PubMed

Food Funct. 2026 Jul 13. doi: 10.1039/d6fo01328g. Online ahead of print.ABSTRACTHyperuricemia, a diet-related metabolic disorder, is primarily managed by targeting xanthine oxidase (XOD), the central enzyme responsible for uric acid production. Conventional screening of natural XOD inhibitors often struggles to deconvolute complex food-derived metabolomes. Here, we establish an integrated framework coupling data-driven feature-based molecular networking (FBMN) with AI-assisted ColabFold structural modeling for the rapid discovery of XOD-inhibitory flavonoids. Applied to the edible plant Gnaphalium affine D. Don, this approach enabled the high-resolution annotation of 65 flavonoids, including 56 previously unreported in this species. Kaempferol 3,4'-diglucoside emerged as the most potent candidate, exhibiting strong structural complementarity to the XOD catalytic center (docking interaction energy = -68.1 kcal mol-1) and potent in vitro inhibitory activity (IC50 = 14.1 ± 0.8 μM). Structural analysis further revealed a multimodal binding mechanism, in which di-glycosylation enhances binding stability and affinity, providing new insights into the structure-activity relationships of flavonoids. Beyond validating G. affine as a functional dietary source, this study offers a scalable, data-driven strategy for the prioritization of potential candidates that may inform the future development of mechanism-oriented functional food ingredients from complex food matrices.PMID:42439056 | DOI:10.1039/d6fo01328g

J Agric Food Chem. 2026 Jul 13. doi: 10.1021/acs.jafc.6c06837. Online ahead of print.ABSTRACTLayered nitrogen (N) fertilization has been proposed to improve wheat productivity, yet its rhizosphere mechanisms remain unclear. In a four-year field experiment, we compared layered fertilization (N1-2-1), surface application (N8), and no N input (NCK). Layered fertilization increased grain yield, anthesis-stage N accumulation, root biomass, and soil nutrient availability relative to N8. It also reshaped rhizosphere microbiomes and metabolomes, reducing overall microbial richness but enriching a Flavobacterium-enriched bacterial module. Network and correlation analyses linked this module with key metabolites, particularly β-thujaplicin and Ingenol mebutate, which were associated with yield, root traits, and improved soil fertility. These findings suggest that layered fertilization enhances wheat performance by coordinating root architecture, rhizosphere metabolite signals, and selective bacterial recruitment. The study provides a mechanistic basis for precision N placement to regulate rhizosphere processes and improve wheat productivity under sustainable management.PMID:42439013 | DOI:10.1021/acs.jafc.6c06837

Endocrinol Metab (Seoul). 2026 Jul 13. doi: 10.3803/EnM.2025.2787. Online ahead of print.ABSTRACTBACKGROUND: The dietary index for gut microbiota (DI-GM) and its associations with mortality risk, as well as the underlying mechanisms, remain underexplored. We aimed to investigate the associations among DI-GM, a corresponding metabolic signature, and all-cause and cardiovascular disease (CVD) mortality.METHODS: We analysed two cohort studies including 170,575 participants from the United Kingdom (UK) Biobank and 26,651 participants from the United States (US) National Health and Nutrition Examination Survey. We calculated DI-GM using 24-hour dietary recall questionnaire data and derived a corresponding metabolic signature using an elastic net regression model. Associations were assessed using Cox proportional hazards regression.RESULTS: Participants in the highest DI-GM group had a lower risk of all-cause mortality (hazard ratio [HR], 0.86, P<0.001 in the UK cohort; HR, 0.79, P<0.001 in the US cohort) and CVD mortality (HR, 0.79, P=0.013 in the UK cohort; HR, 0.68, P=0.007 in the US cohort) than those in the lowest group. Both overall DI-GM and foods beneficial for gut microbiota were inversely associated with mortality risk in a dose-response manner. We identified a DI-GM metabolic signature comprising 124 metabolites in the UK cohort (r=0.25, P<2.2×10-16); this signature was associated with the risk of all-cause mortality (HR, 0.68, P<0.001) and CVD mortality (HR, 0.65, P=0.003) and explained 52.60% of the association between DI-GM and all-cause mortality.CONCLUSION: We identified a close connection between DI-GM, its metabolic signature, and mortality outcomes, highlighting the potential benefits of dietary patterns that support gut microbiota health for longevity.PMID:42438999 | DOI:10.3803/EnM.2025.2787

Plant Biotechnol J. 2026 Jul 13. doi: 10.1111/pbi.70716. Online ahead of print.ABSTRACTLettuce is a critical leafy vegetable consumed worldwide and is a substantial dietary source of health-promoting compounds. Exploring changes in metabolism during lettuce domestication under artificial selection conditions is important to facilitate further breeding and cultivation for quality improvement. A liquid chromatography-mass spectrometry-based metabolomics approach was used to putatively identify 237 metabolites from 40 accessions, of which 130 were identified as metabolite identification level 1. Subsequently, 29 metabolites linked to lettuce quality improvement and their potential associated genes involved in lettuce domestication and differentiation were analysed. Muti-omics approach showed that metabolites involved in flavonol biosynthesis are the main metabolic distinctions between wild and modern cultivars, which is attributable to the selection signal observed in LsF3'H, a key enzyme involved in the catalysis of flavonoid hydroxylation at the 3'-position. These findings provide a comprehensive view of quality- and flavour-related metabolite variation in lettuce, reveal the potential for quality improvement associated with flavonol biosynthesis, and offer valuable insights into the genetic basis for improving lettuce flavour and nutrition.PMID:42438956 | DOI:10.1111/pbi.70716

Drug Des Devel Ther. 2026 Jul 8;20:617793. doi: 10.2147/DDDT.S617793. eCollection 2026.ABSTRACTBACKGROUND: Therapeutic heterogeneity limits the efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Shuyu Wan (SYW), a classic TCM formula, has shown potential in modulating gut microbiota (GM) and enhancing immunotherapy, yet its synergistic mechanism with PD-1 inhibitors remains unclear.MATERIALS AND METHODS: SYW components were identified by UPLC-MS. NSCLC-related targets were integrated with SYW targets for pathway enrichment, and molecular docking validated component-target binding. NSCLC syngeneic mice were treated with SYW and/or PD-1 inhibitor (RMP1-14). Tumor growth, histopathology, serum cytokines, tumor-infiltrating CD8+T cell subsets (flow cytometry), PD-1/PD-L1 expression and co-localization (immunofluorescence), GM composition (16S rRNA), and metabolomics were assessed. FMT verified the role of GM-TME crosstalk.RESULTS: SYW monotherapy showed no significant tumor inhibition, whereas SYW combined with PD-1 inhibitor dose-dependently suppressed NSCLC growth. The combination reduced PD-1 expression and PD-1/PD-L1 co-localization, elevated serum IL-12, IFN-γ, and TNF-α, increased total tumor-infiltrating CD8+ T cells, decreased PD-1+ and TIM-3+ exhausted subsets, and expanded IFN-γ+ and Granzyme B+ effector subsets. Concurrently, it reshaped GM (increased Bacillota, decreased Patescibacteria) and altered metabolites (L-glycine, L-proline). These effects were abolished in antibiotic treated mice and restored by FMT, suggesting GM-TME crosstalk as essential.CONCLUSION: SYW acts as a microbiota-dependent immune sensitizer that potentiates PD-1 inhibitor efficacy in NSCLC by remodeling GM and enhancing effector CD8+ T cell infiltration while reducing exhaustion. GM-TME crosstalk is the potential mechanism, supporting SYW as an adjunct to PD-1 blockade in NSCLC therapy.PMID:42438795 | PMC:PMC13356846 | DOI:10.2147/DDDT.S617793

ISME Commun. 2026 Jun 18;6(1):ycag170. doi: 10.1093/ismeco/ycag170. eCollection 2026 Jan.ABSTRACTAmmonia-oxidizing bacteria (AOB) catalyze the first and rate-limiting step of nitrification. They are essential for nitrogen cycling in engineered and natural environments, yet little is known about their viruses or the consequences of phage infection for host physiology. Here, we report the isolation and characterization of a novel lytic bacteriophage, vB_NeuP-Nir1 (DSM 111086), infecting the model AOB Nitrosomonas europaea. Phage Nir1 ceased ammonia oxidation within hours, and caused complete lysis of host populations even at multiplicities of infection as low as 10-6. Electron microscopy revealed drastic host cell remodeling during infection, including pronounced cell bloating and large-scale disintegration of intracytoplasmic membranes. Integrated transcriptomic and metabolomic analyses showed that loss of these ATP and reducing equivalent generating membrane systems was accompanied by signatures of compromised lipid homeostasis and collapse of autotrophic CO₂ fixation. In parallel, Nir1 infection induced metabolic rewiring of the host, including upregulation of uptake systems for nucleic acids, amino acids, and small organic compounds, increased expression of iron acquisition and putative iron-dependent respiratory components, as well as accumulation of metabolites associated with membrane breakdown and stabilization of viral DNA. Together, these results provide the first detailed mechanistic insight into phage-induced host modulation in a chemolithoautotrophic nitrifier. Our study establishes the Nir1-N. europaea system as a model for investigating virus-host interactions in AOB and lays the foundation for assessing the role of phages in shaping nitrification and nitrogen cycling in engineered and natural ecosystems.PMID:42438735 | PMC:PMC13356812 | DOI:10.1093/ismeco/ycag170

PeerJ. 2026 Jul 9;14:e21313. doi: 10.7717/peerj.21313. eCollection 2026.ABSTRACTThe COVID-19 pandemic has accelerated the integration of metabolomics and Machine Learning in biomedical research, resulting in the creation of numerous datasets with high potential for reuse. However, information regarding their accessibility, quality, and usability remains scattered and inconsistent. This systematic review aims to identify and evaluate publicly available human metabolomic datasets related to COVID-19, providing detailed information on their main characteristics and how to access them, with the goal to inform their potential for reuse in future research. Following PRISMA guidelines and the Kitchenham methodology, we conducted a comprehensive search of the scientific literature and specialized metabolomics repositories, identifying 110 unique datasets. Each dataset was assessed based on 15 variables related to data availability, accessibility, collection methodologies, sample sizes, and the extent of participant metadata provided. These datasets offer significant value for secondary analyses and ML applications, contributing to insights into disease mechanisms, early diagnosis, and patient stratification. By offering a structured overview of dataset characteristics, this review aims to support researchers in identifying suitable resources, encourages data reuse, and promotes best practices for data sharing and standardization in the context of COVID-19 and metabolomics. Nonetheless, our findings reveal critical limitations, including the underuse of dedicated repositories, frequent unavailability of raw data, lack of standardization in processed data, and insufficient metadata-particularly regarding participant demographics and clinical information. Inconsistencies in data formats and reporting standards further hinder dataset findability, interoperability, and reuse. To enhance the value and impact of future metabolomic research, we recommend adopting standardized reporting guidelines, improving metadata completeness, ensuring the availability of raw data, and promoting the use of interoperable repositories to facilitate reproducibility, integration, and broader application of shared datasets.PMID:42438709 | PMC:PMC13356828 | DOI:10.7717/peerj.21313

Food Chem (Oxf). 2026 Jul 5;13:100435. doi: 10.1016/j.fochms.2026.100435. eCollection 2026 Dec.ABSTRACTMicrobial succession during Jiupei fermentation is closely associated with biochemical changes that contribute to Baijiu quality formation; however, the fermentation-induced restructuring of the non-volatile metabolome and its species-level microbial associations remain poorly understood. We hypothesized that species-level microbial succession would be associated with pathway-specific changes in the non-volatile metabolome, and that bacterial and fungal diversity would show contrasting association patterns with different metabolite classes during fermentation. To test these hypotheses, we integrated physicochemical analysis, PacBio SMRT sequencing, and untargeted metabolomics to characterize microbial succession and metabolite dynamics during Light-flavor Baijiu Jiupei fermentation. A total of 1392 peaks were detected, with 134 metabolites annotated, including amino acids, organic acids, carbohydrates, alcohols, and nucleotides. Fermentation was accompanied by marked temporal shifts in the non-volatile metabolite profile, with galactose metabolism and starch and sucrose metabolism identified as the main enriched pathways. Fungal diversity (Shannon index) showed predominantly positive correlations with many metabolites across multiple classes, whereas bacterial diversity showed predominantly negative correlations with most metabolites. At species level, Lactobacillus homohiochii showed the largest number of positive correlations with amino acids (14 edges), alcohols (8 edges), and organic acids (7 edges), while Saccharomyces sp. was positively correlated with 19 amino acids and derivatives. These species-specific correlation patterns provide a correlation-based view of microbe-metabolite dynamics during Jiupei fermentation and generate testable hypotheses for future culture-based and mechanistic studies.PMID:42438488 | PMC:PMC13356748 | DOI:10.1016/j.fochms.2026.100435

United European Gastroenterol J. 2026 Jul;14(6):e70262. doi: 10.1002/ueg2.70262.ABSTRACTBACKGROUND: In patients with liver cirrhosis, intestinal permeability and the composition of the gut microbiome are altered. Thus, the microbiome might be a therapeutic target for the treatment of both liver diseases and intestinal permeability. We aimed to investigate the relationship between the intestinal barrier and microbiome composition in cirrhosis and elucidate potential mechanisms for how bacteria influence permeability.METHODS: We analyzed the fecal permeability biomarker zonulin by ELISA and microbiome composition by 16s rDNA sequencing in a discovery (n = 78) and a validation cohort (n = 90) of patients with liver cirrhosis. In the validation cohort, we analyzed the composition of the fecal metabolome by NMR spectroscopy. For mechanistic exploration, an intestinal barrier cell culture model using T84 cells was used.RESULTS: In the discovery cohort (n = 78, 77% Child-Pugh Grade A, 21% Child-Pugh Grade B, 3% Child-Pugh Grade C), decreasing zonulin levels in stool over 6 months were associated with higher Phascolarctobacterium abundance in the microbiome. Phascolarctobacterium was associated with better liver function (lower bilirubin, p = 0.04, INR p = 0.04, MELD Score, p = 0.02). Lower Phascolarctobacterium levels were observed in decompensated cirrhosis and were associated with 36-month mortality in two cohorts. Metabolomics analysis showed an association between Phascolarctobacterium and lower succinate levels. Succinate increased gut permeability in vitro, and Phascolarctobacterium succinatutens strains improved the intestinal permeability, potentially by alleviating the effect of succinate.CONCLUSION: Phascolarctobacterium may represent a candidate biomarker of adverse outcomes in cirrhosis and a promising target for further investigation as a next-generation probiotic involved in gut barrier function and succinate homeostasis.TRIAL REGISTRATION: NCT01607528, NCT03080129.PMID:42438428 | DOI:10.1002/ueg2.70262

Br J Nutr. 2026 Jul 13:1-23. doi: 10.1017/S0007114526108058. Online ahead of print.ABSTRACTMetabolic dysfunction-associated steatotic liver disease (MASLD) is now the most prevalent liver disease among children and is closely associated with insulin resistance and increased risk of developing type 2 diabetes (T2D). Early intervention in children with MASLD is essential to prevent progression to advanced liver disease and other metabolic disorders. The goal of this ongoing trial is to determine the effect of a weight-maintaining low glycemic, moderately carbohydrate-restricted diet (CRD) vs. fat-restricted diet (FRD) on changes in hepatic lipid content, insulin sensitivity, and metabolomic profile over a 6-month period in adolescents with MASLD. Eligible participants will be children ages 10-17 with a BMI > 75th percentile and a clinical diagnosis of MASLD. This randomized control trial (RCT) consists of two 12-week phases: a controlled feeding phase, during which food will be provided to the family, and a free-living phase. The CRD has a macronutrient composition of < 25% CHO: 25% Protein: > 50% fat, while the FRD is composed of 55% CHO: 25% Protein: 20% fat. Primary outcomes include change in hepatic lipid measured by MRI and MRS, and insulin sensitivity measured via euglycemic clamp and metabolomic profiling measured from fasting blood. Diet tolerance, body weight, and compliance were measured weekly by a Registered Dietitian (RD) during the controlled feeding phase, and then monthly in the free-living phase. Changes in study endpoints will be assessed between intervention groups and across study time points, assessing for effects by group, time, and the group-by-time interaction.PMID:42438408 | DOI:10.1017/S0007114526108058

J Biol Rhythms. 2026 Jul 13:7487304261459478. doi: 10.1177/07487304261459478. Online ahead of print.ABSTRACTCircadian misalignment, as experienced during shiftwork, impairs glucose metabolism and body weight regulation, yet the underlying biochemical mechanisms remain incompletely understood. Characterizing how circadian misalignment alters circulating metabolites provides a promising avenue to help identify these mechanisms. Although data from metabolomics studies have identified circulating metabolites with daily rhythms, it is not comprehensively known which rhythms shift during circadian misalignment and whether such shifts relate to metabolic impairment. We conducted 24-hour (h) metabolomic profiling every 4 h in 14 healthy adults (8 women) aged 26.4 ± 1.2 years (mean ± SD), undergoing a 6-day simulated night-shiftwork protocol. 24-h modeling analyses identified metabolite rhythms influenced by circadian versus behavioral cycles (sleep, food intake) and quantified internal circadian misalignment using acrophase shifts. Metabolic outcomes included glucose homeostasis (test meals) and energy expenditure (EE; whole-room calorimetry). Night-shiftwork produced widespread alterations in metabolite rhythms, with significant internal misalignment in multiple metabolites across pathways including pyrimidine metabolism, bile acid-microbiome signaling, and lipid metabolism. During misalignment, glucose and insulin area under the curve increased (p < 0.05) and EE decreased (p < 0.05). Internal misalignment of uridine and glycoursodeoxycholic acid was associated (p < 0.05) with impaired glucose tolerance, while their circulating concentrations were associated with decreased EE. Misalignment of uridine and glycoursodeoxycholic acid suggests dysregulated pyrimidine and bile acid-microbiome pathways as potential mechanisms linking circadian misalignment to cardiometabolic disease risk.PMID:42438369 | DOI:10.1177/07487304261459478

J Inherit Metab Dis. 2026 Jul;49(4):e70217. doi: 10.1002/jimd.70217.ABSTRACTEarly-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-2 (PEBEL2) is a rare autosomal recessive neurometabolic disorder caused by pathogenic variants in NAXD, in which febrile illness or infection triggers rapid clinical deterioration. We describe nine new cases that expand the clinical and molecular spectrum. Four children showed the typical presentation of severe neurological decline following fever or illness and carried variants affecting the enzyme domain. Four cases presented with illness-triggered cardiac dysfunction associated with variants in the mitochondrial targeting sequence. One case showed severe prenatal neurodegeneration resulting in stillbirth. In two patients, disease onset followed COVID-19 infection. Functional analysis of five missense variants demonstrated impaired NAXD protein solubility, reduced NADHX dehydratase activity and/or decreased thermostability. Patient fibroblasts confirmed accumulation of damaged cofactors (S-, R- and cyclic NADHX) and reduced NAXD protein levels. Comparative proteomic analysis revealed distinct molecular profiles in atypical cardiac and prenatal cases compared with typical neurological presentations. Four patients received high-dose niacin (vitamin B3) and survived repeated febrile episodes. These findings support early recognition and suggest that niacin therapy may improve outcomes across the clinical spectrum of PEBEL2.PMID:42438341 | DOI:10.1002/jimd.70217

Drug Test Anal. 2026 Jul 12. doi: 10.1002/dta.70121. Online ahead of print.ABSTRACTGene therapy is a powerful tool for treating and correcting severe genetic diseases caused by defective genes. However, the same technology could be exploited to introduce exogenous genes that enhance physical performance and endurance in sports, which not only subverts the principles of fair competition but also poses risks to athletes' health. Exogenous transgenes can be delivered into the human body via viral vectors, and recombinant adeno-associated virus (rAAV) vectors are, to date, considered the safest and most reliable viral vectors in that regard for a prolonged effect. Since 2003, the World Anti-Doping Agency (WADA) has included the term "gene doping" in its Prohibited List of Substances and Methods under Article M3 "Gene and Cell Doping." To date, no confirmed case of gene doping in sport has been officially identified. Over the past two decades, several strategies for long-term detection of rAAV-based transgenes in biological fluids have been proposed. These include direct methods such as polymerase chain reaction (PCR), liquid chromatography-high-resolution mass spectrometry (LC-HRMS), and matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF), and next-generation sequencing (NGS)-based approaches. Indirect methods include detection of recombinant protein products, analysis of immune responses (e.g., neutralizing antibodies, T-cell activation), and "omics" technologies such as proteomics, immunopeptidomics, and metabolomics, as well as combinations thereof. This review aims to provide a general overview of the potential of gene therapy for enhancing athletic performance and methods for detecting rAAV-based gene doping.PMID:42438284 | DOI:10.1002/dta.70121

Plant Cell Environ. 2026 Jul 12. doi: 10.1111/pce.70734. Online ahead of print.ABSTRACTExcessive nitrogen (N) application can affect soil health and crop performance, yet the multi-generational effects of prolonged high-N exposure on wheat seed germination remain unclear. We profiled seed metabolomes and endophytic bacterial communities across seven consecutive wheat generations (F1-F7) under normal-N and high-N regimes, and assessed germination of F7 seeds. Spatial metabolomics, spatial transcriptomics and 16S rRNA sequencing were used to resolve embryo- and endosperm-specific responses. Seven generations of high-N treatment delayed progeny seed germination and decreased the germination index by 12.3%, whereas the vigor index was not significantly affected. Spatial omics revealed strong embryo-endosperm heterogeneity and a high-N-associated shift in endosperm metabolism, including a 73.9% decrease in endosperm L-aspartic acid. Compartment-resolved microbiome analysis showed enrichment of Bacillus under high-N exposure. Functional assays showed that L-aspartic acid promoted germination/early outgrowth, whereas Bacillus grew with L-aspartic acid as the sole C/N source and reduced germination under L-aspartic acid-supplemented conditions. These results support a model in which multi-generational high N reduces wheat seed germination through endosperm amino-acid depletion and altered endophytic bacterial assembly.PMID:42438277 | DOI:10.1111/pce.70734

Microb Biotechnol. 2026 Jul;19(7):e70407. doi: 10.1111/1751-7915.70407.ABSTRACTStreptomyces species are prolific sources of antimicrobials, yet their vast biosynthetic capacity remains underexploited due to the rediscovery of common antibiotics (e.g., ~1% for streptomycin and ~10% for streptothricin). To address this challenge, we developed a dual-layer biosynthetic blockade system, designated CI-ARS3, which integrates two orthogonal silencing modules: a competitive transcriptional silencer that represses transcription of the native biosynthetic gene cluster (BGC), and an antisense RNA-based silencer that facilitates the degradation of BGC-derived mRNAs and/or translational inhibition. Implemented on a single attB site-integrating plasmid (pSET152-aafssf) encoding both modules, CI-ARS3 robustly suppresses streptomycin and streptothricin biosynthesis across 54 Streptomyces strains, achieving an inhibition efficiency of over 97% with high specificity for the target compounds under the tested conditions. The removal of these dominant backgrounds led to the discovery of enissomycin, a previously unreported antibacterial molecule. Enissomycin exhibited potent activity against Acinetobacter baumannii (MIC 4-8 μg/mL) and exhibited no significant cytotoxicity, highlighting its promise for drug development. Collectively, CI-ARS3 is a robust platform for the efficient dereplication of streptomycin and streptothricin, thereby expediting the discovery of novel antimicrobial compounds from Streptomyces.PMID:42438233 | DOI:10.1111/1751-7915.70407

Br J Pharmacol. 2026 Jul 12. doi: 10.1111/bph.70568. Online ahead of print.ABSTRACTBACKGROUND AND PURPOSE: Ischaemic stroke is characterised by acute cerebrovascular occlusion, blood-brain barrier (BBB) breakdown and a narrow therapeutic window for recovery. Its treatment is a clinical challenge due to the risk of reperfusion injury and the limited efficacy of thrombolytic therapies; therefore, novel therapeutic approaches are needed. Histone deacetylase inhibitors (HDACi) have emerged as neuroprotective agents in stroke models, but their effect on preserving BBB integrity is unexplored. Our aim was to investigate the effects of the HDACi, suberoylanilide hydroxamic acid (SAHA), on BBB changes in a cell culture model of ischaemic stroke.EXPERIMENTAL APPROACH: The effects of SAHA were tested on a human BBB co-culture model following a 6-h oxygen-glucose deprivation (OGD) under normoxia and during a 24 h reoxygenation (OGD/R).KEY RESULTS: SAHA treatment ameliorated the OGD/R-induced loss of BBB integrity, as shown by an increase in transendothelial electrical resistance and reduced BBB permeability. The expression of genes involved in cell proliferation decreased, whereas an increase was measured for basement membrane protein, glycocalyx-synthesis enzyme and Wnt signalling-related genes. SAHA treatment elevated the claudin-5 protein expression and a metabolic shift from glycolysis to aerobic respiration was observed.CONCLUSION AND IMPLICATIONS: Our results suggest that SAHA could be a potential adjunctive therapeutic drug for the treatment of ischaemia-reperfusion injury via BBB protection. Because SAHA has already been approved for human use as the anticancer drug vorinostat, its repurposing to restore BBB functions and prevent poststroke damages may be greatly facilitated.PMID:42438198 | DOI:10.1111/bph.70568

Am J Respir Cell Mol Biol. 2026 Jul 11:aanag143. doi: 10.1093/ajrcmb/aanag143. Online ahead of print.ABSTRACTSpatial metabolomics enables in situ, pixel-resolved mapping of small molecules across tissues, providing a powerful complement to conventional bulk metabolomics, which lacks cellular and anatomical resolution. By adapting mass spectrometry (MS) ionization approaches such as matrix-assisted laser desorption/ionization (MALDI) and desorption electrospray ionization (DESI), spatial metabolomics generates high-resolution metabolic maps that link metabolite distributions to defined tissue regions, cellular niches, and biological functions. This "metabolic microscopy" enables localization of biosynthetic pathways, identification of region-specific metabolic signatures, and integration with histology and other spatial omics modalities. High-resolution MS platforms support untargeted discovery, while targeted approaches enable sensitive detection of low-abundance metabolites. In respiratory research, spatial metabolomics has begun to reveal regional heterogeneity in lung metabolism, including surfactant remodeling, lipid mediator localization, fibrosis-associated metabolic reprogramming, infection-specific airway responses, and tumor-associated phospholipid dysregulation. These studies highlight the capacity of the method to connect localized biochemistry with pulmonary physiology and disease mechanisms. However, challenges remain, including limited sensitivity, difficulties in metabolite identification and isomer discrimination, restricted quantification strategies, and incompatibility with commonly used FFPE tissue preservation, underscoring the need for standardized fresh-frozen tissue workflows. Future integration of spatial metabolomics with spatial transcriptomics and proteomics promises comprehensive, multi-layered metabolic mapping of the airways, enabling the cross talk between multiple orders of biology to be understood from specific tissue microenvironments. As part of a multimodal spatial biology framework, spatial metabolomics has strong potential to define disease endotypes, inform therapeutic target discovery, and generate spatial metabolic atlases that advance mechanistic understanding and precision medicine in respiratory disease.PMID:42438167 | DOI:10.1093/ajrcmb/aanag143

J Nanobiotechnology. 2026 Jul 13. doi: 10.1186/s12951-026-04804-5. Online ahead of print.ABSTRACTExtracellular vesicles (EVs) have emerged as promising vehicles for drug delivery and disease therapy owing to their intrinsic biocompatibility and capacity to transfer functional biomolecules. However, limitations in current storage technologies, including structural degradation and bioactivity loss during long-term freezing, and the incompatibility of conventional cryoprotectants such as DMSO and glycerol with intravenous administration, pose major barriers to clinical translation. Herein, we developed DDAS, a biomimetic cryoprotectant formulation, rationally designed through generative artificial intelligence (GAI)-assisted prioritization of physiologically relevant candidates from the Human Metabolome Database. DDAS comprises dextran, albumin, and sialic acid, which were selected for their synergistic stabilization and inherent biocompatibility. Compared with standard preservation media, DDAS markedly improved EVs stability during prolonged cryopreservation and repeated freeze-thaw cycles, effectively preserving vesicle morphology, particle concentration, and cargo protein functionality while reducing aggregation and membrane damage. Notably, DDAS exhibited negligible cytotoxicity and excellent biocompatibility, enabling direct intravenous administration without re-isolation or washing. Importantly, stem cell-derived EVs preserved in DDAS fully retained their therapeutic activity in vivo, significantly attenuating inflammation and accelerating wound repair upon systemic administration. Together, this study develops and validates DDAS, a practical, clinically feasible biomimetic cryoprotectant assisted by GAI. DDAS enables the long‑term preservation of EVs with intact functionality and significantly enhances the therapeutic efficacy of stem cell EVs in wound healing, ultimately unlocking their full clinical potential.PMID:42437935 | DOI:10.1186/s12951-026-04804-5

Plant Methods. 2026 Jul 12. doi: 10.1186/s13007-026-01571-0. Online ahead of print.ABSTRACTBACKGROUND: Protein-protein interactions underpin virtually all biological processes in plants, from signal transduction and immune responses to development and stress adaptation. Despite their fundamental importance, the plant interactome remains far from complete, and existing maps are systematically biased by the technical limitations inherent to conventional detection platforms.MAIN BODY: This review critically traces the evolution of protein-protein interaction methodologies, from foundational approaches to advance in vivo and quantitative platforms. Classical techniques such as the yeast two-hybrid system and in vitro pull-down assays operate outside physiological cellular environments and are poorly suited to capturing transient or condition-dependent interactions. Affinity purification coupled with mass spectrometry improves throughput but remains vulnerable to artifacts introduced during cell lysis and to the preferential loss of weak interactors. To address these shortcomings, proximity labeling with engineered biotin ligases, most notably the fast-acting variant TurboID, has emerged as a powerful strategy, enabling covalent biotinylation of protein neighborhoods within living cells prior to lysis and thereby preserving associations that conventional methods routinely miss. Because TurboID reports proximity rather than direct binding, its output requires downstream binary validation. Complementary in planta validation tools are equally critical for moving beyond discovery. Split-luciferase complementation assays based on the NanoLuciferase reporter provide exceptional sensitivity for binary interaction detection under native expression conditions, while Förster Resonance Energy Transfer measured through fluorescence lifetime imaging microscopy offers quantitative biophysical evidence of molecular proximity at endogenous expression levels, serving as a high-confidence validation approach. Emerging technologies, including high-throughput protein microarrays and optogenetically controlled dimerization systems, further expand the methodological repertoire available to the plant biology community.CONCLUSION: We propose a practical, integrative three-tier framework, combining proximity labeling for broad in vivo discovery, split-luciferase complementation for sensitive binary validation, and fluorescence lifetime imaging microscopy for quantitative confirmation, that systematically funnels candidate interactions from initial identification to physiologically rigorous verification. This framework synthesizes established best practices into a structured workflow applicable to mapping dynamic plant interactomes, though its optimal implementation will depend on the biological question, target protein class, and available resources.PMID:42437933 | DOI:10.1186/s13007-026-01571-0

Cardiovasc Diabetol. 2026 Jul 12. doi: 10.1186/s12933-026-03286-x. Online ahead of print.ABSTRACTBACKGROUND: Patients with insulin resistance exhibit reduced cardiorespiratory fitness (CRF), assessed by peak oxygen consumption (VO₂peak), compared with healthy age-matched individuals. Although high-intensity interval training (HIIT) can substantially improve VO₂peak, there is considerable interindividual variability in this response. Therefore, further research is needed to elucidate the molecular mechanisms underlying the heterogeneous response of VO₂peak to HIIT in individuals with prediabetes.METHODS: Proteomic analyses of serum samples, along with fecal metagenomic and targeted metabolomic profiling, were conducted in medication-naïve, overweight and obese Chinese men with prediabetes (n = 35; aged 24-62 years). All participants underwent a 12-week HIIT intervention, and biological samples were collected both before and after the intervention to evaluate exercise-induced alterations in circulating proteins, gut microbial composition, and metabolite profiles.RESULTS: After 12 weeks of HIIT, mean VO₂peak increased by 0.47 L/min with individual responses ranging from 0 to 1.7 L/min. Baseline levels of short-chain fatty acid (SCFA)-producing genera, including Prevotella (β = 105.65, P = < 0.001, FDR = 0.034), Coprococcus (β = 50.22, P = 0.01, FDR = 0.39), and Hungatella (β = 40.72, P = 0.025, FDR = 0.50), were positively associated with ΔVO₂ peak. In contrast, baseline levels of the erythropoiesis-stimulating hormone erythropoietin (EPO) (β = -279.03, P = 0.024, FDR = 0.99) were negatively associated with ΔVO₂ peak. Exercise-induced changes in growth hormone 1 (β = 63.97, P = 0.04, FDR = 0.99) were positively associated with ΔVO₂ peak, whereas exercise-induced changes in BTB and CNC Homology 1 (β = -250.82, P = 0.01, FDR = 0.99), a repressor of heme oxygenase-1, were negatively associated with ΔVO₂ peak. In multiple linear regression analysis including clinical variables, percentage lean mass (β = 64.17, P = 0.0005) was the strongest variable associated with ΔVO₂peak. The clinical model explained 27% of the variance which increased to 37% (P = 0.002) upon inclusion of exercise-associated circulating factors such as EPO.CONCLUSIONS: Our findings reveal that baseline proteomic and metagenomic signatures are associated with VO₂peak adaptations. These multi-omics signatures may support the clinical implementation of personalized exercise interventions to improve CRF in individuals with prediabetes.PMID:42437920 | DOI:10.1186/s12933-026-03286-x