PubMed

BMJ Open. 2025 Mar 13;15(3):e094280. doi: 10.1136/bmjopen-2024-094280.ABSTRACTINTRODUCTION: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis, is characterised by chronic and relapsing inflammation of the gastrointestinal tract, leading to significant morbidity and reduced quality of life. The global rise in IBD incidence is driven by a complex interplay of genetic, environmental, dietary and microbiome-related factors. Despite advancements in treatment, such as biologics, response rates remain variable, highlighting the need for personalised approaches. Recent research suggests that specific microbiome signatures may serve as biomarkers for predicting therapeutic efficacy, offering a potential tool for optimising treatment strategies in CD. The aim of the Optimising IBD Patient Treatment with Integrated Microbiome Investigation for Specialised Therapeutics (OPTIMIST) study is to evaluate microbiome profiles across various sample types in a Canadian CD cohort starting or already on advanced therapy, with the goal of developing predictive models for personalised therapeutics.METHODS AND ANALYSIS: This study is a two-phase, longitudinal, prospective observational pilot study conducted in British Columbia, Canada, involving both CD patients and non-IBD controls. Phase 1 focuses on baseline microbiome differences across participant cohorts through cross-sectional analysis. Phase 2 follows participants over 12 months to assess microbiome changes and their association with treatment response. Stool samples, intestinal biopsies from the left colon, right colon and ileum, as well as mucosal wash samples from the proximal part of the distal colon, will undergo metagenomics, metaproteomics and metabolomics analyses to explore compositional and functional differences. Data will be analysed using alpha and beta diversity metrics, differential abundance analyses and multivariate analyses to identify microbiome-based predictors of therapeutic response.ETHICS AND DISSEMINATION: Ethical approval was received by the Research Ethics Board (REB) of University of British Columbia-Providence Healthcare (UBC-PHC) with a REB number H23-02927. All amendments to the protocol are reported and adapted based on the requirements of the REB. The results of this study will be submitted to peer-reviewed journals and will be communicated in editorials/articles by the IBD Centre of BC and BC Children's Hospital Research Institute.TRIAL REGISTRATION NUMBER: NCT06453720.PROTOCOL VERSION: 2024-06-21, version 3.0.PMID:40082000 | DOI:10.1136/bmjopen-2024-094280

J Proteomics. 2025 Mar 11:105430. doi: 10.1016/j.jprot.2025.105430. Online ahead of print.ABSTRACTThe community of microorganisms inhabiting a specific environment, such as the human gut - including bacteria, fungi, archaea, viruses, protozoa, and others - is known as the microbiota. A holobiont, in turn, refers to an integrated ecological unit where microbial communities function and interact with their host, thus is a more integrative concept. To understand the processes involved, the diversity of microorganisms present must be identified and their molecular components quantified, especially proteins. Indeed, proteins - through their roles as catalytic units, structural components, and signaling molecules - are the main drivers of biological processes. Metagenomics has significantly expanded what we know about the genetic material present in microbiota, revealing their functional potential; metabolomics delivers an overall snapshot of the metabolites produced by the community. But metaproteomics offers a complementary approach to explore microbiome and holobiont functionality by focusing on the active proteins and functional pathways from each taxon. Significant recent advances in high-resolution tandem mass spectrometry have greatly expanded the catalog of peptide sequences accessible in each sample, creating the conditions for unprecedented taxonomical profiling, while also providing more accurate biomass quantification, more detailed protein characterization, and a greater capacity to monitor abundance and distinguish host biomarkers. By integrating artificial intelligence into the metaproteomics pipeline, extended datasets can now be efficiently mined to gain a more comprehensive functional view of complex biological systems, paving the way for next-generation metaproteomics. In this perspective, I discuss the transformative potential of this methodology. We are on the cusp of a remarkable omic revolution that promises to uncover the intricate workings of microbiomes by producing a vast array of new knowledge with multiple applications. SIGNIFICANCE: Metaproteomics provides a powerful lens to investigate microbiome and holobiont functionality by identifying and quantifying active proteins and functional pathways within each taxon. Recent breakthroughs in high-resolution tandem mass spectrometry have dramatically expanded the repertoire of peptide sequences detectable per sample. This progress enables unprecedented taxonomic resolution for microbial identification, more precise biomass quantification, comprehensive protein characterization, abundance monitoring, and the unique identification of host biomarkers. In this commentary, I delve into the distinctive features that make metaproteomics a transformative tool. I discuss the recent advancements in tandem mass spectrometry and argue that the primary challenge in analyzing complex samples is shifting from data acquisition to data interpretation. With the integration of artificial intelligence, I believe next-generation metaproteomics is poised to become the next Big Thing in microbiome research, unlocking profound insights into microbial functionality and ecosystem dynamics.PMID:40081757 | DOI:10.1016/j.jprot.2025.105430

J Heart Lung Transplant. 2025 Mar 11:S1053-2498(25)01836-4. doi: 10.1016/j.healun.2025.03.008. Online ahead of print.ABSTRACTBACKGROUND: Heart transplantation (HT) is the gold standard for end-stage heart disease. Donor heart preservation is an important factor that influences post-transplant success. Recently, temperature-controlled storage has demonstrated reduced primary graft dysfunction compared to standard cold storage though mechanisms are poorly understood. We hypothesized that alterations in gene expression and metabolomics offer insight into improved outcomes observed with temperature-controlled storage.METHODS: We conducted a comprehensive study to investigate the metabolic and transcriptomic responses of donor hearts preserved for six hours using a temperature-controlled hypothermic preservation system (TCHP) compared to conventional static cold storage (SCS). Metabolic assessments were carried out using high-resolution 1H and 31P NMR, and LC-MS analysis on tissues obtained from various cardiac regions. Lactate, alanine, ATP, ADP, AMP, NAD, NADH, phosphocreatine, and inorganic phosphate were measured, and metabolite ratios were calculated. Transcriptomic profiling was conducted using high throughput RNA sequencing followed by bioinformatic analysis to explore gene expression changes associated with different preservation methods.RESULTS: Metabolic analysis revealed similar profiles between hearts preserved with TCHP and SCS. Energy metabolite ratios were comparable between preservation methods. Transcriptomic analysis unveiled a high correlation between preservation methods but also showed differential gene expression in energy metabolism and inflammation/immune-related pathways.CONCLUSIONS: Our study demonstrates that TCHP maintains similar high-energy phosphate reserves to SCS but leads to alterations in gene expression of several metabolic and immunomodulatory pathways. These findings may offer important insight into reduced primary graft dysfunction observed in TCHP preserved hearts.PMID:40081628 | DOI:10.1016/j.healun.2025.03.008

Metabolism. 2025 Mar 11:156188. doi: 10.1016/j.metabol.2025.156188. Online ahead of print.ABSTRACTBACKGROUND: Higher meat intake has been associated with adverse health outcomes, including cardiovascular disease (CVD). This study investigated plasma metabolites associated with meat intake and their relation with cardiometabolic biomarkers, subclinical CVD markers, and incident CVD.METHODS: Associations between self-reported meat intake and 1272 plasma metabolites were investigated in the SCAPIS cohort (n = 8819; ages 50-64). Meat-associated metabolites were further examined for relation with subclinical CVD markers in the POEM cohort (n = 502; age 50) and incident CVD in the EpiHealth cohort (n = 2278; ages 45-75; 107 incident cases over 9.6 years follow-up). Meat intake was categorized into white, unprocessed red, and processed red meat. Linear regression analyzed associations between meat intake, metabolites and cardiometabolic biomarkers, and subclinical CVD markers, while Cox models evaluated association between meat-associated metabolites and incident CVD.RESULTS: After correction for multiple testing, 458, 368, and 403 metabolites were associated with white, unprocessed red, and processed red meat, respectively. Processed red meat-associated metabolites were associated with higher levels of fasting insulin, hemoglobin A1c, and lipoprotein(a), and were inversely associated with maximal oxygen consumption. Two metabolites, 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (hazard ratios (HR: 1.32; 95 % CI: 1.08, 1.62)) and glutamine degradant (HR: 1.35; 95 % CI: 1.07, 1.72), that were inversely associated with intake of all meat types, were also associated with a higher risk of incident CVD.CONCLUSIONS: This study provides comprehensive analysis of self-reported meat intake and plasma metabolites. The findings may enhance our understanding of the relationship between meat intake and CVD, and provide insights into underlying mechanisms.PMID:40081615 | DOI:10.1016/j.metabol.2025.156188

J Ethnopharmacol. 2025 Mar 11:119626. doi: 10.1016/j.jep.2025.119626. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The Jieduquyuziyin prescription (JP) is an enhanced formula derived from the "Sheng Ma Bie Jia Tang" in the Golden Chamber. JP is an empirical formula approved for use in the treatment of systemic lupus erythematosus (SLE) in hospitals across China, demonstrating notable therapeutic effects. It has been shown to suppress B cell activation and alleviate symptoms; however, its underlying mechanism remains unclear.AIM OF THE STUDY: The aim of this study is to investigate the effect of JP on B cell metabolic reprogramming in the treatment of SLE and to elucidate the underlying regulatory mechanisms.MATERIALS AND METHODS: Core targets and pathways regulating B cell activation were identified through sequencing of activated and resting B cells from SLE patients and network pharmacology of JP. Targeted metabolomics was employed to assess JP's effect on B cell metabolism. In vivo experiments evaluated the effects of JP, JP combined with a PKM2 inhibitor, or an AMPK inhibitor on SLE activity, B cell activation and glycolysis.RESULTS: Bioinformatics analyses identified PKM as a core target in B cell activation, which was significantly upregulated and linked to the inhibition of AMPK signaling. JP reduced B cell glycolysis and activation, leading to significant improvements in disease pathology. The combination of JP with an AMPK inhibitor diminished the therapeutic effect. Further studies suggested that JP inhibits glycolysis-dependent B cell activation via the AMPK/PKM2 pathway, reducing germinal center responses and effector B cells.CONCLUSION: This study reveals that the AMPK/PKM2 pathway is a promising therapeutic target for regulating immune metabolic imbalance in SLE B cells. Additionally, it provides evidence that JP may improve SLE by activating the AMPK/PKM2 pathway to inhibit glycolysis-dependent B cell activation, laying the foundation for further investigation of its therapeutic mechanisms.PMID:40081513 | DOI:10.1016/j.jep.2025.119626

Fitoterapia. 2025 Mar 11:106480. doi: 10.1016/j.fitote.2025.106480. Online ahead of print.ABSTRACTPhellinus pini (P. pini) has been widely utilized as a traditional medicinal macrofungus in China and various East Asian countries. Modern pharmacological studies have shown that P. pini has important application value in anti-tumor therapy. However, its main anti-breast cancer active substances and mechanism are still unclear. In this study, we demonstrated that the methanol extract of Phellinus pini (PPE) could significantly inhibit the viability of 4 T1 cells, induce apoptosis, decrease mitochondrial membrane potential and S phase arrest of 4 T1 cells. PPE can restore the imbalance of intestinal flora caused by breast cancer and regulate the content of endogenous metabolites such as amino acids. Q Exactive UPLC-MS/MS analysis showed that polyphenols are the main chemical components that exert the efficacy. These results provide experimental support for the potential future treatment of breast cancer with P. pini.PMID:40081427 | DOI:10.1016/j.fitote.2025.106480

J Pharm Biomed Anal. 2025 Mar 6;260:116789. doi: 10.1016/j.jpba.2025.116789. Online ahead of print.ABSTRACTCytogenetic abnormalities and gene mutations are essential for planning AML treatment. However, in Turkey, test results typically take 14-30 days. This delay emphasizes a critical need for rapid methods to deliver clinical data in urgent cases requiring immediate treatment decisions. To address this need, our objective was to develop a quick prediction method for NPM1 (Nucleophosmin-1) and FLT3 (FMS-like tyrosine kinase 3) mutations using LC-MS/MS (Liquid Chromatography-Tandem Mass Spectrometry) targeted metabolomics to detect these common and clinically important mutations in de novo AML patients (n = 42) through patient groups and a healthy group. We analyzed metabolic patterns using LC-MS/MS measurements of amino acids and acyl carnitines, key components critical to AML prognosis. The data were then subjected to multivariate analysis techniques. Principal Component Analysis (PCA) revealed that the model explained 79 % of the total variance among the sample groups. To further enhance class discrimination, we conducted Partial Least Squares-Discriminant Analysis (PLS-DA), resulting in R2Y and Q2 values of 0.845 and 0.619, respectively. Using the PLS-DA model, VIP (Variable Importance Projection) identified key metabolites with scores > 1.5, including C0 carnitine, glutamic acid, aspartic acid, tryptophan, histidine, isoleucine, and alpha-aminobutyric acid, respectively, highlighting their potential significance in distinguishing mutation groups. To ensure the validity of the PLS-DA model and evaluate potential overestimation, we validated the model using cross-validation and permutation test, demonstrating its robustness and reliability. Our preliminary model, developed through a targeted metabolomics approach, shows strong fit and predictive capability in determining the mutation status of NPM1 and FLT3 in AML patients.PMID:40081307 | DOI:10.1016/j.jpba.2025.116789

Schizophr Res. 2025 Mar 12;278:9-16. doi: 10.1016/j.schres.2025.03.016. Online ahead of print.ABSTRACTBACKGROUND: Schizophrenia (SZ) is a severe and chronic mental illness affecting approximately 1 % of the global population. Although antipsychotic medications can alleviate some symptoms, 20--30 % of patients exhibit resistance to available treatments. Therefore, identifying objective biomarkers related to treatment efficacy is crucial.METHODS: A total of 56 drug-naïve SZ patients were recruited, and after 8 weeks of antipsychotic medication, they were classified as treatment responders (30) and non-responders (26) based on the improvement of their symptoms. Baseline plasma metabolites were measured by targeted metabolomics Biocrates MxP® Quant 500 Kit.RESULTS: A total of 271 metabolites were identified, among which 31 exhibited significant differences between responders and non-responders, including phosphatidylcholine (PC) (14), sphingomyelin (8), ceramide (6), cholesteryl ester (2), and sarcosine (1), which were mainly concentrated in the sphingolipid metabolic pathway. Notably, key differential metabolites included phosphatidylcholine, sphingomyelin, and ceramide, which were predominantly enriched in the sphingolipid metabolism pathway. Through logistic regression analysis, sarcosine, PC aa C28:1, PC ae C34:2, and PC ae C36:3 emerged as significant predictors, yielding a combined area under the curve (AUC) of 0.877 for effectively distinguishing treatment responders from non-responders.CONCLUSION: Our findings suggest that the combination of sarcosine, PC aa C28:1, PC ae C34:2, and PC ae C36:3 could serve as biomarkers for prediction of treatment response in patients with drug-naïve SZ.PMID:40081292 | DOI:10.1016/j.schres.2025.03.016

Talanta. 2025 Mar 8;292:127865. doi: 10.1016/j.talanta.2025.127865. Online ahead of print.ABSTRACTChemotherapy-induced cardiotoxicity (CIC) is a common adverse effect of antineoplastic drugs, manifesting in adult and paediatric populations. The biochemical background of CIC risk remains unclear. However, recent genomics studies linked the condition to specific gene polymorphisms. The application of metabolomics has the potential to improve our understanding of CIC risk, bridging the gap between the genetic predisposition, the chemotherapy and the onset of CIC. Accordingly, an untargeted metabolomics approach was implemented to determine correlations between patients' metabolomics profiles and the risk of CIC during or shortly following their chemotherapy. A UPLC-ESI-QTOF protocol was developed to analyse plasma samples of 89 paediatricpatients collected prior to the initiation of chemotherapy. The metabolomics data were integrated with the a posteriori knowledge of CIC expression in a post-hoc analysis. KODAMA, OPLS-DA, BORUTA, and FDR t-test were used as complementary classification and variables selection methodologies to point out metabolites with an increased probability of being CIC risk-related. An empirical scale of confidence for DIA identification was developed to assure results' reliability. All classification models succeeded in separating the CIC-risk patients. Overall, CIC-risk patients showed early alterations in pathways related to CVDs, inflammation, oxidation, folate deficiency, and inhibition of GSH production. The 3-hydroxy-9-hexadecenoylcarnitine was determined as a potential predictive biomarker.PMID:40081244 | DOI:10.1016/j.talanta.2025.127865

J Pharmacol Exp Ther. 2025 Feb 21;392(4):103403. doi: 10.1016/j.jpet.2025.103403. Online ahead of print.ABSTRACTAttention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with unclear pathological mechanisms. ADHD is treated with both stimulant and nonstimulant medications, but their therapeutic mechanisms and impact on brain metabolites are not fully understood. This study employed an untargeted metabolomics approach with liquid chromatography mass spectrometry to investigate the pathogenesis of ADHD, as well as the effects of established and novel therapeutics. We characterized the metabolomic signatures of the adgrl3.1 mutant zebrafish ADHD model and examined the impact of methylphenidate, guanfacine, atomoxetine, and 5 novel putative therapeutics identified in a prior screen, including amlodipine. Our analysis revealed that the drugs commonly affect pathways related to amino acid and lipid metabolism, specifically involving glycine, serine, threonine, phenylalanine, lysophosphatidylcholine, and sphingomyelin. This convergence on similar metabolic targets was unexpected and suggests a broader, systemic effect of ADHD therapeutics, challenging the traditional view of distinct drug mechanisms. Amlodipine exhibited metabolic effects consistent with established treatments, indicating its potential as a viable alternative or adjunct therapy. These findings provide new insights into the metabolic underpinnings of ADHD and highlight potential targets for developing improved therapeutic strategies. SIGNIFICANCE STATEMENT: This study explores the metabolic pathways affected by attention deficit hyperactivity disorder treatments using a zebrafish adgrl3.1 mutant model. Untargeted metabolomics revealed that both established and novel attention deficit hyperactivity disorder medications influence common amino acid and lipid metabolism pathways, suggesting systemic effects. Notably, amlodipine showed similar impacts as current drugs, offering promise as an alternative therapy.PMID:40081232 | DOI:10.1016/j.jpet.2025.103403

Water Res. 2025 Mar 8;279:123466. doi: 10.1016/j.watres.2025.123466. Online ahead of print.ABSTRACTWide application of zinc oxide nanoparticles (ZnO NPs) and increasing frequency of heatwaves (HWs) have posed a great threat to freshwater ecosystems, while phytotoxicity of ZnO NPs mediated by HWs remains unclear. This study aims to link the physiological responses, bio-nano interactions, and metabolic mechanisms of Chlorella pyrenoidosa with ZnO NPs under heat stress. Results demonstrated a temperature-dependent growth inhibition against ZnO NPs, with a higher reduction of growth rate at 24 °C than 28 °C. Accompanied with lower reactive oxidative stress and cell damage at 28 °C, our results indicated that HW could enhance the adaptability of C. pyrenoidosa to ZnO NPs stress. Furthermore, HW induced the variation of algal surface properties, altered interfacial interactions in the bio-nano system, and decreased cellular Zn uptake. Metabolomics analysis supported the temperature-dependent influences of ZnO NPs on C. pyrenoidosa. The phytotoxicity of ZnO NPs was associated with the disturbance of amino acids, fatty acids, and energy metabolic processes, which were mitigated under HW condition, enhancing the responsiveness of algae to the adverse effects. These results emphasize the importance of taking the impacts of HWs into account when evaluating the environmental risks of ZnO NPs.PMID:40081176 | DOI:10.1016/j.watres.2025.123466

Food Chem. 2025 Mar 9;479:143784. doi: 10.1016/j.foodchem.2025.143784. Online ahead of print.ABSTRACTChinese bayberry fruit is rich in bioactive compounds which are beneficial to health. Fruit hybridization can improve quality and metabolite content, but this has yet to be explored in bayberry. Here, we investigated the effects of hybridization on fruit quality and the metabolomic profile of a newly developed hybrid 'BD-107' compared to the parent 'Biqi' and 'Dongkui', the main cultivars in China. Physiochemical evaluations indicated that 'BD-107' outperformed both parental cultivars in crucial quality attributes such as firmness, sugar content, and vitamin C. Metabolomic analysis revealed that hybridization positively influenced the overall metabolite content, with the highest alterations in terpenoids (21.4 %) and flavonoids (12.2 %). Notably, the novel hybrid 'BD-107' contains seven unique metabolites that are not in either parent; Safranal, Myrcenon, p-Menth-3-en-1-ol, Balanophonin B, Swertisin, Genistein-8-C-glucoside, and Ethanone, 1-(1,4-dimethyl-3-cyclohexen-1-yl), linked to antioxidant and health-promoting properties. Our findings provide valuable insights into the influence of bayberry heterosis on terpenoid and flavonoid biosynthesis, enhancing bioactive metabolites and fruit quality, which meet the demand for health-promoting fruit.PMID:40081069 | DOI:10.1016/j.foodchem.2025.143784

Food Chem. 2025 Mar 7;479:143767. doi: 10.1016/j.foodchem.2025.143767. Online ahead of print.ABSTRACTMetabolomics approaches are frequently constrained by colorless variables for identifying chromogenic compounds. A novel multi-spectral strategy, combining diode-array detector absorption spectra with a newly developed time slicing method, was proposed as an effective tool for rapidly screening colored ingredients. This approach was demonstrated by analyzing black tea from different countries. Compared to conventional metabolomics, colorant-oriented-searching metabolomics significantly decreased analytical time, reduced false positive results by 35.45 %-71.06 %, improved analytical accuracy by 30.00 %-46.66 %, and provided additional spectral characteristics related to color. Furthermore, this approach successfully identified eight p-coumarylated flavonol glycosides with absorbance at 440-450 nm, exhibiting their role in contributing to the red hue of black tea infusions. The time slicing method, with optional parameters including color and intensity options, offered flexibility and high efficiency. Therefore, this approach provided a powerful tool and can readily be applied to search for novel colored ingredients in food science.PMID:40081067 | DOI:10.1016/j.foodchem.2025.143767

mSphere. 2025 Mar 13:e0002425. doi: 10.1128/msphere.00024-25. Online ahead of print.ABSTRACTThe aim of this experiment was to study the effects of herbal preparations on serum metabolites, rumen microorganisms, and their metabolites, and the relationship between them. Hu sheep ram lambs with an average initial weight of (19.57 ± 1.56 kg) at 3 months of age were selected and randomly divided into three groups of six lambs each. The groups were as follows: the control group (Con), which was fed the basic diet; Test I, which was fed a diet with 0.5% herbal preparations added to the concentrate; and Test II, which was fed a diet with 1% herbal preparations added to the concentrate. Also, the main component of herbal medicine is polysaccharide. The pre-experimental period was 10 days and the experimental period was 90 days. The results of the study showed that the addition of herbal preparations resulted in differences in species, abundance, and metabolic functions of rumen microorganisms. The abundance of rumen-dominant bacteria, such as Firmicutes and Proteobacteria, increased after the addition of herbal preparation, which was more conducive to rumen development. In addition, after the addition of 0.5% herbal preparation, there was an increase in the abundance of fermenting carbohydrate (CHO) and fiber-degrading bacteria (e.g., Ruminococcus and Prevotella). Herbal preparations significantly altered rumen microorganisms and serum metabolite compositions. Metabolites such as bile acids, L-glutamine, cytosine, and choline, which contribute to the antiviral and anti-inflammatory effects, nutrient metabolism, and immune responses, and increased rumen microbial activity, were increased in the rumen of the experimental group with the addition of the herbal preparations. The increase in serum metabolites, such as L-tryptophan, and the pathways of tryptophan metabolism and glutathione metabolism in animals were also significantly higher than those in Con. Prevotella and Ruminococcus were significantly positively correlated with histamine and L-arginine. The uncultured_rumen_bacterium was significantly negatively correlated with serum metabolites testosterone and guanine, but Prevotella and Ruminococcus were significantly positively correlated with both metabolite testosterone and guanine.IMPORTANCE: In this study, we investigated the changes in rumen microbes after supplementation with herbal preparations. We used 16S sequencing and metabolomics approaches to explore changes in rumen contents and serum metabolites and their interrelationships. Our findings revealed marked changes in rumen microbial profiles, including changes in species composition, abundance levels, and metabolic activities induced by herbal supplementation. The increased abundance of beneficial bacteria (e.g., fixative and proteobacteria) in the rumen was more favorable for their survival and colonization of the rumen. In addition, a surge in the abundance of fermenting carbohydrate and fiber-degrading bacteria was observed. It was also found that the addition of herbal preparations enhanced antiviral and anti-inflammatory responses, nutrient metabolism, immune function, and stimulation of rumen microbial activity as well as facilitated the acceleration of body metabolism in Hu sheep.PMID:40079596 | DOI:10.1128/msphere.00024-25

mSystems. 2025 Mar 13:e0155624. doi: 10.1128/msystems.01556-24. Online ahead of print.ABSTRACTInflammatory bowel disease (IBD) is an immune-mediated gastrointestinal disorder that significantly impacts the life quality of people worldwide. Genetic factors play crucial roles in the development of IBD. Tas2rs, members of the G protein-coupled receptor (GPCR) superfamily, are known for their roles in bitter taste perception. However, Tas2rs have also been identified in the gut, where they help sense luminal contents and regulate gastrointestinal hormones. Periodontal Tas2r105 has been shown to modulate innate immunity by interacting with metabolites produced by oral bacteria. In this study, we observed increased Tas2r105 in the inflammatory colons induced by dextran sulfate sodium salt (DSS). We also noted that α-gustducin, the α-subunit of GPCRs, is present in the intestine, and that α-gustducin knockout mice exhibit aggravated colitis. Based on these findings, we hypothesize that Tas2r105 may play a role in immune regulation during IBD pathogenesis. To test this hypothesis, we used Tas2r105 knockout (KO) mice in a colitis model. Our results show that the KO mice had significantly shorter colon length, more severe colon inflammation, and greater destruction of the gut barrier compared with control mice. We also observed increased recruitment of macrophages to the lamina propria mucosa in the KO mice. Microbiological analysis revealed a significant increase in Proteobacteria and Bacteroidota, with a concomitant decrease in Firmicutes after Tas2r105 knockout. Metabolomic analysis showed a significant reduction in lysophosphatidylethanolamine (LPE) levels in the KO mice, which is known to have anti-inflammatory effects. Based on these findings, we speculate that Tas2r105 may help protect the intestine from inflammation by influencing the gut microbiota composition and LPE production.IMPORTANCEIncreased Tas2r105 was detected in the inflamed colon of mice outside the tongue. Tas2r105 deletion aggravated mice colon colitis. Tas2r105 might alleviate mice colitis by downregulating the Proteobacteria and the Bacteroidota abundance in the colon. Lysophosphatidylethanolamine (LPE) might be the key metabolite that mediated the intestinal protection of Tas2r105.PMID:40079578 | DOI:10.1128/msystems.01556-24

Plant Cell Environ. 2025 Mar 13. doi: 10.1111/pce.15474. Online ahead of print.ABSTRACTClubroot caused by Plasmodiophora brassicae, a soil-borne pathogen, threatens cruciferous plants, resulting in severe yield reductions. To identify genes and metabolites associated with clubroot resistance and susceptibility, we performed metabolome and transcriptome analyses of Brassica rapa inbred line CRBJN3-2 inoculated with resistant and susceptible P. brassicae strains. Co-expression network analysis revealed that trigonelline accumulation, linked to the nicotinic acid and nicotinamide metabolic pathways, was significantly higher in clubroot-susceptible plants. Furthermore, applying trigonelline externally aggravated clubroot in both B. rapa and Arabidopsis thaliana. Overexpression of the nicotinate N-methyltransferase gene (BrNANMT) responsible for the conversion from nicotinate to trigonelline in these plants increased disease susceptibility, while loss of this gene's function resulted in improved clubroot resistance. Our study is the first to reveal the function of trigonelline in promoting clubroot development and identify BrNANMT as a clubroot susceptibility gene and trigonelline can be used as a marker metabolite in response to P. brassicae infection. Gene editing of BrNANMT provides new insights for the development of Brassica crops with improved resistance to clubroot.PMID:40079515 | DOI:10.1111/pce.15474

Biotechnol Bioeng. 2025 Mar 13. doi: 10.1002/bit.28968. Online ahead of print.ABSTRACTIndustrial-scale microbial fermentation processes often face limitations in mixing and mass transfer, leading to the formation of environmental gradients within the bioreactor. These gradients expose microbes to heterogeneous conditions over time and space. In this study, we evaluated the effects of combined substrate and dissolved oxygen (DO) gradients on the metabolic response of Penicillium chrysogenum at an industrial scale. Three representative heterogeneous environments were simulated in scale-down systems: (1) feed inlet (high glucose, low oxygen (HGLO): CS > 20 mM, DO < 0.012 mM), (2) aeration inlet (high oxygen, low glucose (HOLG): CS < 0.8 mM, DO > 0.2 mM), and (3) global environment (periodic 360 s fluctuation cycle with 45 s of HGLO and 75 s of HOLG conditions). Results showed that prolonged exposure to feed inlet conditions led to a complete loss of penicillin production capacity, accompanied by significant excretion of intracellular metabolites, and this effect was largely irreversible. While, cells randomly walking under the top impeller zone did not lose production capacity but showed signs of premature degeneration due to increased energy demand. When exposed to the global environment, cells finely tuned their metabolism in a periodical manner, with nearly a 50% loss of penicillin productivity. In summary, substrate gradients alone did not cause irreversible effects, but large substrate gradients contributed to reduced productivity. Oxygen gradients, however, not only reduced production but also caused irreversible cellular damage. These findings provide valuable insights for developing scale-up criteria and strain engineering strategies aimed at improving large-scale culture performance.PMID:40079378 | DOI:10.1002/bit.28968

Cardiovasc Res. 2025 Mar 13:cvaf040. doi: 10.1093/cvr/cvaf040. Online ahead of print.ABSTRACTAIMS: Activation of the transcriptional factor Krüppel-like factor 5 (KLF5) is detrimental to chronic heart failure. We explored the involvement of KLF5 in myocardial ischemia/reperfusion injury.METHODS AND RESULTS: Yorkshire pigs underwent 75΄ of ischemia, followed by 3h or 24h of reperfusion. C57BL/6J mice underwent 30΄ of ischemia, followed by 10', 2h, 12h, 24h, or 4 weeks of reperfusion. Hearts and isolated cardiomyocytes were analyzed for gene expression. We assessed cardiac function, infarct size (IS), oxidative stress, and fibrosis in mice subjected to pharmacologic or genetic KLF5 inhibition, as well as pharmacologic inhibition of NADPH oxidases or Glucose Transporter (GLUT)1 and GLUT4. Bulk RNA sequencing, untargeted 1H-NMR metabolomics and LC-MS lipidomics were performed. Isolated primary murine cardiomyocytes were infected with recombinant adenovirus expressing KLF5. During reperfusion, cardiοmyocyte KLF5 expression was increased in porcine and murine hearts. Pharmacologic or cardiomyocyte-specific genetic inhibition of KLF5 reduced IS and improved cardiac function in mice. Importantly, acute KLF5 inhibition during early reperfusion suppressed fibrosis and preserved systolic cardiac function 4 weeks post-ischemia/reperfusion. This improvement was associated with lower NOX4 expression, less oxidative stress, and suppressed inflammation and cell apoptosis. Pharmacologic inhibition of NOX4 conferred the same benefit. Metabolomic analysis indicated that KLF5 inhibition lowered glucose-derived metabolites (UDP-Glucose and Lactate) at early reperfusion. Accordingly, cardiac GLUT1 and GLUT4 levels were increased with ischemia/reperfusion, which was reverted by KLF5 inhibition. Pharmacologic inhibition of both GLUT1/4 reduced IS. Finally, myocardial KLF5 overexpression increased GLUT1 mRNA levels and mouse mortality.CONCLUSIONS: Ischemia/reperfusion increases cardiomyocyte KLF5 expression in pigs and mice. This constitutes a central element of myocardial injury pathophysiology and is associated with stimulation of GLUT1 and GLUT4 expression, activation of NOX4, oxidative stress, inflammation and apoptosis. Acute KLF5 inhibition during reperfusion constitutes a novel therapeutic approach against myocardial ischemia/reperfusion injury.PMID:40079359 | DOI:10.1093/cvr/cvaf040

J Am Heart Assoc. 2025 Mar 13:e038945. doi: 10.1161/JAHA.124.038945. Online ahead of print.ABSTRACTBACKGROUND: Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all HF but has few effective therapies. Recent human myocardial transcriptomics and metabolomics have identified major differences between HFpEF and controls. How this translates at the protein level is unknown.METHODS AND RESULTS: Myocardial tissue from patients with HFpEF and nonfailing donor controls was analyzed by data-dependent acquisition (n=10 HFpEF, n=10 controls) and data-independent acquisition (n=44 HFpEF, n=5 controls) mass spectrometry-based proteomics. Differential protein expression analysis, pathway overrepresentation, weighted coexpression network analysis, and machine learning were integrated with clinical characteristics and previously reported transcriptomics. Principal component analysis (data-dependent acquisition-mass spectrometry) found HFpEF separated into 2 subgroups: one similar to controls and the other disparate. Downregulated proteins in HFpEF versus controls were enriched in mitochondrial transport/organization, translation, and metabolism including oxidative phosphorylation. Proteins upregulated in HFpEF were related to immune activation, reactive oxygen species, and inflammatory response. Ingenuity pathway analysis predicted downregulation of protein translation, mitochondrial function, and glucose and fat metabolism in HFpEF. Expression of oxidative phosphorylation and metabolism genes (higher) versus proteins (lower) was discordant in HFpEF versus controls. Data-independent acquisition-mass spectrometry proteomics also yielded 2 HFpEF subgroups; the one most different from controls had a higher proportion of patients with severe obesity and exhibited lower proteins related to fuel metabolism, oxidative phosphorylation, and protein translation. Three modules of correlated proteins in HFpEF that correlated with left ventricular hypertrophy and right ventricular load related to (1) proteasome; (2) fuel metabolism; and (3) protein translation, oxidative phosphorylation, and sarcomere organization.CONCLUSIONS: Integrative proteomics, transcriptomics, and pathway analysis supports a defect in both metabolism and translation in HFpEF. Patients with HFpEF with more distinct proteomic signatures from control more often had severe obesity, supporting therapeutic efforts targeting metabolism and translation, particularly in this subgroup.PMID:40079330 | DOI:10.1161/JAHA.124.038945

J Sci Food Agric. 2025 Mar 13. doi: 10.1002/jsfa.14215. Online ahead of print.ABSTRACTBACKGROUND: Applying organic amendments to vineyard soil improves soil properties and vine development by increasing soil water retention and nutrient content. However, little is known about how organic mulches modify grapevine phenolic composition. This study analysed the phenolic profile in the leaves, canes, and grape skins of Tempranillo over 3 years in two vineyard locations with three organic mulches: spent mushroom compost (SMC), grapevine pruning debris (GPD) and straw (STR), as well as two conventional soil practices: herbicide (HERB) and tillage (TILL).RESULTS: Seventy phenolic compounds were identified and quantified in leaves, canes and grape skins. The phenolic biosynthetic accumulation differed among the soil management practices according to field conditions. In nutrient-deficient soils, the nutrient-rich SMC mulch enhanced plant nutrition resources for primary metabolism, reducing the phenolic accumulation in grapevine tissues. However, this behaviour was not described in a non-limited soil nutritional content. The GPD and STR mulches, with slow decomposition rates, slightly differed from conventional practices and could have a long-term effect on plant phenolic accumulation. Despite the variations observed between soil treatments, the grape phenolic profile did not change enough to affect the grape quality significantly.CONCLUSIONS: This research represents the most detailed study on the impact of organic mulches on the phenolic profile of grapevine tissues. These findings suggest that organic mulches in vineyards constitute a viable alternative for soil management, benefiting both soil physical and chemical properties and plant development without altering the grape quality. © 2025 Society of Chemical Industry.PMID:40079208 | DOI:10.1002/jsfa.14215