Metabolites

26 pages, 5152 KB

Open AccessArticle

Organ-Resolved Metabolomics of Cibotium barometz Reveals Rhizome-Specific Terpenoid Lactones and Phenolic-Rich Non-Officinal Organs

by Guole Qin, Daizu Xie, Changqin Zhou, Delong Guan and Jing Song

Metabolites 2026, 16(9), 693; https://doi.org/10.3390/metabo16090693 (registering DOI) - 18 Sep 2026

Abstract

Background: Cibotium barometz (L.) J. Sm. is a medicinal fern whose rhizome is the sole officinal part, while roots, stems, leaves and young shoots are discarded as agricultural residues. The chemical rationale for this restriction, and the value of the discarded organs, remain [...] Read more.

Background: Cibotium barometz (L.) J. Sm. is a medicinal fern whose rhizome is the sole officinal part, while roots, stems, leaves and young shoots are discarded as agricultural residues. The chemical rationale for this restriction, and the value of the discarded organs, remain undefined. Materials and methods: Here, untargeted LC–MS/MS metabolomics (UHPLC–Orbitrap) of methanol/acetonitrile/water extracts was applied to five organs of C. barometz (three pooled biological replicates per organ), annotating 2765 polar-to-moderately-polar metabolites. Results: Organ identity dominated the metabolic architecture of the sampled population: the first two principal components separated all five organs, with leaf and root as the two mutually opposed metabolic extremes and stem, young shoot and rhizome forming a contiguous module. Exploratory pairwise OPLS-DA combined with FDR-controlled univariate criteria yielded 193–1223 differentially accumulated metabolites per comparison, and tissue-specificity analysis assigned 2031 metabolites (73.45%) predominantly to a single organ. Discussion: Metabolite accumulation patterns along the phenylpropanoid–flavonoid pathway was spatially partitioned, with flavan-3-ols and isoflavones accumulating in root, flavone/flavonol glycosides in leaf and predominantly hydroxycinnamic acids in rhizome and young shoot. Of 22 previously reported or candidate quality control constituents, putatively annotated terpenoid lactones were detected almost exclusively in the rhizome, whereas several phenolics showed markedly higher relative abundance in root or leaf. Conclusions: These relative-abundance data indicate that the non-officinal organs are chemically complementary potential resources; absolute quantification, bioactivity and safety evaluation are prerequisites before any medicinal valorisation. Full article

(This article belongs to the Section Plant Metabolism)

25 pages, 1535 KB

Open AccessArticle

Incremental Prognostic Value of Albumin-Anchored Inflammatory Ratios Beyond a SOFA-Based Model in a Medical ICU: A Retrospective Cohort Study

by Özkul Yılmaz Çolak, Melda İşevi, Tuğçehan Sezer Akman, Özgür Kılıç and Neslihan Ünal Akdemir

Metabolites 2026, 16(9), 692; https://doi.org/10.3390/metabo16090692 (registering DOI) - 18 Sep 2026

Abstract

Background/Objectives: We compared three albumin-anchored ratios calculated from measurements obtained during the first 24 h, C-reactive protein (CRP)-to-albumin (CAR), procalcitonin-to-albumin (PAR) and lactate-to-albumin (LAR), as predictors of intensive care unit (ICU) mortality beyond an established severity model. Methods: Eligibility required an ICU stay [...] Read more.

Background/Objectives: We compared three albumin-anchored ratios calculated from measurements obtained during the first 24 h, C-reactive protein (CRP)-to-albumin (CAR), procalcitonin-to-albumin (PAR) and lactate-to-albumin (LAR), as predictors of intensive care unit (ICU) mortality beyond an established severity model. Methods: Eligibility required an ICU stay reaching 24 h and a complete early work-up; 372 of 1352 screened admissions qualified, with each ratio using the worst component values in that window. Incremental value over a base model (Sequential Organ Failure Assessment (SOFA) score, sex, age-adjusted Charlson index) was assessed by change in the area under the curve (AUC; DeLong test), reclassification metrics (NRI, IDI) and calibration, with alternative baselines and outcomes, multiplicity adjustment, and selection weights from the excluded admissions. Results: Of 372 patients, 248 (66.7%) died. As standalone predictors, CAR (0.671), PAR (0.689) and LAR (0.642) were indistinguishable and inferior to SOFA (0.730). Only CAR significantly improved AUC discrimination (ΔAUC +0.030, p = 0.024; NRI +0.39; IDI +0.042); PAR and LAR did not significantly improve AUC discrimination. Entered together, CAR remained independent (aOR 1.52, 1.15–2.03), while PAR did not (1.20, 0.89–1.63). The cohort was sicker than the 626 patients excluded for incomplete work-up; after weighting, CAR stayed independent (aOR 1.47) but ΔAUC fell to +0.018. The increment was significant against SOFA alone (+0.033) but not against baselines including admission diagnosis or organ support; it remained significant after Benjamini–Hochberg but not Bonferroni adjustment. With in-hospital mortality it was larger (+0.044), but PAR then also retained independence. Conclusions: The first 24 h CAR provided a well calibrated improvement beyond a parsimonious SOFA-based model, but the increment was small and not robust to richer baselines or to multiplicity correction, and no subgroup-specific claim is supported. These hypothesis-generating findings need prospective validation. Full article

(This article belongs to the Special Issue Metabolite Profiles in Inflammatory Diseases)

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21 pages, 15127 KB

Open AccessReview

Ferroptosis and Ferro-Aging in Obesity: Bibliometric Mapping, Shared Mechanisms, and Translational Perspectives

by Jiaxin Liu, Likun Zheng, Zhengri Cong, Zehao Liu, Chen Hu, Yuxin Liu, Chong Zhang and Mingjun Liu

Metabolites 2026, 16(9), 691; https://doi.org/10.3390/metabo16090691 (registering DOI) - 18 Sep 2026

Abstract

Background: Obesity is a chronic metabolic disease characterized by lipid overload, low-grade inflammation, oxidative stress, and progressive organ dysfunction. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been increasingly implicated in obesity-related complications. However, an acute cell [...] Read more.

Background: Obesity is a chronic metabolic disease characterized by lipid overload, low-grade inflammation, oxidative stress, and progressive organ dysfunction. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been increasingly implicated in obesity-related complications. However, an acute cell death-centered model does not fully explain the chronic senescence-like decline observed in metabolic tissues. The recently proposed concept of ferro-aging provides a potential framework for linking iron-dependent lipid peroxidation to cellular senescence and metabolic aging. Methods: In this review, we combined bibliometric mapping with mechanistic synthesis to characterize the evolving research landscape of ferroptosis in obesity and integrate the emerging concept of ferro-aging into this field. Bibliometric analysis was performed to screen qualified literature, and keyword co-occurrence and co-citation analyses were conducted to extract mainstream research hotspots. We further systematically summarized the pathological microenvironment constructed by obesity and the core molecular mediator connecting ferroptosis and ferro-aging, and proposed a pathological continuum hypothesis for obesity-mediated lipid peroxidation injury. Results: A total of 564 eligible publications were identified, including 455 original articles and 109 reviews, with a marked increase in publication output after 2020. Keyword and co-citation analyses highlighted oxidative stress, lipid peroxidation, iron metabolism, GPX4/Nrf2-mediated antioxidant defense, mitochondrial dysfunction, gut microbiota, NAFLD, and DCM as major research themes. Mechanistically, obesity creates a pro-ferroperoxidative microenvironment through iron dysregulation, polyunsaturated fatty acid enrichment, chronic inflammation, mitochondrial stress, and impaired antioxidant capacity. Within this context, ACSL4 is proposed as a candidate molecular hub that may link acute ferroptotic injury with chronic iron-lipid peroxidation-driven cellular senescence. We proposed a hypothesis-generating framework. In this framework, acute lipid peroxidation may promote ferroptotic cell death. Persistent sublethal iron-lipid peroxidation stress may contribute to ferro-aging-like senescence. Conclusions: To our knowledge, this is the first review to place ferro-aging within the obesity-ferroptosis framework. Targeting the ACSL4-lipid peroxidation axis and restoring antioxidant defense, particularly through Nrf2-GPX4-related pathways, may provide new translational opportunities for stratifying and managing obesity-related complications. However, clinical validation of ferro-aging biomarkers and intervention strategies remains urgently needed. Full article

(This article belongs to the Topic Nutrition, Obesity and Metabolic Diseases)

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27 pages, 11417 KB

Open AccessArticle

Multi-Compartment Metabolic Remodeling in DRA-Deficient Mice Overlaps with Ulcerative Colitis Metabolic Signatures

by Jayson M. Antonio, Shubha Priyamvada, Arivarasu N. Anbazhagan, Harris J. B., Nathan Calzadilla, Rengul C. Atalay, Reena Sethi, Seema Saksena, Ravinder K. Gill, Gokhan M. Mutlu, Waddah A. Alrefai, Ece A. Mutlu, Anoop Kumar and Pradeep K. Dudeja

Metabolites 2026, 16(9), 690; https://doi.org/10.3390/metabo16090690 (registering DOI) - 18 Sep 2026

Abstract

Background/Objectives: Down-regulated in adenoma (DRA/SLC26A3), an IBD (Inflammatory Bowel Diseases) susceptibility gene and major colonic Cl⁻/HCO₃⁻ exchanger, is reduced in ulcerative colitis (UC). Whether reduced DRA is linked to broader metabolic remodeling during intestinal inflammation remains unclear. We [...] Read more.

Background/Objectives: Down-regulated in adenoma (DRA/SLC26A3), an IBD (Inflammatory Bowel Diseases) susceptibility gene and major colonic Cl⁻/HCO₃⁻ exchanger, is reduced in ulcerative colitis (UC). Whether reduced DRA is linked to broader metabolic remodeling during intestinal inflammation remains unclear. We therefore examined DRA-associated metabolic pathways in human UC datasets and metabolic changes across mucosal, luminal, and systemic compartments in DRA-deficient mice. Methods: Six publicly available human colonic transcriptomic cohorts were analyzed to infer KEGG metabolic pathway activity, compare UC with healthy mucosa, and assess associations with DRA expression using random-effects meta-analysis. DRA knockout mice were evaluated by colonic mucosal RNA sequencing, untargeted LC–MS metabolomics of colonic mucosa, feces, and serum, targeted bile acid profiling, MetOrigin analysis, and fecal 16S rRNA sequencing. Results: In the human cohorts, DRA expression was consistently lower in UC. Of the 75 KEGG metabolic pathways evaluated, 48 were altered in UC relative to healthy mucosa, and 45 of these were also associated with DRA expression levels among UC samples. In DRA knockout mice, colonic RNA sequencing identified broad metabolic transcriptional remodeling across 39 KEGG pathways, with metabolic themes that overlapped with the human UC findings. Multi-compartment metabolomics further revealed alterations involving amino acid, nitrogen, redox/cofactor, polyamine, and bile acid metabolism, together with inferred host-microbiota co-metabolic signatures. Conclusions: DRA deficiency was accompanied by broad metabolic remodeling across mucosal, luminal, and systemic compartments. These changes overlapped with DRA-associated signatures in human UC, supporting a role for DRA in epithelial–luminal metabolic homeostasis beyond ion transport. Full article

(This article belongs to the Special Issue Metabolic Disorders and Inflammatory Bowel Diseases)

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19 pages, 8596 KB

Open AccessArticle

Comprehensive Volatile Metabolite Profiling and Bioactive Marker Discovery of Saposhnikoviae Radix via HS-GC-MS/MS Integrated with Chemometrics and Network Pharmacology

by Fangliang He, Xianrui Wang, Jiating Zhang, Lizhi Wan, Haonan Wu, Xianlong Cheng, Jia Chen, Xiangri Li, Wenguang Jing and Feng Wei

Metabolites 2026, 16(9), 689; https://doi.org/10.3390/metabo16090689 (registering DOI) - 18 Sep 2026

Abstract

Background: Saposhnikoviae radix (SR), a valuable Chinese medicinal plant with high medicinal and edible value, suffers from inconsistent quality caused by growth patterns, cultivation duration, and geographical origin. Methods: In this study, comprehensive volatile metabolite profiling using HS-GC-MS/MS combined with multivariate chemometrics was [...] Read more.

Background: Saposhnikoviae radix (SR), a valuable Chinese medicinal plant with high medicinal and edible value, suffers from inconsistent quality caused by growth patterns, cultivation duration, and geographical origin. Methods: In this study, comprehensive volatile metabolite profiling using HS-GC-MS/MS combined with multivariate chemometrics was performed to characterize these quality-related differences. Results: In total, 7, 13, and 11 differential volatile compounds were identified for wild versus cultivated SR, cultivation duration, and geographical origin, respectively. By integrating the three comparisons, 11 recurrent differential compounds were selected for network pharmacology and molecular docking analyses. trans-3-Nonen-2-one, benzaldehyde, and Octanoic acid were predicted to interact with key targets, including TNF, IL1B, ALB, EGFR, and CASP3, which were mainly enriched in inflammation- and pain-related pathways, including the PI3K-Akt signaling pathway, apoptosis, and the HIF-1 signaling pathway. Molecular docking further supported favorable predicted interactions between the selected compounds and core targets. Conclusions: Overall, this study reveals volatile metabolite variation associated with major quality-related factors of SR and identifies candidate bioactive and quality-associated volatile compounds. The integration of volatile metabolite profiling, chemometrics, network pharmacology, and molecular docking provides a complementary strategy for the comprehensive quality evaluation of SR and offers a reliable reference for quality control research on other medicinal Apiaceae species. Full article

(This article belongs to the Topic Metabolomics in Plants)

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17 pages, 1551 KB

Open AccessArticle

Acute Responses to Creatine Monohydrate and L-Arginine, Alone and Combined, on Repeated-Sprint Power, Countermovement Jump Height, and Stroop Reaction Time in Recreationally Active Men: A Randomized Double-Blind Crossover Trial

by Özgür Eken, Halil Uçar, Ahmet Kurtoğlu, Murat Ozan, Yusuf Buzdağlı, Mehmet Söyler and Monira I. Aldhahi

Metabolites 2026, 16(9), 688; https://doi.org/10.3390/metabo16090688 (registering DOI) - 18 Sep 2026

Abstract

Background/Objectives: Creatine monohydrate (CR) and L-arginine (LA) are widely used ergogenic supplements, but whether acute co-ingestion provides additional performance or task-specific cognitive benefits beyond either supplement alone remains uncertain. This study compared placebo, CR, LA, and LA+CR on repeated-sprint power, countermovement jump (CMJ) [...] Read more.

Background/Objectives: Creatine monohydrate (CR) and L-arginine (LA) are widely used ergogenic supplements, but whether acute co-ingestion provides additional performance or task-specific cognitive benefits beyond either supplement alone remains uncertain. This study compared placebo, CR, LA, and LA+CR on repeated-sprint power, countermovement jump (CMJ) height, and Stroop reaction time (RT). Methods: In this randomized, double-blind, four-period crossover trial, 18 recreationally active men completed placebo (CG), CR (0.3 g·kg⁻¹), LA (6 g), and LA+CR conditions separated by at least 72 h (prospectively registered at ClinicalTrials.gov: NCT07548541). Testing began 60 min after ingestion with the Stroop test, followed by CMJ and the Running-Based Anaerobic Sprint Test (RAST). Co-primary outcomes were RAST average power (AP), peak power (PP), CMJ height, and incongruent Stroop median RT. Results: Condition effects were observed for AP, PP, minimum power, CMJ height, and Stroop RT (all p ≤ 0.011), but not fatigue index or Stroop accuracy. All four co-primary omnibus effects remained significant after Holm correction (all pHolm < 0.001). LA+CR produced higher PP than CG (MD 99.01 W; p < 0.001), LA (MD 51.29 W; p = 0.002), and CR (MD 46.71 W; p < 0.001), and greater CMJ height than all comparison conditions (all p < 0.001). LA+CR also produced lower Stroop RT than CG (MD 0.089 s; p < 0.001) and CR (p = 0.041), but not LA (p = 0.271). For AP, LA+CR exceeded CG and CR, but not LA after Bonferroni adjustment. In a secondary 2 × 2 factorial decomposition, no LA×CR interaction for a co-primary outcome survived Holm correction (all pHolm ≥ 0.104). Conclusions: Acute LA+CR produced outcome-specific improvements in peak sprint power and CMJ and selectively reduced Stroop RT, but did not establish biological synergy. Interpretation should remain exploratory given the small male-only sample, unmodelled period/sequence effects, and possible creatine-related carryover. Full article

(This article belongs to the Section Nutrition and Metabolism)

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17 pages, 1837 KB

Open AccessArticle

Exercise Metabolomics Reveals Intensity-Dependent Metabolic Responses Associated with Cardiorespiratory Fitness in Adults with Type 1 Diabetes

by Olivia M. McCarthy, Clara Solà, Chloe Nicholas, Sandra Tawfik, Merete Bechmann Christensen, Signe Schmidt, Kirsten Nørgaard, Richard M. Bracken and Marietta Kokla

Metabolites 2026, 16(9), 687; https://doi.org/10.3390/metabo16090687 (registering DOI) - 18 Sep 2026

Abstract

Purpose: To characterize plasma metabolomic responses to maximal exercise and their associations with cardiorespiratory fitness (CRF) in adults with type 1 diabetes. Methods: In this exploratory pooled secondary analysis, 21 adults (67% female; age, 51.6 ± 13.2 years; HbA1c, 67.5 ± [...] Read more.

Purpose: To characterize plasma metabolomic responses to maximal exercise and their associations with cardiorespiratory fitness (CRF) in adults with type 1 diabetes. Methods: In this exploratory pooled secondary analysis, 21 adults (67% female; age, 51.6 ± 13.2 years; HbA1c, 67.5 ± 7.0 mmol/mol) completed a cycle-ergometer test to exhaustion; metabolomic data were available for 20. Plasma collected at rest, anaerobic threshold (AT), peak exercise, and recovery underwent targeted and untargeted gas chromatography–mass spectrometry profiling. Peak oxygen uptake (V̇O₂peak) quantified CRF. Linear mixed-effects models adjusted for age, sex, HbA1c, and diabetes duration. Results: At the AT, L-(+)-lactic acid and 2-hydroxyisobutyric acid increased relative to rest (both q ≤ 0.010). Peak exercise produced changes in glycolytic, tricarboxylic acid (TCA)-cycle, and purine metabolites, with enrichment of the TCA cycle and nucleotide metabolism. TCA-cycle enrichment persisted during recovery. In exploratory interaction analyses, higher V̇O_2peak was associated with increases in L-(+)-lactic acid at AT (β = 0.032, q = 0.040) and peak exercise (β = 0.031, q = 0.024), and in malic acid at peak exercise (β = 0.063, q = 0.010) and recovery (β = 0.061, q = 0.015). Conclusions: These preliminary findings suggest the presence of intensity-dependent and fitness-associated metabolic responses to exercise in adults with type 1 diabetes. Given the small sample size, particularly for interaction analyses, these findings require confirmation in larger independent cohorts. Full article

(This article belongs to the Special Issue Metabolic Responses to Exercise Training)

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15 pages, 3393 KB

Open AccessArticle

Enzymatic Stability and Comparative Effects of Kisspeptin-14, Kisspeptin-13 and Kisspeptin-10 on Beta-Cell Function, Glucose Homeostasis and Appetite Regulation

by Julie A. Spratt, Neil Tanday, Dearbhla M. McGinn, Chidiebere D. Chukwu, Victor A. Gault and Nigel Irwin

Metabolites 2026, 16(9), 686; https://doi.org/10.3390/metabo16090686 (registering DOI) - 17 Sep 2026

Abstract

Background/Objective: Kisspeptin peptides are being increasingly recognised as regulators of metabolism, but whether these actions differ depending on peptide isoform remains unclear. Methods: The current study compared the enzymatic stability and biological effects of kisspeptin-14 (KP-14), kisspeptin-13 (KP-13) and kisspeptin-10 (KP-10) [...] Read more.

Background/Objective: Kisspeptin peptides are being increasingly recognised as regulators of metabolism, but whether these actions differ depending on peptide isoform remains unclear. Methods: The current study compared the enzymatic stability and biological effects of kisspeptin-14 (KP-14), kisspeptin-13 (KP-13) and kisspeptin-10 (KP-10) on beta-cell health and function, glucose homeostasis and appetite. Peptide stability was assessed in murine plasma and, following confirmation of KISS1R expression in BRIN-BD11 beta-cells, actions on insulin secretion, beta-cell proliferation and apoptosis were investigated, with additional secretory studies in isolated murine islets. Metabolic effects of KP-14, KP-13 and KP-10 were subsequently evaluated in healthy male and female mice. Results: KP-14 was resistant to plasma degradation, whereas KP-13 and KP-10 underwent N-terminal proteolysis, with KP-13 degradation generating KP-10 amongst other fragment peptides. The kisspeptin peptides exerted modest direct effects on insulin secretion from BRIN-BD11 cells, with KP-13 being the most efficacious, a bioactivity profile that was confirmed in islets. In addition, KP-13 significantly enhanced beta-cell proliferation and protected against cytokine-induced apoptosis, producing superior beta-cell proliferative effects compared to exenatide. Acute administration of all kisspeptin peptides elevated circulating glucose concentrations, and while KP-14 and KP-10 impaired glucose tolerance, KP-13 did not. Interestingly, KP-14 enhanced glucose-stimulated insulin secretion, with KP-13 and KP-10 being devoid of such actions. All kisspeptin isoforms suppressed food intake, although only KP-13, and especially KP-10 administration, led to an inhibition of feeding. Conclusions: Taken together, these data identify KP-13 as possessing the most favourable overall metabolic actions, based on a combination of beneficial actions on beta-cell health and function together with inhibition of feeding and lack of prominent glucose-elevating actions, suggesting possible therapeutic application for type 2 diabetes. Full article

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

19 pages, 830 KB

Open AccessReview

Folate: An Emerging Target in Type 2 Diabetes Mellitus and Its Complications

by Xiaoyu Xiao, Siyi Qin, Zijian Jiang, Yuhui Huo, Junlin Li and Minlan Yang

Metabolites 2026, 16(9), 685; https://doi.org/10.3390/metabo16090685 (registering DOI) - 17 Sep 2026

Abstract

Folate, which is also known as folic acid, vitamin B9, is a key coenzyme in one-carbon metabolism (OCM) and participates in nucleic acid synthesis, methylation, and redox regulation. In recent years, numerous studies have demonstrated its close association with type 2 diabetes mellitus [...] Read more.

Folate, which is also known as folic acid, vitamin B9, is a key coenzyme in one-carbon metabolism (OCM) and participates in nucleic acid synthesis, methylation, and redox regulation. In recent years, numerous studies have demonstrated its close association with type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM), and diabetic complications. Serum folate levels are decreased in patients with T2DM, which is associated with increased urinary excretion and metformin-mediated inhibition of folate absorption. The onset of GDM is characterized by a folate dose-dependent imbalance characteristic, high folate combined with vitamin B12 deficiency significantly increases the risk of GDM. Maternal folate status can also modulate offspring insulin sensitivity through epigenetic modifications. The mechanisms by which folate regulates diabetes mainly include lowering homocysteine (Hcy) concentrations, suppressing oxidative stress and inflammatory responses, modulating OCM, and mediating DNA methylation modifications. Cumulative evidence-based data indicate that appropriate folic acid supplementation can improve insulin resistance, restore vascular endothelial function, reduce the risk of cardiovascular diseases (CVDs), diabetic peripheral neuropathy, retinopathy, cognitive impairment, and other complications, and alleviate damage induced by high glucose. This review systematically summarizes the roles and molecular mechanisms of folate in diabetes and its complications, highlighting folate as a potential intervention target for diabetes. Full article

(This article belongs to the Section Lipid Metabolism)

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17 pages, 2664 KB

Open AccessArticle

Leaf Developmental Stage at Harvest Affects Postharvest Senescence and Quality Parameters of Kale

by María Clara Donadelli, Estefanía Bernay, Gricel Alejandra Cagliardi, Gustavo Martínez and Victoria Casajus

Metabolites 2026, 16(9), 684; https://doi.org/10.3390/metabo16090684 - 17 Sep 2026

Abstract

Background: Kale is a vegetable of the Brassicaceae family recognized for its high nutritional value. After harvest, kale leaves undergo senescence, characterized by the loss of green color due to chlorophyll degradation. This deterioration affects organoleptic quality and consumer acceptance. Objective: The [...] Read more.

Background: Kale is a vegetable of the Brassicaceae family recognized for its high nutritional value. After harvest, kale leaves undergo senescence, characterized by the loss of green color due to chlorophyll degradation. This deterioration affects organoleptic quality and consumer acceptance. Objective: The present study investigated the effect of leaf developmental stage at the moment of harvest on postharvest senescence and parameters related to the nutritional quality of kale during postharvest storage at 20 °C. Material and Methods: Kale leaves were harvested at three developmental stages—young inner leaves (~20 cm), middle leaves (central position, 20–30 cm), and mature outer leaves (35–40 cm)—and stored at 20 °C for six days in darkness with an RH of 90–95%. At harvest and after two, four, and six days of storage, superficial color, weight loss, total phenolic and flavonoid contents, antioxidant capacity, total and reducing sugars, and total and soluble proteins were evaluated. Because yellowing is the main postharvest symptom in kale leaves, the relative expressions of chlorophyll catabolic genes such as NYC, NOL, SGR, PPH and PaO were also analyzed. Results: The leaf development stage strongly influenced postharvest life and the biochemical composition of the leaves. Inner leaves showed a lower rate of chlorophyll degradation during postharvest storage and retained a more intense green color, consistent with a reduced expression of chlorophyll catabolic genes. In contrast, middle and outer leaves exhibited greater chlorophyll loss and more pronounced yellowing. Inner leaves maintained the best overall visual quality at the end of storage and showed higher phenolic as well as greater antioxidant capacity compared with middle and outer leaves. Inner leaves also contained higher levels of reducing sugars and soluble proteins. Conclusions: Taken together, these findings indicate that harvesting kale at earlier developmental stages might represent an effective strategy to extend shelf-life and provide a product with improved values in the parameters actually measured. Full article

(This article belongs to the Special Issue Metabolic Changes During Pre- and Post-Harvest Fruit and Vegetable Decay, Ripening and Senescence—2nd Edition)

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19 pages, 2762 KB

Open AccessSystematic Review

Dose–Response Relationships Between Exercise Modalities and Triglyceride Reduction in Adults: A Systematic Review and Model-Based Network Meta-Analysis

by Junru Zeng, Hong Wang and Fengrui Shi

Metabolites 2026, 16(9), 683; https://doi.org/10.3390/metabo16090683 - 17 Sep 2026

Abstract

Background/Objectives: Triglyceride-rich lipoproteins contribute to residual atherosclerotic cardiovascular risk, but the comparative and dose–response effects of exercise modalities on triglycerides (TGs) remain uncertain. We compared aerobic exercise (AE), resistance training (RT), combined exercise (CE), and high-intensity interval training (HIIT) and characterized modality-specific dose–response [...] Read more.

Background/Objectives: Triglyceride-rich lipoproteins contribute to residual atherosclerotic cardiovascular risk, but the comparative and dose–response effects of exercise modalities on triglycerides (TGs) remain uncertain. We compared aerobic exercise (AE), resistance training (RT), combined exercise (CE), and high-intensity interval training (HIIT) and characterized modality-specific dose–response relationships. Methods: Five databases were searched from inception through January 2026. Randomized trials in adults were synthesized using contrast-based random-effects network meta-analysis (NMA) and model-based network meta-analysis (MBNMA), with dose harmonized as MET·min/week. Results: Seventy-six independent trials included 4483 participants in 208 randomized arms. The 122 active arms generated 122 exercise–control contrasts; one CE contrast with zero reported sampling variance was excluded from both network models, leaving 121 analyzed contrasts in 86 independent comparator blocks. Exercise reduced TG by 0.149 mmol/L, on average (95% CI 0.099–0.199), although the prediction interval crossed the null. CE had the largest average network estimate (MD −0.255 mmol/L), followed by HIIT (−0.225) and AE (−0.130); RT was inconclusive. The modality-specific linear model had the lowest AICc. Per 1000 MET·min/week, slopes were −0.128 mmol/L for AE, −0.307 for CE, −0.081 for RT, and −0.239 for HIIT; the RT slope crossed the null. No supported interior optimum was identified. Conclusions: AE, CE, and HIIT were associated with lower TGs, but certainty was low, and 50 trials were at high risk of bias. CE produced the largest average estimate within the available network, not definitive evidence of universal superiority. The reported lowest and upper observed doses are descriptive boundaries rather than efficacy thresholds or prescription targets. Full article

(This article belongs to the Special Issue Novel Insights into Lipid Metabolism in Health and Diseases)

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16 pages, 310 KB

Open AccessArticle

Effects of Traffic-Related Diesel Exhaust Exposure and Moderate Exercise on Obesity, Metabolic Dysfunction, and Inflammatory Responses in Rats

by Nesrullah Ayşin, Süheyla Altuğ Özsoy and Zübeyir Huyut

Metabolites 2026, 16(9), 682; https://doi.org/10.3390/metabo16090682 - 16 Sep 2026

Abstract

Objective: Traffic-related air pollution is recognised as a significant environmental risk factor associated with obesity and metabolic dysfunction. Although the positive effects of regular exercise on metabolic health are well established, its protective role against traffic-related air-pollution-induced metabolic dysfunction has not been fully [...] Read more.

Objective: Traffic-related air pollution is recognised as a significant environmental risk factor associated with obesity and metabolic dysfunction. Although the positive effects of regular exercise on metabolic health are well established, its protective role against traffic-related air-pollution-induced metabolic dysfunction has not been fully elucidated. This study was conducted to investigate the effects of diesel exhaust exposure and moderate exercise on the development of obesity, metabolic changes, adipokine profile, and inflammatory response in rats. Materials and Methods: In this randomised controlled experimental study, 48 female Wistar Albino rats were randomised into six experimental groups. The animals were exposed to diesel exhaust simulating traffic-related air pollution (average 300 μg PM2.5/m³) for 2 or 4 h daily over an eight-week period. Rats in the exercise groups underwent moderate-intensity treadmill exercise for 30 min at a speed of 15 m/min, five days a week, over the same period. At the end of the study, obesity indicators, serum lipid profile, glucose metabolism parameters, adipokines and inflammation markers were assessed. Results: Diesel exhaust exposure caused a significant increase in final body weight, BMI, Lee index and VAI values (p < 0.001). Furthermore, levels of LDL cholesterol, total cholesterol, triglycerides, glucose, adiponectin, leptin, CRP, IL-37, IL-1β, IL-6 and TNF-α increased significantly, whilst HDL cholesterol and insulin levels decreased significantly (p < 0.001). The most pronounced metabolic and inflammatory changes were observed in the 4 h exhaust gas exposure group. Elevations in pro-inflammatory cytokines, accompanied by increased visceral adiposity, supported the development of systemic metabolic inflammation. Exercise significantly reduced weight gain, visceral adiposity, dyslipidaemia, hyperglycaemia, adipokine imbalance and the inflammatory response (p < 0.001). However, exercise could not fully reverse all the changes associated with long-term diesel exhaust exposure. Conclusions: Traffic-related diesel exhaust exposure led to metabolic disorders in rats, characterised by visceral adiposity, dyslipidaemia, impaired glucose homeostasis, adipokine imbalance and chronic low-grade inflammation. Regular moderate-intensity exercise significantly reduced these adverse effects but could not eliminate them entirely. The findings suggest that traffic-related air pollution may contribute to the development of obesity via inflammation-mediated metabolic mechanisms, and that regular physical activity may serve as an important protective strategy in limiting these effects. Full article

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

17 pages, 751 KB

Open AccessArticle

Association Between Obesity Severity and Bioelectrical Impedance Analysis-Derived Metabolic Age in Individuals with Type 2 Diabetes Mellitus

by Hasan Esat Yücel, Tufan Ulcay, Murat Doğan, Saliha Demir, Gizem Çolak, Ruken Oncu, Ebru Ceylan, Muhammed Fırat Aladag, Emre Uguz, Birgül Deniz Doğan and Cahit Ucar

Metabolites 2026, 16(9), 681; https://doi.org/10.3390/metabo16090681 - 16 Sep 2026

Abstract

Background: Metabolic age (Met-Age), a bioelectrical impedance analysis (BIA)-derived index based on basal metabolic rate (BMR) and body composition, has been associated with cardiometabolic risk. However, its relationship with body mass index (BMI)-defined obesity severity in individuals with type 2 diabetes mellitus (T2DM) [...] Read more.

Background: Metabolic age (Met-Age), a bioelectrical impedance analysis (BIA)-derived index based on basal metabolic rate (BMR) and body composition, has been associated with cardiometabolic risk. However, its relationship with body mass index (BMI)-defined obesity severity in individuals with type 2 diabetes mellitus (T2DM) remains unclear. This study investigated the association between obesity severity and Met-Age and identified factors associated with Met-Age. Methods: In this retrospective observational study, 683 adults with T2DM were classified into five BMI categories: normal weight, overweight, and class I, II, and III obesity. Anthropometric, laboratory, and BIA-derived body composition data were analyzed using correlation and sex-stratified multivariable linear regression analyses. Results: Although chronological age did not differ significantly across groups, Met-Age increased progressively with increasing obesity severity (p < 0.001). The Jonckheere–Terpstra test confirmed a significant ordered increase in Met-Age across BMI categories. BMI, fat mass, and waist-to-height ratio (WHtR) also increased progressively with increasing obesity severity. In the multivariable regression analyses, chronological age and WHtR were positively associated with Met-Age in both sexes, whereas muscle mass showed a weak inverse association with Met-Age only in female participants. No significant correlations were found between Met-Age and fasting blood glucose (FBG) or hemoglobin A1c (HbA1c) levels (all p > 0.05). Conclusions: In individuals with T2DM, greater obesity severity was associated with higher BIA-derived Met-Age. WHtR was positively associated with Met-Age in both sexes, whereas muscle mass showed a weak inverse association among female participants. Met-Age may serve as a descriptive index reflecting body composition and metabolic characteristics; however, its incremental clinical value beyond BMI and WHtR remains unproven. Full article

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

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28 pages, 1690 KB

Open AccessReview

Coffee, the Gut Microbiome, and Host Metabolism: Gastrointestinal Fate, Microbial Transformation, Mechanistic Insights, and Prospects for Precision Nutrition

by Lei Yang, Chaowei Wang, Liangyu Cui, Yongxiang Zhu and Xi Wang

Metabolites 2026, 16(9), 680; https://doi.org/10.3390/metabo16090680 - 16 Sep 2026

Abstract

Coffee is one of the most widely consumed beverages worldwide and a major dietary source of bioactive compounds, including caffeine, chlorogenic acids (CGAs), trigonelline, non-digestible polysaccharides, and roasting-derived melanoidins. Habitual coffee consumption has been associated with a lower risk of type 2 diabetes [...] Read more.

Coffee is one of the most widely consumed beverages worldwide and a major dietary source of bioactive compounds, including caffeine, chlorogenic acids (CGAs), trigonelline, non-digestible polysaccharides, and roasting-derived melanoidins. Habitual coffee consumption has been associated with a lower risk of type 2 diabetes (T2D) and more favorable liver-related outcomes, whereas evidence regarding obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) remains heterogeneous. These associations may reflect interactions among coffee constituents, the gut microbiota, and host metabolic phenotypes rather than the effects of individual compounds alone. In this focused narrative review, we integrate evidence on the gastrointestinal fate, microbial transformation, and systemic availability of major coffee constituents, with particular emphasis on short-chain fatty acids, CGA-derived phenolic acids, and microbiota-dependent bile acid metabolism. We examine how these pathways may influence intestinal barrier integrity, mucosal immunity, enteroendocrine signaling, and gut–liver communication then consider their potential relevance to the regulation of energy, glucose, and lipid metabolism. We evaluate the relevance of these pathways to obesity, T2D, and MASLD, as well as major sources of inter-individual variability, including host genetics, baseline microbiota, metabolic phenotypes, background diet, and coffee composition, processing, brewing, filtration, dose, and beverage additives. Finally, we discuss physiologically relevant exposure levels, candidate biomarkers of individual responses, and risk–benefit considerations. Although mechanistic and preclinical evidence is accumulating, human studies directly demonstrating that coffee-induced microbiota changes mediate beneficial metabolic outcomes remain limited. Future randomized and mechanistic studies should integrate chemically characterized coffee exposures with longitudinal microbiome, metabolomic, physiological, and clinically relevant outcome measurements. Full article

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

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15 pages, 632 KB

Open AccessArticle

Effects of Adjunctive Exercise Therapy in Patients with Bipolar Depression: A Pilot Multicenter Cluster-Randomized Controlled Trial

by Fumito Hamada, Hikaru Hori, Hiroki Kumagai, Muneaki Ogata, Hiroyuki Yokoyama, Yuko Tomiyama, Hiroko Sugawara, Ryo Asada, Akito Hatanaka, Masato Masuda, Yuta Okamoto, Ryusei Hatae, Hitoshi Iida, Yoshimi Yamaguchi, Tetsuya Yoshida, Rika Yano and Leo Gotoh

Metabolites 2026, 16(9), 679; https://doi.org/10.3390/metabo16090679 - 15 Sep 2026

Abstract

Background/Objectives: Bipolar depression impairs psychosocial functioning, cognition, and quality of life. Evidence regarding adjunctive exercise remains limited. This pilot study evaluated the clinical and biological effects of adjunctive exercise in patients with bipolar depression. Methods: In this multicenter cluster-randomized controlled trial, [...] Read more.

Background/Objectives: Bipolar depression impairs psychosocial functioning, cognition, and quality of life. Evidence regarding adjunctive exercise remains limited. This pilot study evaluated the clinical and biological effects of adjunctive exercise in patients with bipolar depression. Methods: In this multicenter cluster-randomized controlled trial, 26 hospitalized patients were assigned by facility to treatment as usual plus supervised exercise (TAU + Ex) or supervised stretching (TAU + SC) for 6 weeks. Twenty-four completed the study (TAU + Ex, n = 14; TAU + SC, n = 10). Clinical outcomes and plasma tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-1β, IL-2, brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor-A (VEGF-A) were assessed at baseline and week 6. The trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; UMIN000045877; registered on 1 December 2021). Results: FAST and QIDS-SR scores improved significantly in both the exercise and stretching groups after the 6-week intervention, but no significant group × time interactions were observed. No significant group, time, or group × time effects were observed for any plasma biomarker. Before correction for multiple comparisons, nominal correlations were observed between changes in IL-1β and FAST, BDNF and FAST, and VEGF-A and Spotter performance. None remained statistically significant after Benjamini–Hochberg FDR correction. Conclusions: Adjunctive exercise therapy was not superior to active stretching. The exploratory biomarker–outcome correlations did not remain significant after correction for multiple comparisons and should be considered hypothesis-generating. Larger, adequately powered randomized controlled trials are warranted. Full article

(This article belongs to the Special Issue Biomarkers and Metabolites in Clinical Practice and Research)

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16 pages, 2436 KB

Open AccessCase Report

Lipodystrophy in Central Asia: A Regional Literature Review with a Case Series of Congenital and Acquired Generalized Lipodystrophy

by Marzhan Rakhimzhanova, Bikadisha Bimurat, Aimira Jangashkarova, Assel Issabayeva, Aigul Durmanova, Alina Alzhaxina, Tatyana Ivanova-Razumova and Gulmira Rapilbekova

Metabolites 2026, 16(9), 678; https://doi.org/10.3390/metabo16090678 - 14 Sep 2026

Abstract

Background: Lipodystrophy syndromes are a group of rare disorders characterized by partial or generalized loss of adipose tissue, severe insulin resistance, and multiple metabolic complications. Despite increasing global awareness, lipodystrophy remains underrepresented in the published literature from Central Asia, and its true [...] Read more.

Background: Lipodystrophy syndromes are a group of rare disorders characterized by partial or generalized loss of adipose tissue, severe insulin resistance, and multiple metabolic complications. Despite increasing global awareness, lipodystrophy remains underrepresented in the published literature from Central Asia, and its true regional prevalence remains unknown. This study presents a case series of patients from Central Asia with congenital and acquired generalized lipodystrophy, reviews the existing regional literature, and determines challenges and future directions to improve lipodystrophy care in this region. Methods: We conducted a targeted regional literature review focusing on published reports from five Central Asian countries: Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan. A literature search was performed in electronic databases, including PubMed/MEDLINE, Scopus, and Web of Science, from the earliest available records to 20 July 2026. Results: Reported cases of lipodystrophy from Central Asia were extremely scarce. Our cases also highlighted important barriers to effective care, including limited disease awareness and access to specialized therapies. Discussion: These findings indicate that lipodystrophy is underrepresented in the literature, and the true disease burden and extent of underdiagnosis in Central Asia remain unknown. Improving clinical awareness, developing international collaborations, widening access to genetic testing, and establishing multidisciplinary referral systems could significantly enhance patient outcomes. Conclusions: Lipodystrophy remains an underreported, rare condition in Central Asia. Our findings emphasize the urgent need for improved awareness, regional cooperation, development of expert clinics, and better access to specialized diagnostic and therapeutic resources to optimize care for affected patients. Full article

(This article belongs to the Special Issue Diabetes and Metabolic Diseases: From Prevention to Clinical Management, 2nd Edition)

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14 pages, 11221 KB

Open AccessArticle

Biosynthesis-Informed Putative Annotation Reveals Alkaloid Profiles Across Tissues of Anisodus luridus

by Fangyu Zhao, Yuanjiang Xu, Xiaozhong Lan and Zhen Li

Metabolites 2026, 16(9), 677; https://doi.org/10.3390/metabo16090677 - 14 Sep 2026

Abstract

Background/Objectives: Tropane alkaloids (TAs) and phenylpropanoid polyamine alkaloids (PPAs) are major alkaloid constituents of solanaceous plants; however, the tissue-specific distribution of these compounds in Anisodus luridus, a medicinal plant native to southeastern Xizang, remains incompletely characterized. Methods: A biosynthesis-informed putative [...] Read more.

Background/Objectives: Tropane alkaloids (TAs) and phenylpropanoid polyamine alkaloids (PPAs) are major alkaloid constituents of solanaceous plants; however, the tissue-specific distribution of these compounds in Anisodus luridus, a medicinal plant native to southeastern Xizang, remains incompletely characterized. Methods: A biosynthesis-informed putative annotation workflow was developed using ultra-performance liquid chromatography–high-resolution mass spectrometry (UPLC-HRMS) to characterize alkaloid profiles across seven tissues (root, stem, leaf, calyx, corolla, ovary, and seed). Putative annotations were guided by substrate–product structural relationships, predicted enzyme-catalyzed modifications, and diagnostic tandem mass spectrometry (MS/MS) fragmentation patterns. Results: Eighteen alkaloid features were characterized, comprising 6 TAs and 12 PPAs. Hyoscyamine and scopolamine were identified using authentic standards, and the remaining 16 features were putatively annotated, including dihydroanisodamine, hexosylhyoscyamine, and several PPAs not previously reported in A. luridus. TAs were predominantly enriched in roots and ovaries, whereas PPAs accumulated in floral tissues and leaves. Orthogonal partial least squares discriminant analysis (OPLS-DA) identified scopolamine (variable importance in projection (VIP) = 1.30) as a principal variable associated with separation among tissue metabolic profiles. Conclusions: This workflow supports the putative annotation of alkaloids in non-model medicinal plants. The observed tissue-specific distribution patterns provide a basis for future comparative studies with A. belladonna and for evaluating cultivation, tissue-selective harvesting, and extraction strategies. Full article

(This article belongs to the Special Issue LC-MS/MS Analysis for Plant Secondary Metabolites, 2nd Edition)

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20 pages, 6840 KB

Open AccessArticle

Phenotype-Associated Renal and Systemic Patterns During Short-Term Reduced-Tidal-Volume Mechanical Ventilation in Obese and Endotoxemic Rats: An Exploratory Study

by Luciana Jorge, Bianca Castino Junqueira Silva, Marcia Bastos Convento, Clara Versolato Rasvisckas, Maria Aparecida da Glória, Cassiane Dezoti da Fonseca, Eloiza de Oliveira Silva, Maria de Fatima Fernandes Vattimo and Fernanda Teixeira Borges

Metabolites 2026, 16(9), 676; https://doi.org/10.3390/metabo16090676 - 14 Sep 2026

Abstract

Background: Mechanical ventilation (MV) may be associated with extrapulmonary responses shaped by the host inflammatory-metabolic background. Methods: This exploratory study characterized renal changes during 1 h of reduced-tidal-volume mechanical ventilation in male Wistar rats with diet-induced obesity or lipopolysaccharide (LPS)-induced endotoxemia, together with [...] Read more.

Background: Mechanical ventilation (MV) may be associated with extrapulmonary responses shaped by the host inflammatory-metabolic background. Methods: This exploratory study characterized renal changes during 1 h of reduced-tidal-volume mechanical ventilation in male Wistar rats with diet-induced obesity or lipopolysaccharide (LPS)-induced endotoxemia, together with concurrent respiratory, acid–base, metabolic, and hemodynamic alterations. Arterial blood gas, biochemical, hemodynamic, and urinary variables were assessed at the pre-MV and post-MV time points. Renal protein expression was evaluated only at the post-MV time point. Results: The arterial partial pressure of carbon dioxide (PaCO₂) decreased significantly in both groups. In the Obese group, metabolic acid–base abnormalities persisted and were accompanied by increases in serum urea and the urinary protein-to-creatinine ratio. In the LPS group, lactate increased, bicarbonate decreased, and mean arterial pressure and serum creatinine increased. At the post-MV time point, renal interleukin-6 expression was lower in the LPS group than in the Obese group, whereas renal tumor necrosis factor-alpha expression was higher in the LPS group than in the Obese group. Conclusions: These results support interpreting the physiological and renal changes observed in association with the integrated experimental protocol, including mechanical ventilation, in relation to the host’s underlying pathophysiology and inflammatory-metabolic context. Full article

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

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16 pages, 1930 KB

Open AccessArticle

Urinary Metabolic Profiles Before and After the Winter Training Season in Female Soccer Players

by Hyang Yeon Kim, Jung Dae Lee, Ho-Seong Lee, Ji-Suk Chang, Suhkmann Kim, Gi-Wook Hwang and Kyu-Bong Kim

Metabolites 2026, 16(9), 675; https://doi.org/10.3390/metabo16090675 - 14 Sep 2026

Abstract

Background/Objectives: Female soccer players differ from males in body composition, muscular strength, and hormonal fluctuations, which may influence performance, fatigue, recovery, and injury risk. This study aimed to characterize the time course of urinary metabolic perturbation and its persistence during a 20-day [...] Read more.

Background/Objectives: Female soccer players differ from males in body composition, muscular strength, and hormonal fluctuations, which may influence performance, fatigue, recovery, and injury risk. This study aimed to characterize the time course of urinary metabolic perturbation and its persistence during a 20-day winter training season (WTS) using urinary metabolomics. Methods: Urinary metabolites in female soccer players were analyzed before (Bef) and 1 (After_1D) and 7 days after completion (After_7D) of the 20-day WTS using nuclear magnetic resonance (NMR) spectroscopy combined with multivariate analysis. Results: A total of 84 metabolites were identified in urine samples, and distinct group separation was observed by partial least squares discriminant analysis (PLS-DA) in targeted profiling. Among these, 13 metabolites, including adenine, alanine, citrate, creatine, creatine phosphate (PCr), formate, glutamine, glycine, malonate, mannitol, taurine, trimethylamine N-oxide (TMAO), and urea, showed significant changes in the three groups (Bef, After_1D and After_7D). Conclusions: Of the identified metabolites, six metabolites—alanine, PCr, formate, glutamine, glycine, and malonate—were significantly increased at 1 day post-WTS (After_1D) compared with pre-WTS (Bef) levels. These metabolites were lower at 7 days post-WTS (After_7D) than at 1 day post-WTS (After_1D). However, the metabolic profile had not fully returned to pre-WTS levels by day 7, suggesting that recovery following WTS may require longer than at least 7 days after a 20-day WTS. Full article

(This article belongs to the Section Advances in Metabolomics)

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