Search Results (1,302)

Endothelial dysfunction (ED) arises in multiple pathologies, and its severity correlates with disease progression. Common ED biomarkers could provide prognostic value for associated complications. This study aims to identify shared ED biomarkers and assess their prognostic significance. Endothelial cells in culture (human microvascular endothelial cells, HMEC-1) were exposed to sera from patients in five disease groups (n = 20 patients/group)—liver cirrhosis with portal hypertension, idiopathic pulmonary arterial hypertension, placental disorders such as intrauterine growth restriction, coronary artery disease with acute myocardial infarction, and chronic kidney disease—or matched controls, in the absence/presence of anti-inflammatory (apixaban) and antioxidant (EUK134) compounds. We explored changes in: VCAM-1, ICAM-1, eNOS, VWF, extracellular matrix thrombogenicity, and reactive oxygen species (ROS). In serum samples, proteomics and metabolomics analyses (including lipids, amino acids, and polar metabolites) were performed through an extraction protocol to identify common ED biomarkers. Expression of VCAM-1, ICAM-1, VWF, platelet adhesion, and ROS increased in most groups versus controls (p < 0.05). Both drugs decreased all biomarker levels except eNOS (n = 6 for in vitro experiments). For serum ED biomarkers, 18 metabolites and 24 proteins showed AUC-ROC and hit rates >77.5%, and six metabolites were associated with event-free survival. These diseases share ED driven by systemic inflammatory, oxidative, and metabolic stress, are partially reversible in vitro, and are linked to biomarkers associated with clinical outcomes. Overall, ED emerges as a modifiable pathological axis with potential prognostic value. Full article

Uterine microbiome homeostasis and antioxidant capacity are critical for sow fertility. While high-fiber diets and N-carbamylglutamate (NCG) individually enhance sow fertility, their synergistic effects on the antioxidant status, microbiota, metabolites, and transcriptome remain unclear. Here, sows were assigned to the low-fiber (3.73%) or high-fiber (7.46% crude fiber) group, each without or with 0.05% NCG, throughout the 114-day gestation. Sex hormones and antioxidants in serum were detected. Multi-omics approaches were employed to investigate the impact of a high-fiber diet supplemented with NCG (H + N) on uterine microbiota, metabolites, and gene expression profiles. The study revealed that H + N significantly increased total antioxidant capacity (T-AOC) level in serum. Metagenomic analysis revealed an increased abundance of Clostridium disporicum in the uterine microbiota. Plasma metabolomics identified hydroxylysine as a key metabolite mediating this effect, and this metabolite was positively correlated with elevated abundance of Clostridium disporicum. Subsequent transcriptomic profiling revealed activation of the PI3K-Akt signaling pathway, closely linked to improved T-AOC level. Overall, these findings demonstrated that H + N could modulate the uterine microbiota (specifically Clostridium disporicum), increase hydroxylysine production, and activate the PI3K-Akt signaling pathway. These effects further enhanced hormonal activity and antioxidant capacity, ultimately improving sow reproductive efficiency. Full article

This study focuses on Lacto-N-neotetraose (LNnT), a core component of human milk oligosaccharides. Although LNnT has been demonstrated to promote early intestinal development and maintain gut homeostasis, its protective mechanism against D-galactose-induced intestinal injury and associated cognitive impairment remains unclear. This investigation systematically examined the protective effects and underlying mechanisms of LNnT against D-gal-induced colonic damage and cognitive impairment in mice. The results demonstrated that LNnT not only significantly improved systemic physiological phenotypes and upregulated the expression of colonic tight junction proteins to repair the intestinal barrier, but also effectively enhanced learning and memory abilities in mice. Concurrently, LNnT reduced serum proinflammatory factor levels, elevated the anti-inflammatory factor IL-10, and alleviated oxidative stress. Furthermore, LNnT remodeled the gut microbiome structure by increasing microbial diversity, enhancing beneficial bacteria abundance, and promoting short-chain fatty acid production. Untargeted metabolomics analysis further revealed that LNnT corrected metabolic disturbances by regulating key sphingolipid molecules (ceramide, sphingosine, S1P) and the expression of related metabolic enzymes (ACER2, SphK2). In summary, this study suggests that LNnT mitigates intestinal injury and improves cognitive function, potentially through modulation of the gut microbiota–sphingolipid metabolism axis, although further causal validation is warranted. These findings provide a mechanistic foundation for future studies exploring its potential as a functional dietary ingredient. Full article

Severe winter nutritional deficiencies may impair reproductive performance in Mongolian mares, yet optimal protein requirements during late gestation remain undefined. This study aimed to determine the effects of varying protein levels in complementary feed on gestational performance, physiology, and gut health. Seventeen late-gestating mares were assigned to three isocaloric diets differing in crude protein (CP)—high (HCP, 13.25%), medium (MCP, 12.04%), and low (LCP, 10.85%)—for 40 days. Statistical analysis was conducted using one-way ANOVA followed by Tukey’s HSD post hoc test. Mares fed the MCP diet tended to show more favorable growth performance and nutrient digestibility relative to the HCP group (p < 0.05). Blood analysis suggested that MCP mares had comparatively lower serum creatinine and creatine kinase concentrations, along with higher antioxidant capacity (catalase) and interleukin-1β levels (p < 0.001). Fecal microbiota sequencing showed that MCP was associated with comparatively higher microbial diversity, while HCP was characterized by enrichment of Proteobacteria, and LCP by enrichment of Bacteroidetes. Metabolomics identified 533 differential metabolites linked to protein metabolism. The MCP diet may help balance immune function, antioxidant status, and microbial homeostasis. These findings suggest that a complementary feed containing 12.04% CP may be associated with favorable effects on maternal health-related indicators in late-gestating Mongolian mares during winter. Full article

Venom-mediated systemic toxicity is not fully understood. This study explored the dose-dependent effects of Vespa mandarinia venom (VMV) on mice via integrated transcriptomic and metabolomic analyses. Subcutaneous VMV injection induced dose-dependent hypothermia: 80 μg caused severe transient hypothermia and partial mortality, while 40/60 μg led to reversible hypothermia within 24 h. Whole-blood sequencing identified 2400–3281 differentially expressed genes (DEGs) per group, including 1764 shared DEGs. Immune-related pathways were significantly activated, with hub genes validated by qRT-PCR. Serum metabolomics revealed alterations in organic acids, alkaloids, and other metabolites. Integrative transcriptome–metabolome analysis predicted the potential involvement of various pathways in VMV-induced toxicity, including ferroptosis (shared in low-dose VMV groups) and apoptosis. Cumulatively, this study confirms that VMV induces immunometabolic reprogramming, providing a molecular framework for understanding venom-induced systemic toxicity. Full article

Micro/nanoplastics (MNPs) are emerging contaminants of concern for maternal and fetal health, yet their effects on the maternal–fetal circulation and serum metabolic homeostasis remain unclear. Here, we investigated the maternal and offspring toxicity of polystyrene microplastics (PS-MPs) and serum metabolomic alterations in dams and offspring. PS-MPs accumulated in multiple tissues, including blood, indicating maternal-to-offspring transfer. Continuous exposure reduced litter size, induced hepatic oxidative stress, and increased IL-6 and TNF-α levels in a dose-dependent manner in both dams and offspring. In dams, PS-MPs also decreased red blood cell and platelet counts and altered leukocyte composition, with increased lymphocyte and decreased neutrophil percentages at the high dose. Untargeted serum metabolomics revealed distinct exposure-related metabolic profiles, including 18 putatively annotated signature metabolites and 26 differentially abundant metabolites. Bilirubin and presqualene diphosphate were exclusively detected in exposed animals, whereas metabolites associated with lipid oxidation and mitochondrial fatty acid β-oxidation were elevated after exposure. RT-qPCR further supported altered expression of genes involved in these pathways. Overall, PS-MPs disrupted hematological homeostasis and metabolic regulation, likely through hepatic lipid peroxidation and systemic inflammation, and serum bilirubin and presqualene diphosphate may serve as candidate biomarkers of exposure. Full article

This study evaluated the effects of an Astragalus membranaceus stem and leaf–Angelica sinensis stem and leaf mixture (AASL) as a medicinal feed supplement on immune function, antioxidant status, inflammatory responses, gut microbiota and the serum metabolome in weaned Simmental bull calves. Calves were fed diets containing different levels of AASL, and serum immunoglobulins, inflammatory cytokines, and antioxidant indices were determined. In addition, fecal short-chain fatty acid (SCFA) concentrations, gut microbiota composition, and serum metabolic profiles were analyzed, followed by correlation analyses among the microbiota, SCFAs and metabolites. The results showed that AASL was rich in crude protein, crude fat and trace elements. 4% AASL supplementation increased serum immunoglobulin (IgG and IgM) levels, decreased tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) levels, and enhanced superoxide dismutase (SOD), glutathione (GSH) and total antioxidant capacity (T-AOC) activities (p < 0.01 or p < 0.001), indicating improved immune and antioxidant status and attenuated inflammatory responses. AASL also enriched beneficial bacterial genera, suppressed potentially harmful taxa, and increased SCFA concentrations. Differential metabolites were mainly enriched in tryptophan metabolism, lipid metabolism, neuroactive ligand-receptor interaction, sphingolipid signaling, and ATP-binding cassette (ABC) transporter pathways. Integrated microbiota metabolite analysis further suggested that AASL improved host metabolic status through the coordinated regulation of gut microbiota, SCFAs production and related metabolic pathways. Overall, AASL shows promise as a functional feed supplement for improving calf health. Full article

Mongolians have high overweight prevalence linked to their nomadic lifestyle and diet, but gut microbiota studies in this population are scarce. This study used fecal metagenomic and serum metabolomic analyses of 96 Mongolian participants (normal-weight n = 55, overweight n = 41) to characterize gut microbiome alterations and identify weight-related biomarkers. The analyses revealed that Parabacteroides distasonis, Barnesiella intestinihominis, and Alistipes onderdonkii were significantly reduced in overweight individuals (p < 0.05). Concurrently, the metabolites such as beta-cryptoxanthin, p-cresol, and ribothymidine were significantly down-regulated in the overweight group (p < 0.05). Random forest models from the three datasets showed a strong diagnostic ability for microbial families (AUC > 0.70). A subsequent integrated multi-kingdom classifier that combined microbiota and metabolite data achieved the highest performance (AUC = 0.818). Key features with high predictive contributions were identified, including Lactobacillus crispatus, Alistipes onderdonkii, and Parabacteroides distasonis, and metabolites, such as beta-cryptoxanthin, p-cresol, and picolinic acid. These results show the random forest model has high predictive value for distinguishing normal weight and overweight individuals. In summary, this study identified specific gut microbiota and serum metabolomic profiles linked to overweight in Mongolians. Multi-omics integration established a diagnostic biomarker model, laying a theoretical basis for microbiome-targeted weight management interventions. Full article

Non-muscle-invasive bladder cancer (NMIBC) is characterized by high recurrence rates and necessitates lifelong cystoscopic surveillance, underscoring the need for minimally invasive biomarkers to improve early detection and risk stratification. Therefore, this study aimed to investigate the role of trimethylamine-N-oxide (TMAO) and its precursors as diagnostic biomarkers for NMIBC. A total of 50 male patients with NMIBC (25 pTa and 25 pT1) were included in this study. Additionally, 52 age-matched healthy individuals were included as controls. Serum TMAO and its dietary precursors were quantified using liquid chromatography–tandem mass spectrometry. Group differences were analyzed using nonparametric tests, associations were assessed using Spearman’s correlation, and diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. Multivariate logistic regression was performed to identify independent predictors, and a composite risk score was generated. Serum TMAO, carnitine, and choline levels were significantly higher in patients with NMIBC than in controls (p ≤ 0.0001), whereas betaine showed a nonsignificant trend toward higher levels (p ≥ 0.05). The pathological stage (pTa vs. pT1) showed the strongest correlation with TMAO levels. The ROC analysis revealed that TMAO had the highest individual diagnostic accuracy (area under the curve [AUC] = 0.875, 95% confidence interval [CI] 0.812–0.939), whereas carnitine and choline provided complementary diagnostic performance. In multivariate models, TMAO, carnitine, and choline remained independent predictors of NMIBC (p ≤ 0.0001). A composite risk score integrating all four metabolites demonstrated excellent discriminatory capacity (AUC = 0.958, 95% CI 0.926–0.991). The TMAO metabolic axis can be used as a minimally invasive biomarker panel for NMIBC. Further large, prospective, multicenter studies integrating metabolomic and microbiome profiling are needed to validate the findings. Full article

Background: Acute rejection remains a major complication following liver transplantation, yet reliable noninvasive biomarkers for its early prediction and diagnosis remain unidentified. This exploratory study characterized bile and serum metabolites associated with acute rejection in living donor liver transplantation using comprehensive metabolomic profiling combined with machine learning. Methods: Non-targeted metabolomics were performed on bile samples collected on post-operative day (POD) 1 (n = 38) and serum on POD 14 (n = 45) from liver transplant recipients. Partial least squares discriminant analysis-based variable selection was followed by logistic regression and least absolute shrinkage and selection operator models, which were evaluated via cross-validation in the discovery cohort to explore potential biomarkers for acute rejection. Results: A three-variable, bile-based model for predicting acute rejection achieved a mean cross-validated AUC of 0.872 (95% confidence interval: 0.814–0.930). Glycohyocholic acid and sulfolithocholylglycine were the main contributors. A nine-variable serum model for the Rejection Activity Index, including the change in γ-glutamyl transferase, showed a mean cross-validated R² of 0.728 (95% confidence interval: 0.609–0.846), with methionine, creatine, and oxidized fatty acids contributing prominently. Conclusions: These findings suggest that metabolomic profiling combined with machine learning may provide candidate biomarkers for acute rejection after liver transplantation. However, given the exploratory nature of the study and the lack of external validation, the clinical utility of these metabolite signatures remains to be determined. Therefore, external validation in larger, independent cohorts will be required. Full article

An integrated approach combining metabolomics, network pharmacology, and molecular docking was employed to systematically explore the serum-absorbed components of jujube, their potential targets, and regulatory pathways. UPLC-MS/MS was used to characterize the absorbed components, while network pharmacology was applied to predict potential targets associated with alcoholic liver disease (ALD). A total of 10 absorbed components and 323 common targets were identified. Among the key components, quercetin, (-)-epigallocatechin, and methyl gallate exhibited strong binding affinities to eight core targets, including AKT serine/threonine kinase 1 (AKT1) and mitogen-activated protein kinase 1 (MAPK1), with quercetin showing the highest content. Jujube intervention significantly altered the serum metabolic profiles of healthy rats, with distinct differences observed between the control and jujube-treated groups. Bioinformatics analysis revealed that the differential metabolites were mainly enriched in the diterpenoid biosynthesis pathway. These findings provide a systematic and preliminary characterization of the serum-absorbed components of jujube, their potential ALD-related targets, and their regulatory effects on serum metabolism in healthy rats. This study provides a preliminary theoretical reference and direction for further research on the potential role of jujube in ALD. Full article

Background: Lactopontin (L-OPN) is a pivotal bioactive protein present in breast milk that supports bone development, but its efficacy in a formula matrix is unknown. This study aimed to evaluate the effects of L-OPN-fortified formula on bone growth in a growing rat model and to explore the underlying mechanisms. Methods: Weanling rats (n = 8/group) received daily gavage for four weeks: (1) CON—deionized water; (2) PRO—750 mg/kg·BW mixed protein; or (3) L-OPN—750 mg/kg·BW of the PRO formula fortified with L-OPN. Results: The results showed that the formula fortified with L-OPN could significantly increase bone volume and trabecular bone number (p < 0.05). Furthermore, both femur length and thickness, as well as overall body length, were significantly increased (p < 0.001). In addition, the L-OPN-fortified formula specifically increased the relative abundance of Bacteroides and Parabacteroides in rat feces (p < 0.05). Metabolomic analysis revealed that L-OPN supplementation significantly altered bile acid metabolism, notably increasing serum levels of 12-ketolithocholic acid (12-KLCA), which correlated strongly with bone metrics. Conclusions: These preclinical findings provide a basis for future research in infant formula. Full article

Objectives: To overcome the limitations of invasive diagnostic approaches for ulcerative colitis (UC) diagnosis, this study integrates liquid chromatography–mass spectrometry (LC–MS)-based serum metabolomics with mucosal transcriptomics to elucidate the interplay between systemic metabolic perturbations and neuroendocrine signaling in UC pathogenesis. Methods: Serum metabolites and mucosal differentially expressed genes (DEGs) were identified through multi-omics profiling. Key neurotransmitter receptor-related genes (NRRGs) were prioritized using three machine learning algorithms: LASSO, Random Forest, and SVM-RFE. A three-gene diagnostic nomogram was developed and rigorously validated across multiple independent cohorts (GSE48958, GSE73661) using receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA). Results: The integrated analysis revealed 334 dysregulated metabolites and 3093 DEGs, both converging on the serotonergic synapse pathway. Specific molecular alterations were uncovered, including tryptophan depletion linked to the downregulation of SLC6A4, concomitant with abnormal serotonin accumulation and PTGS2-mediated inflammatory responses. The three-gene signature, HTR3C, RPS6KA6, and NETO2, formed a highly robust diagnostic model, achieving an area under the ROC curve (AUC) exceeding 0.96 in both the training cohort and external validation sets. Conclusions: This multi-omics study delineates a neuroimmune mechanism in UC centered on dysregulation of the serotonergic synapse. The resulting three-gene nomogram identifies a candidate biomarker signature that demonstrates strong discriminative potential; however, given the exceptionally high performance metrics, these findings should be interpreted as a preliminary diagnostic framework rather than a clinically validated tool, and its efficacy relative to standard markers like CRP or fecal calprotectin requires further investigation in prospective real-world cohorts. Nonetheless, this study provides critical mechanistic insights into gut–brain axis dysfunction in UC. Full article

Dietary supplementation with functional nutrients is a safe strategy to improve bone health. This study aimed to investigate the ameliorative effects of Berberine (BBR) on dexamethasone-induced bone loss in mice and its potential mechanisms. Micro-CT, histological staining, ELISA and Western blot were employed to evaluate BBR’s skeletal benefits; 16S rRNA sequencing, serum metabolomics and correlation analysis were used to explore its regulatory mechanisms. In vivo experiments showed that BBR improved bone mineral density and trabecular microarchitecture, and upregulated osteogenic markers (COL1 and BMP2). Intestinal bacterial sequencing showed that BBR altered gut bacterial composition, increasing the abundance of Desulfovibrio and Bacteroides while decreasing opportunistic pathogens. BBR also modulated bacterial richness, evenness, and community stability. Serum metabolomics identified 107 BBR-reversed differential metabolites; of these, 33.64% were lipids and lipid-like molecules, which were mainly involved in glycerophospholipid metabolism. Further correlation analysis revealed that BBR-enriched Desulfovibrio was linked to pathway R04864, producing a key glycerophospholipid metabolite positively correlated with bone mass parameters. Overall, these findings suggest that the attenuation of bone loss by BBR may be associated with alterations in the gut microbiota–glycerophospholipid metabolic axis, supporting its potential as a functional food ingredient for bone health. Full article

Gamma-tocotrienol (GT3) is one of the constituents of vitamin E that demonstrated significant radioprotective efficacy in murine and nonhuman primate (NHP) models. Considering the antioxidant activity of GT3 and its role in terminating lipid peroxidation, we hypothesize that mechanism of radioprotective effect of GT3 may involve the inhibition of irradiation-induced ferroptosis—a form of regulated cell death characterized by excessive, iron-dependent, peroxidation of lipids in cellular membranes. To test this hypothesis, the metabolomic and proteomic data from serum samples of GT3- or vehicle-treated NHPs exposed to 12 Gy (partial- or total-body) radiation was analyzed with focus on lipid peroxidation markers and proteins involved in iron metabolism. Four secondary lipid peroxidation products were identified including 4-oxo-2-nonenal (4-ONE), 4-hydroperoxy-2-nonenal (4-HPNE), 3,4-epoxynonanal (3,4-ENA), and trans-4,5-epoxy-(2E)-decenal (4,5-EDE). In vehicle-treated animals, their concentrations increased significantly as soon as 4 h after irradiation and then gradually declined. GT3 treatment mitigated this radiation-induced increase. In addition to lipid peroxidation products, similar patterns of change were observed for several polyunsaturated, monounsaturated, and saturated fatty acids as well as amino acids such as lysine and its derivatives. Taken together, these metabolomic changes suggest that irradiation induces cellular membrane damage through enhanced lipid peroxidation, while GT3 exerts a protective effect against this process. In addition, GT3 increased serum levels of haptoglobin and hemopexin—two plasma scavenger proteins that play complementary protective roles in iron and heme homeostasis. Although the present study does not conclusively demonstrate that GT3 mediates radioprotection via inhibition of ferroptosis, the data suggest that GT3 limits membrane damage and reduces susceptibility to ferroptosis by enhancing iron and heme scavenging. Further investigation into the interaction between GT3 and key components of ferroptosis following exposure to ionizing radiation is therefore warranted. Full article