Metabolites[JOURNAL]
Sun
200 papers
Lactate Metabolism Dysregulation Drives the Pathogenesis of Acute Kidney Injury.
Li Y, Liu J, Mai D … +3 more , Tan R, Wang C, Mo Z
Metabolites · 2026 Jun · PMID 42346414 · Full text
BACKGROUND: Acute kidney injury (AKI) remains a condition with limited effective therapeutic options, partly due to challenges in early diagnosis and timely intervention. While lactate accumulation is a hallmark of ische...
BACKGROUND: Acute kidney injury (AKI) remains a condition with limited effective therapeutic options, partly due to challenges in early diagnosis and timely intervention. While lactate accumulation is a hallmark of ischemic and septic AKI, the underlying mechanisms remain unclear. METHODS: This study integrated single-cell RNA sequencing data from AKI patients (GEO database) with lactate metabolism-related genes (LMRGs) to identify key therapeutic targets. RESULTS: Collecting duct (CD) cells exhibited the highest LMRG expression. Machine learning algorithms and validation in bilateral ischemia/reperfusion injury (bIRI) and lipopolysaccharide (LPS)-induced AKI mouse models, as well as hypoxia/reoxygenation (H/R)-stimulated renal cells, identified as a core gene. Disruption of lactate metabolism via BAY876 (selective GLUT1 inhibitor) or siRNA-mediated knockdown significantly attenuated kidney injury, reduced inflammatory cytokines (IL-1β, IL-6, TNF-α), and decreased reactive oxygen species in vitro and in vivo. CONCLUSIONS: These findings reveal that lactate metabolism is reprogrammed in AKI, particularly in CD cells, and identify LDHB as a novel potential therapeutic target for this condition, though further mechanistic studies are required to establish causality.
Librarian: An Open-Access Web Application for High-Resolution Mass Spectral Library Assembly.
Ahlberg Weidenfors J, Bonnefille B, Papazian S
Metabolites · 2026 Jun · PMID 42346413 · Full text
: Confident chemical annotation in nontarget small-molecule mass spectrometry critically depends on the availability of high-quality tandem mass spectral (MS) reference libraries. While community efforts have driven sign...
: Confident chemical annotation in nontarget small-molecule mass spectrometry critically depends on the availability of high-quality tandem mass spectral (MS) reference libraries. While community efforts have driven significant expansion of open-access repositories, technical challenges in assembling standardized, metadata-rich records continue to limit broader participation, underscoring the need for improved computational tools to assist contributors. : To promote the creation and sharing of standardized reference MS spectral records, we have developed Librarian, a free, open-access web application designed for rapid and scalable assembly of high-resolution MS libraries. Librarian integrates automated retrieval and harmonization of chemical identifiers and metadata from PubChem, compound mixture design for high-resolution mass spectrometry (HRMS) acquisition, and assembly of curated MS spectra into repository-ready records compatible with public spectral databases. : Through a simple in-browser interface, Librarian offers a flexible end-to-end workflow compatible with popular open-source pre-processing tools to lower technical barriers and facilitate broader community participation in library development. As a demonstration, we used Librarian to create and deposit a spectral library comprising over 1500 new MS records into MassBank, which was further applied in retrospective analysis of environmental datasets. : Librarian streamlines the creation of standardized, metadata-rich and repository-ready MS reference records. Addressing a key bottleneck in community spectral library development and sharing, Librarian supports the continued growth of open-access resources for metabolomics, exposomics, and environmental mass spectrometry. The Librarian web application is publicly accessible via the SciLifeLab Serve platform.
Purine Metabolism Alterations in Patients with Chronic Heart Failure: A Cross-Sectional Study of Associations with Iron Status, Oxidative Stress, and Anemia.
Konysbek Y, Turar A, Molotov-Luchanskiy VB … +1 more , Ponamareva OA
Metabolites · 2026 Jun · PMID 42346412 · Full text
: Anemia and iron dysregulation are common in chronic heart failure (CHF), but additional metabolic mechanisms may contribute to these alterations. This study aimed to evaluate purine metabolism and oxidative stress mark...
: Anemia and iron dysregulation are common in chronic heart failure (CHF), but additional metabolic mechanisms may contribute to these alterations. This study aimed to evaluate purine metabolism and oxidative stress markers in patients with CHF and to explore their potential relationship with anemia. : In this cross-sectional study, 176 patients with CHF and 29 control individuals were included. CHF phenotypes were classified according to left ventricular ejection fraction (HFpEF, HFmrEF, HFrEF). Purine metabolites (guanine, hypoxanthine, adenine, xanthine, and uric acid) were measured using high-performance liquid chromatography, while lipid peroxidation (LPO) and advanced oxidation protein products (AOPPs) were assessed spectrophotometrically. Non-parametric statistical tests with correction for multiple comparisons were applied. : Anemia was present in 40.3% of patients with CHF. Serum iron and platelet counts were significantly lower in CHF compared with controls ( = 0.001). Among purine metabolites, adenine levels were higher in CHF (nominal = 0.009), whereas other metabolites did not differ significantly between groups. LPO levels were lower and AOPP levels were higher in CHF ( = 0.021 and = 0.008, respectively). No statistically significant associations were observed between hemoglobin levels and purine metabolites. : CHF is associated with alterations in iron status and oxidative stress markers, as well as changes in purine metabolism. However, no significant associations between purine metabolites and anemia were identified in this cohort, and these findings should be interpreted cautiously given the exploratory design and sample size limitations.
The Gut Microbiome in Heart Failure: Pathways to Inflammation and Therapeutic Targets.
Vankayala USA, Sohail A, George B … +5 more , Singh M, Khayat O, Kreidieh M, Hasham A, Quiel L
Metabolites · 2026 Jun · PMID 42346411 · Full text
Heart failure (HF) continues to be a major global health burden, with persistent morbidity and mortality despite guideline-directed and device-based therapies. Evidence suggests the gut-heart axis is a critical and under...
Heart failure (HF) continues to be a major global health burden, with persistent morbidity and mortality despite guideline-directed and device-based therapies. Evidence suggests the gut-heart axis is a critical and underrecognized contributor to HF progression. Alterations in cardiac output and systemic venous congestion in HF lead to intestinal hypoperfusion, mucosal edema, and loss of barrier integrity, increasing intestinal permeability, gut dysbiosis, and translocation of microbial products. This systemic translocation is associated with chronic low-grade inflammation that activates innate immune pathways that correlate with endothelial dysfunction, oxidative stress, fibroblast activation, and adverse cardiac remodeling. Gut-derived metabolites derived by microbial metabolism modulate cardiovascular health by altering the metabolic profiles. Dysbiosis results in loss of protective short-chain fatty acid (SCFA)-producing bacteria and enriches pro-inflammatory taxa such as trimethylamine N-oxide (TMAO)-producing bacteria. Elevated TMAO is associated with increased mortality and hospitalization in HF, whereas SCFAs enhance barrier integrity and immune tolerance. Secondary bile acids and uremic toxins such as indoxyl sulfate and p-cresyl sulfate further link dysbiosis to fibrosis and vascular stiffness. Circulating markers such as TMAO, lipopolysaccharide-binding protein (LBP), and soluble CD14 carry prognostic value beyond traditional cardiac biomarkers. This review highlights current experimental, translational, and clinical evidence describing gut dysbiosis and its molecular links to HF progression. Targeting the gut-heart axis represents a novel therapeutic approach in HF. Dietary modulation, probiotics/prebiotics, fecal microbiota transplantation, and inhibitors of microbial metabolic pathways show promise. Future research should emphasize microbiota-based interventions in HF management.
Metabolic Mechanisms of Hexavalent Chromium-Induced Splenic Immune Injury via Oxidative Stress and Ferroptosis Pathways in New Zealand Rabbits.
Yuan J, Zhang J, Song J … +4 more , Liu L, Liu H, Jin S, Ren X
Metabolites · 2026 Jun · PMID 42346410 · Full text
: Hexavalent chromium (Cr(VI)) is a widespread environmental toxic heavy metal with strong oxidative properties; however, its immunotoxicity and metabolic mechanisms in rabbit spleen remain largely unclear. : In this stu...
: Hexavalent chromium (Cr(VI)) is a widespread environmental toxic heavy metal with strong oxidative properties; however, its immunotoxicity and metabolic mechanisms in rabbit spleen remain largely unclear. : In this study, New Zealand rabbits were exposed to 0, 12.5, 25, and 50 mg/L Cr(VI) (as potassium dichromate, KCrO) via drinking water for four weeks to investigate splenic damage and the underlying molecular pathways. Spleen pathological injury was evaluated by hematoxylin and eosin (H&E) staining, and the distribution of T cells, B cells, and macrophages was assessed by immunohistochemistry. Antioxidant enzyme activities and antioxidant substance levels were determined using ELISA, and the relative mRNA expression of immune factor genes, antioxidant-related genes, and ferroptosis-related genes was quantified by quantitative real-time PCR (qRT-PCR). In addition, the distribution of iron in splenic tissue was detected by enhanced Prussian blue staining. : Our results demonstrate that high-dose Cr(VI) significantly inhibited body weight gain, induced lymphocyte atrophy, vacuolization, and widening of intercellular spaces in the splenic white pulp. Furthermore, Cr(VI) reduced T and B lymphocyte populations, promoted macrophage infiltration and inflammatory cytokine gene expression in a concentration-dependent manner, impaired total antioxidant capacity, and led to a decrease in glutathione (GSH) levels in the spleen. Additionally, Cr(VI) exposure increased iron accumulation, activated the ACSL4-NOX lipid peroxidation cascade, and downregulated expression, ultimately triggering ferroptosis. : These findings reveal that Cr(VI) causes splenic immune injury by disrupting oxidative homeostasis and inducing ferroptosis, providing novel insights for evaluating immunotoxicity and identifying metabolic targets under Cr(VI) pollution.
Improving Speed and Efficiency of DESI Imaging with the Xevo MRT Mass Spectrometer for Analyte Mapping.
Towers M, Claude E, Towers L … +2 more , Yates H, Ballantyne J
Metabolites · 2026 Jun · PMID 42346409 · Full text
Recent technology improvements have enabled desorption electrospray ionisation (DESI) mass spectrometry imaging to achieve down to 5 µm (pixel) image resolution. However, operating at this resolution introduces challenge...
Recent technology improvements have enabled desorption electrospray ionisation (DESI) mass spectrometry imaging to achieve down to 5 µm (pixel) image resolution. However, operating at this resolution introduces challenges, particularly regarding increased total analysis time and the need for sufficient instrument sensitivity to detect analytes from very small tissue areas. High mass and image resolution DESI imaging was performed on rat brain tissue using a Xevo™ MRT benchtop mass spectrometer equipped with a multi-reflecting time-of-flight mass analyser and a DESI XS source. Data acquisition was conducted at speeds of up to 100 Hz. Sensitivity was assessed using a dilution series of five Active Pharmaceutical Ingredients (APIs) spotted onto porcine liver tissue. Signal detection limits were evaluated using extracted ion chromatograms (XICs) with signal-to-noise (S/N) calculations against blank samples. Additionally, enhanced duty cycle (EDC) was applied to evaluate improvements in analyte signal intensity across specific mass ranges in both positive and negative ionisation modes. At acquisition speeds of up to 100 Hz, excellent data quality was achieved, with signal intensity remaining suitable for analytical applications. All five tested APIs were detectable at concentrations of 25 pg/mm. Three of the five compounds were further detected at concentrations as low as 2.5 pg/mm², with signal-to-noise ratios greater than 5. The application of EDC resulted in a significant increase in analyte signal intensity within the targeted mass ranges, particularly for small molecule endogenous metabolites and lipids, in both ionisation modes. Furthermore, the system demonstrated substantially improved spectral quality, achieving mass resolution up to 100,000 FWHM. This enabled the resolution of previously indistinguishable analytes with significantly improved mass accuracy compared to systems operating at approximately 30,000 FWHM. The Xevo™ MRT mass spectrometer with DESI XS source enables high-resolution DESI imaging at speeds up to 100 Hz without compromising data quality or sensitivity. The system demonstrates excellent detection limits for pharmaceutical compounds and improved performance through enhanced duty cycle operation. Overall, the combination of high spatial resolution, increased mass resolution, and improved spectral quality allows for more accurate analyte differentiation, representing a significant advancement over lower-resolution systems.
MSTune: A Data-Driven Approach to Parameter Tuning Using Grid Search and Differential Evolution for Gas Chromatography-Mass Spectrometry-Based Compound Identification.
Dlugas H, Li J, Zhang X … +1 more , Kim S
Metabolites · 2026 Jun · PMID 42346408 · Full text
: In gas chromatography-mass spectrometry (GC-MS) library-based compound identification, spectrum preprocessing and associated tuning parameters critically influence identification performance. These parameters are conve...
: In gas chromatography-mass spectrometry (GC-MS) library-based compound identification, spectrum preprocessing and associated tuning parameters critically influence identification performance. These parameters are conventionally optimized using grid search, which requires predefined parameter spaces and becomes computationally inefficient as dimensionality increases, often failing to identify optimal values because of discretization. Differential evolution (DE), a population-based metaheuristic optimization algorithm, provides a flexible alternative through efficient global exploration of the parameter space. This study compared the performance of DE and grid search for optimizing compound identification. : Cosine similarity was applied to the NIST GC-MS library. DE was used to maximize either cross-validated accuracy or mean reciprocal rank (MRR). Results were compared with those from a grid search over five equally spaced parameter values. Identification performance was evaluated using accuracy, MRR, and area under the receiver operating characteristic curve (AUC). : When all four parameters were optimized simultaneously, DE achieved slightly higher cross-validated accuracy and MRR than grid search, although the absolute differences were modest. More pronounced differences were observed in specific unidimensional tuning scenarios, particularly for the intensity weight factor. Simultaneous multidimensional parameter optimization yielded better performance than isolated parameter tuning. : Grid search may be computationally advantageous when the parameter space is known and limited, whereas DE provides a more flexible approach for unknown or high-dimensional search spaces. Overall, DE achieved comparable identification performance to grid search, with modest improvements observed in some optimization settings. A command line Julia-based tool, MSTune, was developed for spectrum preprocessing parameter optimization and is publicly available on GitHub.
Impact of a Dietary Fish Oil Supplementation on the Plasma Lipidome of Healthy Adult Cats.
Paßlack N, Veit H, Funk H … +2 more , Zentek J, Schuchardt S
Metabolites · 2026 Jun · PMID 42346407 · Full text
: Dietary fish oil supplementation has been associated with lower total plasma triacylglycerols in felines. The present study aimed to characterize this effect in more detail, using lipidomic analyses. : Plasma samples o...
: Dietary fish oil supplementation has been associated with lower total plasma triacylglycerols in felines. The present study aimed to characterize this effect in more detail, using lipidomic analyses. : Plasma samples of cats ( = 10), receiving a complete basic diet, with and without the addition of 0.5 g and 1.0 g fish oil/kg body weight/day, each for 21 days, in a randomized crossover design, were analyzed by an FIA MS/MS-based targeted metabolomics approach. : The results demonstrated that 360 metabolites were affected by the dietary treatments, predominantly belonging to triacylglycerols ( = 124), phosphatidylcholines ( = 68), phosphatidylethanolamines ( = 63), phosphatidylglycerols ( = 33), and phosphatidylinositols ( = 21). Lowering effects of fish oil supplementation on plasma triacylglycerols could be confirmed. However, increased levels of specific triacylglycerols were also observed, especially of those containing eicosapentaenoic or docosahexaenoic acid. The decreased triacylglycerols showed a lower number of carbons and a lower degree of unsaturation than the enhanced triacylglycerols. Such a lipid profile is assumed to be beneficial in human medicine; its relevance for feline health, however, is unclear so far. : In conclusion, the lipidomic analyses provided a detailed characterization of the feline plasma lipidome and its modulation by a dietary fish oil supplementation. The clinical relevance of these findings warrants further investigation.
TyG Index and Frailty as Composite Biomarkers of Cardiometabolic Risk and Mortality Across CKM Stages 0-3.
Luo Y, Zeng P, Huang S … +5 more , Peng Z, Zheng J, Shi Z, Sharma M, Zhao Y
Metabolites · 2026 Jun · PMID 42346406 · Full text
: Cardiovascular disease and mortality are common outcomes of cardiovascular-kidney-metabolic (CKM) syndrome. The integrated role of metabolic dysfunction and frailty, quantified by the triglyceride-glucose-frailty index...
: Cardiovascular disease and mortality are common outcomes of cardiovascular-kidney-metabolic (CKM) syndrome. The integrated role of metabolic dysfunction and frailty, quantified by the triglyceride-glucose-frailty index (TyG-FI), remains insufficiently explored. This study examined the association between TyG-FI and incident composite outcomes among participants with CKM stages 0-3. : Data were obtained from two large cohort studies conducted in China and the United States. The analysis focused on participants classified as CKM stages 0-3. Cox proportional hazards models were used to estimate the relationship between TyG-FI and incident composite outcomes. Nonlinear associations were explored using spline functions. Additional analyses were performed across different subgroups and under varied assumptions. Model performance over time was also assessed. : Significant differences in outcome incidence were observed across TyG-FI levels. Higher quartiles showed a gradual increase in risk and displayed a dose-response pattern, with inflection points at 1.01 and 2.29. Associations were consistent across subgroups, and TyG-FI demonstrated moderate discrimination (AUCs 0.714 and 0.744). : In the CHARLS and HRS cohorts, higher TyG-FI scores were independently associated with an increased risk of incident composite outcomes among participants with CKM stages 0-3, with a nonlinear relationship observed. Its discriminatory power was moderate, suggesting that TyG-FI may serve as a supplementary indicator for risk stratification in the early to mid-stages, although its clinical predictive value requires further validation.
Efficacy of Oral Vitamin K2 Supplementation in Experimental Knee Osteoarthritis.
Uzun E, Tekeoğlu İ, Çakıroğlu H … +5 more , Budak Ö, Şahin E, Nas K, Sahin MZ, Kamanlı A
Metabolites · 2026 Jun · PMID 42346405 · Full text
: Although vitamin K has been implicated in osteoarthritis pathophysiology, the specific effects of vitamin K2 (menaquinone) on cartilage degeneration remain poorly characterized. This study aimed to investigate the effe...
: Although vitamin K has been implicated in osteoarthritis pathophysiology, the specific effects of vitamin K2 (menaquinone) on cartilage degeneration remain poorly characterized. This study aimed to investigate the effect of oral vitamin K2 supplementation in a monosodium iodoacetate-induced osteoarthritis model. : Twenty-four male Sprague Dawley rats were included in the study and divided into 3 equal groups: sham group, control (osteoarthritis) group, and treatment group. Saline was applied to the right knee of the sham group, and MIA was applied intra-articularly to the right knee of the control and treatment groups to create an osteoarthritis model. Rats in the treatment group were given 8 micrograms (μg)/day of vitamin K2 orally in addition to the standard diet. After 28 days of follow-up, all rats were euthanized. The right knee articular cartilage was examined histologically with Hematoxylin-Eosin and Safranin O and immunohistochemically with type II collagen alpha 1 and Matrix Metalloproteinase-13. : Histological evaluation demonstrated significantly lower Mankin scores in the treatment group (4.25 ± 0.83) compared with the control group (11.10 ± 0.83). Immunohistochemical analysis showed more intense type II collagen staining and reduced matrix metalloproteinase-13 staining in the treatment group relative to the control group. : Oral vitamin K2 administration was associated with reduced cartilage degeneration and improved matrix preservation at the 28-day endpoint in an induced MIA osteoarthritis rat model.
Gut-Liver Axis Mechanisms Underlying Spontaneous Reversal of Liver Fibrosis: A Gut Microbiota-Metabolomics Analysis.
Zhao Y, Chang H, Hou C … +2 more , Yang B, Li Y
Metabolites · 2026 Jun · PMID 42346404 · Full text
The reversal of liver fibrosis is crucial for improving outcomes in chronic liver disease. The gut-liver axis, mediated by the intestinal microbiota, plays a significant role in this process. However, its dynamic changes...
The reversal of liver fibrosis is crucial for improving outcomes in chronic liver disease. The gut-liver axis, mediated by the intestinal microbiota, plays a significant role in this process. However, its dynamic changes and mechanisms during reversal remain unclear. This study aimed to systematically reveal these dynamics and explore the link between gut microbiota and metabolism in a spontaneous reversal model. Intestinal contents were collected from mouse model groups (fibrosis, 4-week reversal, and 12-week reversal). The use of 16S rRNA gene sequencing was employed to analyze gut microbiota structure, and untargeted metabolomics was used to profile metabolic changes. Differential metabolites and microbial taxa were identified using multivariate statistical analysis, followed by pathway enrichment analysis. Spearman correlation analysis was used to construct metabolite-microbiota association networks across different reversal stages. Metabolomic analysis showed significant alterations in multiple pathways during reversal. Linoleic and α-linolenic acid metabolism had a high impact in later stages. Taurine and biotin metabolism remained active throughout. Branched-chain amino acid degradation was enriched later. Microbiota analysis revealed significant structural shifts via beta-diversity. Bacteroidota decreased while Firmicutes increased in 4 weeks. Butyrate-producing families increased, and Akkermansia was enriched later. Integrated analysis demonstrated significant correlations between specific bacteria and metabolites, indicating a close microbiota-metabolism association during reversal. This integrated multi-omics study delineates the potential dynamic reorganization of the gut microbiota and host metabolism during spontaneous liver fibrosis reversal. These findings provide a theoretical basis for understanding the gut-liver axis mechanism in fibrosis reversal and for developing microbiota-targeted intervention strategies.
Malic Enzyme 1 Limits Acetaminophen-Induced Liver Injury by Sustaining Redox and Bioenergetic Homeostasis.
Guo C, Tang Z
Metabolites · 2026 Jun · PMID 42346403 · Full text
: Acetaminophen (APAP) overdose remains a major cause of acute liver injury. Although N-acetylcysteine (NAC) is the clinically established antidote for APAP toxicity, its efficacy is greatest when administered early, and...
: Acetaminophen (APAP) overdose remains a major cause of acute liver injury. Although N-acetylcysteine (NAC) is the clinically established antidote for APAP toxicity, its efficacy is greatest when administered early, and additional therapeutic strategies are still needed for patients with delayed presentation or progressive injury. Because APAP hepatotoxicity involves coupled disturbances in redox control, mitochondrial performance, and cellular metabolism, metabolic enzymes that sustain NADPH availability may critically influence disease severity. Malic enzyme 1 (ME1), a cytosolic NADPH-generating enzyme, has not been functionally defined in this context. : To determine the contribution of ME1 to APAP-induced liver injury (AILI), we used hepatocyte-specific ME1 knockout mice, hepatic overexpression and reconstitution approaches, primary mouse hepatocytes, and an enzymatically inactive ME1 mutant. Liver injury and associated changes in oxidative stress, mitochondrial function, energy metabolism, autophagic flux, and endoplasmic reticulum (ER) stress were evaluated using biochemical, histological, molecular, and ultrastructural analyses, together with pharmacological interventions. : Genetic loss of ME1 did not substantially alter early APAP metabolic activation-related indices, including APAP-protein adduct formation, but markedly increased hepatocellular metabolic vulnerability after APAP challenge. This phenotype was characterized by enhanced lipid peroxidation, impaired mitochondrial polarization, reduced ATP availability, defective autophagic flux, and amplified ER stress, leading to more severe liver damage. In contrast, ME1 overexpression or reconstitution promoted a more adaptive metabolic response and limited tissue injury. These effects depended largely on ME1 catalytic activity, as protection was markedly weakened with the mutant enzyme. Pharmacological analyses further supported the involvement of AMPK/mTOR-associated autophagy regulation and ER stress adaptation in the downstream actions of ME1. Malic acid also partially attenuated APAP-induced hepatotoxicity in vivo and in vitro. : ME1 functions as an endogenous metabolic factor that influences the outcome of APAP-induced liver injury. Its catalytic activity supports hepatocyte survival primarily by preserving reductive capacity, bioenergetic balance, and adaptive stress responses, rather than by altering APAP metabolic activation.
Sex Differences in the Socioeconomic Gradient of Latent Cardiometabolic Phenotypes in a Working-Age Population from the Balearic Islands (Spain): A Population-Based Analysis.
Vicente-Herrero MT, Tárraga López PJ, Busquets-Cortés C … +3 more , Rodas Cañellas L, López González ÁA, Ramírez-Manent JI
Metabolites · 2026 Jun · PMID 42346402 · Full text
BACKGROUND: Cardiometabolic diseases are shaped by complex interactions between biological and social determinants. While socioeconomic inequalities in cardiometabolic risk are well established, less is known about how t...
BACKGROUND: Cardiometabolic diseases are shaped by complex interactions between biological and social determinants. While socioeconomic inequalities in cardiometabolic risk are well established, less is known about how these inequalities are distributed across multidimensional cardiometabolic phenotypes and whether they differ by sex. OBJECTIVE: We aimed to examine sex differences in the socioeconomic gradient of cardiometabolic phenotypes using latent class analysis in a working-age population. METHODS: A cross-sectional study was conducted in 3108 adults aged 18-65 years undergoing occupational health assessments in the Balearic Islands (Spain). Educational level was used as an indicator of socioeconomic position. Cardiometabolic risk was assessed using obesity, insulin resistance (METS-IR), metabolic dysfunction-associated steatotic liver disease (FLI), atherogenic index of plasma, and metabolic syndrome. Latent class analysis was applied to identify cardiometabolic phenotypes. Multinomial logistic regression models stratified by sex and interaction analyses were used to assess associations between educational level and class membership. Tests for linear trend and predicted probabilities were also estimated. RESULTS: Four cardiometabolic phenotypes were identified: low-risk (40.8%), obesity-dominant (24.1%), dysmetabolic (19.3%), and high-risk multimorbid (15.8%). A clear socioeconomic gradient was observed, with lower educational attainment associated with a higher likelihood of belonging to adverse cardiometabolic profiles. This gradient was stronger among women. For the high-risk multimorbid class, the relative risk ratio comparing low vs. high educational level was 1.82 (95% CI 1.34-2.46) in men and 2.47 (95% CI 1.68-3.64) in women ( for interaction = 0.012). A significant linear trend across educational levels was observed in both sexes ( for trend < 0.001). Predicted probabilities further confirmed a steeper increase in high-risk profiles among women with lower educational attainment. CONCLUSIONS: Cardiometabolic risk is structured into distinct phenotypic profiles that are socially patterned. Socioeconomic inequalities are strongly associated with adverse cardiometabolic phenotypes, with a more pronounced gradient among women. These findings highlight the need for gender-sensitive strategies addressing social determinants to reduce cardiometabolic health inequalities.
Ceramide-Driven Mechanisms in Pulmonary Fibrosis.
Li Z, Li Y, Mao N … +4 more , Gao X, Xu H, Cai W, Li T
Metabolites · 2026 Jun · PMID 42346401 · Full text
Pulmonary fibrosis, particularly idiopathic pulmonary fibrosis (IPF), is a chronic and progressive interstitial lung disease characterized by alveolar epithelial injury, fibroblast activation, and excessive extracellular...
Pulmonary fibrosis, particularly idiopathic pulmonary fibrosis (IPF), is a chronic and progressive interstitial lung disease characterized by alveolar epithelial injury, fibroblast activation, and excessive extracellular matrix deposition, which collectively lead to respiratory failure. Despite the availability of antifibrotic agents, disease-modifying therapies remain limited. Emerging evidence has identified dysregulated sphingolipid metabolism, especially ceramide accumulation, as a key driver of fibrotic pathogenesis. Ceramide is a central bioactive lipid in the sphingolipid pathway that regulates multiple cellular processes, including apoptosis, inflammation, endothelial barrier dysfunction, and fibroblast activation, all of which contribute to pulmonary fibrosis. This review is a narrative review that systematically summarizes the biosynthetic and metabolic pathways of ceramide, with an emphasis on chain length-specific functions and the ceramide to S1P rheostat. We further discuss the mechanistic roles of ceramide in alveolar epithelial cell apoptosis, inflammatory responses, and vascular barrier disruption in fibrotic lung disease. Finally, we highlight emerging therapeutic strategies that target ceramide metabolism, including inhibitors of acid sphingomyelinase (ASMase) and serine palmitoyltransferase (SPT), and propose future directions for clinical translation.
Melatonin Modulates Macrophage Polarization and Immunometabolic Responses in the Colostrum of Obese Mothers.
Silva SHBRGD, França DCH, Silva KMR … +6 more , França ECH, Luz VF, Sfredo ADS, Morais TC, França EL, Honorio-França AC
Metabolites · 2026 Jun · PMID 42346400 · Full text
: Obesity is a major public health problem associated with chronic inflammation and functional alterations in multiple organs and systems. Few studies have examined colostrum from obese mothers, particularly with respect...
: Obesity is a major public health problem associated with chronic inflammation and functional alterations in multiple organs and systems. Few studies have examined colostrum from obese mothers, particularly with respect to macrophage function, enzyme and cytokine concentrations, and the role of melatonin in immune modulation. This study aimed to evaluate melatonin levels and their effects on macrophage polarization, cytokine concentrations, nitric oxide synthase [iNOS], and arginase in colostrum from obese mothers. Colostrum samples were collected from eutrophic mothers [BMI: 18.5-24.9 kg/m] and obese mothers [BMI: ≥30 kg/m]. : Macrophages were isolated by density gradient and treated with melatonin. The expression of M1 and M2 macrophages and cytokine concentrations were assessed by flow cytometry, while melatonin levels in colostrum supernatants, iNOS, and arginase in cell lysates were determined by ELISA. : An endogenous increase in melatonin was also observed in the colostrum of obese mothers. Maternal obesity has been shown to reduce M1 and M2 macrophage expression, increase nitric oxide synthase [NOS] activity, and elevate interleukin-6 [IL-6] and interleukin-17 [IL-17] levels. However, melatonin treatment restored M1 and M2 macrophage levels and reduced inducible nitric oxide synthase [iNOS] and arginase production to levels similar to those observed in mothers of healthy weight. : these findings suggest that maternal obesity creates a pro-inflammatory environment in colostrum, characterized by altered macrophage polarization, altered cytokine secretion, and an imbalance in the enzymatic activities of iNOS and arginase within the L-arginine metabolic pathway. Both natural and supplemental melatonin exhibited immunomodulatory, antioxidant, and anti-inflammatory effects, helping to restore immune balance in colostrum. These results emphasize the potential benefits of melatonin as an immunometabolic modulator and its contribution to understanding immunometabolic regulation in obese mothers.
Identification and Transcriptomic Analysis of Mitochondria-Related Gene Signatures in Obesity.
Yun H, Liu C, Gao B … +1 more , Chen P
Metabolites · 2026 Jun · PMID 42346399 · Full text
: This study aimed to identify core genes associated with mitochondria-related transcriptomic signatures and evaluate their potential as computational biomarkers, immune characteristics, regulatory mechanisms, and potent...
: This study aimed to identify core genes associated with mitochondria-related transcriptomic signatures and evaluate their potential as computational biomarkers, immune characteristics, regulatory mechanisms, and potential therapeutic relevance. : Obesity-related transcriptome datasets were obtained from the GEO database. Differentially expressed genes (DEGs) were intersected with mitochondria-related genes (MRGs) to identify obesity-related MRGs. Functional enrichment, protein-protein interaction (PPI) analysis, CytoHubba, LASSO and random forest algorithms were used to screen core genes. External validation, ROC analysis, immune infiltration analysis, regulatory network construction, candidate drug prediction, and molecular docking were further performed. : A total of 527 DEGs and 15 differentially expressed MRGs were identified. Enrichment analysis suggested that these mitochondria-related genes were mainly associated with disrupted mitochondrial energy metabolism, lipid metabolic remodeling, and altered substrate utilization. , , , and were identified as core MRGs; these genes are respectively associated with mitochondrial metabolic regulation, de novo fatty acid synthesis, N-acetylaspartate-related mitochondrial metabolism, and lysine degradation. These genes were significantly downregulated in obesity and showed good diagnostic performance. Immune infiltration analysis revealed alterations in the immune microenvironment, and the core genes were negatively correlated with multiple immune cell types. Molecular docking showed that Genistein had the lowest predicted binding free energy with NAT8L (-8.89 kcal/mol), suggesting relatively favorable binding among the tested ligand-target pairs. : , , , and may serve as candidate computational biomarkers, among which represents a known lipid metabolism-related gene, supporting the biological plausibility of the workflow.
Gα Is a Heterotrimeric G-Protein Subunit That Directs the Selectivity of PPARγ-Induced Gene Pathways Toward Energy-Related Processes Rather than Adiposity.
Bates EA, Kipp ZA, Lee WH … +4 more , Martinez GJ, Pauss SN, Scherer PE, Hinds TD
Metabolites · 2026 Jun · PMID 42346398 · Full text
BACKGROUND/OBJECTIVES: Signaling mediators of PPARγ influence pathways involved in adipogenesis, lipid storage, inflammation, energy-related processes, and glucose utilization. Recent research indicates that PPARγ coregu...
BACKGROUND/OBJECTIVES: Signaling mediators of PPARγ influence pathways involved in adipogenesis, lipid storage, inflammation, energy-related processes, and glucose utilization. Recent research indicates that PPARγ coregulators, recruited or released during ligand binding, govern specific gene pathways. It was recently discovered that Gα, a heterotrimeric G protein subunit, also signals to PPARγ and may significantly affect adipogenesis and glucose sensitivity. METHODS: To explore Gα's role in adipocytes, we generated CRISPR-mediated Gα () knockout ( KO) and scramble control cells from 3T3-L1 preadipocytes. RESULTS: The absence of Gα resulted in increased lipid accumulation and elevated serine 273 (but not serine 112) phosphorylation of PPARγ. Gα deficiency also decreased mitochondrial abundance and respiration in response to PPARγ ligands such as rosiglitazone, pioglitazone, and troglitazone. RNA sequencing comparing differentiated KO and control adipocytes identified over 800 differentially expressed genes, including those associated with enhanced lipid metabolism and reduced inflammation. Corresponding PamGene kinome profiling showed increased serine/threonine kinase activity and decreased phosphotyrosine kinase signaling in KO adipocytes. CONCLUSIONS: These findings support Gα as a regulator of adipocyte function, linking kinase signaling pathways to PPARγ-mediated transcription. This research provides mechanistic insights into targeting Gα as a potential treatment for individuals with obesity and metabolic disorders.
Roles of Metabolites Unveiled by Metabolomics in , and .
Xia Y, Su S, Tang X … +3 more , Qin L, Lu J, Xia S
Metabolites · 2026 Jun · PMID 42346397 · Full text
Rapeseed is a major source of vegetable oil and contains a wide variety of metabolites. Recent advances, particularly the integration of metabolomics with other omics approaches, have enabled not only comprehensive but a...
Rapeseed is a major source of vegetable oil and contains a wide variety of metabolites. Recent advances, particularly the integration of metabolomics with other omics approaches, have enabled not only comprehensive but also detailed analyses of key metabolites that respond to specific conditions. To date, these recent advances in the metabolomics of crops have not yet been fully clarified. In this review, we seek to summarize the recent progresses in metabolomics studies of , and , introduce the key metabolites spanning nucleic acids, amino acids, fatty acids, lipids, organic acids, alkaloids, phenylpropanoids, terpenoids, flavonoids and glucosinolates uncovered by this approach, focusing on those associated with growth and development, and abiotic/biotic stresses, including macronutrient availability, temperature, water stress, salt stress, aluminum and cadmium toxicity, and infection of , , and . Future perspectives and current challenges in metabolomics integrating with other omics are also discussed, along with its potential for breeding applications, especially in new marker discovery, trait prediction, and even metabolic selection, aimed at developing new rapeseed varieties with stable, high-yielding, and quality traits.
Immunometabolic Stratification of Autism Spectrum Disorder by CD4 T-Cell Phenotype Reveals Subtype-Specific Energetic Deficit and Coordinated Suppression of Micronutrient Acquisition Pathways.
Dervishi A
Metabolites · 2026 Jun · PMID 42346396 · Full text
BACKGROUND: Autism spectrum disorder (ASD) is associated with immune dysregulation in a subset of individuals, though findings remain heterogeneous and poorly defined, particularly regarding immune subtypes and metabolic...
BACKGROUND: Autism spectrum disorder (ASD) is associated with immune dysregulation in a subset of individuals, though findings remain heterogeneous and poorly defined, particularly regarding immune subtypes and metabolic context. METHODS: We analyzed whole-blood microarray data from GSE18123 (GPL570: ASD n = 46, controls n = 19; GPL6244: ASD n = 68, controls n = 21) using an integrated immunometabolic framework. CD4 T-cell transcriptional programs were used to assign dominant immune phenotypes (TH1, TH2, TH17, Tfh, FOXP3 Treg, Tr1-like). Metabolic demand was quantified via the τ-axis; execution capacity was assessed using cytosolic and mitochondrial energy compensation ratios (CECR, MECR). Induction-execution mismatch was captured by three Gap metrics (Cytosolic, Warburg, Global). Functional validation correlated these metrics with transcriptional signatures of folate transport, one-carbon metabolism, receptor-mediated micronutrient uptake (LRP2-CUBN-AMN), cobalamin processing, and vitamin D activation across both platforms. RESULTS: Six immunometabolic CD4 subtypes were identified within ASD. τ-axis discrimination was strongest for Tr1-like (AUC = 0.811) and Tfh (AUC = 0.825) states, while TH17 profiles were indistinguishable from controls. Despite variation in metabolic demand, CECR and MECR remained relatively preserved, indicating decoupling between induction and execution capacity. Global Gap values were most negative in Tfh and TH1 states and positive in TH17 and controls. Negative Gap states showed coordinated suppression of ATP-intensive micronutrient acquisition pathways, including folate transport (FOLR1/2, SLC19A1), megalin-cubilin-mediated uptake (r ≈ 0.77-0.79), and vitamin D activation (CYP27B1). Intracellular cobalamin processing was upregulated in proportion to metabolic demand (r > 0.9). Findings were directionally replicated across both datasets. CONCLUSIONS: These data demonstrate that ASD exhibits structured immunometabolic heterogeneity characterized by subtype-specific demand-capacity imbalance. The Global Gap framework provides transcriptomic evidence of energetic deficit in Tfh- and Tr1-like-dominant states. Future clinical studies should incorporate subtype-stratified assessment of micronutrient status and metabolic execution capacity.
Discriminative Ability of TyG, TyG-WC, BAI, FGIR, and QUICKI Indexes in Identifying Metabolic Syndrome in a Pediatric Population with Obesity.
Tamini S, Bondesan A, Caroli D … +2 more , Frigerio F, Sartorio A
Metabolites · 2026 Jun · PMID 42346395 · Full text
: Pediatric obesity is closely associated with metabolic syndrome (MetS), a condition linked to increased cardiometabolic risk. Early identification of high-risk individuals remains challenging. This study aimed to evalu...
: Pediatric obesity is closely associated with metabolic syndrome (MetS), a condition linked to increased cardiometabolic risk. Early identification of high-risk individuals remains challenging. This study aimed to evaluate the diagnostic performance of selected anthropometric, metabolic dysfunction and insulin resistance indexes for identifying MetS in children and adolescents with obesity. : In this retrospective, cross-sectional, single-center study, 758 children and adolescents with obesity (mean age 14.8 ± 2.1 years; 59.9% females) hospitalized for a body weight-reduction program were included. MetS was defined according to International Diabetes Federation criteria, in which central obesity is a mandatory diagnostic component. The triglyceride-glucose (TyG), TyG-waist circumference (TyG-WC), body adiposity index (BAI), fasting glucose-to-insulin ratio (FGIR), and quantitative insulin sensitivity check index (QUICKI) were calculated. Receiver operating characteristic curve analysis was used to assess their discriminative ability. : The prevalence of MetS was 27.8% and was significantly higher in males than females (34.9% vs. 23.1%, < 0.0001). TyG and TyG-WC showed the best discriminative performance (AUC 0.75 and 0.76, respectively), although with only moderate sensitivity and specificity. FGIR and QUICKI demonstrated lower accuracy (AUC 0.64 and 0.63), whereas BAI showed no discriminative ability (AUC 0.48). These findings were consistent across sexes, although sex-specific differences in both MetS prevalence and optimal cut-off values were observed. Correlation analyses confirmed moderate associations between TyG-based indexes and MetS, whereas other indexes showed weaker relationships. : In the present cohort of children and adolescents with obesity, TyG and TyG-WC showed the best performance in identifying MetS compared with the other evaluated indexes. However, their performance remained moderate, and the proposed cut-off values require validation in independent populations. These indexes may represent simple supportive screening and risk-stratification tools but should be used alongside comprehensive clinical assessment and established diagnostic criteria rather than as stand-alone diagnostic measures.
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