PubMed

BMC Bioinformatics. 2024 Dec 18;25(1):383. doi: 10.1186/s12859-024-05994-1.ABSTRACTBACKGROUND: Metabolomics is a high-throughput technology that measures small molecule metabolites in cells, tissues or biofluids. Analysis of metabolomics data is a multi-step process that involves data processing, quality control and normalization, followed by statistical and bioinformatics analysis. The latter step often involves pathway analysis to aid biological interpretation of the data. This approach is limited to endogenous metabolites that can be readily mapped to metabolic pathways. An alternative to pathway analysis that can be used for any classes of metabolites, including unknown compounds that are ubiquitous in untargeted metabolomics data, involves defining metabolite-metabolite interactions using experimental data. Our group has developed several network-based methods that use partial correlations of experimentally determined metabolite measurements. These were implemented in CorrelationCalculator and Filigree, two software tools for the analysis of metabolomics data we developed previously. The latter tool implements the Differential Network Enrichment Analysis (DNEA) algorithm. This analysis is useful for building differential networks from metabolomics data containing two experimental groups and identifying differentially enriched metabolic modules. While Filigree is a user-friendly tool, it has certain limitations when used for the analysis of large-scale metabolomics datasets.RESULTS: We developed the DNEA R package for the data-driven network analysis of metabolomics data. We present the DNEA workflow and functionality, algorithm enhancements implemented with respect to the package's predecessor, Filigree, and discuss best practices for analyses. We tested the performance of the DNEA R package and illustrated its features using publicly available metabolomics data from the environmental determinants of diabetes in the young. To our knowledge, this package is the only publicly available tool designed for the construction of biological networks and subsequent enrichment testing for datasets containing exogenous, secondary, and unknown compounds. This greatly expands the scope of traditional enrichment analysis tools that can be used to analyze a relatively small set of well-annotated metabolites.CONCLUSIONS: The DNEA R package is a more flexible and powerful implementation of our previously published software tool, Filigree. The modular structure of the package, along with the parallel processing framework built into the most computationally extensive steps of the algorithm, make it a powerful tool for the analysis of large and complex metabolomics datasets.PMID:39695921 | DOI:10.1186/s12859-024-05994-1

Stem Cell Res Ther. 2024 Dec 18;15(1):479. doi: 10.1186/s13287-024-04092-6.ABSTRACTBACKGROUND: Multi-lineage differentiation of mesenchymal adult stem cells (m-ASCs) is crucial for tissue regeneration and accompanied with metabolism reprogramming, among which dental-pulp-derived m-ASCs has obvious advantage of easy accessibility. Stem cell fate determination and differentiation are closely related to metabolism status in cell microenvironment, which could actively interact with epigenetic modification. In recent years, glutamine-α-ketoglutarate (αKG) axis was proved to be related to aging, tumorigenesis, osteogenesis etc., while its role in m-ASCs still lack adequate research evidence.METHODS: We employed metabolomic analysis to explore the change pattern of metabolites during dental-pulp-derived m-ASCs differentiation. A murine incisor clipping model was established to investigate the influence of αKG on dental tissue repairment. shRNA technique was used to knockdown the expression of related key enzyme-dehydrogenase 1(GLUD1). RNA-seq, m6A evaluation and MeRIP-qPCR were used to dig into the underlying epigenetic mechanism.RESULTS: Here we found that the glutamine-αKG axis displayed an increased tendency along with the osteo/odontogenic differentiation of dental-pulp-derived m-ASCs, same as expression pattern of GLUD1. Further, the key metabolite αKG was found able to accelerate the repairment of clipped mice incisor and promote dentin formation. Exogenous DM-αKG was proved able to promote osteo/odontogenic differentiation of dental-pulp-derived m-ASCs, while the inhibition of glutamine-derived αKG level via GLUD1 knockdown had the opposite effect. Under the circumstance of GLUD1 knockdown, extracellular matrix (ECM) function and PI3k-Akt signaling pathway was screened out to be widely involved in the process with insulin-like growth factor 2 (IGF2) participation via RNA-seq. Inhibition of glutamine-αKG axis may affect IGF2 translation efficiency via m6A methylation and can be significantly rescued by αKG supplementation.CONCLUSION: Our findings indicate that glutamine-αKG axis may epigenetically promote osteo/odontogenic differentiation of dental-pulp-derived m-ASCs and dentin regeneration, which provide a new research vision of potential dental tissue repairment therapy method or metabolite-based drug research.PMID:39695862 | DOI:10.1186/s13287-024-04092-6

Environ Microbiome. 2024 Dec 18;19(1):109. doi: 10.1186/s40793-024-00647-5.ABSTRACTWhile waves, swells and currents are important drivers of the ocean, their specific influence on the biocolonization of marine surfaces has been little studied. The aim of this study was to determine how hydrodynamics influence the dynamics of microbial communities, metabolic production, macrofoulers and the associated vagile fauna. Using a field device simulating a shear stress gradient, a multi-scale characterization of attached communities (metabarcoding, LC-MS, biochemical tests, microscopy) was carried out for one month each season in Toulon Bay (northwestern Mediterranean). Shear stress appeared to be the primary factor influencing biomass, EPS production and community structure and composition. Especially, the transition from static to dynamic conditions, characterized by varying shear stress intensities, had a more pronounced effect on prokaryotic and eukaryotic beta-diversity than changes in shear stress intensity or seasonal physico-chemical parameters. In static samples, mobile microbe feeders such as arthropods and nematodes were predominant, whereas shear stress favored the colonization of sessile organisms and heterotrophic protists using the protective structure of biofilms for growth. The increase in shear stress resulted in a decrease in biomass but an overproduction of EPS, specifically exopolysaccharides, suggesting an adaptive response to withstand shear forces. Metabolite analysis highlighted the influence of shear stress on community dynamics. Specific metabolites associated with static conditions correlated positively with certain bacterial and algal groups, indirectly indicating reduced grazer control with increasing shear stress.PMID:39695832 | DOI:10.1186/s40793-024-00647-5

Parasit Vectors. 2024 Dec 18;17(1):522. doi: 10.1186/s13071-024-06610-0.ABSTRACTBACKGROUND: Toxoplasma gondii is an obligate protozoan parasite capable of infecting a wide range of warm-blooded animals and humans. Current treatment options, primarily pyrimethamine and sulfadiazine, have limitations, such as high recurrence rates, long treatment durations, and limited effectiveness against T. gondii. There is an unmet need for novel, safe, low-toxicity, and highly effective treatments. This study aimed to evaluate the anti-T. gondii effects of glabridin, a natural compound derived from the roots of a widely used medicinal plant.METHODS: The cytotoxicity of glabridin in Vero cells was assessed using a CCK-8 cell viability assay. Quantitative polymerase chain reaction (qPCR) targeting the Tg-529 gene was developed to quantify T. gondii and assess the inhibitory effects of glabridin on parasite proliferation. Ultrastructural changes in T. gondii after treatment were examined using electron microscopy. The levels of reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were examined to assess the effects of glabridin on ROS levels and ΔΨm in T. gondii tachyzoites. Additionally, metabolomics and transcriptomics analyses were conducted to investigate the mechanisms underlying glabridin's anti-T. gondii effects.RESULTS: Glabridin exhibited low toxicity to host cells and effectively inhibited T. gondii invasion and proliferation in vitro in a time-dependent manner. Glabridin-treated tachyzoites exhibited significant structural alterations, along with increased ROS production and a reduction in ΔΨm. Metabolomic analysis indicated that glabridin significantly affected amino acid metabolism pathways in T. gondii. In vivo, glabridin treatment significantly improved survival rates in T. gondii-infected BALB/c mice at a dosage of 100 mg/kg.CONCLUSIONS: This study demonstrates that glabridin has potent anti-T. gondii effects in vitro and in vivo, likely through disruption of amino acid metabolism in the parasite. These findings highlight glabridin's potential as a promising therapeutic agent for toxoplasmosis.PMID:39695816 | DOI:10.1186/s13071-024-06610-0

Cell Commun Signal. 2024 Dec 18;22(1):599. doi: 10.1186/s12964-024-01983-2.ABSTRACTBACKGROUND: The innate immune system serves as the host's first line of defense against invading pathogens. Stimulator of interferon genes (STING) is a key component of this system, yet its relationship with glucose metabolism, particularly in antiviral immunity, remains underexplored.METHODS: Metabolomics analysis was used for detecting metabolic alterations in spleens from STING knockout (KO) and wild-type (WT) mice. Co-immunoprecipitation was employed for determining ubiquitination of TKT. Mass spectrometry was used for detecting interaction proteins of STING. Enzyme activity kits were used for detecting the activities of TKT and G6PD.RESULTS: In this study, we demonstrate that herpes simplex virus (HSV) infection activates the pentose phosphate pathway (PPP) in host cells, thereby initiating an antiviral immune response. Using STING-manipulated cells and systemic knockout mice, we show that STING positively regulates PPP, which, in turn, limits HSV infection. Inhibition of the PPP significantly reduced the production of antiviral immune factors and dampened STING-induced innate immune responses. Mechanistically, we discovered that STING interacts with transketolase (TKT), a key enzyme in the non-oxidative branch of the PPP, and reduces its ubiquitination via the E3 ubiquitin ligase UBE3A, stabilizing TKT. Silencing TKT or inhibiting its activity with oxythiamine diminished antiviral immune factor production.CONCLUSION: Our findings reveal that the PPP plays a synergistic role in generating antiviral immune factors during viral infection and suggest that PPP activation could serve as an adjunct strategy for antiviral therapy.PMID:39695767 | DOI:10.1186/s12964-024-01983-2

Cardiovasc Diabetol. 2024 Dec 18;23(1):446. doi: 10.1186/s12933-024-02505-7.ABSTRACTBACKGROUND: Type 2 diabetes (T2D) has become a worldwide pandemic. While ceramides may serve as intermediary between obesity-related lipotoxicity and T2D, the relationship with simple glycosphingolipids remains uncertain. The aim of this study was to characterize the associations between blood glycosphingolipid and ceramide species with T2D and to identify a circulating sphingolipid profile that could serve as novel biomarker for T2D risk.METHODS: Cross-sectional relationship between sphingolipid levels, insulin resistance, and T2D prevalence were evaluated in 2,072 American adults from MIDUS cohort. Prospectively, the association between sphingolipid species and the incidence of T2D was analyzed using a case-cohort design nested within the PREDIMED trial (250 cases and a random sample of 692 participants, with 3.8 years of median follow-up). Circulating levels of sphingolipid species in both populations were measured using LC/MS. Hazard ratios were estimated with weighted Cox regression models using Barlow weights.RESULTS: In American adults, only CER18:0 and CER22:0 were linked to insulin resistance and a higher prevalence of T2D. Conversely, three lactosylceramides (LCER 14:0, 16:0, and 24:1) showed a strong inverse relationship with both insulin resistance and T2D. These findings led to development of two sphingolipid scores. In the prospective analysis, these scores consistently predicted a reduced risk of T2D incidence in PREDIMED (HR: 0.64, 95% CI 0.44 to 0.94 and 0.58, 0.40 to 0.85 respectively) between extreme quartiles, with 5-year absolute risk differences of 9.6% (95% CI: 0.3-20.5%) and 11.4% (1.0-21.6%). They were validated in the same trial with samples obtained after 1 year of follow-up.CONCLUSIONS: Our findings support the potential usefulness of circulating sphingolipid profiles as novel biomarkers for T2D risk. Moreover, this study opens the door for future research on the predictive value and possible protective roles of lactosylceramides in T2D.PMID:39695759 | DOI:10.1186/s12933-024-02505-7

Nutr Metab (Lond). 2024 Dec 18;21(1):106. doi: 10.1186/s12986-024-00876-y.ABSTRACTIntermittent fasting is currently a highly sought-after dietary pattern. To explore the potential biomarkers of intermittent fasting, untargeted metabolomics analysis of fecal metabolites in two groups of mice, intermittent fasting and normal feeding, was conducted using UPLC-HRMS. The data was further analyzed through interpretable machine learning (ML) to data mine the biomarkers for two dietary patterns. We developed five machine learning models and results showed that under three-fold cross-validation, Random Forest model was the most suitable for distinguishing the two dietary patterns. Finally, Shapely Additive exPlanations (SHAP) were explored to perform a weighted explanatory analysis on the Random Forest model, and the contribution of each metabolite to the model was calculated. Results indicated that Ganoderenic Acid C is the potential biomarkers to distinguish the two dietary patterns. Our work provides new insights for metabolic biomarker analysis and lays a theoretical foundation for the selection of a healthieir dietary lifestyle.PMID:39695671 | DOI:10.1186/s12986-024-00876-y

BMC Biol. 2024 Dec 18;22(1):292. doi: 10.1186/s12915-024-02087-6.ABSTRACTBACKGROUND: Many members of the oxysterol-binding protein-related protein (ORP) family have been characterized in detail over the past decades, but the lipid transport and other functions of ORP7 still remain elusive. What is known about ORP7 points toward an endoplasmic reticulum and plasma membrane-localized protein, which also interacts with GABA type A receptor-associated protein like 2 (GABARAPL2) and unlipidated Microtubule-associated proteins 1A/1B light chain 3B (LC3B), suggesting a further autophagosomal/lysosomal association. Functional roles of ORP7 have been suggested in cholesterol efflux, hypercholesterolemia, and macroautophagy. We performed a hypothesis-free multi-omics analysis of chemical ORP7 inhibition utilizing transcriptomics and lipidomics as well as proximity biotinylation interactomics to characterize ORP7 functions in a primary cell type, human umbilical vein endothelial cells (HUVECs). Moreover, assays on angiogenesis, cholesterol efflux, and lipid droplet quantification were conducted.RESULTS: Pharmacological inhibition of ORP7 leads to an increase in gene expression related to lipid metabolism and inflammation, while genes associated with cell cycle and cell division were downregulated. Lipidomic analysis revealed increases in ceramides and lysophosphatidylcholines as well as saturated and monounsaturated triacylglycerols. Significant decreases were seen in all cholesteryl ester and in some unsaturated triacylglycerol species, compatible with the detected decrease of mean lipid droplet area. Along with the reduced lipid stores, ATP-binding cassette subfamily G member 1 (ABCG1)-mediated cholesterol efflux and angiogenesis decreased. Interactomics revealed an interaction of ORP7 with AKT1, a central metabolic regulator.CONCLUSIONS: The transcriptomics results suggest an increase in prostanoid as well as oxysterol synthesis, which could be related to the observed upregulation of proinflammatory genes. We envision that the defective angiogenesis in HUVECs subjected to ORP7 inhibition could be the result of an unfavorable plasma membrane lipid composition and/or reduced potential for cell division. To conclude, the present study suggests multifaceted functions of ORP7 in lipid homeostasis, angiogenic tube formation, and gene expression of lipid metabolism, inflammation, and cell cycle in primary endothelial cells.PMID:39695567 | DOI:10.1186/s12915-024-02087-6

BMC Cancer. 2024 Dec 18;24(1):1545. doi: 10.1186/s12885-024-13286-3.ABSTRACTOBJECT: Aim to investigate the multi-omic characteristics of the bone marrow supernatant of relapsed acute myeloid leukemia (AML) and search for proteins and metabolites associated with relapse.METHODS: A total of 40 bone marrow supernatant from 7 patients with relapsed AML and 33 patients with non-relapsed AML were collected for proteomics and metabonomics analysis. Unsupervised clustering was used to discover the characteristics of proteins and metabolites. The prognostic significances of proteins were assessed concerning the relapse status(including death) and relapse-free survival.RESULT: Totally 996 proteins and 4,831 metabolites were identified in bone marrow supernatant, and two of 7 clusters were revealed through unsupervised clustering and were associated with ASXL1, TP53, and RUNX1 mutations, which were listed as high-risk factors in the 2022 edition of the WHO classification of tumors of the hematopoietic and lymphoid tissues. Among the identified proteins and metabolites, 57 proteins and 190 metabolites were found to be closely related to relapse.CONCLUSION: This study has revealed a significant correlation between protein expression in the bone marrow microenvironment of AML and three high-risk mutations: ASXL1, TP53, and RUNX1. Based on this finding, we further identified 227 differential proteins closely associated with these three mutations, as well as 57 proteins directly related to disease recurrence. Additionally, lipid metabolism plays a crucial role in the occurrence and development of AML within its bone marrow microenvironment.PMID:39695514 | DOI:10.1186/s12885-024-13286-3

Clin Proteomics. 2024 Dec 18;21(1):66. doi: 10.1186/s12014-024-09514-4.ABSTRACTBACKGROUND: Tuberculosis (TB) diagnostic monitoring is paramount to clinical decision-making and the host biomarkers appears to play a significant role. The currently available diagnostic technology for TB detection is inadequate. In the present study, we aimed to identify biomarkers for diagnosis of pulmonary tuberculosis (PTB) using urinary metabolomic and proteomic analysis.METHODS: In the study, urine from 40 PTB, 40 lung cancer (LCA), 40 community-acquired pneumonia (CAP) patients and 40 healthy controls (HC) was collected. Biomarker panels were selected based on random forest (RF) analysis.RESULTS: A total of 3,868 proteins and 1,272 annotated metabolic features were detected using pairwise comparisons. Using AUC ≥ 0.80 as a cutoff value, we picked up five protein biomarkers for PTB diagnosis. The five-protein panel yielded an AUC for PTB/HC, PTB/CAP and PTB/LCA of 0.9840, 0.9680 and 0.9310, respectively. Additionally, five metabolism biomarkers were selected for differential diagnosis purpose. By employment of the five-metabolism panel, we could differentiate PTB/HC at an AUC of 0.9940, PTB/CAP of 0.8920, and PTB/LCA of 0.8570.CONCLUSION: Our data demonstrate that metabolomic and proteomic analysis can identify a novel urine biomarker panel to diagnose PTB with high sensitivity and specificity. The receiver operating characteristic curve analysis showed that it is possible to perform non-invasive clinical diagnoses of PTB through these urine biomarkers.PMID:39695396 | DOI:10.1186/s12014-024-09514-4

Gut Microbes. 2025 Dec;17(1):2440120. doi: 10.1080/19490976.2024.2440120. Epub 2024 Dec 18.ABSTRACTDiet is one of the main factors shaping the human microbiome, yet our understanding of how specific dietary components influence microbial consortia assembly and subsequent stability in response to press disturbances - such as increasing resource availability (feeding rate) - is still incomplete. This study explores the reproducible re-assembly, metabolic interplay, and compositional stability within microbial consortia derived from pooled stool samples of three healthy infants. Using a single-step packed-bed reactor (PBR) system, we assessed the reassembly and metabolic output of consortia exposed to lactose, glucose, galacto-oligosaccharides (GOS), and humanized GOS (hGOS). Our findings reveal that complex carbohydrates, especially those containing low inclusion (~1.25 gL-1) components present in human milk, such as N-acetyl-lactosamine (LacNAc), promote taxonomic, and metabolic stability under varying feeding rates, as shown by diversity metrics and network analysis. Targeted metabolomics highlighted distinct metabolic responses to different carbohydrates: GOS was linked to increased lactate, lactose to propionate, sucrose to butyrate, and CO2, and the introduction of bile salts with GOS or hGOS resulted in butyrate reduction and increased hydrogen production. This study validates the use of single-step PBRs for reliably studying microbial consortium stability and functionality in response to nutritional press disturbances, offering insights into the dietary modulation of microbial consortia and their ecological dynamics.PMID:39695352 | DOI:10.1080/19490976.2024.2440120

Cell Death Dis. 2024 Dec 18;15(12):901. doi: 10.1038/s41419-024-07300-6.ABSTRACTBreast cancer (BC) is a common malignant tumor in women and requires a comprehensive understanding of its pathogenesis for the development of new therapeutic strategies. Polyunsaturated fatty acids (PUFAs) metabolism-driven inflammation is a causative factor in cancer development. However, the function of PUFAs' metabolism in BC remains largely unknown. Here we report the role and underlying mechanism of epoxyoctadecenoic acids (EpOMEs), the metabolites of linoleic acid mediated by cytochrome P450 (CYP) monooxygenases, in promoting the development of BC, particularly triple-negative BC (TNBC). A metabolomics study identified that EpOMEs were significantly increased in the plasma of BC patients and MMTV-PyMT mice, which accounted for the upregulation of CYP2J2 in BC tumor tissues and tumor cells. Decreased EpOMEs by treatment of CYP monooxygenase inhibitors significantly alleviated tumor development in MMTV-PyMT mice. Treatment with EpOMEs and overexpression of CYP2J2 to increase EpOMEs in TNBC cells significantly promoted cellular proliferation, migration, tumor growth, and metastasis. Whereas knockdown of CYP2J2 to decrease EpOMEs inhibited tumorigenesis and lung metastasis of TNBC, which was reversed by EpOME administration. Transcriptomics and proteomics analyses revealed CXCL9 and PLEC were critical for EpOME-mediated promotion of TNBC. Knockdown of CXCL9 and PLEC inhibited TNBC progression and EpOME-mediated promotion of TNBC. Both overexpression of CYP2J2 and EpOME treatment upregulate PLEC, while PLEC upregulates NFκB1, which is a transcription regulator of CXCL9. This study extends the understanding of the function of PUFAs metabolism in BC development, providing potential therapeutic targets and dietary guidelines for patients with TNBC and other BCs. The illustration of the hypothetical mechanism CYP2J2/EpOMEs promotes the tumorigenesis and metastasis of TNBC via PLEC/NFKB1/CXCL9 signaling pathway.PMID:39695149 | DOI:10.1038/s41419-024-07300-6

Geroscience. 2024 Dec 18. doi: 10.1007/s11357-024-01454-z. Online ahead of print.ABSTRACTExtracellular vesicles (EVs) play crucial roles in aging. In this National Institutes on Aging-funded study, we sought to identify circulating extracellular vesicle (EV) biomarkers indicative of longevity. The plasma EV proteome of 48 older adults (mean age 77.2 ± 1.7 years [range 72-80]; 50% female, 50% Black, 50% < 2-year survival, 50% ≥ 10-year survival) was analyzed by high-resolution mass spectrometry and flow cytometry. The ability of EV peptides to predict longevity was evaluated in discovery (n = 32) and validation (n = 16) datasets with areas under receiver operating characteristic curves (AUCs). Longevity-associated large EV (LEV) plasma subpopulations were mainly related to immune cells (HLA-ABC+, CD9+, and CD31+) and muscle cells (MCAD+ and RyR2+). Of 7960 identified plasma EV peptides (519 proteins), 46.4% were related to the immune system and 10.1% to muscle. Compared with short-lived older adults, 756 EV peptides (131 proteins) had a higher abundance, and 130 EV peptides (78 proteins) had a lower abundance in long-lived adults. Among longevity-associated peptides, 437 (58 proteins) were immune system related, and 12 (2 proteins) were muscle related. Using just three to five plasma EV peptides (mainly complement components C2-C6), we achieved high predictive accuracy for longevity (AUC range 0.91-1 in a hold-out validation dataset). Our findings suggest that immune cells produce longevity-associated plasma EVs and elucidate fundamental mechanisms regulating aging and longevity. EV longevity predictors suggest there may be merit in targeting complement pathways to extend lifespan, for instance, with any one of the multiple complement inhibitors currently available or in clinical development.PMID:39695065 | DOI:10.1007/s11357-024-01454-z

J Ethnopharmacol. 2024 Dec 16:119247. doi: 10.1016/j.jep.2024.119247. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Ischemic stroke (IS) is a leading cause of death and disability in China. Danhong Injection (DHI) is a traditional Chinese medicine preparation made from Salvia miltiorrhiza var. miltiorrhiza and Carthamus tinctorius L. It is used for treating stroke in China with proven safety and efficacy. Microglia M1/M2 polarization is a key factor in IS inflammatory response. However, the key transcription factors that regulate microglia polarisation are unknown. It is also not clear how DHI exerts its mechanism in the treatment of IS.AIM OF THE STUDY: This research aimed to investigate the effect of DHI on microglial polarization and neuroinflammation associated with IS and to elucidate the underlying mechanisms, with an emphasis on the JUNB/NF-κB signaling pathway.MATERIALS AND METHODS: An oxygen-glucose deprivation (OGD) damage cell model and a permanent middle cerebral artery occlusion (pMCAO) model in C57BL/6 mice were employed. Neurological deficits, cerebral infarct volume, and microglial activation were assessed. Non-targeted metabolomics analysis with UHPLC-QE-MS and molecular biology methods, including RT-qPCR and Western blot, were applied to investigate the mechanisms.RESULTS: In vivo, DHI decreased inflammation, reduced brain damage, and enhanced neurological function. DHI also ameliorated microglial activation and OGD-induced apoptosis in vitro. Metabolomics analysis identified significant metabolic changes, particularly in amino acid metabolism. Additionally, DHI treatment decreased the upregulated mRNA levels of ASS1 and ASL after OGD, indicating an influence on the arginine biosynthesis pathway, which is crucial for microglial function. DHI modulated the M1 to M2 phenotypes of microglial polarization and regulated microglial polarization through the JUNB/NF-κB signaling pathway. This was confirmed by JUNB silencing experiments.CONCLUSIONS: DHI exhibits neuroprotective effects via suppressing ASS1 through the JUNB/NF-κB pathway, promoting the M2 state of microglia, and lowering the expression of inflammatory cytokines. This research unveils the potential therapeutic target of JUNB for IS treatment and sheds light on the novel intervention mechanism of DHI in microglial cells.PMID:39694424 | DOI:10.1016/j.jep.2024.119247

Int J Biol Macromol. 2024 Dec 16:138864. doi: 10.1016/j.ijbiomac.2024.138864. Online ahead of print.ABSTRACTBACKGROUND: Ensiling technology shows promise for preserving and providing high-quality forage. However, the high polymeric content and compact properties of fiber result in low biodigestibility. This study aimed to evaluate the use of ensiling technology for storing wheat straw. It also analyzed changes in fermentation-related products, chemical components, bacterial communities, and metabolite profiles of wheat straw ensiled with or without cellulase or Lactiplantibacillus plantarum (L. plantarum).RESULTS: The results showed that inoculation with L. plantarum, either alone or with cellulase, produced abundant organic acids, degraded fiber, suppressed most microbes, and increased certain metabolites in wheat straw silage. Wheat straw inoculated with L. plantarum, either alone or with cellulase, exhibited significantly lower neutral detergent fiber and acid detergent fiber contents compared to the control treatment. Additionally, higher lactic acid and acetic acid contents were observed in these treatments. The microbiome analysis revealed that Lactobacillus was dominant, while Kosakonia was suppressed. Metabolic analysis showed a significant increase in amino acids, peptides, analogues, and organic acid derivatives.CONCLUSIONS: Overall, wheat straw inoculated with L. plantarum, either alone or with cellulase, produced well-preserved silage, providing new insights into recycling and utilizing wheat straw through bacterial-enzyme synergy.PMID:39694364 | DOI:10.1016/j.ijbiomac.2024.138864

Toxicol Appl Pharmacol. 2024 Dec 16:117207. doi: 10.1016/j.taap.2024.117207. Online ahead of print.ABSTRACTAcute kidney injury (AKI) is one of the most important indications of severe clinical symptoms in patients with diquat poisoning and is closely related to poor prognosis. However, current studies have rarely focused on early warnings of diquat-related AKI, which is not conducive to the treatment of patients with early clinical diquat poisoning. In this study, untargeted plasma metabolomics was employed to reveal the differences between diquat-poisoned patients with and without AKI, as well as between patients and healthy volunteers. The results showed that 48 metabolites were significantly changed in the patients, among which 3-hydroxybutyrylcarnitine, SAICAR, dodecanoic acid, and tetrahydrofolyl-[Glu](2) could be used to effectively differentiate the above three groups. Based on the ratios of the first two metabolites and the ratios of the last two metabolites, a decision tree model for the early warning of diquat-induced AKI was established with an accuracy rate of 88.7 %. This model provides great support for accurate clinical diagnosis and intervention regarding the AKI risk of diquat-exposed patients.PMID:39694104 | DOI:10.1016/j.taap.2024.117207

Thromb Haemost. 2024 Dec 18. doi: 10.1055/a-2504-0903. Online ahead of print.ABSTRACTBackground and Purpose This study aimed to explore the relationship between lipidomic domains, particularly free fatty acids (FFAs), and the presence of AF in patients with acute stroke, and to identify mechanisms of AF-associated stroke through genetic studies. Methods A total of 483 patients of stroke in patients without AF (n = 391) and with AF (n = 92) were selected from a prospectively collected stroke registry. Lipidomic profiling was conducted and the lipid components associated with AF were explored using fold-change analyses and clustering. Genotyping was conducted through trait comparison. Colocalization was also performed. Results Among the lipidomic domains, the free fatty acid (FFA) class was positively associated with AF. Long-chain fatty acids with 14-24 carbons and unsaturated FFAs distinguished AF. Clustering analysis based on FFAs revealed differences in AF proportion across groups. GWAS identified two loci associated with clustered groups of FFA metabolites: near MIR548F3 associated with FFA 20:1, FFA 20:2, FFA 22:5, and FFA 22:6; and near RPL37A associated with FFA 22:5 and FFA 22:6. These loci were associated with increased fibrinogen levels. In the GWAS for the FFA metabolite-quantitative trial locus analysis, loci near rs28456 and rs3770088, and FFA 20:4-QTLs were co-localized with the eQTLs of FADS2, a gene involved in the peroxisome proliferative-activated receptor gamma-related signaling pathway, in the whole blood, left ventricle, and atrial appendage tissue. Conclusion Elevated FFA levels, especially those of long-chain unsaturated FFAs, are strongly associated with AF-associated stroke. This relationship is regulated by the peroxisome proliferator-activated receptor gamma-related signaling pathway.PMID:39694057 | DOI:10.1055/a-2504-0903

Poult Sci. 2024 Oct 28;104(1):104381. doi: 10.1016/j.psj.2024.104381. Online ahead of print.ABSTRACTFree-caged rearing modes, which prioritize animal welfare, are believed to enhance the quality of animal products. The impact of rearing modes on meat quality may play a key role in the superior quality of local chicken breeds. This study analyzed the cecal contents of free-range and caged black-bone chickens at different ages using metagenomic and metabolomic sequencing. We identified 32 metabolites and 367 microbial species significantly affected by the rearing mode. Linear discriminant analysis Effect Size (LefSe) highlighted five key microorganisms, Gemmiger formicilis, Bacteria unclassified, Bacteroides sp. ET225, Massilistercora timonensis, and Bacteroidales unclassified, that showed distinct abundance patterns across all age points. Among them, Bacteroides sp. ET225 and Massilistercora timonensis were positively associated with certain phospholipids and plant-derived metabolites, while negatively correlated with others like demissidine and acylcarnitine. Functional analysis revealed that rearing modes impact gut metabolites involved in gut metabolism as well as broader processes such as signal transduction, protein digestion, and autophagy. This study offers new insights into how rearing modes influence gut microbiota and metabolites, shedding light on the study of rearing mode-mediated muscle development and fat deposition.PMID:39693966 | DOI:10.1016/j.psj.2024.104381

Biomed Pharmacother. 2024 Dec 17;182:117773. doi: 10.1016/j.biopha.2024.117773. Online ahead of print.ABSTRACTIfosfamide causes neurotoxicity, including sometimes fatal encephalopathy, in a small number of patients. Why and how this occurs is not fully understood. It is generally believed that N-dechloroethylation of ifosfamide to 2-chloroacetaldehyde is the cause. A total of 61 patients were investigated, 49 who received ifosfamide and pazopanib and 12 treated with ifosfamide and sunitinib. Plasmas were analyzed by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS) and by gas chromatography-mass spectrometry (GC-MS). Neurotoxicity occurred in 25/61 patients, including four with encephalopathy. UPLC-QTOFMS revealed that N-dechloroethylation was unlikely to be the cause but did divulge in plasma that 2-chloroethylamine, 3-phosphoserine, uridine 3'-diphosphate 5'-diphosphate, Cer(d16:1/17:0), Cer(d16:0/16:0), and thyroxine were associated with encephalopathy. GC-MS analysis showed that palmitic, oleic and stearic acids increased significantly in plasma only in nonencephalopathic patients, suggesting impaired long-chain fatty acid oxidation but an alternative metabolic pathway in encephalopathic patients. Glycine, alanine, serine, glutamate and 5-oxoproline all decreased significantly only in encephalopathic plasmas, signifying increased de novo GSH synthesis. Taken together, these findings indicate three new putative mechanisms of ifosfamide encephalopathy: (i) failure to convert 3-phosphoserine to serine due to inhibition of O-phosphoserine phosphohydratase; (ii) failure to incorporate ceramides into cerebrosides and (iii) oxidative injury of the cerebral cortex requiring de novo GSH synthesis.PMID:39693904 | DOI:10.1016/j.biopha.2024.117773

BMC Plant Biol. 2024 Dec 18;24(1):1180. doi: 10.1186/s12870-024-05875-y.ABSTRACTBACKGROUND: Priming plants with natural products is extensively studied in the agricultural field to reduce the use of synthetic and copper-based pesticides. Previous studies have shown that Oregano essential oil vapour (OEOV) is an effective priming agent against downy mildew (DM) in grapevine (Vitis vinifera L. cv. Chasselas), activating different transcriptomic regulated defence mechanisms.RESULTS: In the present study, we complement transcriptomic data with metabolomic insights, confirming some previous regulating patterns and highlighting new mechanisms underlying OEOV-induced resistance. A significant modulation of the phenylpropanoid pathway was noted. The data also confirmed the induction of an oxidative stress response indicated by an up-regulation of reactive oxygen species (ROS)-related genes and a congruent depletion of putative L-glutathione. Interestingly, OEOV promoted the accumulation of organic metabolites such as terpenes and other potential phytoalexins, which could potentially contribute to grapevine innate immune response to Plasmopara viticola.CONCLUSION: Overall, this study uncovered a diverse influence of OEOV on V. vinifera defence mechanisms against DM, enhancing our comprehension of the mode of action of essential oils. This insight offers various prospects for crafting innovative biocontrol products, fostering a more dynamic and sustainable approach to agriculture.PMID:39695378 | DOI:10.1186/s12870-024-05875-y