PubMed

J Hazard Mater. 2025 Jan 21;488:137310. doi: 10.1016/j.jhazmat.2025.137310. Online ahead of print.ABSTRACTCigarette smoke (CS), an indoor environmental pollution, is an environmental risk factor for diverse neurological disorders. However, the neurotoxicological effects and mechanisms of CS on Alzheimer's disease (AD) progression remain unclear. We found that CS accelerated the progression of AD, including increasing β-amyloid (Aβ) plaque deposition and exacerbating cognitive decline. Mechanistically, CS exposure increased the levels of NOD-like receptor protein 3 (NLRP3), which impaired autophagic flux in microglia by activating the mammalian target of rapamycin (mTOR) signal. Metabolomics analysis revealed an upregulation of lactate levels and an increase in global protein lysine lactylation in the brain tissue of CS-exposed AD-transgenic mice. Immunoprecipitation-Mass Spectrometry and chromatin immunoprecipitation assays demonstrated that CS elevates H4K12 lactylation (H4K12la) levels, which accumulate at the promoter region of NLRP3, leading to the activation of its transcription. Via inhibiting lactate or NLRP3 activation, oxamate and MCC950 alleviates these CS-induced effects. Therefore, our data suggest that the CS-induced increase in lactate levels triggers NLRP3 transcriptional activation through H4K12la, which subsequently leads to mTOR-mediated autophagy dysfunction in microglia, promoting microglial activation and resulting in Aβ plaque accumulation in AD-transgenic mice. This provides a new mechanism and potential therapeutic target for AD associated with environmental factors.PMID:39862777 | DOI:10.1016/j.jhazmat.2025.137310

Ecotoxicol Environ Saf. 2025 Jan 24;290:117758. doi: 10.1016/j.ecoenv.2025.117758. Online ahead of print.ABSTRACTGlyphosate, a widely used herbicide globally, has prompted concerns regarding its potential health impacts. This study aimed to explore the link between glyphosate exposure and renal function by combining NHANES, a zebrafish model, and metabolomics. A cross-sectional analysis of 2013-2014 NHANES data investigated the relationship between glyphosate exposure and renal function [albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR)]. A subsequent zebrafish experiment was conducted to verify this association. Embryos (0.75 hpf-96 hpf) were exposed to different glyphosate concentrations dissolved in water (0, 30, 60, 90, 120 μg/mL). The underlying mechanism of the association between glyphosate and renal function was explored by the real-time quantitative polymerase chain reaction (RT-qPCR) and non-targeted metabolomics analysis [embryos (0.75 hpf-96 hpf) were exposed to 90 μg/mL glyphosate]. 1170 participants were enrolled in the NHANES study. The NHANES-based study found a positive association between glyphosate and ACR [0.07 (0.01, 0.13)]. Higher urinary glyphosate levels, particularly in the third quartile group, were negatively linked to eGFR [-3.72 (-5.98, -1.46)]. Further zebrafish experiments indicated that zebrafish exposed to 90 μg/mL glyphosate exhibited increased mortality rates, higher fluorescence intensity, up-regulated the havcr1 expression level, and cystic dilatation of the kidney. Non-targeted metabolomics analysis identified differential metabolites (e.g., 5-Hydroxyindole acetic acid) and pathways (e.g., ABC transporters) influenced by glyphosate. Glyphosate exposure is negatively associated with renal function in community adults. The damage to the kidneys caused by glyphosate may be mediated through the regulation of metabolic pathways, and the specific mechanisms require further experimental investigation.PMID:39862699 | DOI:10.1016/j.ecoenv.2025.117758

Ecotoxicol Environ Saf. 2025 Jan 24;290:117763. doi: 10.1016/j.ecoenv.2025.117763. Online ahead of print.ABSTRACTOxytetracycline (OTC), a crop-absorbable antibiotic, poses a health risk to humans through the food chain. Conversely, 24-epibrassinolide (EBL), a plant growth hormone, mitigates the toxic effects of various pollutants on plants. However, the mechanism by which exogenous EBL affects the growth of rape seedlings exposed to OTC remains largely unknown. In this study, we found that environmental OTC concentrations significantly inhibited plant growth and metabolism, whereas exogenous EBL could restore plant growth characteristics. Exogenous EBL significantly decreased reactive oxygen species (ROS) accumulation, alleviating OTC-induced cell membrane lipid peroxidation. This was achieved by increasing the antioxidant capacity and secondary metabolism levels. Notably, our findings suggested that EBL stimulated glutathione S-transferase (GST) and glutathione reductase (GR) activities, enhancing reduced glutathione synthesis and participating in plant OTC detoxification. OTC residues in EBL + OTC-treated seedlings at 21 d were significantly reduced by 29 % compared with OTC alone. Further transcriptomic and metabolomic analyses revealed that the differentially expressed genes and metabolites in the EBL and OTC alone or combined treatment groups were primarily involved in the regulation of phenylpropanoid biosynthesis, glutathione metabolism, and lant hormone signal transduction pathways in response to phytotoxic effects and detoxification mechanisms, as compared to the control group.PMID:39862695 | DOI:10.1016/j.ecoenv.2025.117763

Parasit Vectors. 2025 Jan 25;18(1):27. doi: 10.1186/s13071-024-06654-2.ABSTRACTBACKGROUND: Nippostrongylus brasiliensis-a nematode of rodents-is commonly used as a model to study the immunobiology of parasitic nematodes. It is a member of the Strongylida-a large order of socioeconomically important parasitic nematodes of animals. Lipids are known to play essential roles in nematode biology, influencing cellular membranes, energy storage and/or signalling.METHODS: The present investigation provides a comprehensive, untargeted lipidomic analysis of four developmental stages/sexes (i.e. egg, L3, adult female and adult male stages) of N. brasiliensis utilising liquid chromatography coupled to mass spectrometry.RESULTS: We identified 464 lipid species representing 18 lipid classes and revealed distinct stage-specific changes in lipid composition throughout nematode development. Triacylglycerols (TGs) dominated the lipid profile in the egg stage, suggesting a key role for them in energy storage at this early developmental stage. As N. brasiliensis develops, there was a conspicuous transition toward membrane-associated lipids, including glycerophospholipids (e.g. PE and PC) and ether-linked lipids, particularly in adult stages, indicating a shift toward host adaptation and membrane stabilisation.CONCLUSIONS: We provide a comprehensive insight into the lipid composition and abundance of key free-living and parasitic stages of N. brasiliensis. This study provides lipidomic resources to underpin the detailed exploration of lipid biology in this model parasitic nematode.PMID:39863914 | DOI:10.1186/s13071-024-06654-2

Metabolomics. 2025 Jan 25;21(1):22. doi: 10.1007/s11306-024-02203-1.NO ABSTRACTPMID:39863829 | DOI:10.1007/s11306-024-02203-1

Lupus Sci Med. 2025 Jan 25;12(1):e001401. doi: 10.1136/lupus-2024-001401.ABSTRACTOBJECTIVE: Metabolic reprogramming plays a critical role in modulating the innate and adaptive immune response, but its role in cutaneous autoimmune diseases, such as cutaneous lupus erythematosus (CLE), is less well studied. An improved understanding of the metabolic pathways dysregulated in CLE may lead to novel treatment options, biomarkers and insights into disease pathogenesis. The objective was to compare metabolomic profiles in the skin and sera of CLE and control patients using liquid chromatography-mass spectrometry (LC-MS).METHODS: This was a cross-sectional pilot study comparing metabolomic sera and skin profiles of patients with CLE and normal controls. Patients were recruited from outpatient dermatology clinics at the University of Texas Southwestern and Parkland Health in Dallas, Texas, from January 2019 to October 2020. Skin and serum samples underwent LC-MS analysis. Disease sample metabolite levels were compared with controls, with significance levels adjusted for multiple hypothesis testing.RESULTS: 17 serum samples (9 CLE, 8 control) and 11 skin samples (5 CLE, 6 control) were analysed using LC-MS, yielding 313 known unique metabolic structures from CLE samples. Patients with CLE were found to have 11 metabolites of differential abundance in the skin, but only 2 in the sera. CLE skin showed increased levels of citrulline (log2 fold change (FC)=1.15, p=0.02) and uracil (log2FC=1.79, p=0.04), and downregulation of cyclic ADP ribose (cADPr) (log2FC=0.83, p=0.04), nicotinamide mononucleotide (NMN) (log2FC=0.75, p=0.016) and nicotinamide adenine dinucleotide (NAD+) (log2FC=0.86, p=0.016) versus control skin. CLE sera had increased arabinose (log2FC=1.17, p=0.02) and cystine (log2FC=1.04, p=0.03) compared with control sera.CONCLUSIONS: Metabolites associated with the NAD+ pathway may be dysregulated in the skin of patients with CLE. Available treatments including nicotinamide supplementation and anti-CD38 biologics that can correct these abnormalities can be further investigated in patients with CLE.PMID:39863305 | DOI:10.1136/lupus-2024-001401

Int J Biol Macromol. 2025 Jan 23:140242. doi: 10.1016/j.ijbiomac.2025.140242. Online ahead of print.ABSTRACTIn this study, we successfully integrated the full-length genome of the cyanophage PP into the non-host cyanobacterium Synechococcus elongatus PCC 7942, facilitated by conjugation via Escherichia coli. To address the challenge posed by the toxic open reading frames (ORFs) of PP in E. coli, we first identified and characterized three toxic ORFs. The PP genome was subsequently rearranged, and the expression of these toxic ORFs was controlled using a tandem-induction switch system. The full-length PP genome was then successfully integrated into the genome of S. elongatus PCC 7942. Interestingly, the integration of the PP genome led to a reduction in photosynthesis and carbon fixation in S. elongatus PCC 7942, resembling the effects typically associated with cyanophage infection. Transcriptomic analysis showed that 32 of the 41 ORFs in the PP genome were actively transcribed in S. elongatus PCC 7942, significantly affecting energy metabolism and carbon fixation pathways. These effects were further confirmed by metabolomic analysis.PMID:39863235 | DOI:10.1016/j.ijbiomac.2025.140242

Int J Biol Macromol. 2025 Jan 23:140288. doi: 10.1016/j.ijbiomac.2025.140288. Online ahead of print.ABSTRACTUnderstanding the global transcriptomic and metabolic changes during mulberry growth and development is essential for the enhancing fruit quality and optimizing breeding strategies. By integrating phenotypic, metabolomic, and transcriptomic data across 18 developmental and ripening stages of Da10 mulberry fruit, a global map of gene expression and metabolic changes was generated. Analysis revealed a gradual progression of morphological, metabolic, and transcriptional changes throughout the development and ripening phases. In this study, a new transcriptome transition, which was highly related to stress resistance, was observed after the full ripening stage. Moreover, a novel method was devised by integrating metabolome and phenotypic data to assess fruit quality and determine optimal harvest times early in the supply chain. Phase-specific co-expression networks involved in photosynthesis, quality regulation, and plant immunity were also constructed. Notably, eight flavonoids and six hub genes emerged as potential natural edible coatings or gene-editing targets for mulberry fruit to enhance resistance against biotic and abiotic stress. These findings should facilitate further research on stress resistance, post-harvest management, and sustainable agricultural development.PMID:39863218 | DOI:10.1016/j.ijbiomac.2025.140288

Phytomedicine. 2025 Jan 16;138:156397. doi: 10.1016/j.phymed.2025.156397. Online ahead of print.ABSTRACTBACKGROUND: Huangkui capsule (HKC), a Chinese patent medicine, is clinically used for treating diabetic nephropathy. However, the core disease-specific biomarkers and targets of type 2 diabetic nephropathy (T2DN) and the therapeutic mechanism of HKC are not fully elucidated.PURPOSE: This study aimed to investigate the therapeutic effects and underlying molecular mechanisms of HKC for T2DN.STUDY DESIGN: The db/db mouse model was used to evaluate the efficacy of HKC for T2DN, and the core pathways regulated by HKC were studied to determine its kidney protective mechanism.METHODS: High-throughput UPLC-MS/MS and multivariate analysis were employed to analyze the serum and kidney metabolic profiles of db/db mice, identifying potential core biomarkers of T2DN. Atmospheric pressure matrix-assisted laser desorption/ionization mass spectrometry imaging was used to locate in situ spatial distribution of core biomarkers and drug active ingredients in kidney tissues. Biochemical indicators, histopathology, immunohistochemistry, immunofluorescence, molecular docking, and western blotting were combined to reveal therapeutic effects, pathways, and targets of HKC.RESULTS: HKC substantially improved pathological characteristics, kidney function, oxidative stress, inflammation, and lipid metabolism indicators of T2DN. Twelve core disease-specific biomarker that significantly influenced clustering were identified and its unique spatial distribution information in the kidneys was revealed. 3-dehydrosphinganine, retinyl ester, and 9-cis-retinoic acid (9cRA) could serve as novel disease-specific biomarkers for T2DN. Based on newly discovered biomarkers, quercetin, myricetin, and isorhamnetin were found to act on key enzymes SPT, ALDH1A1, AOX, LRAT, and DGAT1 in retinol and sphingolipid metabolism pathways. Western blotting showed that HKC ameliorated T2DN by targeting these enzymes, upregulating 9cRA and retinyl ester, downregulating 3-dehydrosphinganine, increasing TGF-β signal transduction, inhibiting the expression of the immune fibrosis proteins OX-8, Col-I and α-SMA, inhibiting Th17 cell development and ceramide synthesis, reducing IL-1β, TNF-α, MDA, TC, LDL-C, and TG levels, and increaseing SOD activity.CONCLUSIONS: HKC exerts significant therapeutic effects on T2DN. HKC corrects the metabolic disorder of sphingolipids and retinol, and improves T2DN by regulating the activities of SPT, ALDH1A1, AOX, LRAT, and DGAT1. This study provides valuable ideas and new mechanistic insights for the treatment of T2DN with HKC.PMID:39862790 | DOI:10.1016/j.phymed.2025.156397

Talanta. 2025 Jan 20;287:127603. doi: 10.1016/j.talanta.2025.127603. Online ahead of print.ABSTRACTThere is no consensus in the literature regarding the ideal protocol for obtaining and preparing cell samples for untargeted metabolomics. Nevertheless, the procedures must be carefully evaluated for proper and reliable results for each organism under study. This work proposes a novel protocol for determining intracellular metabolites in Leishmania promastigotes and is fully optimized for application in conjunction with gas chromatography-mass spectrometry platforms. Sample harvesting consisted of stopping metabolic activity by placing the parasite cells in a dry ice bath and removing extracellular interferants with two wash steps using cold PBS. The extraction is carried out with 1.0x108 promastigotes per sample using a mixture of cold 1:1 methanol:water and ultrasound mixing (1 min at 30 % power). Dried extracts were derivatized by oximation (at room temperature for 90 min), followed by silylation (at 40 °C for 30 min). The method developed here can cover a wide range of the Leishmania parasite metabolome, including amino acids and derivatives, organic and fatty acids, carbohydrates and derivatives, and steroids.PMID:39862521 | DOI:10.1016/j.talanta.2025.127603

Sci Total Environ. 2025 Jan 24;964:178604. doi: 10.1016/j.scitotenv.2025.178604. Online ahead of print.ABSTRACTPolyethylene nanoplastics (NPs) are widely diffused in terrestrial environments, including soil ecosystems, but the stress mechanisms in plants are not well understood. This study aimed to investigate the effects of two increasing concentrations of NPs (20 and 200 mg kg-1 of soil) in lettuce. To this aim, high-throughput hyperspectral imaging was combined with metabolomics, covering both primary (using NMR) and secondary metabolism (using LC-HRMS), along with lipidomics profiling (using ion-mobility-LC-HRMS) and plant performance. Hyperspectral imaging highlighted a reduced plant growth pattern. Several vegetative indexes indicated plant toxicity, with 20 mg kg-1 NPs significantly decreasing lettuce density and vegetation health (as indicated by NDVI and plant senescence reflectance indexes). Consistently, photosynthetic activity also decreased. At the biochemical level, metabolomics and lipidomics pointed out a multi-layered broad biochemical reprogramming of primary and secondary metabolism involving a decrease in sterols, sphingolipids, glycolipids, and glycerophospholipids in response to NPs. The reduction in phosphatidylinositol coincided with an accumulation of diacylglycerols (DAG), suggesting the activation of the phospholipase C lipid signaling pathway. Moreover, nanoplastic treatments down-modulated different biosynthetic pathways, particularly those involved in N-containing compounds and phenylpropanoids. Our mechanistic basis of NPs stress in plants will contribute to a better understanding of their environmental impact.PMID:39862496 | DOI:10.1016/j.scitotenv.2025.178604

J Cereb Blood Flow Metab. 2025 Jan 25:271678X251314331. doi: 10.1177/0271678X251314331. Online ahead of print.ABSTRACTCurrent metabolomics technologies can measure hundreds of chemical entities in tissue extracts with good reliability. However, long-recognized requirements to halt enzyme activities during the initial moments of sample preparation are usually overlooked, allowing marked postmortem shifts in levels of labile metabolites representing diverse pathways. In brain many such changes occur in a matter of seconds. These comments overview the concern, contrast representative studies, and specify approaches to consider as standards in the field going forward. Comparison with established metabolite signatures of in vivo brain is an essential validation step when implementing any collection method.PMID:39862175 | DOI:10.1177/0271678X251314331

STAR Protoc. 2025 Jan 24;6(1):103589. doi: 10.1016/j.xpro.2024.103589. Online ahead of print.ABSTRACTThe intestine features a two-front nutrient supply environment, comprising an enteral side enriched with microbial and dietary metabolites and a serosal side supplied by systemic nutrients, collectively supporting intestinal and systemic homeostasis, but there is currently no optimal approach for extracting and assessing the local intestinal microenvironment. Here, we present a protocol for constructing a nutrient supply model in mice and extracting gut interstitial fluid (GIF) via centrifugation. This model and the extracted GIF are suitable for downstream analyses. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.PMID:39862429 | DOI:10.1016/j.xpro.2024.103589

J Agric Food Chem. 2025 Jan 25. doi: 10.1021/acs.jafc.4c07330. Online ahead of print.ABSTRACT2-Amino-3-methylimidazole [4,5-f] quinoline (IQ) is a kind of heterocyclic amine (HCAs) with high carcinogenicity in hot processed meat. Rutin (Ru) is a flavonoid compound with anti-inflammatory and antioxidant properties. However, whether Ru is scatheless under IQ-stimulated potential unhealthy conditions, especially liver function, in vivo, is unknown. In this study, we explored the effects and underlying mechanism of Ru on liver injury induced by a low dose of IQ in mice. Results showed that Ru supplement led to liver injury upon low-dose IQ alone administration, as shown by histological analysis, inflammatory, and serum biochemical indexes. Additionally, nontargeted metabolomics analysis revealed that coexposure of Ru and IQ disrupted liver metabolic balance, leading to significant changes in metabolites and metabolic pathways, hinting at a possible relationship with intestinal microbiota. Furthermore, the 16S rRNA sequencing data indicated that a combination of Ru and IQ caused gut microbiota dysbiosis and decreased the level of short-chain fatty acids (SCFAs). Correlation analysis between gut microbiota, SCFAs, liver metabolites, and liver damage markers highlighted the crucial role of the gut-liver axis in IQ and Ru coexposure-induced liver injury in vivo. In general, this study offers a valuable perspective on flavones and HCA compounds in the realms of food safety and human health.PMID:39862407 | DOI:10.1021/acs.jafc.4c07330

Bioinformatics. 2025 Jan 25:btaf045. doi: 10.1093/bioinformatics/btaf045. Online ahead of print.ABSTRACTMetabolomics extensively utilizes Nuclear Magnetic Resonance (NMR) spectroscopy due to its excellent reproducibility and high throughput. Both one-dimensional (1D) and two-dimensional (2D) NMR spectra provide crucial information for metabolite annotation and quantification, yet present complex overlapping patterns which may require sophisticated machine learning algorithms to decipher. Unfortunately, the limited availability of labeled spectra can hamper application of machine learning, especially deep learning algorithms which require large amounts of labelled data. In this context, simulation of spectral data becomes a tractable solution for algorithm development.Here, we introduce MetAssimulo 2.0, a comprehensive upgrade of the MetAssimulo 1.0 metabolomic 1H NMR simulation tool, reimplemented as a Python-based web application. Where MetAssimulo 1.0 only simulated 1D 1H spectra of human urine, MetAssimulo 2.0 expands functionality to urine, blood, and cerebral spinal fluid (CSF), enhancing the realism of blood spectra by incorporating a broad protein background. This enhancement enables a closer approximation to real blood spectra, achieving a Pearson correlation of approximately 0.82. Moreover, this tool now includes simulation capabilities for 2D J-resolved (J-Res) and Correlation Spectroscopy (COSY) spectra, significantly broadening its utility in complex mixture analysis. MetAssimulo 2.0 simulates both single, and groups, of spectra with both discrete (case-control, e.g. heart transplant vs healthy) and continuous (e.g. BMI) outcomes and includes inter-metabolite correlations. It thus supports a range of experimental designs and demonstrating associations between metabolite profiles and biomedical responses.By enhancing NMR spectral simulations, MetAssimulo 2.0 is well positioned to support and enhance research at the intersection of deep learning and metabolomics.AVAILABILITY AND IMPLEMENTATION: The code and the detailed instruction/tutorial for MetAssimulo 2.0 is available at https://github.com/yanyan5420/MetAssimulo_2.git The relevant NMR spectra for metabolites are deposited in MetaboLights with accession number MTBLS12081.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.PMID:39862393 | DOI:10.1093/bioinformatics/btaf045

Br J Hosp Med (Lond). 2025 Jan 24;86(1):1-19. doi: 10.12968/hmed.2024.0568. Epub 2025 Jan 14.ABSTRACTAims/Background Hypertension (HT) is a prevalent medical condition showing an increasing incidence rate in various populations over recent years. Long-term hypertension increases the risk of the occurrence of hypertensive nephropathy (HTN), which is also a health-threatening disorder. Given that very little is known about the pathogenesis of HTN, this study was designed to identify disease biomarkers, which enable early diagnosis of the disease, through the utilization of high-throughput untargeted metabolomics strategies. Methods The participants of this study were patients admitted to The Second Affiliated Hospital of Chengdu Medical College, Nuclear Industry 416 Hospital, who were randomly divided into three groups: Normal group (n = 11), HT group (n = 10), and HTN group (n = 12). Urine exosomes were extracted, purified, and subjected to untargeted metabolomics analysis. Differential metabolites and their significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified. The least absolute shrinkage and selection operator (LASSO) regression analysis was then employed to establish a diagnostic model for early-stage HTN. Finally, logistic regression and receiver operating characteristic (ROC) curve analysis were performed to identify biomarkers related to early HTN. Results Orthogonal partial least squares-discriminant analysis (OPLS-DA) revealed significant differences in the metabolic profiles of the three patient groups. Compared to subjects of the Normal group, the HT and HTN groups exhibited significantly upregulated and downregulated profiles of differential metabolites, respectively. LASSO regression analysis results indicated that 4-hydroxyphenylacetic acid, bilirubin, uracil, and iminodiacetic acid are potential biomarkers for HTN or HT. Conclusion With untargeted metabolomics analysis, we successfully identified differential metabolites in HTN. A further LASSO regression analysis revealed that four key metabolites, namely 4-hydroxyphenylacetic acid, bilirubin, uracil, and iminodiacetic acid, hold promise for the diagnosis of early-stage HTN.PMID:39862038 | DOI:10.12968/hmed.2024.0568

Plant Commun. 2025 Jan 23:101261. doi: 10.1016/j.xplc.2025.101261. Online ahead of print.ABSTRACTUDP-glycosyltransferases (UGTs) constitute the largest glycosyltransferase family in the plant kingdom. They are responsible for transferring sugar moieties onto various small molecules to control many metabolic processes. However, their physiological significance in plants is largely unknown. Here, we revealed the function and mechanism of two Arabidopsis UGT genes, UGT73C3 and UGT73C4, which can be strongly induced by Pseudomonas syringae pv. tomato DC3000. Their overexpression significantly enhanced plant immune response, while the loss of their functions in double mutants resulted in the more sensitive phenotype to pathogen infection, although their single mutants had no obvious alteration in pathogen resistance. To understand the regulatory mechanism of UGT3C3/C4 in plant immunity, a completely secondary metabolome analysis and glycoside quantification were conducted. More accumulation of pinoresinol diglucosides was revealed in the UGT73C3 and UGT73C4 overexpression lines than that in wild-type plants whether before or after Pst DC3000 treatment, whereas the double mutants accumulated less pinoresinol diglucosides. Further, the in vitro and in vivo experiments demonstrated that UGT73C3 and UGT73C4 were capable of glycosylating pinoresinol to form pinoresinol monoglucoside and diglucoside. Moreover, we found that pinoresinol glycosylation promoted plant immune response by enhancing ROS production and callose deposition. Additionally, the transcriptional factor HB34 was identified to be responsible for the activation of UGT73C3 and UGT73C4 transcription and play a key role in plant immune responses. Overall, this study revealed a new pathway of plant immune responses via UGT73C3/C4 mediated pinoresinol glycosylation under the HB34 regulation.PMID:39861946 | DOI:10.1016/j.xplc.2025.101261

Pharmaceutics. 2025 Jan 15;17(1):115. doi: 10.3390/pharmaceutics17010115.ABSTRACTBackground/Objectives: Although donepezil, a reversible acetylcholinesterase inhibitor, has been in use since 1996, its metabolic characteristics remain poorly characterized. Therefore, this study aims to investigate the in vivo metabolism of donepezil using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) based on a molecular networking (MN) approach integrated with a non-targeted metabolomics approach. Methods: After the oral administration of donepezil (30 mg/kg) in rats, urine, feces, and liver samples were collected for LC-HRMS analysis. Chromatographic and spectrometric data were processed through MN and multivariate data analysis to identify the in vivo metabolites of donepezil. Results: A total of 50 metabolites were characterized, including 23 newly identified metabolites. Donepezil was biotransformed by O-demethylation, N-debenzylation, and hydroxylation, and these metabolites are further conjugated with glucuronic acid and sulfurous acid. N-Desbenzyldonepezil (M4), didesmethyldonepezil (M5), and N-desbenzyldonepezil (M4) were identified as the most abundant metabolites in urine, feces, and liver samples, respectively. Conclusions: The metabolic characteristics of donepezil in rats were comparable to those in humans, indicating that a rat is a reliable model for studying donepezil metabolism. This study indicates that a MN approach combined with a metabolomics approach is a reliable tool to identify unknown metabolites of drugs and drug candidates.PMID:39861762 | DOI:10.3390/pharmaceutics17010115

Pharmaceutics. 2025 Jan 13;17(1):97. doi: 10.3390/pharmaceutics17010097.ABSTRACTBackground: The mechanism of Dendrobium officinale polysaccharide-based nanocarriers in enhancing photodynamic immunotherapy in colorectal cancer (CRC) remains poorly understood. Methods: The effects of TPA-3BCP-loaded cholesteryl hemisuccinate-Dendrobium officinale polysaccharide nanoparticles (DOP@3BCP NPs) and their potential molecular mechanism of action in a tumor-bearing mouse model of CRC were investigated using non-targeted metabolomics and transcriptomics. Meanwhile, a histopathological analysis (H&E staining, Ki67 staining, and TUNEL assay) and a qRT-PCR analysis revealed the antitumor effects of DOP@3BCP NPs with and without light activation. Results: Through metabolomics and transcriptomics analysis, we found an alteration in the metabolome and functional pathways in the examined tumor tissues. The metabolic analysis showed 69 and 60 differentially expressed metabolites (DEMs) in positive- and negative-ion modes, respectively, in the treated samples compared to the Control samples. The transcriptomics analysis showed that 1352 genes were differentially expressed among the three groups. The differentially regulated functional pathways were primally related to the antitumor immune response. The results of the pathological histology assay and qRT-PCR analysis verified the findings of the integrated metabolomics and transcriptomics analysis. Conclusions: Overall, our findings elucidate the potential antitumor mechanisms of the D. officinale polysaccharide-based nanocarrier in enhancing photodynamic immunotherapy in CRC.PMID:39861745 | DOI:10.3390/pharmaceutics17010097

Pharmaceutics. 2024 Dec 30;17(1):35. doi: 10.3390/pharmaceutics17010035.ABSTRACTBackground/Objectives: Fluoxetine (FLX) is the inhibitor of serotonin reuptake most prescribed in pregnant women with depression. This study evaluates the influence of gestational diabetes mellitus (GDM) on the enantioselective pharmacokinetics and transplacental distribution of FLX and its metabolite norfluoxetine (norFLX). Methods: Ten pregnant women diagnosed with GDM (GDM group) were investigated in the third trimester of gestation after they achieved good glycemic control. They received a single oral dose of 20 mg FLX, and blood samples were collected from 0 to 672 h. On the day of delivery, after another single oral dose of 20 mg FLX, blood samples of maternal vein, umbilical vessels and intervillous space were collected at birth. The pharmacokinetics parameters obtained for pregnant women diagnosed with GDM were compared with a group of healthy pregnant women (n = 9) previously investigated using Kruskal-Wallis's rank-sum test with the Dunn-Bonferroni post hoc test. Results: The area under the plasma over time curve (AUC0-∞) were 197.93 and 109.62 ng∙h/mL for FLX and 600.39 and 960.83 ng∙h/mL for norFLX, respectively, for their R-(+)- and S-(-)- enantiomers. The umbilical vein/maternal vein ratio for FLX and norFLX enantiomers was nearly 0.3, inferring low placental transfer. The umbilical artery/umbilical vein ratios were nearly 0.7 for both FLX and norFLX enantiomers, indicating absence or small fetal metabolism. Conclusions: The GDM did not alter the pharmacokinetics of FLX and norFLX enantiomers in patients with good glycemic control evaluated in the third trimester of gestation.PMID:39861684 | DOI:10.3390/pharmaceutics17010035