Search Results (258)

Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) remains a major contributor to late allograft dysfunction in kidney transplant recipients. Although detailed mechanisms remain incompletely understood, our previous metabolomic studies revealed disruptions in carnitine-related and redox pathways, suggesting impaired mitochondrial β-oxidation of fatty acids. To further characterize metabolic alterations associated with this condition, we conducted an untargeted lipidomic analysis of renal tissues using a murine model of TAC nephrotoxicity. TAC (1 mg/kg/day) or saline was subcutaneously administered to male ICR mice for 28 days, and kidney tissues were harvested for comprehensive lipidomic profiling. Lipidomic analysis was performed with liquid chromatography–tandem mass spectrometry (p < 0.05, n = 5/group). Triacylglycerols (TGs) were the predominant lipid class identified. TAC-treated mice exhibited reduced levels of unsaturated TG species with low carbon numbers, whereas TGs with higher carbon numbers and various degrees of unsaturation were increased. All detected TGs containing docosahexaenoic acid (DHA) showed an increasing trend in TAC-treated kidneys. Although accumulation of polyunsaturated TGs has been previously observed in chronic kidney disease, the preferential increase in DHA-containing TGs appears to be a unique feature of TAC-induced nephrotoxicity. These results suggest that DHA-enriched TGs may serve as a metabolic signature of TAC nephrotoxicity and offer new insights into its pathophysiology. Full article

Root-knot nematode (Meloidogyne incognita) is a globally destructive plant-parasitic nematode that severely impedes the sustainable production of horticultural crops. Metabolic reprogramming in plant roots represents the host response to M. incognita infection that can also be exploited by the nematode to facilitate its parasitism. In this study, untargeted metabolomics was employed to analyze metabolic changes in cucumber roots following nematode inoculation, with the goal of identifying differentially accumulated metabolites that may influence M. incognita behavior. Metabolomic analysis revealed that M. incognita significantly altered the cucumber root metabolome, triggering an accumulation of lipids and organic acids and enriching biotic stress-related pathways such as alkaloid biosynthesis and linoleic acid metabolism. Among differentially accumulated metabolites, myristic acid and hexadecanal were selected for further study due to their potential roles in nematode inhibition. In vitro assays demonstrated that both metabolites suppressed egg hatching and reduced infectivity of M. incognita, while pot experiments indicated a correlation between their application and reduced root gall formation. Chemotaxis assays further revealed that both metabolites exerted repellent effects on the chemotactic migration of M. incognita J2 and suppressed the transcriptional expression of two motility-and feeding-related neuropeptides, Mi-flp-1 and Mi-flp-18. In conclusion, this study demonstrates the significant potential of differentially accumulated metabolites induced by M. incognita infection for nematode disease control, achieved by interfering with nematode chemotaxis and subsequent infection. This work also provides deeper insights into the metabolomic mechanisms underlying the cucumber-M. incognita interaction. Full article

Background: Type 2 diabetes (T2D) is a global health epidemic with rising prevalence within Asian populations, particularly amongst individuals with high visceral adiposity and ectopic organ fat, the so-called Thin-Outside, Fat-Inside phenotype. Metabolomic and microbiome shifts may herald T2D onset, presenting potential biomarkers and mechanistic insight into metabolic dysregulation. However, multi-omics datasets across ethnicities remain limited. Methods: We performed cross-sectional multi-omics analyses on 171 adults (99 Asian Chinese, 72 European Caucasian) from the New Zealand-based TOFI_Asia cohort at 4-years follow-up. Paired plasma and faecal samples were analysed using untargeted metabolomic profiling (polar/lipid fractions) and shotgun metagenomic sequencing, respectively. Sparse multi-block partial least squares regression and discriminant analysis (DIABLO) unveiled signatures associated with ethnicity, glycaemic status, and sex. Results: Ethnicity-based DIABLO modelling achieved a balanced error rate of 0.22, correctly classifying 76.54% of test samples. Polar metabolites had the highest discriminatory power (AUC = 0.96), with trigonelline enriched in European Caucasians and carnitine in Asian Chinese. Lipid profiles highlighted ethnicity-specific signatures: Asian Chinese showed enrichment of polyunsaturated triglycerides (TG.16:0_18:2_22:6, TG.18:1_18:2_22:6) and ether-linked phospholipids, while European Caucasians exhibited higher levels of saturated species (TG.16:0_16:0_14:1, TG.15:0_15:0_17:1). The bacteria Bifidobacterium pseudocatenulatum, Erysipelatoclostridium ramosum, and Enterocloster bolteae characterised Asian Chinese participants, while Oscillibacter sp. and Clostridium innocuum characterised European Caucasians. Cross-omic correlations highlighted negative correlations of Phocaeicola vulgatus with amino acids (r = −0.84 to −0.76), while E. ramosum and C. innocuum positively correlated with long-chain triglycerides (r = 0.55–0.62). Conclusions: Ethnicity drove robust multi-omic differentiation, revealing distinctive metabolic and microbial profiles potentially underlying the differential T2D risk between Asian Chinese and European Caucasians. Full article

Breast cancer (BC) is a neoplasm characterized by high heterogeneity and is influenced by intrinsic molecular subtypes and clinical stage, aspects that remain underexplored in the Colombian population. This study aimed to characterize metabolic alterations associated with subtypes and disease progression in a group of newly diagnosed, treatment-naive Colombian women using an untargeted metabolomics approach. To improve metabolite coverage, samples were analyzed using LC-QTOF-MS and GC-QTOF-MS, along with amino acid profiling. The Luminal B subtype exhibited elevated levels of long-chain acylcarnitines and higher free fatty acid concentrations than the other subtypes. It also presented elevated levels of carbohydrates and essential glycolytic intermediates, suggesting that this subtype may adopt a hybrid metabolic phenotype characterized by increased glycolytic flux as well as enhanced fatty acid catabolism. Tumor, Node, and Metastasis (TNM) staging analysis revealed progressive metabolic reprogramming of BC. In advanced stages, a sustained increase in phosphatidylcholines and a decrease in lysophosphatidylcholines were observed, reflecting lipid alterations associated with key roles in tumor progression. In early stages (I-II), plasma metabolites with high discriminatory power were identified, such as glutamic acid, ribose, and glycerol, which are associated with dysfunctions in energy and carbohydrate metabolism. These results highlight metabolomics as a promising tool for the early diagnosis, clinical follow-up, and molecular characterization of BC. Full article

Cholesterol stress profoundly modulates cellular processes, but its underlying mechanisms remain incompletely understood. To investigate cholesterol-responsive networks, we performed integrated transcriptome (RNA-seq) and metabolome (LC-MS) analyses on HeLa cells treated with cholesterol for 6 and 24 h. Through transcriptomic analysis of cholesterol-stressed HeLa cells, we identified stage-specific responses characterized by early-phase stress responses and late-phase immune-metabolic coordination. This revealed 1340 upregulated and 976 downregulated genes after a 6 h cholesterol treatment, including induction and suppression of genes involved in cholesterol efflux and sterol biosynthesis, respectively, transitioning to Nuclear Factor kappa-B (NF-κB) activation and Peroxisome Proliferator-Activated Receptor (PPAR) pathway modulation by 24 h. Co-expression network analysis prioritized functional modules intersecting with differentially expressed genes. We also performed untargeted metabolomics using cells treated with cholesterol for 6 h, which demonstrated extensive remodeling of lipid species. Interestingly, integrated transcriptomic and metabolic analysis uncovered GFPT1-driven Uridine Diphosphate-N-Acetylglucosamine (UDP-GlcNAc) accumulation and increased taurine levels. Validation experiments confirmed GFPT1 upregulation and ANGPTL4 downregulation through RT-qPCR and increased O-GlcNAcylation via Western blot. Importantly, clinical datasets further supported the correlations between GFPT1/ANGPTL4 expression and cholesterol levels in Non-Alcoholic Steatohepatitis (NASH) liver cancer patients. This work establishes a chronological paradigm of cholesterol sensing and identifies GFPT1 and ANGPTL4 as key regulators bridging glycosylation and lipid pathways, providing mechanistic insights into cholesterol-associated metabolic disorders. Full article

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, comprises embryonal (ERMS) and alveolar (ARMS) subtypes with distinct histopathological features, clinical outcomes, and therapeutic responses. To better characterize their molecular distinctions, we performed untargeted plasma proteomics and metabolomics profiling in children with ERMS (n = 18), ARMS (n = 17), and matched healthy controls (n = 18). Differential expression, functional enrichment (GO, KEGG, RaMP-DB), co-expression network analysis (WGCNA/WMCNA), and multi-omics integration (DIABLO, MOFA) revealed distinct molecular signatures for each subtype. ARMS displayed elevated oncogenic and stemness-associated proteins (e.g., cyclin E1, FAP, myotrophin) and metabolites involved in lipid transport, fatty acid metabolism, and polyamine biosynthesis. In contrast, ERMS was enriched in immune-related and myogenic proteins (e.g., myosin-9, SAA2, S100A11) and metabolites linked to glutamate/glycine metabolism and redox homeostasis. Pathway analyses highlighted subtype-specific activation of PI3K-Akt and Hippo signaling in ARMS and immune and coagulation pathways in ERMS. Additionally, the proteomics and metabolomics datasets showed association with clinical parameters, including disease stage, lymph node involvement, and age, demonstrating clear molecular discrimination consistent with clinical observation. Co-expression networks and integrative analyses further reinforced these distinctions, uncovering coordinated protein–metabolite modules. Our findings reveal novel, subtype-specific molecular programs in RMS and propose candidate biomarkers and pathways that may guide precision diagnostics and therapeutic targeting in pediatric sarcomas. Full article

Quercus acutissima seeds exhibit high desiccation sensitivity, posing significant challenges for long-term preservation. This study investigates the physiological and metabolic responses of soluble osmoprotectants—particularly soluble proteins and proline—during the desiccation process. Seeds were sampled at three critical moisture content levels: 38.8%, 26.8%, and 14.8%, corresponding to approximately 99%, 52%, and 0% germination, respectively. We measured germination ability, soluble protein content, and proline accumulation, and we performed untargeted metabolomic profiling using LC-MS. Soluble protein levels increased early but declined later during desiccation, while proline levels continuously increased for sustained osmotic adjustment. Metabolomics analysis identified a total of 2802 metabolites, with phenylpropanoids and polyketides (31.12%) and lipids and lipid-like molecules (29.05%) being the most abundant. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that differentially expressed metabolites were mainly enriched in key pathways such as amino acid metabolism, energy metabolism, and nitrogen metabolism. Notably, most amino acids decreased in content, except for proline, which showed an increasing trend. Tricarboxylic acid cycle intermediates, especially citric acid and isocitric acid, showed significantly decreased levels, indicating energy metabolism imbalance due to uncoordinated consumption without effective replenishment. The reductions in key amino acids such as glutamic acid and aspartic acid further reflected metabolic network disruption. In summary, Q. acutissima seeds fail to establish an effective desiccation tolerance mechanism. The loss of soluble protein-based protection, limited capacity for proline-mediated osmotic regulation, and widespread metabolic disruption collectively lead to irreversible cellular damage. These findings highlight the inherent metabolic vulnerabilities of recalcitrant seeds and suggest potential preservation strategies, such as supplementing critical metabolites (e.g., TCA intermediates) during storage to delay metabolic collapse and mitigate desiccation-induced damage. Full article

Burnout syndrome is characterized mainly by three criteria (emotional exhaustion, depersonalization, and low personal accomplishment), and further exacerbated by night shift work, with profound implications for individual and societal well-being. The Maslach Burnout Inventory survey applied to 97 medical care professionals (with day and night work) revealed different scores for these criteria. Blood metabolic profiles were obtained by UHPLC-QTOF-ESI⁺-MS untargeted metabolomics and multivariate statistics using the Metaboanalyst 6.0 platform. The Partial Least Squares Discrimination scores and VIP values, Random Forest graphs, and Heatmaps, based on 99 identified metabolites, were complemented with Biomarker Analysis (AUC ranking) and Pathway Analysis of metabolic networks. The data obtained reflected the biochemical implications of night shift work and correlated with each criterion’s burnout scores. Four main metabolic pathways with important consequences in burnout were affected, namely lipid metabolism, especially steroid hormone synthesis and cortisol, the energetic mitochondrial metabolism involving acylated carnitines, fatty acids, and phospholipids as well polar metabolites’ metabolism, e.g., catecholamines (noradrenaline, acetyl serotonin), and some amino acids (tryptophan, tyrosine, aspartate, arginine, valine, lysine). These metabolic profiles suggest potential strategies for managing burnout levels in healthcare professionals, based on validated criteria, including night shift work management. Full article

The gut microbiota critically influences lipid metabolism and fat deposition in pigs, processes that underpin pork quality preferences and differentiate the meat traits of Chinese indigenous breeds (fat-type) from those of Western commercial breeds (lean-type). To explore the mechanisms underlying breed-specific fatty acid absorption, we compared the rectal and colonic microbiota and metabolite profiles of Huainan and Large White pigs using 16S rRNA sequencing and untargeted metabolomics. HN pigs exhibited enriched Lactobacillus johnsonii and Lactobacillus amylovorus, along with a significantly higher Firmicutes/Bacteroidetes ratio. Functional predictions further revealed elevated microbial pathways related to glycolysis, pyruvate metabolism, and ABC transporters in HN pigs. Conversely, LW pigs showed increased abundance of potentially pro-inflammatory bacteria and enriched pathways for lipopolysaccharide (LPS) biosynthesis. Metabolites such as 4-ethyl-2-heptylthiazole and picolinic acid were significantly upregulated in HN pigs and served as robust biomarkers (Area Under the Curve, AUC = 1.0),with perfect discrimination observed in both rectal and colonic samples. Integrative analysis identified 52 co-enriched microbial and metabolic pathways in HN pigs, including short-chain fatty acid (SCFA) production, lipid biosynthesis and transport, amino acid metabolism, ABC transporter activity, and the PPAR signaling pathway, supporting a microbiota–metabolite axis that enhances fatty acid absorption and gut immune balance. These findings provide mechanistic insight into breed-specific fat deposition and offer candidate biomarkers for improving pork quality via precision nutrition and breeding. Full article

This study multidimensionally investigates the comprehensive effects of Lactobacillus plantarum (LP)-fermented feed on growth performance, intestinal health, and metabolic regulation in Pacific abalone (Haliotis discus hannai). The results demonstrate that LP fermentation significantly alters feed’s physical properties and nutritional profile, softening texture, increasing viscosity, and emitting an acidic aroma. Notably, it enhanced contents of cis-9-palmitoleic acid, α-linolenic acid (ALA), and functional amino acids (GABA, L-histidine, and L-asparagine), indicating that fermentation optimized ω-3 fatty acid accumulation and amino acid profiles through the modulation of fatty acid metabolic pathways, thereby improving feed biofunctionality and stress-resistant potential. Further analyses revealed that fermented feed markedly improved intestinal morphology in abalone, promoting villus integrity and upregulating tight junction proteins (ZO-1, Claudin) to reinforce intestinal barrier function. Concurrently, it downregulated inflammatory cytokines (TNF-α, NF-κB, IL-16) while upregulating anti-inflammatory factors (TLR4) and antioxidant-related genes (NRF2/KEAP1 pathway), synergistically mitigating intestinal inflammation and enhancing antioxidant capacity. Sequencing and untargeted metabolomics unveiled that fermented feed substantially remodeled gut microbiota structure, increasing Firmicutes abundance while reducing Bacteroidetes, with the notable enrichment of beneficial genera such as Mycoplasma. Metabolite profiling highlighted the significant activation of lipid metabolism, tryptophan pathway, and coenzyme A biosynthesis. A Spearman correlation analysis identified microbiota–metabolite interactions (such as Halomonas’ association with isethionic acid) potentially driving growth performance via metabolic microenvironment regulation. In conclusion, LP-fermented feed enhances abalone growth, immune response, and aquaculture efficiency through multi-dimensional synergistic mechanisms (nutritional optimization, intestinal homeostasis regulation, microbiota–metabolome crosstalk), providing critical theoretical foundations for aquafeed development and probiotic applications in aquaculture. Full article

Background: Endometrial cancer (EC) is the sixth most common cancer among women globally, with an estimated 420,000 new cases diagnosed annually. Methods: This study comprised patients with endometrial cancer (EC) (n = 17), hyperplasia (HY) (n = 17), and controls (CO) (n = 20). Tissue was collected from the endometrium of all 54 patients, including patients with HY, EC, and CO, who underwent total hysterectomy. EC and HY diagnoses were confirmed based on histological examination. Untargeted metabolomics profiling was conducted using LC-HRMS. The partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA) models were used for univariate and multivariate statistical analysis. The fitness of the model (R2Y) and predictive ability (Q2) were used to create OPLS-DA models. ROC analysis was carried out, followed by network analysis using Ingenuity Pathway Analysis. Results: The top metabolites that can discriminate EC and HY from CO were identified. This revealed a decrease in the levels of the lipid species, specifically phosphatidic acid (PA) (PA (14:1/14:0), PA(10:0/17:0), PA(18:1-O(12,13)/12:0)), PG(a-13:0/a-13:0), ganglioside GA1 (d18:1/18:1), PS(14:1/14:0), TG(20:0/18:4/14:1), and CDP-DG(PGF2alpha/18:2), while the levels of 3-Dehydro-L-gulonate, Uridine diphosphate-N-acetylglucosamine, ganglioside GT2 (d18:1/14:0), gamma-glutamyl glutamic acid and oxidized glutathione were increased in cases of EC and HY as compared to CO. Bioinformatics analysis, specifically using Ingenuity Pathway Analysis (IPA), revealed distinct pathway enrichments for EC and HY. For EC, the most highly scored pathways were associated with cell-to-cell signaling and interaction, skeletal and muscular system development and function, and small-molecule biochemistry. In contrast, HY cases showed the highest scoring pathways related to inflammatory disease, inflammatory response, and organismal injury and abnormalities. Conclusions: Developing sensitive biomarkers could improve diagnosis and guide treatment decisions, particularly in identifying which patients with HY may safely avoid hysterectomy and be managed with hormonal therapy. Full article

Background: Informal electronic waste (e-waste) recycling practices release a complex mixture of pollutants, particularly heavy metals, into the environment. Chronic exposure to these contaminants has been linked to a range of health risks, but the molecular underpinnings remain poorly understood. In this study, we investigated the alterations in metabolic profiles due to e-waste exposure and linked these metabolites to systemic biological effects. Methods: We applied untargeted high-resolution metabolomics using dual-column LC-MS/MS and a multi-step analysis workflow combining MS1 feature detection, MS2 annotation, and chemical ontology classification, to characterize urinary metabolic alterations in 91 e-waste workers and 51 community controls associated with the Agbogbloshie site (Accra, Ghana). The impacts of heavy metal exposure in e-waste workers were assessed by establishing linear regression and four-parameter logistic (4PL) models between heavy metal levels and metabolite concentrations. Results: Significant metal-associated metabolomic changes were identified. Both linear and nonlinear models revealed distinct sets of exposure-responsive compounds, highlighting diverse biological responses. Ontology-informed annotation revealed systemic effects on lipid metabolism, oxidative stress pathways, and xenobiotic biotransformation. This study demonstrates how integrating chemical ontology and nonlinear modeling facilitates exposome interpretation in complex environments and provides a scalable template for environmental biomarker discovery. Conclusions: Integrating dose–response modeling and chemical ontology analysis enables robust interpretation of exposomics datasets when direct compound identification is limited. Our findings indicate that e-waste exposure induces systemic metabolic alterations that can underlie health risks and diseases. Full article

Mesenchymal stem cells (MSCs) exhibit low immunogenicity, multipotency, and are abundantly present in adipose tissue, making this tissue an easily accessible resource for regenerative medicine. Different commercial procedures have been developed to micro-fragment the adipose tissue aspirate from patients before its reinjection. We explored a commercial device which mechanically micro-fragments human lipoaspirate (LA) resulting in a homogeneous micro-fragmentation of fat tissue (MFAT). This device has been successfully employed in several clinical applications involving autologous adipose tissue transplantation. Here, we compare the untargeted/targeted lipidomic profile of LA and MFAT looking for differences in terms of qualitative modifications occurring during the handling of the original LA material. In MFAT, different lipid subclasses such as diacylglycerols, triacylglycerols, phospholipids, and sphingolipids are more represented than in LA. In addition, via targeted fatty acids analysis, we found a lower abundance of monounsaturated fatty acids in MFAT. The biological implications of these findings must be better investigated to contribute to a better understanding of the clinical efficacy of MFAT and for its potential use as a scaffold for drug delivery applications. Full article

In patients with respiratory diseases, a panel of markers is often used to assess disease severity and progression. Here we test whether the serum lipid signature may surge as a reliable alternative marker to monitor systemic hypoxia, a frequent unfavourable outcome in acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary diseases (COPD). We recruited 9 healthy controls, 10 COPD patients, and 10 ARDS patients. Various markers related to inflammation, redox imbalance, and iron handling were measured alongside lipid profiles obtained through untargeted lipidomic analysis. The results show that serum lipids were moderately lower in COPD patients and significantly reduced in ARDS patients compared to the controls. Six lipid classes (cholesteryl esters, coenzyme Q, phosphatidylinositol, sterols, hexosylceramides, and phosphatidylethanolamine) exhibited significant changes (ANOVA p < 0.05) and correlated with the Horowitz index (P/F), suggesting their potential as markers of hypoxia severity. While conventional markers also correlated with P/F, the lipid signature was more specific and reliable. This study highlights that hypoxia in pulmonary diseases depresses circulating lipids, with certain lipid classes offering more precise predictions of hypoxia severity. Expanding this research to larger populations could support the lipid signature as a clinical tool. Full article

The aim of this study is to investigate the physiological characteristics and regulatory mechanisms of porcine intramuscular fat (IMF), subcutaneous fat (take back fat (BF), for example), and visceral fat (take perienteric fat (PF), for example) to address the challenge of optimizing meat quality without excessive fat deposition. Many improved breed pigs have fast growth rates, high lean meat rates, and low subcutaneous fat deposits, but they also have low IMF content, resulting in poor meat quality. There is usually a positive correlation between intramuscular fat and subcutaneous fat deposits. This study selected eight-month-old female Tibetan pigs as experimental subjects. After slaughter, fat samples were collected. Histological differences in adipocyte morphology were observed via hematoxylin–eosin (HE) staining of tissue sections, and phenotypic characteristics of different adipose tissues were analyzed through fatty acid composition determination. Transcriptome sequencing and untargeted metabolomics were employed to perform pairwise comparisons between different fatty tissues to identify differentially expressed genes and metabolites. A siRNA interference model was constructed and combined with Oil Red O staining and lipid droplet optical density measurement to investigate the regulatory role of WNT16 in adipocyte differentiation. Comparative analysis of phenotypic and fatty acid composition differences in adipocytes from different locations revealed that IMF adipocytes have significantly smaller areas and diameters compared to other fat depots and contain higher levels of monounsaturated fatty acids. Integrated transcriptomic and metabolomic analyses identified differential expression of WNT16 and L-tyrosine, both of which are involved in the melanogenesis pathway. Functional validation showed that inhibiting WNT16 in porcine preadipocytes downregulated adipogenic regulators and reduced lipid droplet accumulation. This cross-level regulatory mechanism of “phenotype detection–multi-omics analysis–gene function research” highlighted WNT16 as a potential key regulator of site-specific fat deposition, providing new molecular targets for optimizing meat quality through nutritional regulation and genetic modification. Full article