Metabolites

29 pages, 21085 KB

Open AccessArticle

Metabolomic Signatures of Biotrauma Associated with Mortality in ICU Patients Requiring Invasive Mechanical Ventilation and ECMO

by Tiago A. H. Fonseca, Cristiana P. Von Rekowski, Rúben Araújo, Gonçalo C. Justino, M. Conceição Oliveira, Luís Bento and Cecília R. C. Calado

Metabolites 2026, 16(7), 516; https://doi.org/10.3390/metabo16070516 - 22 Jul 2026

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Abstract

Background: Biotrauma from invasive mechanical ventilation (IMV) and extracorporeal membrane oxygenation (ECMO) drives systemic inflammation, metabolic dysregulation, and organ dysfunction in critically ill patients. Therefore, this study aimed to identify clinical and metabolomic features associated with ICU mortality in patients receiving IMV [...] Read more.

Background: Biotrauma from invasive mechanical ventilation (IMV) and extracorporeal membrane oxygenation (ECMO) drives systemic inflammation, metabolic dysregulation, and organ dysfunction in critically ill patients. Therefore, this study aimed to identify clinical and metabolomic features associated with ICU mortality in patients receiving IMV or ECMO, as these remain incompletely characterized. Methods: The retrospective analysis included 30 ICU patients on IMV and 22 on ECMO. Metabolomic and proteomic profiling were performed using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS), and serum spectral analysis by Fourier-transform infrared spectroscopy (FTIRS). Significant variables were incorporated into multivariate logistic regression models, ranked by AIC, AUC, and statistical significance. Model performance was evaluated using stratified 5-fold cross-validation. Final models were adjusted for relevant demographic and clinical covariates. Results: The IMV cohort showed discriminatory FTIRS wavenumbers across all preprocessings, and 155 metabolites plus 14 proteins were significantly altered, with unadjusted models achieving mean AUCs above 0.9. The ECMO cohort showed discriminatory FTIRS wavenumbers in one preprocessing, and 15 metabolites plus 3 proteins were highlighted. FTIRS, metabolomic, and proteomic models reached mean AUCs of 0.967, 0.867, and 0.783, respectively, with lower stability during cross-validation. Adjustment for demographic and clinical covariates reduced model robustness. Conclusions: Stronger and more reproducible molecular signatures related to ICU mortality were observed in the IMV cohort, whereas the ECMO cohort showed reduced model stability, likely reflecting increased biological heterogeneity and small sample size. These findings support the utility of integrated omics for characterizing critical illness and outcome stratification, while reinforcing the need for validation in larger and independent cohorts. Full article

(This article belongs to the Special Issue Metabolomics for Clinical Biomarkers Discovery)

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17 pages, 8317 KB

Open AccessArticle

Effects of Dietary Metabolizable Energy and Crude Protein on Postprandial Metabolite Dynamics and Lactation Performance in Dairy Goats

by Xiuqing Li, Lingbo Wang, Zhiyong Hu, Qiuling Hou, Yun Wang, Yizhao Shen, Yingyu Mu, Xueyan Lin and Zhonghua Wang

Metabolites 2026, 16(7), 515; https://doi.org/10.3390/metabo16070515 - 22 Jul 2026

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Abstract

Background: Dietary metabolizable energy (ME) and crude protein (CP) levels are important for lactation performance and metabolic responses in dairy ruminants. This study aimed to evaluate the effects of dietary ME and CP levels on lactation performance and postprandial metabolic responses in lactating [...] Read more.

Background: Dietary metabolizable energy (ME) and crude protein (CP) levels are important for lactation performance and metabolic responses in dairy ruminants. This study aimed to evaluate the effects of dietary ME and CP levels on lactation performance and postprandial metabolic responses in lactating dairy goats. Methods: Goats were randomly assigned to a 4 × 4 two-factor Latin square experiment consisting of four 14 d periods. The dietary treatments were high energy, high protein (HEHCP); high energy, low protein (HELCP); low energy, high protein (LEHCP); and low energy, low protein (LELCP). Serial postprandial arterial blood samples were collected at 17 daytime time points to characterize temporal changes in plasma amino acids, biochemical parameters and hormones. Results: Increasing CP supply elevated milk yield (+6%) and lactose yield (+5%) but decreased milk fat yield (−8%; p ≤ 0.04). Increasing ME supply tended to enhance milk yield and milk fat yield and increased milk lactose content only under the high CP condition (ME × CP interaction: p = 0.04), suggesting that the response to ME supply depended partly on dietary CP level. High CP increased plasma branched chain amino acid concentrations, whereas high ME reduced Leu and Val under the high CP condition. Most plasma amino acids exhibited marked postprandial dynamics, decreasing initially and then stabilizing, with CP × time interactions observed for Leu, Met, and Phe (p ≤ 0.05). High ME decreased plasma AST activity and tended to reduce urea N concentration and also reduced ALT activity and increased glucose concentration under the high CP diet. Following morning feeding, plasma urea N showed a progressive postprandial decline (p = 0.02), with glucagon decreasing and both prolactin and growth hormone increasing, despite no dietary effects on mean plasma hormone concentrations. Conclusions: Overall, dietary ME and CP levels affected lactation performance and selected plasma metabolic indicators in lactating dairy goats. Coordinated energy and protein supply should be considered when formulating diets for lactating dairy goats. Serial postprandial sampling further revealed temporal changes in plasma metabolites and hormones, providing useful information for refining precision nutrition strategies during lactation. Full article

(This article belongs to the Special Issue Metabolic Responses to Feed and Nutrition in Livestock)

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28 pages, 5883 KB

Open AccessSystematic Review

Effects of High-Intensity Interval Training on Body Composition and Cardiometabolic Health in Physically Inactive Individuals: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

by Cunyu Lan, Beibei Lei, Juerui Li, Wenjie Huang, Kun Yang and Bo Gou

Metabolites 2026, 16(7), 514; https://doi.org/10.3390/metabo16070514 - 22 Jul 2026

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Abstract

Background/Objectives: Increasing physical activity is important for reducing cardiometabolic risk. However, evidence on the effects of high-intensity interval training (HIIT) in physically inactive individuals, including those with extremely sedentary behavior, remains inconsistent. We evaluated the effects of HIIT on body composition and cardiometabolic [...] Read more.

Background/Objectives: Increasing physical activity is important for reducing cardiometabolic risk. However, evidence on the effects of high-intensity interval training (HIIT) in physically inactive individuals, including those with extremely sedentary behavior, remains inconsistent. We evaluated the effects of HIIT on body composition and cardiometabolic outcomes compared with a non-exercise control (CON) and moderate-intensity continuous training (MICT). Methods: PubMed, Web of Science, Embase, the Cochrane Library, Ovid-hosted resources, and ClinicalTrials.gov were searched through 8 July 2026. The protocol was registered (PROSPERO CRD420251230848). Random-effects models were used. Risk of bias, evidence certainty, and robustness were assessed using the Cochrane Risk of Bias 2 (RoB 2) tool, Grading of Recommendations Assessment, Development and Evaluation (GRADE), and leave-one-out analyses, respectively. Results: Twenty-four randomized trials involving 877 participants were analyzed. A conservative study-level summary classified all studies as having at least some concerns, including five at high risk of bias. Compared with CON, HIIT reduced body weight (weighted mean difference [WMD] = −1.60 kg), systolic blood pressure (WMD = −2.85 mmHg), diastolic blood pressure (WMD = −6.57 mmHg), low-density lipoprotein cholesterol (WMD = −0.29 mmol/L), and total cholesterol (WMD = −0.42 mmol/L), and increased maximal oxygen uptake (VO₂max; WMD = 7.72 mL/kg/min). Compared with MICT, most outcomes showed no statistically significant differences, but HIIT produced a greater VO₂max increase (WMD = 3.72 mL/kg/min). Several findings were sensitive to individual-study removal, and certainty of evidence was low or very low. No serious adverse events were reported in 11 studies; attendance or adherence was generally high in 15 studies, despite incomplete reporting and supervised interventions. Conclusions: HIIT may improve selected body composition and cardiometabolic outcomes, with VO₂max showing a relatively consistent direction of effect. However, the certainty of evidence for most outcomes was low or very low; therefore, these findings should be interpreted with caution. Current evidence is insufficient to establish equivalence to MICT or identify an optimal HIIT protocol. Larger, longer-term, high-quality trials using objective measures of sedentary behavior are needed, particularly in extremely sedentary populations. Full article

(This article belongs to the Special Issue Metabolic Adaptations to Exercise: Mechanisms, Modulators, and Health Impacts)

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15 pages, 1914 KB

Open AccessArticle

Untargeted Metabolomics Reveals Distinct Metabolic Signatures of Lactic Acid Bacteria in Food Fermentation and the Same Pipeline Applied to Foodborne Pathogen Detection

by Hao Li and Yuchen Tao

Metabolites 2026, 16(7), 513; https://doi.org/10.3390/metabo16070513 - 22 Jul 2026

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Abstract

Background/Objectives: Lactic acid bacteria (LAB) are essential drivers of food fermentation, yet systematic metabolic comparisons across different LAB strains remain underexplored. This study characterized and contrasted the metabolic fingerprints of Lactiplantibacillus plantarum and Lacticaseibacillus rhamnosus in vegetable fermentation and subsequently evaluated whether [...] Read more.

Background/Objectives: Lactic acid bacteria (LAB) are essential drivers of food fermentation, yet systematic metabolic comparisons across different LAB strains remain underexplored. This study characterized and contrasted the metabolic fingerprints of Lactiplantibacillus plantarum and Lacticaseibacillus rhamnosus in vegetable fermentation and subsequently evaluated whether the same untargeted metabolomics pipeline could be applied to rapid foodborne pathogen detection. Methods: A multi-platform untargeted metabolomics strategy integrating GC-MS and UPLC-Q-TOF-MS was applied to profile four experimental conditions: non-fermented control, L. plantarum monoculture, L. rhamnosus monoculture, and mixed-culture fermentation. Multivariate statistical tools (PCA and PLS-DA) were used to identify differential metabolites and perturbed pathways. The identical analytical workflow was then applied to beef samples artificially contaminated with Escherichia coli O157:H7, Salmonella enterica, or Listeria monocytogenes. Results: Across all samples, 847 metabolites were annotated, of which 312 showed significant abundance changes upon fermentation. PLS-DA delivered robust group discrimination (R²X = 0.89, R²Y = 0.95, Q² = 0.91). Organic acids (32.0%) and amino acids (24.0%) dominated the metabolic landscape, with lactic acid, acetic acid, diacetyl, and acetoin as the most elevated compounds. KEGG analysis highlighted glycolysis/gluconeogenesis, pyruvate metabolism, and branched-chain amino acid degradation as the most heavily rewired pathways. When the same pipeline was applied to pathogen detection, it yielded AUC values of 0.89, 0.87, and 0.88 for E. coli O157:H7, S. enterica, and L. monocytogenes, respectively, with detection times of 18 h, 24 h, and 30 h. Conclusions: This work delivers a side-by-side metabolic atlas of two prominent LAB species and demonstrates the technical portability of an untargeted metabolomics pipeline from a fermentation model system to a pathogen detection scenario. The identified biomarker panels warrant further validation in diverse food matrices, and translation to routine monitoring will require matrix-specific model training and validation. Full article

(This article belongs to the Section Food Metabolomics)

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18 pages, 8417 KB

Open AccessArticle

Comprehensive Evaluation of Fruit Traits and Altitudinal Adaptability of 189 Wild Camellia oleifera Germplasms in East Guizhou, China

by Tanming Ye, Bingqian Wu and Chengjiang Ruan

Metabolites 2026, 16(7), 512; https://doi.org/10.3390/metabo16070512 - 22 Jul 2026

Cited by 1 | Viewed by 401

Abstract

Background: Eastern Tongren City, Guizhou Province, China, possesses abundant wild germplasm resources of Camellia oleifera Abel.; however, there is a lack of systematic evaluation, and the promotion of superior varieties is insufficient. This study aimed to evaluate 21 trait indices of 189 wild [...] Read more.

Background: Eastern Tongren City, Guizhou Province, China, possesses abundant wild germplasm resources of Camellia oleifera Abel.; however, there is a lack of systematic evaluation, and the promotion of superior varieties is insufficient. This study aimed to evaluate 21 trait indices of 189 wild C. oleifera accessions from four regions in the Tongren area to clarify their variation characteristics, assess the effects of altitude on trait expression, and identify candidate germplasms with outstanding comprehensive performance. Methods: A total of 21 traits spanning fruit morphology, oil content, fatty acid composition, and bioactive components (tocopherols, squalene, and polyphenols) were measured. Principal Component Analysis (PCA) was employed to construct a comprehensive evaluation score (Z_n) for quantitative ranking and screening. Trait differences between a low-altitude group (400–800 m, n = 139) and a high-altitude group (800–1200 m, n = 50) were compared using Welch’s t-test. Results: The germplasms exhibited abundant phenotypic variation, with coefficients of variation (CV) ranging from 5.29% (total unsaturated fatty acids) to 124.42% (beta + gamma-tocopherol). Bioactive components showed the highest variability, while fatty acid composition was relatively stable. Altitude had a significant effect on six of the 21 traits. Seed oil content and kernel oil content were significantly higher in the high-altitude group, with mean differences of 5.92 and 5.74 percentage points, respectively (both p < 0.001). However, oleic acid, total unsaturated fatty acids, fruit morphological traits, and most bioactive components showed no significant altitudinal differences (p > 0.05). The first five principal components explained 65.0% of the total variance. CL40 achieved the highest comprehensive score (Z_n = 4.15), followed by MJX2 (Z_n = 2.56). Among the top 10 individuals, eight were from the low-altitude group. Conclusions: This study revealed rich phenotypic variations and distinct altitudinal effects among wild C. oleifera germplasms in eastern Guizhou. The superior germplasms identified (such as CL40 and MJX2) can serve as candidate materials for locally adapted variety improvement. This study was primarily based on single-season phenotypic data, and the genetic stability of the selected germplasms should be validated through clonal trials and molecular marker analysis in future research. Full article

(This article belongs to the Section Plant Metabolism)

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25 pages, 23572 KB

Open AccessArticle

Temporal Partitioning of Carotenoid, Flavonoid and Anthocyanin Biosynthesis Underlies the Ontogenetic Petal Color Transition in Weigela japonica

by Mei Zhang, Siyang Duan, Ji Zhang, Riwen Fei, Xiuting Zhao, Changbo Ji and Li Liu

Metabolites 2026, 16(7), 511; https://doi.org/10.3390/metabo16070511 - 22 Jul 2026

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Abstract

Background: Ontogenetic flower color change is a prevalent adaptive phenomenon in plants, yet the temporal orchestration of multiple pigment pathways during rapid developmental transitions remains poorly understood. This study aims to elucidate the metabolic and transcriptional basis of the petal basal marking color [...] Read more.

Background: Ontogenetic flower color change is a prevalent adaptive phenomenon in plants, yet the temporal orchestration of multiple pigment pathways during rapid developmental transitions remains poorly understood. This study aims to elucidate the metabolic and transcriptional basis of the petal basal marking color transition in Weigela japonica from yellow through yellow-orange to purple-red within a 4-day blooming period. Methods: Metabolomic analysis of flavonoids, anthocyanins, and carotenoids was conducted using UPLC-MS/MS across four developmental stages (S0–S3). Differentially accumulated metabolites were screened based on VIP > 1, |Log₂FC| ≥ 1, and p < 0.05. Transcriptome sequencing was performed using the NovaSeq 6000 platform, and differentially expressed genes were identified using DESeq2. Weighted gene co-expression network analysis (WGCNA) was employed to identify hub genes associated with pigment accumulation. Key structural genes were validated by qRT-PCR. Results: Metabolomics revealed distinct stage-specific pigment accumulation: carotenoids peaked during the yellow-orange stage (S2), while anthocyanins and flavonoids surged in the final purple-red stage (S3). KEGG enrichment indicated that carotenoid metabolism operates as a discrete module, anthocyanin biosynthesis as a terminal-specific route, and flavonoid metabolism as an intermediary hub bridging the two pathways. Transcriptome analysis identified stage-specific gene expression patterns: PAL and C4H were active at S0–S1, CHS/CHI/F3H peaked at S1-S2, and DFR/ANS were maximally expressed at S2–S3. Carotenoid genes (PSY, LCY, ZDS) showed synchronous expression during the yellow-orange phase. WGCNA identified MYB44, bHLH92, and ERF3 as hub genes strongly correlated with the S3 anthocyanin surge. Conclusions: These findings suggest a sequential activation model in W. japonica, in which temporally partitioned pigment metabolism and stepwise transcriptional regulation converge to orchestrate rapid ontogenetic color change. The study provides a framework for understanding developmental color transitions in ornamental plants, though causal regulatory relationships remain to be functionally validated. Full article

(This article belongs to the Special Issue Biological Activity and Chemical Biodiversity of Plant Secondary Metabolites)

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15 pages, 4071 KB

Open AccessArticle

Longitudinal Transitions of Metabolic-Obesity Phenotypes and Subsequent Cardiovascular Disease Risk: A Prospective Analysis of the CHARLS Cohort

by Wenjing Yan, Xiaona Zhang, Qingqing Man, Shanshan Jia, Wenjing Feng, Lili Chen, Rongzhen Li, Lianlong Yu, Liangkai Chen, Jian Zhang and Pengkun Song

Metabolites 2026, 16(7), 510; https://doi.org/10.3390/metabo16070510 - 21 Jul 2026

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Abstract

Background/Objectives: Metabolic-obesity phenotypes are dynamic, yet little is known about how their longitudinal transitions affect cardiovascular disease (CVD) risk. We aimed to characterize these transitions and examine their associations with incident CVD in middle-aged and older Chinese adults. Methods: We included [...] Read more.

Background/Objectives: Metabolic-obesity phenotypes are dynamic, yet little is known about how their longitudinal transitions affect cardiovascular disease (CVD) risk. We aimed to characterize these transitions and examine their associations with incident CVD in middle-aged and older Chinese adults. Methods: We included 4516 participants from the China Health and Retirement Longitudinal Study (CHARLS) who were free of CVD at the follow-up baseline (wave 3). Metabolic-obesity phenotypes (metabolically healthy non-obese [MHNO], metabolically unhealthy non-obese [MUNO], metabolically healthy obese [MHO], and metabolically unhealthy obese [MUO]) were assessed in 2011 and 2015, and six trajectory patterns were defined. Incident CVD (heart disease or stroke) was ascertained from 2015 to 2020. Cox proportional hazards models estimated associations between trajectory groups and incident CVD, and Kaplan–Meier curves compared cumulative incidence across groups. Results: Stable MHNO accounted for 35.96% of the cohort, whereas the stable non-MHNO group accounted for 28.06%. After multivariable adjustment, the small obesity recovery group (n = 89) showed an elevated CVD risk estimate compared with the stable MHNO (HR 2.32, 95% CI 1.33–4.05), while stable non-MHNO group were associated with higher CVD risk (HR 1.72, 95% CI 1.36–2.18). Incident obesity showed elevated but non-significant risk (HR 1.71, 95% CI 0.94–3.10), and metabolic decline showed borderline significance (HR 1.36, 95% CI 1.00–1.85). Sex-stratified analyses showed heterogeneous risk patterns. Conclusions: Metabolic-obesity phenotypes are dynamic, but unfavorable phenotypes often persist. The obesity recovery group, defined using BMI, may represent a heterogeneous group and does not necessarily indicate true cardiometabolic recovery; the observed association should not be interpreted as evidence that weight loss itself increases CVD risk. These findings highlight the importance of jointly considering longitudinal changes in metabolic health and obesity when examining their associations with incident CVD. Full article

(This article belongs to the Special Issue Biomarkers in Obesity, Metabolic Syndrome, and Weight Loss: Advances in Diagnosis, Risk Stratification, and Personalized Management)

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34 pages, 4409 KB

Open AccessSystematic Review

Candidate Metabolic Biomarkers for Physical Fatigue Assessment: An Integrative Meta-Analysis and Exploratory Liquid Chromatography–Mass Spectrometry Pilot Study of Acute Exercise Responses

by Lintao Huang, Wenhui Yang, Pengyu Fu, Xingrong Li, Menglu Pi, Ruilin Shi, Xuehao Wang, Hangfei Qi, Chunyu Zhu, Zhonghuan Jiang, Zifeng Yue, Hange Guo, Jiashuai Tong, Zhihao Chen, Ye Tian and Airong Qian

Metabolites 2026, 16(7), 509; https://doi.org/10.3390/metabo16070509 - 21 Jul 2026

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Abstract

Background: Objective body-fluid biomarkers may help characterize exercise-induced physical fatigue; however, heterogeneity in exercise protocols, biological matrices, and analytical platforms complicates biomarker interpretation. Purpose: This study aimed to identify candidate acute exercise-responsive metabolic biomarkers associated with physical fatigue assessment by integrating conventional biomarker [...] Read more.

Background: Objective body-fluid biomarkers may help characterize exercise-induced physical fatigue; however, heterogeneity in exercise protocols, biological matrices, and analytical platforms complicates biomarker interpretation. Purpose: This study aimed to identify candidate acute exercise-responsive metabolic biomarkers associated with physical fatigue assessment by integrating conventional biomarker evidence, exercise-related metabolomics, and exploratory targeted Liquid chromatography–mass spectrometry (LC-MS) analysis. Methods: We conducted three complementary analyses: (1) a systematic review and random-effects meta-analysis of quantitative biomarkers measured in body-fluid matrices, including blood, plasma, serum, saliva, sweat, urine, and interstitial fluid, at pre-exercise and post-exercise time points; (2) a descriptive fold-change-based synthesis of exercise-related metabolomics studies; and (3) an exploratory paired plasma–saliva liquid chromatography–mass spectrometry pilot analysis in seven apparently healthy young male volunteers. Eligible studies included apparently healthy human participants without reported acute or chronic diseases, major injuries, pregnancy, or clinically diagnosed pathological fatigue, undergoing endurance, resistance, high-intensity interval, or mixed exercise protocols. Biomarkers reported in ≥10 independent comparisons were pooled using log-transformed post-exercise/pre-exercise response ratios. Results: The systematic review and meta-analysis included 110 articles, 129 experiments, and 1826 participants. Lactate showed the strongest pooled response after exercise (response ratio = 4.43, 95% CI: 3.74–5.25, p < 0.00001; I² = 98%), followed by IL-6 (2.15, 95% CI: 1.50–3.07, p < 0.0001; I² = 87%), CK (1.70, 95% CI: 1.56–1.86, p < 0.00001; I² = 90%), and LDH (1.23, 95% CI: 1.11–1.35, p < 0.0001; I² = 93%). Metabolomics synthesis identified lactate, pyruvate, hypoxanthine and xanthine as frequently reported exercise-responsive metabolites related to glycolysis and purine degradation. Exploratory LC-MS analysis showed consistent directional changes in these metabolites in paired plasma and saliva samples. Conclusions: Lactate, pyruvate, hypoxanthine, and xanthine represent candidate metabolism-based acute exercise-responsive biomarkers associated with physical fatigue. However, their fatigue specificity remains to be established and requires validation using independent fatigue criteria, non-fatiguing exercise controls, matrix-specific analyses, and adequately powered diverse cohorts. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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14 pages, 4376 KB

Open AccessReview

The Potential Target Value of ADP-Ribosylation Factor 6 in Insulin Secretion Regulation and the Treatment of Metabolic Disorders

by Yangyang Wang

Metabolites 2026, 16(7), 508; https://doi.org/10.3390/metabo16070508 - 21 Jul 2026

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Abstract

Obesity and type 2 diabetes mellitus (T2DM) represent pandemic metabolic illnesses hallmarked by defective pancreatic β-cell function and blunted insulin release. As a conserved small GTPase (guanosine triphosphatase), ADP-ribosylation factor 6 (ARF6) governs fundamental cellular events encompassing vesicle trafficking, cytoskeleton remodeling and lipid [...] Read more.

Obesity and type 2 diabetes mellitus (T2DM) represent pandemic metabolic illnesses hallmarked by defective pancreatic β-cell function and blunted insulin release. As a conserved small GTPase (guanosine triphosphatase), ADP-ribosylation factor 6 (ARF6) governs fundamental cellular events encompassing vesicle trafficking, cytoskeleton remodeling and lipid metabolic turnover. Emerging data confirm that ARF6 acts as a master rheostat of glucose-stimulated insulin secretion (GSIS) in β-cells through downstream cell division control protein 42/Ras-related C3 botulinum toxin substrate 1 (Cdc42/Rac1) cascades. Pathogenic ARF6 hyperactivation triggers a cascade of β-cell lesions: mitochondrial impairment, autophagic suppression and exacerbated inflammatory signaling, accelerating the progression of obesity and T2DM. First-line therapeutics ranging from GLP-1 (Glucagon-like peptide-1) receptor agonists and metformin to SGLT2 (Sodium-Glucose Cotransporter 2) inhibitors partially restore metabolic homeostasis by rectifying aberrant ARF6-dependent signaling axes. This review comprehensively delineates ARF6’s canonical cellular roles, mechanistic bridges connecting ARF6 to β-cell failure and metabolic deterioration, and functional crosstalk between ARF6 and established anti-metabolic pharmacotherapies. We further address unresolved research gaps and prospective translational avenues, offering actionable perspectives to advance ARF6 as a tractable therapeutic target for obesity and T2DM management. Full article

(This article belongs to the Special Issue Management of Diabetes and Its Metabolic Complications)

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17 pages, 888 KB

Open AccessArticle

4-Bromomethcathinone (4-BMC) Revisited: The First Reported Fatal Case and Toxicological Insights

by Karolina Nowak, Paweł Szpot, Marcin Zawadzki and Agnieszka Chłopaś-Konowałek

Metabolites 2026, 16(7), 507; https://doi.org/10.3390/metabo16070507 - 21 Jul 2026

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Abstract

Background: 4-bromomethcathinone (4-BMC) has been present on the illicit drug market since 2011. Recent EUDA data indicate renewed availability of 4-BMC in Europe, including substantial seizures reported in 2024. Despite numerous seizures of this compound across Europe during its fourteen-year presence, no fatal [...] Read more.

Background: 4-bromomethcathinone (4-BMC) has been present on the illicit drug market since 2011. Recent EUDA data indicate renewed availability of 4-BMC in Europe, including substantial seizures reported in 2024. Despite numerous seizures of this compound across Europe during its fourteen-year presence, no fatal intoxication involving 4-BMC has been reported so far. This paper presents the first documented fatal intoxication involving 4-BMC reported worldwide. Methods: Quantitative determination of 4-BMC in post-mortem blood and urine was performed using the Ultra-High Performance Liquid Chromatography coupled with Triple Quadrupole Mass Spectrometry (UHPLC-QqQ-MS/MS) method, together with complementary toxicological analyses. Results: The 4-BMC concentrations were 16,601 ng/mL in blood and over 50,000 ng/mL in urine. Both matrices also contained 3-chloromethcathinone at 1.7 ng/mL in blood and 122.2 ng/mL in urine. No other drugs, medications, or new psychoactive substances were detected apart from bromomethcathinone and chloromethcathinone metabolites. Conclusions: This first fatal case associated with 4-BMC underscores the necessity for enhanced monitoring of this compound by both forensic and clinical toxicologists. The re-emergence of 4-BMC after more than a decade demonstrates that previously known xenobiotics may reappear and again pose a serious threat to human health. Full article

(This article belongs to the Special Issue Old Challenges, New Tools: Modern Mass Spectrometry in Forensic Toxicology)

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19 pages, 6919 KB

Open AccessArticle

Restoring Metabolic-Inflammatory Homeostasis: Curcumin’s Multi-Layered Defense Against Chondrocyte Dysfunction

by Cong Wang, Yanran Li, Huihui Meng, Gaocheng Shi, Yifan Sun, Ke Che and Hao Yu

Metabolites 2026, 16(7), 506; https://doi.org/10.3390/metabo16070506 - 19 Jul 2026

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Abstract

Background: Osteoarthritis (OA) pathogenesis involves inflammatory-metabolic crosstalk driving cartilage destruction, yet the mechanisms of potential therapeutics like curcumin remain poorly defined. Methods: We integrated untargeted metabolomics, transcriptomic analysis of four GEO datasets (GSE12021, GSE55235, GSE55457, GSE82107), and three machine learning algorithms (LASSO, Random [...] Read more.

Background: Osteoarthritis (OA) pathogenesis involves inflammatory-metabolic crosstalk driving cartilage destruction, yet the mechanisms of potential therapeutics like curcumin remain poorly defined. Methods: We integrated untargeted metabolomics, transcriptomic analysis of four GEO datasets (GSE12021, GSE55235, GSE55457, GSE82107), and three machine learning algorithms (LASSO, Random Forest, XGBoost) to characterize curcumin’s effects on IL-1β-induced human chondrocytes. Results: Metabolomic profiling demonstrated that IL-1β caused significant depletion of TCA cycle intermediates compared to blank controls, including pyruvate (log2FC = −1.34, p < 0.001) and malate (log2FC = −0.54, p < 0.001). High-dose curcumin (10 μM) significantly restored these metabolites towards normal levels (pyruvate log2FC = −0.01 vs. model; malate log2FC = −0.20 vs. model). Three machine learning algorithms converged on a six-gene inflammatory-metabolic signature (NFKBIA, MMP9, LCK, TDO2, HADHA, VEGFA), all showing excellent discriminative performance for OA (individual AUCs > 0.75). qRT-PCR validation confirmed that high-dose curcumin significantly downregulated pro-inflammatory genes compared to IL-1β treatment alone: JUN (log2FC = −0.68, p < 0.001), IL6 (log2FC = −1.13, p < 0.001), PTGS2 (log2FC = −0.94, p < 0.001), CCL20 (log2FC = −1.51, p < 0.001), and MMP9 (log2FC = −0.42, p < 0.001). Conversely, curcumin significantly upregulated the NF-κB inhibitor NFKBIA (log2FC = 0.40, p < 0.001), whose expression was initially suppressed by IL-1β (−log2FC = 0.76 vs. blank, p < 0.001). Conclusions: This systems-level analysis suggests curcumin modulates metabolic-inflammatory networks in OA chondrocytes, with NFKBIA as a candidate mediator, offering a mechanistic framework for drug-like molecule development despite curcumin’s own translational limitations. Full article

(This article belongs to the Special Issue Metabolomics in Plant Natural Products Research, 2nd Edition)

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17 pages, 1442 KB

Open AccessArticle

The Effects of Short-Term N-Acetylcysteine Supplementation on Biochemical Parameters in Endurance-Trained Adults: A Randomized Clinical Trial

by Marcin Sadowski, Emilia Zawieja, Agata Muzsik-Kazimierska, Ewa Bulczak and Agata Chmurzynska

Metabolites 2026, 16(7), 505; https://doi.org/10.3390/metabo16070505 - 18 Jul 2026

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Abstract

Background: The main aim of this study was to assess the effects of short-term N-acetylcysteine (NAC) supplementation on concentrations of homocysteine (Hcy) and reduced glutathione (rGSH), blood lipid profile and liver enzyme activities in endurance-trained adults, and to determine whether these effects [...] Read more.

Background: The main aim of this study was to assess the effects of short-term N-acetylcysteine (NAC) supplementation on concentrations of homocysteine (Hcy) and reduced glutathione (rGSH), blood lipid profile and liver enzyme activities in endurance-trained adults, and to determine whether these effects are modified by methylenetetrahydrofolate reductase (MTHFR) C677T and glutathione S-transferase Pi 1 (GSTP1) A313G. Methods: A total of 56 males and 21 females completed a randomized, double-blind, placebo-controlled crossover trial. Participants received 1200 mg of NAC or a placebo for seven days in a crossover design. Serum Hcy and plasma rGSH concentrations were assessed using dedicated biochemical assays, while blood lipid profile and liver enzyme activities were measured using the biochemical analyzer Konelab 20i. Genotyping was conducted using TaqMan probes. A series of within-subject/between-subject repeated-measures analysis of variance (ANOVA) within a general linear model framework were performed to compare Hcy, rGSH, blood lipid profile and liver enzymes activities before and after the intervention. Results: Hcy concentrations significantly decreased following NAC supplementation (18.58 ± 5.45 µmol/L vs. 16.51 ± 4.97 µmol/L; p = 0.009), although subgroup analysis indicated that the decrease was significant only among females (15.40 ± 4.96 µmol/L vs. 13.60 ± 3.68 µmol/L; p = 0.002) without any significant effect among males. We did not observe any significant changes in rGSH, lipid profile, or liver enzyme activities. There was no interaction between NAC supplementation, MTHFR and GSTP1 genotypes and the changes noted in the parameters we analyzed. Conclusions: In conclusion, short-term NAC supplementation may reduce circulating Hcy concentrations in endurance-trained adults, particularly in females. No consistent effects were observed for rGSH, lipid profile, or liver enzyme activities. Full article

(This article belongs to the Special Issue Nutrition and Dietary Supplementation in the Context of Health, Disease, and Physical Performance)

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35 pages, 62454 KB

Open AccessArticle

Comparing the Effect of Biochar and Poultry Manure on the Metabolomic Profile of Tomatoes (Solanum lycopersicum L.)

by Rolivhuwa Carol Mudau and Lufuno Ethel Nemadodzi

Metabolites 2026, 16(7), 504; https://doi.org/10.3390/metabo16070504 - 17 Jul 2026

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Abstract

Background: In the coming decades, the agricultural system will increasingly rely on organic amendments to sustain crop production, maintain soil health and ensure long-term food security. While inorganic fertilizers remain widely used for vegetable production due to their rapid nutrient availability, their [...] Read more.

Background: In the coming decades, the agricultural system will increasingly rely on organic amendments to sustain crop production, maintain soil health and ensure long-term food security. While inorganic fertilizers remain widely used for vegetable production due to their rapid nutrient availability, their prolonged application has been shown to degrade soil quality, disrupt microbial communities and limit the nutritional quality of harvested produce. Consequently, there is a growing need to explore organic alternatives such as biochar and poultry manure that can enhance both crop productivity and functional quality. Objective: This study aimed to determine the influence of different application rates of biochar (5/T₁, 10/T₂, and 20/T₃ t/ha), poultry manure (10/T₁, 20/T₂, 30/T₃ t/ha), and NPK (2:3:4) as control on the metabolomic profile of tomato fruit. Methods: The metabolomic profile was determined using 1H-nuclear magnetic resonance (NMR). Results: Common metabolites across biochar rates included allantoin, asparagine and betaine, while rate-specific released metabolites such as inosine (T₁), epicatechin (T₂) and kynurenine (T₃) were also identified. Similarly, poultry manure showed an array of metabolites at the highest application rate, with metabolites such as cellobiose, creatinine and maltose, while histamine (T₁) and ADP (T₃) were also detected as distinct metabolites. Full article

(This article belongs to the Special Issue Bioactive Compounds: Plant Stress Responses, Metabolic Regulation, and Therapeutic Insights)

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14 pages, 3695 KB

Open AccessArticle

Maternal Vitamin D Deficiency During Pregnancy Alters Hepatic Metabolism in Adult Female Offspring Without Overt Metabolic Dysfunction

by Miyu Isogai, Norihiro Imai, Tadashi Ogawa and Yumi Hayashi

Metabolites 2026, 16(7), 503; https://doi.org/10.3390/metabo16070503 - 17 Jul 2026

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Abstract

Background/Objectives: Vitamin D deficiency (VDD) is a major global health concern. Although maternal VDD during pregnancy may influence metabolic health in offspring, previous studies have focused predominantly on male offspring, leaving its effects in females insufficiently characterized. This study aimed to comprehensively [...] Read more.

Background/Objectives: Vitamin D deficiency (VDD) is a major global health concern. Although maternal VDD during pregnancy may influence metabolic health in offspring, previous studies have focused predominantly on male offspring, leaving its effects in females insufficiently characterized. This study aimed to comprehensively assess hepatic metabolic profiles in female offspring exposed to maternal VDD during gestation. Methods: Pregnant 129/Sv mice were fed either a control diet or a vitamin D-deficient diet throughout pregnancy. After weaning, female offspring were maintained on a normal diet and analyzed at 12 weeks of age following a 16 h fast. Hepatic metabolomic profiling was conducted using GC–MS/MS, followed by multivariate analysis. To evaluate the potential contribution of fasting, publicly available liver RNA-seq data from ad libitum-fed and 16 h-fasted mice (GSE130127) were also analyzed. Results: No overt metabolic abnormalities were detected between the groups. However, principal component analysis revealed differences in hepatic metabolic profiles between the Control and VDD groups. Levels of 4-aminobutyric acid and proline were significantly elevated in the VDD group. Pathway analysis revealed significant alterations in arginine and proline metabolism and purine metabolism, along with changes in pathways associated with amino acid and energy metabolism. Comparison with fasting-associated liver RNA-seq data revealed minimal overlap, although the potential influence of fasting cannot be completely excluded. Conclusions: Maternal VDD during pregnancy was associated with altered hepatic metabolic profiles in female offspring despite the absence of overt metabolic abnormalities. These findings suggest that maternal VDD may influence hepatic metabolism in female offspring and indicate that the potential long-term effects of maternal VDD on offspring metabolism warrant further investigation. Full article

(This article belongs to the Section Nutrition and Metabolism)

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25 pages, 3493 KB

Open AccessReview

Metagenomics in the Interplay Among Oral and Gut Dysbiosis

by Morena Munzone, Giorgia Maria Marmo, Alessandro Polizzi, Elena Jovanova, Angela Angjelova, Saturnino Marco Lupi and Gaetano Isola

Metabolites 2026, 16(7), 502; https://doi.org/10.3390/metabo16070502 - 16 Jul 2026

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Abstract

Periodontitis is a chronic inflammatory disease increasingly recognized as a manifestation of complex microbial dysbiosis extending beyond the oral cavity. Recent advances in spatial metagenomics provide unprecedented resolution to investigate microbial community structure, function, and localization within periodontal niches and along the oral–gut [...] Read more.

Periodontitis is a chronic inflammatory disease increasingly recognized as a manifestation of complex microbial dysbiosis extending beyond the oral cavity. Recent advances in spatial metagenomics provide unprecedented resolution to investigate microbial community structure, function, and localization within periodontal niches and along the oral–gut axis. This review aims to explore how spatially resolved metagenomic approaches refine our understanding of the ecological and functional shifts in bacterial populations associated with periodontitis and their systemic implications. By integrating spatial mapping with shotgun metagenomics, we highlight distinct microenvironmental signatures within periodontal pockets, characterized by anaerobic pathobionts, metabolic reprogramming, and localized inflammatory gradients. Furthermore, we examine evidence supporting bidirectional interactions between oral and gut microbiota, suggesting that oral-derived taxa may contribute to gut dysbiosis through translocation and ecological disruption. From a basic science perspective, spatial metagenomics reveals niche-specific microbial functions and interspecies interactions that are not captured by bulk sequencing. Clinically, these insights open avenues for precision diagnostics and targeted therapeutics, including microbiome modulation strategies tailored to spatial microbial organization. Overall, this work underscores the importance of spatial context in metagenomic analyses and advances the conceptual framework linking periodontal disease to systemic microbial dysbiosis. Full article

(This article belongs to the Section Microbiology and Ecological Metabolomics)

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43 pages, 5799 KB

Open AccessReview

Molecular Mechanisms Associated with Metabolic Dysfunction: Contributions of Nutritional Genomics

by Natália Ellen Delmicon, Nathália dos Reis Franco, Giovanna Cavanha Corsi, Roberta Mi Kyong Kim Cho, Helen Cristina Vidal and Marcelo Macedo Rogero

Metabolites 2026, 16(7), 501; https://doi.org/10.3390/metabo16070501 - 16 Jul 2026

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Abstract

Nutritional genomics has expanded our understanding of how dietary exposures interact with genetic and epigenetic mechanisms involved in metabolic dysfunction. In this context, metabolic dysfunction associated with excessive visceral adiposity arises from a multifaceted interaction between systemic inflammation, insulin resistance, and inter-individual biological [...] Read more.

Nutritional genomics has expanded our understanding of how dietary exposures interact with genetic and epigenetic mechanisms involved in metabolic dysfunction. In this context, metabolic dysfunction associated with excessive visceral adiposity arises from a multifaceted interaction between systemic inflammation, insulin resistance, and inter-individual biological susceptibility. Obesity, particularly when driven by diets rich in saturated fatty acids, disrupts intestinal homeostasis, thereby triggering metabolic endotoxemia and contributing to low-grade systemic inflammation and adipose tissue dysfunction. Advances following the Human Genome Project have broadened our understanding of the molecular mechanisms of metabolic diseases, highlighting the role of genetic variability and epigenetic regulation in obesity-related insulin resistance. In nutritional science, the integration of genomics and proteomics has further elucidated how dietary exposures interact with the biological pathways involved in this dysfunction. From a nutrigenomic perspective, this narrative review aims to discuss how genetic variability and diet-related molecular mechanisms contribute to obesity-related metabolic dysfunction, with emphasis on single-nucleotide polymorphisms in key genes, including FTO, MC4R, PPAR, APOA, and FADS, involved in the regulation of energy homeostasis and insulin secretion. Additionally, we analyze studies on epigenetic mechanisms, including DNA methylation and the action of microRNAs, which act as post-transcriptional regulators sensitive to nutritional and inflammatory stimuli. We also address how dietary patterns, such as the Mediterranean Diet, as well as nutrients and bioactive compounds, can influence epigenetic regulation. We conclude that integrating multiomics data may improve our understanding of the molecular mechanisms underlying metabolic dysfunction and may support the future development of personalized nutritional strategies and molecular biomarkers for obesity and cardiometabolic diseases. Full article

(This article belongs to the Special Issue Nutrition and Metabolic Diseases: Mechanistic Insights and Personalized Dietary Strategies)

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40 pages, 1664 KB

Open AccessReview

Extracellular Vesicle-Associated microRNAs as Candidate Biomarkers and Mediators of Diabetic Complications: Clinical and Translational Evidence Across Neuropathy, Diabetic Kidney Disease, Retinopathy, and MASLD

by Raúl Ibarra-Salce, José Luis Eduardo Doval-Caballero, Daniel Uribe-Cortés, Genesis Dinora Eugenio-Ponce, Mariela Ibarra-Salce, Omar Jaime-Leal and Manuel Ramón García-Sáenz

Metabolites 2026, 16(7), 500; https://doi.org/10.3390/metabo16070500 - 16 Jul 2026

Viewed by 1593

Abstract

Background/Objectives: Type 2 diabetes is increasingly recognized as a systemic disorder driven not only by chronic hyperglycemia and insulin resistance, but also by dysregulated interorgan communication. Extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as biologically active carriers of proteins, lipids, and [...] Read more.

Background/Objectives: Type 2 diabetes is increasingly recognized as a systemic disorder driven not only by chronic hyperglycemia and insulin resistance, but also by dysregulated interorgan communication. Extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as biologically active carriers of proteins, lipids, and microRNAs capable of modulating gene expression in recipient cells. This narrative review integrates clinical, experimental, and translational evidence on EV-associated microRNAs as candidate biomarkers and potential mediators of diabetic complications, with emphasis on diabetic neuropathy, diabetic kidney disease, diabetic retinopathy, and metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: This review was aligned with the SANRA framework and focused on biological plausibility, evidence from tissue and biofluids, biomarker potential, therapeutic implications, and barriers to clinical translation. Studies were additionally interpreted according to biological matrix, EV-carrier specificity, analytical platform, study design, and level of functional validation. Results: Across complications, EV-associated microRNAs appear to participate in shared pathogenic processes, including oxidative stress, inflammation, endothelial dysfunction, fibrosis, angiogenesis, neurodegeneration, and metabolic memory. In diabetic neuropathy, microRNAs such as miR-146a, miR-155, miR-21-5p, and miR-148a-3p have been linked to neuroinflammation, Schwann-cell dysfunction, axonal injury, and neuropathic pain. In diabetic kidney disease, miR-21, miR-29, miR-30, and miR-126 are implicated in podocyte injury, tubulointerstitial fibrosis, albuminuria, and microvascular dysfunction. In diabetic retinopathy, microRNAs including miR-146a, miR-155, miR-21, miR-126, and miR-200b contribute to neurovascular injury, inflammation, barrier disruption, and angiogenesis. In MASLD associated with diabetes, hepatocyte-derived EVs carrying microRNAs such as miR-1 and miR-126a-3p may link hepatic lipotoxicity to endothelial inflammatory and β-cell dysfunction. Conclusions: Although EV-associated microRNAs offer promising opportunities for biomarker discovery, risk stratification, and targeted therapies, clinical translation remains limited by heterogeneity in EV isolation, microRNA quantification, biological matrices, and outcome definitions. Distinguishing EV-associated miRNAs from total circulating extracellular miRNAs remains essential for biological interpretation. Standardized, longitudinal, and externally validated studies are required before these signals can be implemented as actionable tools in precision diabetes care. Full article

(This article belongs to the Special Issue Management of Diabetes and Its Metabolic Complications)

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9 pages, 657 KB

Open AccessEditorial

The Liver Left Behind: GLP-1 Receptor Agonists and the Prospect of Metabolic Adjuvant Therapy After HCC Resection

by Amedeo Lonardo and Ralf Weiskirchen

Metabolites 2026, 16(7), 499; https://doi.org/10.3390/metabo16070499 - 15 Jul 2026

Viewed by 331

Abstract

Hepatocellular carcinoma (HCC), the most common histological type of primary liver cancer (PLC), remains one of the most consequential malignancies arising in chronic liver disease, in part because its incidence and mortality rates remain closely aligned [...] Full article

(This article belongs to the Special Issue Metabolomics and MASLD: Pathways, Biomarkers, and Clinical Insights)

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15 pages, 629 KB

Open AccessArticle

Metabolomic Profiling Has the Potential to Differentiate Between Iron Deficiency Anemia and Anemia of Inflammation

by Triin Paabo, Eliis Grigor, Egon Taalberg, Natalja Luppova, Eliise-Rosalinda Raudmäe, Piret Mihkelson, Alan Altraja, Ain Kaare, Rando Porosk and Kalle Kilk

Metabolites 2026, 16(7), 498; https://doi.org/10.3390/metabo16070498 - 15 Jul 2026

Viewed by 452

Abstract

Background/Objectives: Discrimination between iron deficiency anemia (IDA) and anemia of inflammation (AI), the major causes of anemia, remains a challenge and novel biomarkers are needed. This prospective study characterizes metabolomic changes in patients with anemia, compares IDA and AI, and evaluates the ability [...] Read more.

Background/Objectives: Discrimination between iron deficiency anemia (IDA) and anemia of inflammation (AI), the major causes of anemia, remains a challenge and novel biomarkers are needed. This prospective study characterizes metabolomic changes in patients with anemia, compares IDA and AI, and evaluates the ability of metabolomic profiling to categorize otherwise unclassifiable anemia (UA) cases. Methods: In the single-center cross-sectional study, patients with anemia were classified as IDA, AI, or their combination (IDA + AI) according to traditional iron biomarkers. Targeted metabolomic analysis was conducted with tandem mass spectrometry using the MxP^® Quant 500 kit, with 617 individual metabolites and 227 calculated parameters in the final analysis. Results: The final cohort included 70 patients with anemia and 27 controls. The concentrations of six metabolites and six calculated parameters were significantly different in patients with anemia compared to controls. Anemia was associated with decreased concentrations of several polyunsaturated fatty acid (PUFA)-containing triglycerides (n = 3) and phosphatidylcholines (n = 2), as well as with increased asparagine/aspartate and docosahexaenoic acid/eicosapentaenoic acid ratio. Multivariate analysis using only metabolomic data differentiated between IDA and AI with a general classification accuracy of 88%. Unclassifiable anemia samples were reclassified mostly as IDA (n = 11) or IDA + AI (n = 6), with one sample reclassified as AI. Conclusions: Metabolomic markers of PUFAs differ between patients with anemia and controls, indicating possible alterations in lipid metabolism. Our preliminary findings suggest that metabolomic data may be capable of distinguishing between IDA and AI. However, owing to several limitations of the current study, the potential utility of metabolome-based approaches should be confirmed in independent validation studies. Full article

(This article belongs to the Section Advances in Metabolomics)

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21 pages, 1313 KB

Open AccessArticle

Longitudinal Assessment of Twelve-Month Weight Loss Outcomes Post-Sleeve Gastrectomy: The Role of Serum and Fecal Metabolomic Biomarkers

by Maya Nassif, Wendy M. Miller, Kathryn M. Ziegler, Nadia Ashrafi, Romana Mimi Ashrafi, Abdullah Khalid, Sumeyya Akyol, Jay Idler, Milda Milčiūtė, Vilija Lomeikaitė, Austėja Jankevičiūtė, Matthew D. Sims, Michael E. Maddens, Ali Yilmaz and Stewart F. Graham

Metabolites 2026, 16(7), 497; https://doi.org/10.3390/metabo16070497 - 15 Jul 2026

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Abstract

Background/Objectives: Metabolomics has emerged as a tool to gain insight into the body’s biological responses to therapeutic interventions. Bariatric surgery remains the most effective treatment for severe obesity and associated comorbidities, leading to significant weight and metabolic improvements. Using a multi-platform, multi-compartment metabolomics [...] Read more.

Background/Objectives: Metabolomics has emerged as a tool to gain insight into the body’s biological responses to therapeutic interventions. Bariatric surgery remains the most effective treatment for severe obesity and associated comorbidities, leading to significant weight and metabolic improvements. Using a multi-platform, multi-compartment metabolomics approach, this study systematically characterizes longitudinal changes in fecal and serum metabolomes of 45 patients following sleeve gastrectomy (SG). Participants were stratified by weight loss outcomes to identify metabolic signatures associated with differential responses, which may serve as predictors of weight loss and provide mechanistic insights in developing targeted therapeutic strategies. Methods: Metabolomic and lipidomic responses to SG were analyzed using multivariable linear mixed-effects models based on data collected pre-operatively and at 3 and 12 months post-operatively. Results: The percentage total weight loss for the highest versus lowest weight loss tertiles (T₃ vs. T₁) at twelve months was 35.81 + 5.4% and 19.49 + 2.62%, p < 0.001, respectively. Substantial alterations in fecal metabolites and lipid species were observed among T3 after twelve months, including aspartate, tyrosine, carnitine, glycine, PC.ae.C36.4, PC.aa.C38.0, PC.ae.C44.4, PC.ae.C40.2, and PC.aa.C40:5. Specifically, changes in serum lipid species including SM.OH.C22:1, PC.ae.C32:1, PC.aa.C34:4, PC.aa.C36:6, PC.ae.C34:3, PC.ae.C34:1, and PC.ae.C32:2, support serum lipidomics as a minimally invasive marker of gut remodeling and adaptation following SG. Sex-stratified analysis revealed unique fecal and serum metabolic changes, highlighting the significance of personalized metabolic monitoring and obesity treatment. Conclusions: Our findings identify metabolic alterations associated with response variability following SG and highlight the potential utility of machine learning to predict weight-loss trajectories and inform personalized interventions. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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21 pages, 1923 KB

Open AccessArticle

Beneficial Changes in Apolipoprotein Concentrations After Bariatric Surgery in Obese Women

by Bartłomiej Łukaszuk, Adrian Chabowski, Andrzej Ziemba, Barbara Choromańska, Piotr Myśliwiec, Katarzyna Supruniuk and Agnieszka Mikłosz

Metabolites 2026, 16(7), 496; https://doi.org/10.3390/metabo16070496 - 14 Jul 2026

Viewed by 390

Abstract

Background: Lipoproteins are molecules composed of phospholipids and apolipoproteins that transport triacylglycerol and cholesterol in blood and are implicated in the development of many diseases. Methods: In this study, we fill a knowledge gap by precisely characterizing the apolipoprotein profile (with Bio-Plex Human [...] Read more.

Background: Lipoproteins are molecules composed of phospholipids and apolipoproteins that transport triacylglycerol and cholesterol in blood and are implicated in the development of many diseases. Methods: In this study, we fill a knowledge gap by precisely characterizing the apolipoprotein profile (with Bio-Plex Human Apolipoprotein Assay) in three metabolically separate groups of individuals (lean individuals and obese individuals without and with metabolic syndrome) and at four distinct time points (0, 3, 6, and 12 months post bariatric surgery). Results: Obese patients had a higher baseline ApoB/ApoA1 ratio, which returned to the reference level over the follow-up period. The above is of clinical importance, as the ratio is a predictor of adverse cardiovascular events common in obese subjects. Interestingly, plasma concentrations of most of the investigated apolipoproteins appeared to be relatively stable at the onset of the experiment, with changes observed later in time. We detected significant drops in the levels of ApoC3, ApoD, and ApoH that occurred as early as three months post intervention. On the other hand, the levels of ApoA2, ApoE, and ApoJ increased with time. Of the above, ApoE is known to be involved in the removal of TAGs and cholesterol from the blood. Conversely, ApoJ appears to be one of the determinants of the tissues’ responsiveness to insulin. Thus, it may be an indicator of the reduced insulin resistance observed a few months after the surgery. Conclusions: Overall, the investigated proteins have a documented role in the development and progression of vascular pathologies. Hence, our results may be interpreted as a sign of improved cardiovascular fitness of our patients. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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16 pages, 1101 KB

Open AccessReview

The Liver as the Central Regulator of Cholesterol Homeostasis: Statins, Gut Microbiota, Hepatic Inflammation, and the Proposed Oral–Gut–Liver–Artery Axis in Atherogenesis

by Mark Cannon, John Peldyak and Eleanor Campbell

Metabolites 2026, 16(7), 495; https://doi.org/10.3390/metabo16070495 - 13 Jul 2026

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Abstract

Background/Objectives: Cholesterol homeostasis is often framed as a dietary problem, but circulating low-density lipoprotein (LDL) biology is governed largely by endogenous sterol handling, with the liver acting as the principal integrative organ for cholesterol synthesis, LDL receptor-mediated clearance, very-low-density lipoprotein (VLDL) export, bile [...] Read more.

Background/Objectives: Cholesterol homeostasis is often framed as a dietary problem, but circulating low-density lipoprotein (LDL) biology is governed largely by endogenous sterol handling, with the liver acting as the principal integrative organ for cholesterol synthesis, LDL receptor-mediated clearance, very-low-density lipoprotein (VLDL) export, bile acid production, and biliary sterol disposal. This narrative review evaluates the hepatic basis of cholesterol regulation, statin pharmacology, gut microbial sterol metabolism, chronic hepatic inflammation, and a proposed oral–gut–liver–artery axis in atherogenesis. The aim of this narrative review is to clarify which elements of the proposed axis are established, which are supported but incomplete, and which remain hypothesis-generating. Methods: Mechanistic, translational, clinical, and review literature were synthesized to separate established mechanisms from emerging and speculative links. PubMed/MEDLINE, Scopus, and Google Scholar were searched from January 2000 through May 2026. Primary search terms included: cholesterol homeostasis, LDL receptor, SREBP2, statin pleiotropic effects, statin-associated muscle symptoms, gut microbiota cholesterol, bile salt hydrolase, MASLD, Porphyromonas gingivalis liver, phosphorylated dihydroceramides, serine dipeptide lipids Bacteroidetes, ceramide atherosclerosis, and oral–gut–liver–artery axis. Results: LDL/apoB causality and hepatic statin mechanism are well-established. Gut microbiota can alter cholesterol absorption, coprostanol formation, bile acid pools, and portal signaling, but these effects are context-dependent. Hepatic free cholesterol loading and lysosomal sterol stress are strongly implicated in the biology of metabolic dysfunction-associated steatotic liver disease (MASLD). Periodontal pathogens, especially Porphyromonas gingivalis, may contribute to liver and vascular inflammation through bacteremia, oral–gut translocation, innate immune activation, and bioactive bacterial sphingolipids. Phosphorylated dihydroceramides (PDHCs) and Bacteroidetes-derived serine dipeptide lipids have been detected in human arterial specimens and shown to enter host ceramide pools, providing a direct lipid metabolic pathway linking microbial community composition to vascular disease. Viridans streptococci and the Streptococcus anginosus group are inflammatory cofactors rather than proven causes of hepatic cholesterol overproduction. Conclusions: The strongest model involves microbial amplification of hepatic cholesterol dysmetabolism, endothelial activation, foam-cell formation, and plaque vulnerability acting on a host-derived LDL/apoB scaffold. This model is testable and should complement guideline-based LDL-lowering therapy. Full article

(This article belongs to the Special Issue Lipids and Fatty Acid Metabolism in Cardiovascular Diseases)

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30 pages, 3522 KB

Open AccessArticle

LipiDecipher: A Structure-Oriented Analytical Framework for Interpretable Clinical Lipidomics

by Anliang Huang, Yunshu Zhang, Baoning Wu, Tingting Bai, Xiaoyang Yuan, Dong Shang, Shurong Ma, Rihong Huang and Peiyuan Yin

Metabolites 2026, 16(7), 494; https://doi.org/10.3390/metabo16070494 - 13 Jul 2026

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Abstract

Background: Clinical lipidomics can capture disease-associated molecular alterations at high resolution, yet translating complex lipid species data into interpretable biological insight remains challenging. Existing workflows often emphasize statistical discrimination while underutilizing the structural information embedded in lipid species. To address this gap, we [...] Read more.

Background: Clinical lipidomics can capture disease-associated molecular alterations at high resolution, yet translating complex lipid species data into interpretable biological insight remains challenging. Existing workflows often emphasize statistical discrimination while underutilizing the structural information embedded in lipid species. To address this gap, we developed LipiDecipher, a structure-oriented analytical framework designed to summarize lipidomic alterations into interpretable structural patterns and to provide database-supported biological contextualization. Methods: LipiDecipher integrates differential lipid analysis, structure-resolved summarization, multivariate discrimination, and knowledge-based lipid-to-protein/pathway contextualization. We applied this framework to a retrospective serum lipidomics dataset comprising healthy controls and patients with acute myocardial infarction or post-PCI recurrent myocardial infarction. To improve transparency and robustness, the revised analysis includes sex-disaggregated reporting, covariate-adjusted sensitivity analyses for sex and age, and internal separation stability assessment of category-specific LDA projections through resampling-based feature stability analysis, repeated cross-validation, and permutation testing. Results: The framework identified distinct lipid alterations across study groups, including changes in phosphatidylinositols, ceramides, and triglyceride remodeling patterns. These alterations became more interpretable when summarized at the structural level, including lipid class composition, acyl-chain length, and degree of unsaturation. Internal discrimination analyses suggested separability between groups, while repeated resampling highlighted a subset of recurrently selected lipid features. Knowledge-based mapping prioritized lipid-associated biological contexts related to glycerophospholipid metabolism, sphingolipid metabolism, membrane remodeling, inflammatory signaling, and energy-related processes. Importantly, these protein- and pathway-level outputs are presented as database-supported hypotheses rather than direct evidence of target engagement or pathway activation in the studied cohort. Conclusions: LipiDecipher provides a structure-oriented and interpretation-focused framework for clinical lipidomics. In a retrospective acute myocardial infarction cohort, it enabled the prioritization of candidate lipid signatures and biologically plausible hypotheses from complex lipidomic data. These findings support its use as a hypothesis-generating analytical tool, while external validation and experimental follow-up remain necessary before mechanistic or clinical claims can be established. Full article

(This article belongs to the Special Issue Lipids and Fatty Acid Metabolism in Cardiovascular Diseases)

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27 pages, 8544 KB

Open AccessArticle

Impact of Ear Stage Drought Stress on Yield and Rhizosphere Metagenomic Profiles in Maize Cultivars with Contrasting Drought Tolerance

by Qi Lu, Hongqun Zhao, Kureshi RuKeye, Yao Geng, Jincheng Du, Liyang Chen, Qiuhui Zhu, Congfang Xi and Jianbin Li

Metabolites 2026, 16(7), 493; https://doi.org/10.3390/metabo16070493 - 13 Jul 2026

Viewed by 307

Abstract

Background/Objectives: Drought stress is a primary constraint on maize productivity, yet the role of rhizosphere microbial communities in modulating cultivar-specific drought resilience remains poorly understood. This study aimed to investigate the physiological and microbiome-mediated responses underlying differences in drought tolerance between contrasting cultivars [...] Read more.

Background/Objectives: Drought stress is a primary constraint on maize productivity, yet the role of rhizosphere microbial communities in modulating cultivar-specific drought resilience remains poorly understood. This study aimed to investigate the physiological and microbiome-mediated responses underlying differences in drought tolerance between contrasting cultivars to better understand drought tolerance mechanisms. Methods: Two maize cultivars with contrasting drought tolerance—NK718 (tolerant) and Zhongdan 808 (sensitive)—were subjected to drought stress at the V12 stage. We assessed yield components, oxidative stress indicators (Malondialdehyde (MDA)), and antioxidant enzyme activities (Superoxide Dismutase (SOD), Peroxidase (POD), Catalase (CAT)). Metagenomic sequencing was employed to analyze structural and functional shifts in the rhizosphere microbiota. Results: Drought significantly suppressed yield and physiological performance in both cultivars. However, the sensitive cultivar suffered more pronounced yield losses and severe oxidative stress, indicated by elevated Malondialdehyde (MDA) and decreased antioxidant enzyme activities. Conversely, the tolerant cultivar maintained superior physiological homeostasis. Metagenomic sequencing revealed drought-induced microbial shifts, including decreased Proteobacteria and Ascomycota, alongside increased Actinobacteriota and Mucoromycota. Notably, the drought-tolerant cultivar exhibited enhanced microbial community stability and more complex co-occurrence networks. Furthermore, it enriched specific functional pathways, such as phenylpropanoid biosynthesis, which positively correlated with yield stability and antioxidant capacity. Conclusions: Maize drought tolerance is underpinned by the coordinated regulation of plant physiological adaptation and the structural and functional stabilization of the rhizosphere microbiome. These findings offer a theoretical framework for developing breeding strategies that leverage root-microbe interactions to optimize maize yields under water-limited conditions. Full article

(This article belongs to the Special Issue Metabolomics and Plant Defence, 2nd Edition)

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23 pages, 11845 KB

Open AccessFeature PaperArticle

Six Rotation Years Drive Dynamic Shifts in Agronomic Traits, Photosynthesis, and Tuber Metabolomics of Dioscorea opposita Thunb

by Yange Yu, Dandan Dai, Guixiao La, Xiangyang Li, Xiaoyang Guo, Yi Wen and Tiegang Yang

Metabolites 2026, 16(7), 492; https://doi.org/10.3390/metabo16070492 - 13 Jul 2026

Viewed by 362

Abstract

Background/Objectives: Dioscorea opposita Thunb. is widely cultivated as a nutritious crop; however, the dynamic effects of different rotation years on its agronomic traits, photosynthetic performance, and tuber metabolome remains poorly understood. This study aimed to systematically investigate the effects of varying rotation [...] Read more.

Background/Objectives: Dioscorea opposita Thunb. is widely cultivated as a nutritious crop; however, the dynamic effects of different rotation years on its agronomic traits, photosynthetic performance, and tuber metabolome remains poorly understood. This study aimed to systematically investigate the effects of varying rotation years on these parameters. Methods: Six field treatments were established: Y0 (0-year rotation, continuous cropping), Y1 (1-year), Y2 (2-year), Y3 (3-year), Y4 (4-year), and CK (fallow land with ≥8 years of rotation). Tuber metabolomic profiling was performed using UPLC-MS/MS. Results: Rotation years <4 showed no differences in tuber length or yield, with tuber length ranging from 35.42 to 47.18 cm and yield from 103.31 to 133.77 g. Shorter rotations (<4 years) exhibited significantly reduced chlorophyll content, as well as diminished photosynthetic parameters (Pn, Gs, and Tr). Metabolomic analysis identified 93 metabolites, of which 30 were differential, with 11 showing enrichment in Y4. Notably, procyanidin B1, kaempferol, dihydroquercetin, pyridoxine, and L-cystine exhibited higher levels in Y0. Sinapic acid, tyramine, glutamine, dibutyl phthalate, and fructose reached peak levels in fallow land (CK). All pairwise comparisons except Y4 vs. CK were enriched in the flavonoid and flavone biosynthesis pathway, with flavonoids representing the predominant class of differential metabolites. Cluster analysis showed that metabolites in clusters 1 and 7 peaked at Y4, while those in clusters 3, 4, 5, and 6 reached minimum levels at Y4. Conclusions: Rotation years of less than 4 years led to restricted growth, reduced yield, impaired chlorophyll synthesis, and altered metabolic profiles. A four-year rotation is identified as a critical turning point in metabolite accumulation, providing valuable guidance for sustainable D. opposita cultivation. Full article

(This article belongs to the Section Plant Metabolism)

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11 pages, 637 KB

Open AccessArticle

Developmental Stage Modulates Mineral–Hormonal Adaptation After Roux-en-Y Gastric Bypass: A Translational Life-Course Study

by Mariana Luna, Bruno Rodrigues and Andréa Ramalho

Metabolites 2026, 16(7), 491; https://doi.org/10.3390/metabo16070491 - 13 Jul 2026

Viewed by 305

Abstract

Background: Vitamin D deficiency is highly prevalent in individuals with severe obesity and may worsen after malabsorptive bariatric procedures. Adolescence represents a critical period of skeletal and metabolic maturation and may influence mineral–hormonal adaptation after Roux-en-Y gastric bypass (RYGB). Objective: To investigate whether [...] Read more.

Background: Vitamin D deficiency is highly prevalent in individuals with severe obesity and may worsen after malabsorptive bariatric procedures. Adolescence represents a critical period of skeletal and metabolic maturation and may influence mineral–hormonal adaptation after Roux-en-Y gastric bypass (RYGB). Objective: To investigate whether developmental stage influences longitudinal mineral–hormonal adaptation after RYGB in adolescents and adults with severe obesity. Methods: This prospective observational cohort study included 120 participants undergoing RYGB: 60 adolescents (15–19 years) and 60 adults (20–49 years) with a history of severe obesity. Assessments were performed preoperatively and at 6 and 12 months postoperatively. Serum 25-hydroxyvitamin D, ionized calcium, phosphorus, and parathyroid hormone (PTH) were measured. Group comparisons were performed using non-parametric tests within a translational life-course framework. Results: Vitamin D inadequacy (<30 ng/mL) was highly prevalent at baseline in both groups (78.3% vs. 85.0%). Despite substantial weight loss in both cohorts, adolescents exhibited higher frequencies of hypocalcaemia and hypophosphataemia (p < 0.001), progressive elevation of PTH levels, and a higher prevalence of secondary hyperparathyroidism at 12 months. Adults showed a comparatively less pronounced endocrine–mineral response but also experienced persistent increases in PTH throughout follow-up. Vitamin D inadequacy remained highly prevalent in both groups despite standardized supplementation. Conclusions: Postoperative mineral–hormonal adaptation after RYGB differs according to developmental stage. Adolescents exhibited greater endocrine–mineral vulnerability during a critical period of skeletal maturation, suggesting that biological stage may influence postoperative adaptation beyond anthropometric response alone. These findings support developmental stage-specific monitoring and individualized postoperative management after metabolic surgery. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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22 pages, 2812 KB

Open AccessArticle

TyG-Centered Endocrine–Metabolic Architecture in Patients with Thyroid Dysfunction: A Systems Phenotyping Study

by Mirela Frandes, Adriana Gherbon, Anca Tudor, Oana Albai, Mihaela Maria Vlad and Călin Muntean

Metabolites 2026, 16(7), 490; https://doi.org/10.3390/metabo16070490 - 12 Jul 2026

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Abstract

Background: Metabolic dysfunction is a complex process arising from coordinated interactions among insulin resistance, dyslipidemia, hepatic dysfunction, obesity, low-grade inflammation, and endocrine alterations. The triglyceride–glucose (TyG) index is a simple, reproducible surrogate of insulin resistance, but most studies have evaluated it through isolated [...] Read more.

Background: Metabolic dysfunction is a complex process arising from coordinated interactions among insulin resistance, dyslipidemia, hepatic dysfunction, obesity, low-grade inflammation, and endocrine alterations. The triglyceride–glucose (TyG) index is a simple, reproducible surrogate of insulin resistance, but most studies have evaluated it through isolated association-based analyses. We characterized the endocrine–metabolic architecture associated with TyG in patients with thyroid dysfunction using a systems-phenotyping approach. Methods: In this retrospective, single-center, cross-sectional study of 387 adults evaluated for thyroid dysfunction, unsupervised phenotypes were derived by principal component analysis (PCA), K-means, Gaussian mixture models (GMM), and hierarchical (Ward) clustering using fully measured primary metabolic variables (fasting glucose, triglycerides, HDL- and LDL-cholesterol, body mass index, alanine, and aspartate aminotransferase). TyG was then examined as a descriptor of the identified architecture. Model-based latent profile analysis (BIC, entropy) and a censoring-aware, rank-based Gaussian graphical model (GGM) of partial correlations were additionally estimated. Results: Three overlapping, clinically interpretable phenotypic partitions of an underlying metabolic continuum were identified: a metabolically preserved phenotype (MP), an intermediate hepatic-dominant phenotype (IHD), and a severe insulin-resistance-dominant phenotype (SIRD), characterized by obesity, atherogenic dyslipidemia, and hyperuricemia. TyG values increased monotonically across the three partitions (medians 8.24, 8.74, and 8.87 in MP, IHD, and SIRD, respectively; p < 0.001), providing an accessible single-number summary of the metabolic gradient. Cluster separation was modest (silhouette = 0.17), consistent with a continuum, but the three-profile solution was supported by latent profile analysis (ΔBIC = −96.7; relative entropy = 0.75) and was reproduced across frameworks (adjusted Rand index of 0.75 with GMM and 0.46 with Ward). In the censoring-aware GGM, metabolic and thyroid variables formed two near-orthogonal blocks (maximum absolute metabolic–thyroid partial correlation: 0.16; median: 0.05). Conclusions: The systems phenotyping approach identified three clinically interpretable phenotypic partitions (MP, IHD, SIRD) along a metabolic continuum in patients evaluated for thyroid dysfunction. TyG values increased monotonically across partitions (medians 8.24, 8.74, 8.87) and provided a pragmatic single-number summary of the principal metabolic axis. The IHD phenotype indicates that hepatic dysregulation can emerge as a distinct early stage rather than solely a late consequence of insulin resistance. Metabolic and thyroid axes were near-orthogonal, positioning thyroid autoimmunity as a parallel modulatory layer. These findings support TyG as an accessible descriptor for multidimensional endocrine–metabolic risk stratification. Full article

(This article belongs to the Special Issue Exploring Pathological Mechanisms in Obesity, Diabetes, and Metabolic Syndrome: 2nd Edition)

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48 pages, 2736 KB

Open AccessReview

Mitochondrial Dysfunction in Metabolic-Syndrome-Related MASLD/MASH: Metabolic Mechanisms and Therapeutic Perspectives

by Jin Jin and Yang Cheng

Metabolites 2026, 16(7), 489; https://doi.org/10.3390/metabo16070489 - 11 Jul 2026

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Abstract

Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and metabolic-dysfunction-associated steatohepatitis (MASH) arise in the setting of obesity, insulin resistance, type 2 diabetes, and metabolic syndrome. This review examines how mitochondrial dysfunction participates in the transition from lipid accumulation to hepatocyte injury, inflammation, and fibrosis, [...] Read more.

Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and metabolic-dysfunction-associated steatohepatitis (MASH) arise in the setting of obesity, insulin resistance, type 2 diabetes, and metabolic syndrome. This review examines how mitochondrial dysfunction participates in the transition from lipid accumulation to hepatocyte injury, inflammation, and fibrosis, and how evidence from human, animal, and in vitro studies should be interpreted. Methods: We provide a narrative synthesis of mechanistic, translational, and clinical studies on hepatic mitochondrial metabolism, fatty acid oxidation, oxidative phosphorylation, redox stress, organelle crosstalk, mitophagy, mitochondrial biogenesis and proteostasis, mitochondrial danger signals, the gut-liver-mitochondria axis, and mitochondria-related therapeutic strategies. Results: In early metabolic overload, mitochondrial oxidation may increase as an adaptive response. With persistent substrate pressure, this adaptation can become inefficient, with impaired fatty acid disposal, less efficient oxidative phosphorylation, reactive oxygen species production, redox imbalance, defective mitochondrial quality control, altered mitochondrial biogenesis, mitochondrial unfolded protein response (UPRmt)-related proteostatic stress and mtDNA instability. Mitochondrial DNA and RNA released from damaged organelles may also activate cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), inflammasome, and RNA-sensing pathways, linking hepatocyte stress to macrophage activation, stellate cell activation, extracellular matrix deposition, and fibrosis. Conclusions: The current evidence supports mitochondria as a stage-dependent amplifier of metabolic liver injury rather than a uniform initiating event. Clinically, the strongest evidence remains with upstream metabolic unloading and liver-directed metabolic therapy, whereas direct mitochondrial restoration and quality-control targeting remain promising but less mature. Full article

(This article belongs to the Special Issue Exploring Pathological Mechanisms in Obesity, Diabetes, and Metabolic Syndrome: 2nd Edition)

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18 pages, 886 KB

Open AccessArticle

Phenotype-Specific Profiles of Isthmin-1, Trimethylamine N-Oxide, and Nitric Oxide in Polyendocrine Metabolic Ovarian Syndrome (Formerly PCOS): An Exploratory Biomarker Study

by Alihan Tigli, Yakup Baykus, Rulin Deniz, Guzide Ece Akinci, Nazli Sener, Yasemin Ercan Degirmenci, Oguzhan Karakoc, Muhammet Bora Uzuner, Sefer Ustebay, Sermin Kilic, Engin Korkmazer, Murat Erdemir and Suleyman Aydin

Metabolites 2026, 16(7), 488; https://doi.org/10.3390/metabo16070488 - 11 Jul 2026

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Abstract

Background: This study aimed to evaluate the phenotype-specific profiles of serum Isthmin-1 (ISM-1), Trimethylamine N-Oxide (TMAO) and Nitric Oxide (NO) levels in women diagnosed with Polyendocrine Metabolic Ovarian Syndrome (PMOS, formerly known as Polycystic Ovary Syndrome—PCOS) according to the Rotterdam criteria. Methods: [...] Read more.

Background: This study aimed to evaluate the phenotype-specific profiles of serum Isthmin-1 (ISM-1), Trimethylamine N-Oxide (TMAO) and Nitric Oxide (NO) levels in women diagnosed with Polyendocrine Metabolic Ovarian Syndrome (PMOS, formerly known as Polycystic Ovary Syndrome—PCOS) according to the Rotterdam criteria. Methods: This cross-sectional study enrolled 90 reproductive-aged women, divided equally into five groups (n = 18 per group) with similar baseline metabolic parameters: healthy controls and PMOS Phenotypes A, B, C, and D. To minimize confounding effects, individuals with recent use of specific medications were excluded, and 24 h dietary recalls were obtained. Fasting blood samples were collected during the early follicular phase. Serum ISM-1, TMAO, and NO levels were quantified via ELISA, and insulin resistance was determined using the HOMA-IR index. Data were adjusted for potential confounders, including age, BMI, and smoking status, using multivariate linear regression models. Results: No statistically significant differences were observed between the groups in key parameters such as BMI and HOMA-IR. Serum ISM-1 levels did not show a significant difference between the groups (p = 0.501). In contrast, NO levels were found to be significantly lower in all PMOS phenotypes compared to the control group (p < 0.001), and this reduction remained independent in regression models. TMAO levels, however, exhibited a phenotype-specific distribution; in the non-hyperandrogenic Phenotype D, they were found to be significantly lower than in the control group and hyperandrogenic phenotypes A and B. In the multivariate regression analysis, it was confirmed that Phenotype D was independently associated with low TMAO levels (B = −0.131, p = 0.027). Conclusions: Although PMOS patients share a similar profile of obesity and insulin resistance, they exhibit marked biochemical heterogeneity. Whilst the reduction in NO levels may indicate a generalised vascular change affecting all phenotypes, the observation of low TMAO levels specifically in the non-hyperandrogenic Phenotype D highlights a distinct biochemical signature associated with this subgroup, observed in the absence of hyperandrogenism. Our findings support the notion that adopting phenotype-specific, individualised approaches in the management of PMOS may be beneficial. Full article

(This article belongs to the Special Issue Research on Metabolic Biomarkers in Different Diseases)

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40 pages, 12329 KB

Open AccessArticle

Integrated Elementomics–Genomics–Metabolomics Analysis Reveals Plasma Biomarker Networks and Diagnostic Potential for Gastric Cancer

by Ruoyu Li, Guofeng Li, Shilin Chen, Xuejie Lv, Dan Wang, Jianjun Xiang, Yu Jiang, Dong Tan and Chuancheng Wu

Metabolites 2026, 16(7), 487; https://doi.org/10.3390/metabo16070487 - 10 Jul 2026

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Abstract

Background: Gastric cancer remains a leading cause of cancer-related deaths worldwide. Although significant progress has been made in clinical diagnosis and treatment, the molecular mechanisms underlying gastric cancer have not yet been fully elucidated. To address this, this study employs a multi-omics approach [...] Read more.

Background: Gastric cancer remains a leading cause of cancer-related deaths worldwide. Although significant progress has been made in clinical diagnosis and treatment, the molecular mechanisms underlying gastric cancer have not yet been fully elucidated. To address this, this study employs a multi-omics approach to systematically analyze the molecular characteristics of gastric cancer. Methods: This case–control study enrolled 218 GC patients and 218 healthy controls, and adopted a multi-omics strategy combining inductively coupled plasma mass spectrometry (ICP-MS), element-related genome-wide association study (eGWAS), and untargeted metabolomics to explore the element-gene-metabolite regulatory axis in GC. Results: A total of nine plasma differential elements associated with gastric cancer were identified, with a combined diagnostic accuracy of 0.918. Specifically, elements such as Fe, Co, and Li showed significant correlations with 63 genes involved in key signaling pathways, including MAPK, SMAD, and Wnt. Genome-wide association studies (GWAS) revealed that gastric cancer-related genes were significantly enriched in cancer-associated pathways and signaling cascades such as Rap1. Metabolomic analysis further demonstrated that 20 elements in the gastric cancer cohort correlated with 94 metabolites, predominantly enriched in pyrimidine and glutathione metabolism pathways. Conclusions: These nine plasma differential elements showed high combined diagnostic efficacy and were associated with genes and metabolites enriched in cancer-related signaling, metabolic reprogramming, and DNA damage response pathways. Together, these findings suggest potential multi-level associations among plasma elemental alterations, genetic variation, and metabolic dysregulation in GC, providing candidate circulating biomarkers and mechanistic clues for future investigation. Full article

(This article belongs to the Topic Biomarkers of Disease: Discovery and Clinical Applications)

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Metabolites, Volume 16, Issue 7 (July 2026) – 82 articles

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