093/plphys/kiaf005. Online ahead of print.ABSTRACTStylo (Stylosanthes guianensis) is a tropical legume that exhibits considerable tolerance to manganese (Mn) toxicity, which severely constrains plant growth in acidic soils. To elucidate the Mn detoxification mechanisms in stylo, this study investigated the excess Mn-regulated metabolic profile of stylo roots and examined the role of metabolic enzymes in Mn tolerance. Excess Mn triggered oxidative stress in the two stylo genotypes tested. However, Mn-stimulated activation of antioxidant defense systems was observed in the Mn-tolerant genotype RY5 but not in the Mn-sensitive genotype TF0317. Metabolomic analysis of the Mn-tolerant RY5 roots revealed numerous excess Mn-responsive metabolites, mainly related to flavonoids and phenolic acids. Furthermore, a set of genes involved in the phenylpropanoid/flavonoid pathway were upregulated by excess Mn in stylo roots, especially in RY5. We characterized the excess Mn-inducible gene SgPAL2, encoding phenylalanine ammonia-lyase. SgPAL2 localized to the endoplasmic reticulum. Compared to control plants, SgPAL2 overexpression led to increases in shoot and root dry weights under Mn-excess conditions, whereas SgPAL2 suppression had the opposite effect. Moreover, SgPAL2 overexpression dramatically altered secondary metabolism, particularly flavonoid metabolism. In a bioassay, the inhibition of root elongation caused by excess Mn was alleviated by treatment with exogenous calycosin, an SgPAL2-regulated isoflavonoid, suggesting calycosin can detoxify Mn. Taken together, these findings indicate that SgPAL2 plays a critical role in enhancing Mn tolerance in stylo through metabolic regulation.PMID:39761536 | DOI:10.1093/plphys/kiaf005

Tree Physiol. 2025 Jan 6:tpaf003. doi: 10.1093/treephys/tpaf003. Online ahead of print.ABSTRACTNorway maple and sycamore belong to the Acer genus and produce desiccation-tolerant and desiccation-sensitive seeds, respectively. We investigated the seed germination process at the imbibed and germinated stages using metabolomic and proteomic approaches to determine why sycamore seeds germinate earlier and are more successful at establishing seedlings than Norway maple seeds under controlled conditions. Embryonic axes and embryonic axes with protruded radicles were analyzed at the imbibed and germinated stages, respectively. Among the 212 identified metabolites, 44 and 67 differentially abundant metabolites were found at the imbibed and germinated stages, respectively, in both Acer species. Higher levels of amines, growth and defense stimulants, including B vitamins, were found in sycamore. We identified 611 and 447 proteins specific to the imbibed and germinated stages, respectively, in addition to groups of proteins expressed at different levels. Functional analysis of significantly regulated proteins revealed that proteins with catalytic and binding activity were enriched during germination, and proteins possibly implicated in nitrogen metabolism and metabolite interconversion enzymes were the predominant classes. Proteins associated with the control of plant growth regulation and seed defense were observed in both species at both germination stages. Sycamore proteins possibly involved in abscisic acid signal transduction pathway, stress tolerance and alleviation, ion binding and oxygenase activities appeared to accompany germination in sycamore. We identified peptides containing methionine (Met) oxidized to methionine sulfoxide (MetO), and functional analyses of proteins with significantly regulated MetO sites revealed that translation, plant growth and development, and metabolism of nitrogen compounds were the main processes under Met/MetO redox control. We propose that higher levels of storage proteins and amines together with higher levels of B vitamins supported more efficient nitrogen utilization in sycamore, resulting in faster seedling growth. In conclusion, omic signatures identified in sycamore seem to predispose germinated sycamore seeds to better postgerminative growth.PMID:39761348 | DOI:10.1093/treephys/tpaf003