PubMed

Anal Bioanal Chem. 2025 Feb 5. doi: 10.1007/s00216-025-05760-z. Online ahead of print.ABSTRACTMicrosampling, especially dried blood spots (DBS), emerged in recent years as a viable alternative to conventional blood collection since it is rapid, simple, minimally invasive, and has user-friendly characteristics. Moreover, DBS are able to avoid analyte degradation thanks to their great stability. Due to their versatility, clinical applications with DBS have increased, including mass spectrometry-based metabolomics and lipidomics studies. In this work, we evaluated and optimized extraction protocols testing five different extraction solutions to perform metabolomics and lipidomics studies on the same spot considering three commercially available microsampling devices, Capitainer, Whatman, and Telimmune. Parallelly, we also evaluated the short-term stability of the three devices at room temperature for up to 5 days. Our results showed that pure methanol was the best compromise to simultaneously extract from the same spot both the lipidome and polar metabolome. However, we also propose a two-step protocol combining methanol and water extraction that improves polar metabolite extraction and shows improved reproducibility in Capitainer and Whatman. Short-term stability results highlighted that both polar metabolites and lipids were stable for up to 6 days using the Capitainer device, while with Whatman and Telimmune, some significant variations were observed after 3 days for some classes of metabolites/lipids, suggesting the need for cold-chain storage when working with these devices.PMID:39907755 | DOI:10.1007/s00216-025-05760-z

Am J Physiol Renal Physiol. 2025 Feb 5. doi: 10.1152/ajprenal.00201.2024. Online ahead of print.ABSTRACTPodocyte injury plays a critical role in the pathogenesis and progression of focal and segmental glomerulosclerosis (FSGS). Transmembrane protein 30A (TMEM30A) downregulation participates in podocyte injury. This study aimed to identify the critical pathways and molecules associated with the downregulation of TMEM30A in the context of FSGS podocyte injury. In our study, we found TMEM30A and podocyte marker Synaptopodin were significantly downregulated in kidney tissues from patients with FSGS compared to those in normal controls. Using transcriptomic and metabolomic analyses, we characterized Tmem30a knockdown (KD) and normal mouse podocytes to identify differentially expressed genes and metabolites. Then, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and Protein-Protein Interaction (PPI) network were constructed, and the differentially expressed genes and metabolites were enriched into glycolytic pathway. Furthermore, we found the key glycolytic enzymes were downregulated in patients with FSGS, podocyte-specific Tmem30aLoxP/LoxP; NPHS2-Cre mice, and Tmem30a KD mouse podocytes. For rescue experiments, shTmem30a-resistant cDNA (resTmem30a) was created to intervene Tmem30a KD mouse podocytes. And we observed that podocyte-related molecules were downregulated in the Tmem30a KD group, along with glycolysis-related molecules, but the resTmem30a partially reversed this trend. Our findings clarified TMEM30A downregulation initiates podocyte injury by reducing glycolysis-related molecules (ALDOA, HK2, LDHA, and GAPDH) in FSGS and have implications for early diagnosis, prevention, and treatment.PMID:39907744 | DOI:10.1152/ajprenal.00201.2024

J Chem Inf Model. 2025 Feb 5. doi: 10.1021/acs.jcim.4c02040. Online ahead of print.ABSTRACTSpecificity, sensitivity, and high metabolite coverage make mass spectrometry (MS) one of the most valuable tools in metabolomics and lipidomics. However, translation of metabolomics MS methods to multiyear studies conducted across multiple batches is limited by variability in electrospray ionization response, making batch-to-batch comparisons challenging. This limitation creates an artificial divide between nontargeted discovery work that is broad in scope but limited in terms of absolute quantitation ability and targeted work that is highly accurate but limited in scope due to the need for matched isotopically labeled standards. These issues are often observed in stem cell studies using metabolomic and lipidomic MS approaches, where patient recruitment can be a years-long process and samples become available in discrete batches every few months. To bridge this gap, we developed a machine learning model that predicts electrospray ionization sensitivity for lipid classes that have shown correlation with stem cell potency. Molecular descriptors derived from these lipids' chemical structures are used as model input to predict electrospray response, enabling quantitation by MS with moderate accuracy (semiquantitation). Model performance was evaluated via internal and external validation using cultured cells from various stem cell donors, achieving global percent errors of 40% and 20% for positive and negative electrospray ion modes, respectively. Although this accuracy is typically insufficient for traditional targeted lipidomics experiments, it is sufficient for semiquantitative estimation of lipid marker concentrations across batches without the need for specific chemical standards that many times are unavailable. Furthermore, the precision for model-predicted concentrations was 16.9% for the positive mode and 7.5% for the negative mode, indicating promise for data harmonization across batches. The set of molecular descriptors used by the models described here was able to yield higher accuracy than those previously published in the literature, showing high promise toward semiquantitative lipidomics.PMID:39907635 | DOI:10.1021/acs.jcim.4c02040

Biomol Biomed. 2025 Feb 3. doi: 10.17305/bb.2025.11835. Online ahead of print.ABSTRACTThis study investigates the safety and underlying mechanisms of fecal microbiota transplantation (FMT) in treating radiation enteritis (RE). A rat model of RE was established with six groups: NC, RT, H-FMT, modified FMT (M-FMT), L-FMT, and BTAC. The therapeutic effects of FMT were assessed using the Disease Activity Index (DAI), histological analysis, and biochemical tests, including ink-propelling, xylitol exclusion, and enzyme-linked immunosorbent assay (ELISA). Gut microbiota alterations and fecal metabolism were analyzed via 16S rDNA sequencing and targeted metabolomics. The results demonstrated that FMT, particularly in the M-FMT group, effectively alleviated RE by reducing DAI scores, histological damage, and inflammatory markers while enhancing enzyme activity, superoxide dismutase (SOD) levels, and intestinal absorption. FMT also modulated gut microbiota composition, increasing beneficial species, such as Blautia wexlerae and Romboutsia timonensis while decreasing Enterococcus ratti. Metabolomics analysis revealed that FMT influenced niacin, nicotinamide, and starch metabolism, with notable changes in pantothenic acid and fatty acid levels. Spearman correlation analysis further indicated that these microbial shifts were associated with improved metabolic profiles. Overall, FMT mitigates RE by regulating gut microbiota and metabolites, with pantothenic acid and fatty acids emerging as potential therapeutic targets. Further research is needed to explore the underlying mechanisms in greater detail.PMID:39907559 | DOI:10.17305/bb.2025.11835

Pest Manag Sci. 2025 Feb 5. doi: 10.1002/ps.8701. Online ahead of print.ABSTRACTBACKGROUND: The ascomycete Magnaporthe oryzae is a destructive phytopathogenic fungus that causes rice blast disease and can greatly reduce rice yields. Due to the widespread use of synthesized chemical fungicides and the frequent occurrence of fungicide resistance and environmental pollution as a result, it has become increasingly urgent to develop environmentally friendly biocontrol alternatives, including plant crude extracts.RESULTS: In this study, the crude extracts of the tropical plant Millettia pachyloba were screened out and exhibited excellent preventive effects against M. oryzae at 200 μg mL-1. Bio-guided isolation of M. pachyloba was conducted and three isoflavonoids, rotenolone, durmillone, and durallone, whose chemical structures were determined using spectroscopic and spectrometric analyses, were obtained. The three isoflavonoids exhibited antifungal activities on conidial germination and appressorium formation in M. oryzae. Rotenolone had the strongest effect, with EC50 values of 57.81 μg mL-1 on conidial germination and 19.14 μg mL-1 on appressorium formation. Comparative metabolomics showed that differential metabolites were enriched in ABC transporter pathways and amino acid metabolic pathways when M. oryzae conidia were treated with rotenolone, suggesting that rotenolone interferes with amino acid transportation. Moreover, the M. pachyloba crude extract also effectively inhibited the infection of other fungal pathogens on tomato, apple, wheat, and maize.CONCLUSION: The results suggest that isoflavones extracted from M. pachyloba prevent rice blast by inhibiting the infection-related morphogenesis of M. oryzae and may interfere with amino acid transport, demonstrating that M. pachyloba crude extract exhibits potential as a bio-fungicide for controlling fungal diseases in plants. © 2025 Society of Chemical Industry.PMID:39906930 | DOI:10.1002/ps.8701

Evol Lett. 2024 Nov 11;9(1):150-162. doi: 10.1093/evlett/qrae062. eCollection 2025 Feb.ABSTRACTShared developmental, physiological, and molecular mechanisms can generate strong genetic covariances across suites of traits, constraining genetic variability, and evolvability to certain axes in multivariate trait space ("variational modules" or "syndromes"). Such trait suites will not only respond jointly to selection; they will also covary across populations that diverged from one another by genetic drift. We report evidence for such a genetically correlated trait suite that links traits related to energy metabolism along a "power-endurance" axis in Drosophila melanogaster. The "power" pole of the axis is characterized by high potential for energy generation and expenditure-high expression of glycolysis and TCA cycle genes, high abundance of mitochondria, and high spontaneous locomotor activity. The opposite "endurance" pole is characterized by high triglyceride (fat) reserves, locomotor endurance, and starvation resistance (and low values of traits associated with the "power" pole). This trait suite also aligns with the first principal component of metabolome; the "power" direction is characterized by low levels of trehalose (blood sugar) and high levels of some amino acids and their derivatives, including creatine, a compound known to facilitate energy production in muscles. Our evidence comes from six replicate "Selected" populations adapted to a nutrient-poor larval diet regime during 250 generations of experimental evolution and six "Control" populations evolved in parallel on a standard diet regime. We found that, within each of these experimental evolutionary regimes, the above traits strongly covaried along this "power-endurance" axis across replicate populations which diversified by drift, indicating a shared genetic architecture. The two evolutionary regimes also drove divergence along this axis, with Selected populations on average displaced towards the "power" direction compared to Controls. Aspects of this "power-endurance" axis resemble the "pace of life" syndrome and the "thrifty phenotype"; it may have evolved as part of a coordinated organismal response to nutritional conditions.PMID:39906580 | PMC:PMC11790217 | DOI:10.1093/evlett/qrae062

Front Pharmacol. 2025 Jan 21;15:1466504. doi: 10.3389/fphar.2024.1466504. eCollection 2024.ABSTRACTBACKGROUND AND PURPOSE: Nicotinic acetylcholine receptors (nAChRs), which are expressed throughout the mammalian brain, mediate a variety of physiological functions. Despite their widespread presence, the functions of nAChRs are not yet fully understood. α-Conotoxins, which are peptides derived from the venom of marine cone snails, target different subtypes of nAChRs. Specifically, α-Conotoxins [D1G, ΔQ14] LvIC, identified from Conus lividus, have demonstrated strong activity on α6β4* nAChRs in vitro. However, the effects of [D1G, ΔQ14] LvIC have not been investigated in vivo. This study aims to examine the activities of [D1G, ΔQ14] LvIC and explore its potential mechanisms in vivo.METHODS: The study involved the injection of [D1G, ΔQ14] LvIC into the lateral cerebral ventricle (LV) of mice. Following this procedure, behavioral tests were conducted to assess changes in the mice's behavior. To investigate the molecular alterations in the mice's brains, untargeted metabolomics and label-free Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) were employed. Subsequently, Western blot (WB) and quantitative reverse transcription PCR (RT-qPCR) techniques were utilized to detect specific molecular changes induced by [D1G, ΔQ14] LvIC.RESULTS: The injection of [D1G, ΔQ14] LvIC led to a decrease in locomotor activity in mice. This treatment also resulted in reduced expression of neuronal calcium sensor 1 (NCS-1) and neuroligin 3 (NLGN-3) in the prefrontal cortex (PFC), hippocampus (Hip), and caudate putamen (CPu). Both NCS-1 and NLGN-3 are crucial for neuronal development, synapse formation, and neuron activity, and their reduction is associated with decreased synapse strength. Despite these changes, results from the Morris water maze (MWM) indicated that [D1G, ΔQ14] LvIC did not impair the learning and memory abilities of the mice.CONCLUSION: Our findings indicate that α-conotoxin [D1G, ΔQ14] LvIC significantly decreased locomotor activity in mice. Additionally, it altered gene expression primarily in areas related to neuronal development, synapse formation, and neuron activity, while also reducing synapse strength. This study first proposed that [D1G, ΔQ14] LvIC could modulate mice's locomotor activity. However, further investigation is needed to understand the therapeutic effects of [D1G, ΔQ14] LvIC.PMID:39906393 | PMC:PMC11790622 | DOI:10.3389/fphar.2024.1466504

J Orthop Translat. 2025 Jan 22;51:37-50. doi: 10.1016/j.jot.2024.12.008. eCollection 2025 Mar.ABSTRACTBACKGROUND: Fresh osteochondral allografts (OCAs) contain numerous immunogenic components in the subchondral bone (SB). Whether high-speed centrifugation (HSC) reduces immune rejection by removing bone marrow elements (BMEs), compared to methods without HSC, remains unknown. This study aimed to validate the efficacy and safety of HSC in reducing immune rejection by removing allogeneic BMEs.METHODS: OCAs were obtained from the femoral condyles of the stifle joint in 18 pigs. Gross observations, histological staining, weight measurements, and DNA extraction were performed to assess the effects of centrifugation speed and duration on BMEs removal in OCAs. The effect of HSC on OCAs preservation was determined in vitro using microbiological testing, live/dead cell staining, and histological staining. Moreover, the co-culture effect of RAW264.7 cells and OCAs with or without HSC in vitro was evaluated using enzyme-linked immunosorbent assay (ELISA), histological staining, and immunohistochemical staining. The transplantation effect of OCAs with or without HSC was examined in vivo using a subcutaneous mouse model. Finally, the residues in the centrifuge tubes were analysed using ELISA, haematoxylin and eosin (HE) staining, and metabolomic analysis.RESULTS: Centrifugal speeds of 12000 rpm for 1 min were sufficient to reduce BMEs by over 90 %. HSC had a protective effect on chondrocytes and the extracellular matrix during the in vitro preservation of OCAs. In addition, OCAs using the HSC method exhibited reduced recognition by the host immune system compared with OCAs without HSC, thereby reducing immune rejection. Lipids were the most abundant and difficult-to-remove antigenic components and are the most likely to affect host macrophage polarisation, playing an important role in immune rejection.CONCLUSION: Our study demonstrated that HSC method significantly reduces immune rejection by removing BMEs from OCAs.THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our study demonstrated that HSC is a simple, efficient, and safe physical method for removing antigenic components from OCAs, effectively reducing immune rejection and highlighting its clinical potential.PMID:39906333 | PMC:PMC11791335 | DOI:10.1016/j.jot.2024.12.008

Front Vet Sci. 2025 Jan 21;12:1527284. doi: 10.3389/fvets.2025.1527284. eCollection 2025.ABSTRACTCottonseed meal is a promising alternative to soybean meal in poultry feed, but concerns over free gossypol limit its use. Although the general toxicity of free gossypol is well-known, its specific effects on the liver-the primary site where it accumulates-are less thoroughly studied, particularly at the molecular level. This study investigated the hepatotoxic effects of gossypol acetate (GA) on goslings through a comprehensive analysis combining morphology, transcriptomics, and metabolomics. Forty-eight 7-day-old male goslings with similar body weight (BW) were randomly assigned to two groups: a control group, receiving a saline solution (0.9%, 2.5 mL/kg BW), and a GA-treated group, administered GA at 50 mg/kg BW orally for 14 days. Histological analysis revealed signs of liver damage, including granular degeneration, hepatocyte enlargement, necrosis, and mitochondrial injury. Transcriptomic analysis identified 1,137 differentially expressed genes, with 702 upregulated and 435 downregulated. Key affected pathways included carbon metabolism, glycolysis/gluconeogenesis, pyruvate metabolism, propanoate metabolism, TCA cycle, fatty acid degradation, primary bile acid biosynthesis, tryptophan metabolism, cysteine and methionine metabolism, focal adhesion, and the PPAR signaling pathway. Metabolomic analysis revealed 109 differential metabolites, 82 upregulated and 27 downregulated, implicating disruptions in linoleic acid metabolism, arachidonic acid metabolism, cAMP signaling, and serotonergic synapse pathways. Overall, GA-induced hepatotoxicity involves impaired energy production, disrupted lipid metabolism, and abnormal liver focal adhesion, leading to liver cell dysfunction. These findings highlight the vulnerability of mitochondria and critical metabolic pathways, providing insights into the molecular mechanisms of GA toxicity and guiding future studies on mitigating GA-induced liver damage in goslings.PMID:39906302 | PMC:PMC11792171 | DOI:10.3389/fvets.2025.1527284

Front Plant Sci. 2025 Jan 21;15:1483538. doi: 10.3389/fpls.2024.1483538. eCollection 2024.ABSTRACTAstragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao (AMM) is an important medicinal plant that is used for both medicine and food. It is widely used in Asia and South Asia. It is normally cultivated by transplanting the annual rhizomes. Understanding the dormancy of underground buds of AMM is essential for its harvest and transplantation. Despite thorough research on bud dormancy in perennial woody plants, perennial herbs, and especially medicinal plants, such as AMM, have rarely been studied. We analyzed the transcriptome and non-targeted metabolome of dormant buds stage-by-stage to investigate the regulatory mechanism of the transition from endo- to ecodormancy. A total of 1,069 differentially accumulated metabolites (DAMs) participated in amino acid and carbohydrate metabolism. Transcriptome analysis revealed 16,832 differentially expressed genes (DEGs). Functional enrichment analysis indicated that carbohydrate metabolism, hormone signaling pathways, and amino acid metabolism contributed to the transition from endo- to ecodormancy. Starch and sucrose metabolism and hormone signaling pathways were mainly analyzed in the transition between different dormancy states. During the transition from endo- to ecodormancy, the highest content of indole-3-acetic acid (IAA) and the highest number of DEGs enriched in the IAA signaling pathway demonstrated that IAA may play a key role in this process. We obtained candidate genes through co-expression network analysis, such as BGL, GN, glgC, and glgB, which are involved in starch and sucrose metabolism. The transcription factors MYB, ERF, bHLH, zinc finger, and MADS-box may regulate the genes involved in hormone signal transduction and starch and sucrose metabolism, which are critical for regulating the transition from endo- to ecodormancy in AMM buds. In summary, these results provide insights into the novel regulatory mechanism of the transition of endo- to ecodormancy in underground buds of AMM and offer new analytical strategies for breaking dormancy in advance and shortening breeding time.PMID:39906223 | PMC:PMC11790638 | DOI:10.3389/fpls.2024.1483538

Anal Chem. 2025 Feb 5. doi: 10.1021/acs.analchem.4c05530. Online ahead of print.ABSTRACT1H NMR spectroscopy has enabled the quantitative profiling of metabolites in various biofluids, emerging as a possible diagnostic tool for metabolic disorders and other diseases. To boost the signal-to-noise ratio and detect proton resonances near the water signal, current 1H NMR experiments require solvent suppression schemes (e.g., presaturation, jump-and-return, WATERGATE, excitation sculpting, etc.). Unfortunately, these techniques affect the quantitative assessment of analytes containing exchangeable protons. To address this issue, we introduce two new one-dimensional (1D) 1H NMR techniques that eliminate the water signal, preserving the intensities of exchangeable protons. Using GENETICS-AI, a software that combines an evolutionary algorithm and artificial intelligence, we tailored new water irradiation devoid (WADE) pulses and optimized the 1D 1H NOESY sequence for metabolomic analysis. When applied to human urine samples, kidney tissue extract, and plasma, the WADE technique allowed for accurate measurement of typical metabolites and direct quantification of urea, which is usually challenging to measure using standard NMR experiments. We anticipate that these new NMR techniques will significantly improve the accuracy and reliability of metabolite quantitative assessment for a wide range of biological fluids.PMID:39905912 | DOI:10.1021/acs.analchem.4c05530

Small. 2025 Feb 5:e2410638. doi: 10.1002/smll.202410638. Online ahead of print.ABSTRACTThe development of matrices has shown great potential for fluid metabolic analysis in disease detection. However, single-fluid metabolomic analysis has been recognized as insufficient to fully capture the complexities of diseases such as liver disease, which limits detection accuracy. To this end, the hollow dodecahedral nanocages-based analytical tool is developed, featuring four-high characteristics of speed, throughput, efficiency, and patient compliance, to enhance extraction of multifluid metabolic profiles. The cross-referencing of these profiles among different liver diseases, including hepatocellular carcinoma (HCC), chronic liver disease (CLD), and healthy controls, enhances the diagnosis of liver diseases, particularly achieving near-perfect discrimination for HCC with an AUC value of 0.990, significantly outperforming any single fluid analysis. Additionally, the dynamic changes in expression levels of the key biomarkers throughout disease progression are explored, providing insights into their temporal evolution, and highlighting their role in monitoring disease status. This work highlights that multifluid metabolic analysis can comprehensively and sensitively reflect the disease status, enabling precise identification of complex diseases and facilitating personalized treatment.PMID:39905898 | DOI:10.1002/smll.202410638

Clin Mol Hepatol. 2025 Feb 5. doi: 10.3350/cmh.2024.0694. Online ahead of print.ABSTRACTBACKGROUND: Hepatitis B virus (HBV) hijacks host cell metabolism, especially host glutamine metabolism, to support its replication. Glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme crucial for glutamine metabolism, can interact with histone demethylases to regulate gene expression through histone methylation. However, the mechanisms underlying GDH1-mediated glutamine metabolism reprogramming and the roles of key metabolites during HBV infection remain unclear.METHODS: Transcriptomic and metabolomic analyses of HBV-infected cell were performed. Both HBV-infected cells and humanized liver chimeric mice were used to elucidate the effect of glutamine metabolism on HBV.RESULTS: HBV infection leads to the abnormal activation of glutamine metabolism, including upregulation of key enzymes and metabolites involved in glutamine metabolism. The viral core protein (HBc) mediates the translocation of GDH1 into the nucleus, where GDH1 activates covalently closed circular DNA (cccDNA) transcription by converting glutamate to α-ketoglutarate (αKG). Mechanistically, the promoting effect of GDH1-derived αKG on cccDNA transcription is independent of its conventional role. Rather, αKG directly interacts with the lysine-specific demethylase KDM4A and enhances KDM4A demethylase activity to regulate αKG-dependent histone demethylation, controlling cccDNA transcription.CONCLUSIONS: Our findings highlight the importance of glutamine metabolism in HBV transcription and suggest that glutamine deprivation is a potential strategy for silencing cccDNA transcription.PMID:39905842 | DOI:10.3350/cmh.2024.0694

J Cell Biochem. 2025 Feb;126(2):e70002. doi: 10.1002/jcb.70002.ABSTRACTGlioblastoma multiforme (GBM), a highly heterogeneous CNS tumor known for its highest incidence rates and poor prognosis has shown limited success in the therapies due to hypoxia-driving immune-suppression in the tumor microenvironment (TME). Emerging evidence highlights the involvement of tumor cell-derived exosomes in tumor-associated microglia polarization via transfer of exosomal onco-proteins and miRNAs. Although the regulatory role of long noncoding RNAs (lncRNAs) in immune signaling are known, its mechanism in microglial polarization via exosomes in GBM still remains poorly understood. In our study, we found that in comparison to the normoxic GBM-derived exosomes lncRNA H19 was significantly upregulated in hypoxic GBM-derived exosomes. Hypoxic GBM-derived exosomes and secretome (conditioned media) caused the reduction in the % phagocytosis of microglia as compared with the control group. Moreover, GBM secretome caused increase in the M2-specific genes (IL10, STAT-3, CD163, CD206) in microglia indicating its polarization to the protumorigenic (M2) phenotype. LncRNA H19 knocked down GBM-secretome treatment in microglia further reduced the STAT-3 expression indicating H19 mediated signaling. Overall, our results suggest the involvement of hypoxic exosomes and lncRNA H19 in microglial polarization and H19 as a potential target.PMID:39905831 | DOI:10.1002/jcb.70002

Mol Cancer. 2025 Feb 4;24(1):43. doi: 10.1186/s12943-025-02242-9.ABSTRACTThe diagnosis and treatment of non-small cell lung cancer in clinical settings face serious challenges, particularly due to the lack of integration between the two processes, which limit real-time adjustments in treatment plans based on the patient's condition and drive-up treatment costs. Here, we present a multifunctional pH-sensitive core-shell nanoparticle containing quercetin (QCT), termed AHA@MnP/QCT NPs, designed for the simultaneous diagnosis and treatment of non-small cell lung cancer. Mechanistic studies indicated that QCT and Mn2+ exhibited excellent peroxidase-like (POD-like) activity, catalysing the conversion of endogenous hydrogen peroxide into highly toxic hydroxyl radicals through a Fenton-like reaction, depleting glutathione (GSH), promoting reactive oxygen species (ROS) generation in mitochondria and endoplasmic reticulum, and inducing ferroptosis. Additionally, Mn2+ could activate the cGAS-STING signalling pathway and promote the maturation of dendritic cells and infiltration of activated T cells, thus inducing tumor immunogenic cell death (ICD). Furthermore, it exhibited effective T2-weighted MRI enhancement for tumor imaging, making them valuable for clinical diagnosis. In vitro and in vivo experiments demonstrated that AHA@MnP/QCT NPs enabled non-invasive imaging and tumor treatment, which presented a one-stone-for-two-birds strategy for combining tumor diagnosis and treatment, with broad potential for clinical application in non-small cell lung cancer therapy.PMID:39905491 | DOI:10.1186/s12943-025-02242-9

Microbiome. 2025 Feb 4;13(1):36. doi: 10.1186/s40168-024-02011-8.ABSTRACTBACKGROUND: Disorder in bile acid (BA) metabolism is known to be an important factor contributing to diarrhea. However, the pathogenesis of BA disorder-induced diarrhea remains unclear.METHODS: The colonic BA pool and microbiota between health piglets and BA disorder-induced diarrheal piglets were compared. Fecal microbiota transplantation and various cell experiments further indicated that chenodeoxycholic acid (CDCA) metabolic disorder produced CDCA-3β-glucuronide, which is the main cause of BA disorder diarrhea. Non-targeted metabolomics uncovered the inhibition of the BA glucuronidation by Lactobacillus reuteri (L. reuteri) is through deriving indole-3-carbinol (I3C). In vitro, important gene involved in the reduction of BA disorder induced-diarrhea were screened by RNA transcriptomics sequencing, and activation pathway of FXR-SIRT1-LKB1 to alleviate BA disorder diarrhea and P53-mediated apoptosis were proposed in vitro by multifarious siRNA interference, CO-IP, immunofluorescence, and so on, which mechanism was also verified in a variety of mouse models.RESULTS: Here, we reveal for the first time that core microbiota derived I3C represses gut epithelium glucuronidation, particularly 3β-glucuronic CDCA production, which reaction is mediated by host UDP glucuronosyltransferase family 1 member A4 (UGT1A4) and necessary of BA disorder induced diarrhea. Mechanistically, L. reuteri derived I3C activates aryl hydrocarbon receptor to decrease UGT1A4 transcription and CDCA-3β-glucuronide content, thereby upregulating FXR-SIRT1-LKB1 signal. LKB1 binds with P53 based on protein interaction, ultimately resists to apoptosis and diarrhea. Moreover, I3C assists CDCA to attain the ameliorative effects of FXR activation in BA disorder diarrhea, through reversion of abnormal metabolism pathway, improving the outcomes of CDCA supplement.CONCLUSION: These findings uncover the crucial interplay between gut epithelial cells and microbes, highlighting UGT1A4-mediated conversion of CDCA-3β-glucuronide as a key target for ameliorating BA disorder-induced diarrhea. Video Abstract.PMID:39905483 | DOI:10.1186/s40168-024-02011-8

Microb Cell Fact. 2025 Feb 4;24(1):36. doi: 10.1186/s12934-025-02657-5.ABSTRACTAcetic acid, a by-product of cytidine synthesis, competes for carbon flux from central metabolism, which may be directed either to the tricarboxylic acid (TCA) cycle for cytidine synthesis or to overflow metabolites, such as acetic acid. In Escherichia coli, the acetic acid synthesis pathway, regulated by the poxB and pta genes, facilitates carbon consumption during cytidine production. To mitigate carbon source loss, the CRISPR-Cas9 gene-editing technique was employed to knock out the poxB and pta genes in E. coli, generating the engineered strains K12ΔpoxB and K12ΔpoxBΔpta. After 39 h of fermentation in 500 mL shake flasks, the cytidine yields of strains K12ΔpoxB and K12ΔpoxBΔpta were 1.91 ± 0.04 g/L and 18.28 ± 0.22 g/L, respectively. Disruption of the poxB and pta genes resulted in reduced acetic acid production and glucose consumption. Transcriptomic and metabolomic analyses revealed that impairing the acetic acid metabolic pathway in E. coli effectively redirected carbon flux toward cytidine biosynthesis, yielding a 5.26-fold reduction in acetate metabolism and an 11.56-fold increase in cytidine production. These findings provide novel insights into the influence of the acetate metabolic pathway on cytidine biosynthesis in E. coli.PMID:39905471 | DOI:10.1186/s12934-025-02657-5

J Transl Med. 2025 Feb 4;23(1):149. doi: 10.1186/s12967-025-06146-6.ABSTRACTBACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown aetiology characterised by symptoms of post-exertional malaise (PEM) and fatigue leading to substantial impairment in functioning. Other key symptoms include cognitive impairment and unrefreshing sleep, with many experiencing pain. To date there is no complete understanding of the triggering pathomechanisms of disease, and no quantitative biomarker available with sufficient sensitivity, specificity, and adoptability to provide conclusive diagnosis. Clinicians thus eliminate differential diagnoses, and rely on subjective, unspecific, and disputed clinical diagnostic criteria-a process that often takes years with patients being misdiagnosed and receiving inappropriate and sometimes detrimental care. Without a quantitative biomarker, trivialisation, scepticism, marginalisation, and misunderstanding of ME/CFS continues despite the significant disability for many. One in four individuals are bed-bound for long periods of time, others have difficulties maintaining a job/attending school, incurring individual income losses of thousands, while few participate in social activities.MAIN BODY: Recent studies have reported promising quantifiable differences in the biochemical and electrophysiological properties of blood cells, which separate ME/CFS and non-ME/CFS participants with high sensitivities and specificities-demonstrating potential development of an accessible and relatively non-invasive diagnostic biomarker. This includes profiling immune cells using Raman spectroscopy, measuring the electrical impedance of blood samples during hyperosmotic challenge using a nano-electronic assay, use of metabolomic assays, and certain techniques which assess mitochondrial dysfunction. However, for clinical application, the specificity of these biomarkers to ME/CFS needs to be explored in more disease controls, and their practicality/logistics considered. Differences in cytokine profiles in ME/CFS are also well documented, but finding a consistent, stable, and replicable cytokine profile may not be possible. Increasing evidence demonstrates acetylcholine receptor and transient receptor potential ion channel dysfunction in ME/CFS, though how these findings could translate to a diagnostic biomarker are yet to be explored.CONCLUSION: Different biochemical and electrophysiological properties which differentiate ME/CFS have been identified across studies, holding promise as potential blood-based quantitative diagnostic biomarkers for ME/CFS. However, further research is required to determine their specificity to ME/CFS and adoptability for clinical use.PMID:39905423 | DOI:10.1186/s12967-025-06146-6

BMC Pulm Med. 2025 Feb 4;25(1):60. doi: 10.1186/s12890-025-03519-x.ABSTRACTBACKGROUND: Aspiration pneumonia (AP) is a type of lung inflammation caused by the aspiration of food, oropharyngeal secretions, or gastric contents. This condition is particularly common in older adults and individuals with impaired swallowing or consciousness. While the diagnosis of AP relies on clinical history, swallowing assessments, and imaging, these methods have significant limitations, often leading to underdiagnosis or misdiagnosis. Reliable biomarkers for AP diagnosis are lacking, making early detection and treatment challenging.METHODS: Nineteen patients diagnosed with pneumonia were included in this study, divided into two groups: AP (n = 10) and non-AP (n = 9). Biological fluid samples, including bronchoalveolar lavage fluid (BALF), saliva, serum, sputum, and urine, were analyzed using non-targeted liquid chromatography with tandem mass spectrometry (LC-MS/MS). Differential metabolites were identified using fold change analysis, statistical significance, and receiver operating characteristic (ROC) curve analysis to evaluate their diagnostic potential. Spearman correlation was used to examine the relationship between selected metabolites and clinical parameters.RESULTS: Significant metabolic differences were found between AP and non-AP patients, with many different metabolites identified across biological fluids. Dehydroepiandrosterone sulfate (DHEAS), Androstenediol-3-sulfate (ADIOLS), and beta-muricholic acid were identified as key biomarkers through fold change analysis and ROC curve analysis, showing consistent increasing or decreasing trends in BALF, sputum, and serum samples. DHEAS was found to be negatively correlated with the Acute Physiology and Chronic Health Evaluation II (APACHE II) (r = - 0.619, p = 0.005) in BALF sample. The area under curve (AUC) values showed that these molecules could serve as effective biomarkers for AP.CONCLUSIONS: This study identifies DHEAS, ADIOLS and beta-muricholic acid as promising biomarkers for AP, with the potential to improve early diagnosis and treatment. These findings underscore the clinical value of metabolomics in developing diagnostic tools for AP, facilitating better clinical management and patient outcomes. Further research is required to validate these biomarkers in larger cohorts and explore their mechanistic roles in AP pathophysiology.PMID:39905415 | DOI:10.1186/s12890-025-03519-x

Breast Cancer Res. 2025 Feb 4;27(1):18. doi: 10.1186/s13058-025-01970-6.ABSTRACTBACKGROUND: Mammographic breast density (MBD), a strong predictor of breast cancer, is highly influenced by body mass index (BMI) in childhood and early adulthood, but the mechanisms underlying these associations are not fully understood. Our goal is to identify biomarkers that mediate the associations of BMI at ages 10 and 18 with MBD in premenopausal women.METHODS: This study consists of 705 premenopausal women who had their screening mammogram at Washington University in St. Louis, MO, and provided a fasting blood sample. Our comprehensive metabolomic and lipidomic profiling yielded complete data for 828 metabolites and 857 lipid species after imputation. We used Volpara to determine volumetric measures of MBD. We performed high dimensional mediation analysis using the HIMA R package, adjusted for confounders, to determine whether lipid species and metabolites mediate the associations of BMI at 10 and 18 with MBD. We applied a false discovery rate (FDR) p-value < 0.1.RESULTS: Four metabolites (glutamate, β-cryptoxanthin, cortolone glucuronide (1), phytanate) significantly mediated the association of BMI at 10 with volumetric percent density (VPD), and two (glutamate, β-cryptoxanthin) mediated the association of BMI at 18 with VPD. Glutamate was the strongest mediator across time points. Glutamate mediated 6.7% (FDR p-value = 0.06) and 9.3% (FDR p-value = 0.008) of the association between BMI at age 10 and 18, respectively. Four lipid species (CER(18:0), LCER(14:0), LPC(18:1), PC(18:1/18:1)), mediated the association of BMI at 10 with VPD, while five lipid species (CER(18:0), LCER(14:0), PC(18:1/18:1), TAG56:5-FA22:5, TAG52:2-FA16:0) mediated the association of BMI at 18 with VPD. The strongest mediator was PC(18:1/18:1), which mediated 9.7%, (FDR-p = 0.009) and 7.7%, (FDR-p = 0.04) of the association of BMI at age 10 and 18 with VPD, respectively.CONCLUSIONS: Metabolites in amino acid, lipid, cofactor/vitamin, and xenobiotic super-pathways as well as lipid species across the phospholipid, neutral complex lipid and sphingolipid super-pathways mediated the associations of BMI in early-life and MBD in premenopausal women. This study offers insight into the biological mechanisms underlying the link between early-life adiposity and MBD, which can support future research into breast cancer prevention.PMID:39905412 | DOI:10.1186/s13058-025-01970-6