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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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21 pages, 2216 KB  
Review
Pleiotropic Cholesterol Signaling in Drosophila and Mammalian Systems
by Yueyang Kang, Muhammad Atif and Youngseok Lee
Metabolites 2026, 16(4), 220; https://doi.org/10.3390/metabo16040220 - 27 Mar 2026
Viewed by 1229
Abstract
Growth, reproduction, and survival are fundamental biological priorities that animals balance by evaluating dietary cues. Cholesterol occupies a unique position among nutrients, serving both as a structural component of cellular membranes and as a precursor for steroid hormones, yet its regulation differs fundamentally [...] Read more.
Growth, reproduction, and survival are fundamental biological priorities that animals balance by evaluating dietary cues. Cholesterol occupies a unique position among nutrients, serving both as a structural component of cellular membranes and as a precursor for steroid hormones, yet its regulation differs fundamentally across taxa. In mammals, cholesterol availability is buffered by endogenous synthesis and post-ingestive metabolic control. In contrast, insects have evolutionarily lost sterol biosynthesis and are therefore sterol auxotrophs that rely entirely on dietary sources. Here, we synthesize current understanding of cholesterol biology in Drosophila melanogaster, with a focus on sterol auxotrophy, life-stage–specific allocation, and endocrine and lifespan outcomes in a comparative framework. We highlight cholesterol not only as a metabolic substrate but also as a sensory-encoded nutrient that shapes feeding behavior. We further examine how lipophorin (Lpp)-mediated transport, Niemann–Pick type C proteins, ATP-binding cassette transporters, and the nuclear receptor DHR96 coordinate systemic sterol distribution and endocrine output in the absence of endogenous synthesis. By integrating these mechanisms across development, we illustrate how cholesterol availability governs larval growth, ecdysteroid production, adult reproduction, neural function, and lifespan through coupled endocrine and nutrient-signaling networks. This review positions cholesterol as a multifunctional signal linking sensory perception, metabolic regulation, and life-history strategy in sterol-auxotrophic insects, offering a framework for understanding how evolutionary loss of biosynthetic capacity reshapes nutrient sensing and homeostatic control. Full article
(This article belongs to the Section Animal Metabolism)
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13 pages, 3305 KB  
Article
Comparison of Mass Spectrometry Imaging by Desorption Electrospray Ionization (DESI) and Desorption Electro-Flow Focusing Ionization (DEFFI)
by Yunshuo Tian, Ruolun Wei, Yifan Meng and Richard N. Zare
Metabolites 2026, 16(4), 219; https://doi.org/10.3390/metabo16040219 - 27 Mar 2026
Viewed by 793
Abstract
Background: Among atmospheric-pressure mass spectrometry imaging (MSI) methods, desorption electrospray ionization (DESI) and desorption electro-flow focusing ionization (DEFFI) represent cost-effective, high-throughput approaches that utilize pneumatically assisted charged solvent droplets to directly desorb and ionize analytes from sample surfaces. Methods and Results: In this [...] Read more.
Background: Among atmospheric-pressure mass spectrometry imaging (MSI) methods, desorption electrospray ionization (DESI) and desorption electro-flow focusing ionization (DEFFI) represent cost-effective, high-throughput approaches that utilize pneumatically assisted charged solvent droplets to directly desorb and ionize analytes from sample surfaces. Methods and Results: In this study, we systematically compare the performance of conventional DESI-MSI with previously reported DEFFI-MSI configurations on the Orbitrap mass spectrometer platform, focusing on evaluating the lateral spatial resolution, signal intensity, and imaging speed. By scanning a standard patterned sample which has sharp edges, DESI-MSI achieved a spatial resolution of 70 µm, while DEFFI-MSI achieved 15 µm (approximately 4.7-fold improvement). For the representative ion at m/z 782.5621, DEFFI-MSI demonstrated significantly higher signal intensity across solvent flow rates ranging from 0.5 to 1.5 µL min−1. The enhanced ion yield directly translates to improved Orbitrap-based MSI efficiency: in both negative- and positive-ion modes, DEFFI generates rich full-scan mass spectra within the maximum 10 ms ion injection time, whereas DESI produces weaker mass spectra under the same conditions. Conclusions: Taken together, these results quantify the key performance metrics between DESI-MSI and DEFFI-MSI, demonstrating that DEFFI is the preferred method on Orbitrap-based MSI, because it simultaneously enhances spatial resolution, signal intensity, and imaging speed. Full article
(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics for Advancing Personalized Medicine)
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17 pages, 1963 KB  
Article
Dietary Citrus Peel Supplementation Enhances Hepatic Energy Metabolism, Muscle 9-HODE Generation and Isoleucine Catabolism in Beef Cattle
by Susumu Muroya, Koichi Ojima, Arata Banno, Hirotaka Nagai, Kazumasa Kakibuchi, Takuma Higuchi, Shuji Sakamoto and Kazutsugu Matsukawa
Metabolites 2026, 16(3), 201; https://doi.org/10.3390/metabo16030201 - 18 Mar 2026
Viewed by 1090
Abstract
Background: Citrus components potentially suppress adipogenic differentiation and lipid accumulation, and exhibit anti-inflammatory and antioxidant effects. We hypothesized that the bioactive compounds in Citrus junos Sieb ex Tanaka (yuzu) fruit peel can alter the systemic metabolism and productivity of beef cattle. Methods: Japanese [...] Read more.
Background: Citrus components potentially suppress adipogenic differentiation and lipid accumulation, and exhibit anti-inflammatory and antioxidant effects. We hypothesized that the bioactive compounds in Citrus junos Sieb ex Tanaka (yuzu) fruit peel can alter the systemic metabolism and productivity of beef cattle. Methods: Japanese Brown (JBR) steers were fed with a diet supplemented with 2.5% yuzu peel during the last month of the finishing period. To investigate the effect of dietary yuzu supplementation (DYS) on beef and liver metabolism, we explored the metabolomic profiles of longissimus thoracis (LT, loin) muscle at 14 d postmortem using capillary electrophoresis (CE-TOF/MS) and high-performance liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS). Results: The DYS treatment enhanced the beef fat score compared to that recorded in beef in the no-DYS (None) group (p = 0.050); however, the other carcass quality traits were not significantly different between the DYS and None groups. CE-TOF/MS and LC-TOF/MS revealed 242 and 107 annotated peaks, respectively, for the LT muscle. DYS significantly increased 9(S)-hydroxyoctadecadienoic acid (9-HODE, a beef flavor precursor), cyclo(-Leu-Pro), spermidine, asymmetric dimethylarginine, and 7α-hydroxycholesterol levels and reduced 2-ethylhydracrylic acid (2-EHAA), γ-tocopherol, coenzyme Q10 (CoQ10), sphingomyelin(d18:1/16:0), Cys-Gly, Tyr-Arg, and palmitoylcarnitine levels in postmortem LT muscle (p < 0.050). Concomitantly, in the fresh liver, DYS increased acetyl-CoA, 6-phosphogluconic acid, S-methylglutathione, ATP, ribulose 5-phosphate, and ADP levels and suppressed the content of thiamine, Ala-Ala, riboflavin, and ascorbate 2-sulfate (p < 0.050). Conclusion: Collectively, yuzu ingredients activated ATP production in the liver through the elevation of hepatic energy metabolism primarily in the citrate cycle and β-oxidation, and potentially altered muscle metabolism, including linoleic acid oxidation, FAD-mediated electron transport chain, and isoleucine catabolism, as demonstrated in the reduced accumulation of 2-EHAA and CoQ10 in DYS beef. Moreover, DYS likely affects the gut microbiome by enhancing the production of cyclo(-Leu-Pro), an antimicrobial dipeptide. Full article
(This article belongs to the Special Issue Muscle Metabolic Response and Adaptation to Exercise, Diet, and Environment: 2nd Edition)
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18 pages, 829 KB  
Review
Nexus of IDO1/Kynurenine Pathway to T-Cell Exhaustion: Hypoxia-Induced Tryptophan Metabolism in Glioblastoma
by Matthew Abikenari, George Nageeb, Joseph H. Ha, Matthew Adam Sjoholm, Justin Liu, Brandon Bergsneider, Jocelyn Valenzuela, James Poe, Kwang Bog Cho, Rohit Verma, Caren Wu, Vivek Sanker, Ravi Medikonda, Lily H. Kim, John Choi, Matei A. Banu and Michael Lim
Metabolites 2026, 16(3), 185; https://doi.org/10.3390/metabo16030185 - 10 Mar 2026
Cited by 2 | Viewed by 2098
Abstract
Glioblastoma (GBM) is a universally fatal cancer for which the standard of care has remained largely unchanged for the last 20 years. Recent work has demonstrated that most therapeutic trials for GBM fail due to complex mechanisms of immunosuppression mediated by both the [...] Read more.
Glioblastoma (GBM) is a universally fatal cancer for which the standard of care has remained largely unchanged for the last 20 years. Recent work has demonstrated that most therapeutic trials for GBM fail due to complex mechanisms of immunosuppression mediated by both the innate and adaptive immune systems. Various metabolic alterations in the tumor microenvironment help maintain this local and systemic immunosuppression, of which the axis of hypoxia-driven tryptophan degradation has garnered substantial attention over the last decade. This paper synthesizes a much-needed elucidation of the immunometabolic reshaping of glioma, myeloid, endothelial, and lymphoid cell lineages induced by hypoxia. The current paper critically evaluates the role of IDO1/TDO2-mediated breakdown of tryptophan and the consequent accumulation of kynurenine, a metabolite that triggers GCN2- and AHR-mediated CD8+ T-cell exhaustion and supports regulatory T-cell differentiation and expansion. Furthermore, we propose a synthesis of mechanistic evidence that establishes a role for the Trp-GCN2-ATF4-VEGFA axis in hypoxia-induced immunosuppression, supporting that pro-tumoral metabolic dysregulation is directly linked to angiogenesis. In GBM, hypoxia and tryptophan–kynurenine pathway dysregulation operate as an integrated metabolic circuit that drives widespread immunosuppression. These mechanisms can be captured by a metabolic signature shared across nearly every cell type in the GBM microenvironment. Drawing on recent spatial transcriptomic, metabolomic, and pharmacologic studies, we outline how this metabolic axis shapes disease biology and how it can be targeted to restore effective antitumor immunity. Full article
(This article belongs to the Special Issue Mechanistic Insights into Metabolic Interactions with the Tumor Microenvironment)
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15 pages, 3209 KB  
Article
An NMR-Based Protocol for Profiling the Endo- and Exo-Metabolomes in Aβ1-42 Treated Human Astrocytes from Healthy and Alzheimer’s Disease Donors
by Elisa Bientinesi, Alessia Vignoli, Sara Ristori, Maria Salobehaj, Gianmarco Bertoni, Daniela Monti and Leonardo Tenori
Metabolites 2026, 16(3), 173; https://doi.org/10.3390/metabo16030173 - 6 Mar 2026
Viewed by 736
Abstract
Background/Objectives: Astrocytes play a critical role in maintaining brain homeostasis and are increasingly recognized as active contributors to neurodegenerative processes. Metabolic dysfunction in astrocytes has been implicated in the onset and progression of Alzheimer’s disease (AD), yet the underlying metabolic alterations remain [...] Read more.
Background/Objectives: Astrocytes play a critical role in maintaining brain homeostasis and are increasingly recognized as active contributors to neurodegenerative processes. Metabolic dysfunction in astrocytes has been implicated in the onset and progression of Alzheimer’s disease (AD), yet the underlying metabolic alterations remain poorly characterized. Methods: We used an optimized protocol for untargeted metabolomic profiling of both intracellular and extracellular compartments of primary human astrocytes derived from AD patients and healthy subjects (HS) using 1H nuclear magnetic resonance (NMR) spectroscopy. Cells were treated with oligomeric Aβ1-42 to model pathological conditions. Results: Aβ1-42 treatment induced intracellular metabolic alterations in both AD and HS astrocytes, including a consistent reduction in phosphocreatine, potentially indicating impaired energy-buffering capacity. Notably, a decrease in β-alanine was observed only in AD astrocytes, suggesting alterations in carnosine-related antioxidant defence. Analysis of conditioned media revealed differential responses between groups: AD astrocytes showed increased extracellular levels of 2-oxoglutarate, citrate, and glycine, whereas HS astrocytes exhibited reduced extracellular levels of leucine and isoleucine, suggesting distinct adaptive metabolic responses to Aβ-induced stress. However, none of these differences remained statistically significant after correction for multiple testing. Conclusions: These findings suggest that NMR-based metabolomics can detect subtle metabolic shifts in human astrocyte models of AD and HS exposed to amiloidogenic challenge. Given the limited sample size and the exploratory design adopted, the results should be interpreted as preliminary and require validation in larger, better-matched cohorts. Nevertheless, this study provides a methodological framework and generates biologically plausible hypotheses regarding astrocyte metabolic responses relevant to AD pathophysiology. Full article
(This article belongs to the Special Issue Advances in NMR- and MS-Based Metabolomics and Its Applications)
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22 pages, 12922 KB  
Article
Acute High-Intensity Noise Exposure Induces Cognitive Impairment and Arachidonic Acid Metabolism-Related Molecular Alterations in Rats: A Multi-Omics Study
by Yane Liu, Mengping Diao, Yihan Hao, Zhongqi Liu, Hao Ma, Yong Zou, Lizhen Ma, Lifeng Wang, Weijia Zhi and Qiong Yu
Metabolites 2026, 16(2), 143; https://doi.org/10.3390/metabo16020143 - 20 Feb 2026
Viewed by 801
Abstract
Background: Acute high-intensity noise exposure represents a critical environmental stressor; however, its impact on brain function and the underlying mechanisms remain incompletely understood. This study aimed to investigate the effects of acute high-intensity noise exposure on cognitive function in rats, utilizing multi-omics [...] Read more.
Background: Acute high-intensity noise exposure represents a critical environmental stressor; however, its impact on brain function and the underlying mechanisms remain incompletely understood. This study aimed to investigate the effects of acute high-intensity noise exposure on cognitive function in rats, utilizing multi-omics analysis to explore potential mechanisms. Methods: Rats were exposed to acute noise at 120 dB, and brain function was evaluated using the novel object recognition (NOR) test, recordings of electroencephalographic activity, and histopathological examination. Longitudinal serum metabolomics and fecal metagenomics were performed on samples collected at 0 h, 7, 14, and 28 days post-exposure. Quantitative profiling of oxylipins and proteomics were conducted at a critical time point, followed by integrative multi-omics network analysis. Results: Acute high-intensity noise exposure significantly reduced the recognition index in the NOR test, increased theta-band power, and induced hippocampal neuronal damage. Multi-omics analyses revealed time-dependent alterations in gut microbiota and metabolic profiles, identifying day 7 as the critical response window, with arachidonic acid (AA)-derived metabolites consistently downregulated across omics layers. Integrated analysis revealed a coordinated microbiota–oxylipins–proteins network, highlighting key AA-derived oxylipins (e.g., 8-HETE, 12-HETE) that correlated with specific gut microbiota and proteins involved in lipid metabolism and inflammation. Conclusions: Acute high-intensity noise exposure induces cognitive impairment and systemic molecular disturbances. AA-centered lipid metabolism acts as a key hub linking gut microbiota dysbiosis with inflammatory and metabolic protein alterations, providing multi-omics evidence for coordinated microbiota–lipid–protein dysregulation underlying noise-induced neurobiological dysfunction. Full article
(This article belongs to the Special Issue Environmental Metabolites Insights into Health and Disease)
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17 pages, 5292 KB  
Article
Metabolome Reprogramming During Fruit Ripening and Post-Harvest Storage in Ten Crop Species
by Michael Wittenberg, Yanitsa Ilieva and Tsanko Gechev
Metabolites 2026, 16(2), 133; https://doi.org/10.3390/metabo16020133 - 13 Feb 2026
Cited by 1 | Viewed by 1000
Abstract
Background/Objectives: Plants alter metabolites of their fruits during the ripening process, leading to improved nutritional properties and taste. In addition, metabolite compositions continue to change on the shelf after harvest. However, the dynamics of these important processes are species-specific and so this study [...] Read more.
Background/Objectives: Plants alter metabolites of their fruits during the ripening process, leading to improved nutritional properties and taste. In addition, metabolite compositions continue to change on the shelf after harvest. However, the dynamics of these important processes are species-specific and so this study aimed to contrast the ripening dynamics of ten different fruit species simultaneously. Methods: Plant material was collected from the fruits of apple, banana, blueberry, kiwifruit, pear, plum, peach, strawberry, raspberry, and tomato at three different stages: unripe, fully ripe, and overripe fruits. Comparative metabolome analysis by GCMS was performed to identify differentially abundant metabolites across the species of this study and to examine their dynamics across ripening and post-harvest storage. These results were complemented by elemental compositions derived from a literature search. Results: In a first, this study demonstrated that both baseline metabolite abundances and their dynamics across ripening clustered species vary largely according to their phylogeny. Comparisons across ripe fruit identified differences in nutritional properties, highlighting species such as banana to be of especially high nutritional value and blueberry and peach to be prominent sources of antioxidants. Comparing the ripening dynamics of all species identified common patterns, such as the conversion of organic acids to sugars and cell wall dynamics, although species-specific responses were also acknowledged, in particular, kiwi and the Rosaceae berries, which may explain differences in post-harvest shelf-life. Conclusions: The observed inter- and intra-specific variation in nutritionally relevant metabolites and elements serves as a reference for both producers and consumers and emphasizes that consuming a variety of fruits, not only across species but also across cultivars within a species, can maximize the intake of beneficial phytonutrients, sugars, amino acids, and antioxidants. 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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20 pages, 1940 KB  
Article
Evidence for a Cytokine-Sensitive Network of Iron-Associated Genes That Protects Pancreatic Islets Against Ferroptosis
by Kira G. Slepchenko, Grace P. Counts, Poonam R. Sharma, Si Chen, Kathryn L. Corbin, Farhan M. Qureshi, Robert A. Colvin, C. Martin Lawrence and Craig S. Nunemaker
Metabolites 2026, 16(2), 112; https://doi.org/10.3390/metabo16020112 - 4 Feb 2026
Viewed by 889
Abstract
Background/Objectives: The micronutrient iron is closely connected to inflammation and is among the complex factors contributing to beta-cell failure in diabetes. High levels of dietary iron increase the risk of developing type 2 diabetes, and excessive iron uptake by beta-cells can cause [...] Read more.
Background/Objectives: The micronutrient iron is closely connected to inflammation and is among the complex factors contributing to beta-cell failure in diabetes. High levels of dietary iron increase the risk of developing type 2 diabetes, and excessive iron uptake by beta-cells can cause oxidative stress and inhibit function. Elevated levels of proinflammatory cytokines in obese individuals, such as interleukin (IL)-1beta and IL-6, increase the risk of developing type 2 diabetes, and there is evidence that these low levels of circulating cytokines can lead to islet dysfunction. Methods: In this study, gene microarray and other data were analyzed for expression differences in islets treated for 48 h with 10 pg/mL IL-1beta + 20 pg/mL IL-6 as a model of low-grade inflammation versus untreated. Results: Three iron-associated genes were among the most cytokine-sensitive in the mouse genome: Hamp, Steap4, and Lcn2. These proteins are all involved with increasing/retaining cellular iron. We hypothesized that increased cellular iron would lead to increased susceptibility to ferroptosis. Surprisingly, 24 h pre-exposure to low-grade inflammation, which upregulates this iron-gene network, prevented subsequent erastin-induced ferroptosis. We also found that Steap4 overexpression reduced islet dysfunction caused by high-dose proinflammatory cytokines (10× low-dose), suggesting an overall protective effect. Steap4 overexpression also upregulated Hamp and Lcn2, suggesting Steap4 regulates these cytokine-sensitive iron genes.; in contrast, ferritin and ferroportin gene expression, which are not sensitive to cytokines, were unchanged. Conclusions: These data suggest an inflammation-induced network of genes involved in cellular iron uptake and retention plays a protective role in islets against oxidative stress and ferroptosis. Full article
(This article belongs to the Special Issue Role of Metabolic Factors and Their Interactions on Diabetes and Its Complications)
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14 pages, 1428 KB  
Article
Negative Energy Balance in Transition Cows Induces Complex Changes in Lipid Profile of Milk
by Zhiqian Liu, Vilnis Ezernieks, Joanne E. Hemsworth, Coralie M. Reich, Carolyn R. Bath, Monique J. Berkhout, Muhammad S. Tahir, Leah C. Marett, Amanda J. Chamberlain, Mike E. Goddard, Ruidong Xiang and Simone J. Rochfort
Metabolites 2026, 16(2), 103; https://doi.org/10.3390/metabo16020103 - 30 Jan 2026
Viewed by 1014
Abstract
Background: Negative energy balance (NEB) during the transition period is associated with profound changes in the body condition and metabolic dynamics of dairy cows. However, the detailed lipidomic changes in milk induced by NEB are unclear, and lipid biomarkers that indicate the energy [...] Read more.
Background: Negative energy balance (NEB) during the transition period is associated with profound changes in the body condition and metabolic dynamics of dairy cows. However, the detailed lipidomic changes in milk induced by NEB are unclear, and lipid biomarkers that indicate the energy status of cows remain to be established. Methods: Using a combination of GC-FID, HILIC-MS and RP-LC-MS, we performed a systematic comparison of lipid composition between early lactating (DIM: 5–14) and mid-lactating (DIM: 65–80) milk. Results: We found that NEB in cows caused a profound modification in the profile of all the lipid classes surveyed, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), sphingomyelin (SM), lysophosphatidylcholine (LPC), PC-plasmalogen (PCP), PE-plasmalogen (PEP), lactosylceramide (LacCer), acylcarnitine (AcylCar) and triglycerides (TAGs). Except for LPC and AcylCar, which were reduced and increased, respectively, by NEB, the responses of other lipid classes varied across different species. For phospholipids and TAGs, species containing de novo FAs (C4:0–C16:0) and odd-chain FAs (C15:0 and C17:0) were markedly downregulated, whereas those comprising long-chain preformed FAs were upregulated by NEB. Conclusions: Comprehensive lipidomic profiling of early and mid-lactating milk from two large cohorts of cows allowed us to identify nine lipids (PE 33:1, LacCer 32:1, LacCer 39:1, LacCer 41:1, SM 36:1, SM 36:2, SM 37:1, PEP 38:4 and PEP 38:5) as potential biomarkers of NEB in dairy cows. Full article
(This article belongs to the Section Animal Metabolism)
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21 pages, 2287 KB  
Article
Chemical Attributes of UK-Grown Tea and Identifying Catechin and Metabolite Dynamics in Green and Black Tea Using Metabolomics and Machine Learning
by Amanda J. Lloyd, Jasen Finch, Alina Warren-Walker, Alison Watson, Laura Lyons, MJ Pilar Martinez Martin, Thomas Wilson and Manfred Beckmann
Metabolites 2026, 16(1), 84; https://doi.org/10.3390/metabo16010084 - 21 Jan 2026
Cited by 1 | Viewed by 538
Abstract
The Dartmoor Estate Tea plantation in Devon, UK, benefits from a unique microclimate and diverse soil conditions, which, together with its different processing methods, contribute to the distinctive flavours and chemical profiles of its teas. Objectives: The chemical diversity of Dartmoor tea was [...] Read more.
The Dartmoor Estate Tea plantation in Devon, UK, benefits from a unique microclimate and diverse soil conditions, which, together with its different processing methods, contribute to the distinctive flavours and chemical profiles of its teas. Objectives: The chemical diversity of Dartmoor tea was assessed via samples collected during processing of green and black tea. Methods: Leaf samples were collected during the processing of green and black tea and analysed using Flow Infusion Electrospray Ionisation Mass Spectrometry (FIE-MS). Results: For green tea processing, random forest regression identified features associated with the processing steps, resulting in a total of 272 m/z explanatory features. The analysis of black tea processing (4 h and overnight oxidation prior to roasting) yielded 209 discriminatory m/z features (4 h) and the model for the overnight oxidation and roasting treatments yielded 605 discriminatory m/z features. K-means clustering was performed on the percentage of relative abundance of the discriminatory m/z features. This grouped the discriminatory m/z features into 15 clusters of features showing similar trends across the processing stages. Functional and structural enrichment analysis was performed on each of the clusters and significant metabolic pathways included metabolism and biosynthesis of flavonoids, amino acids and lipids, the Pentose phosphate pathway, and the TCA cycle. Many discriminatory features were putatively classified as catechin-derived flavan-3-ols and flavonol glycosides. Conclusions: This research highlights the complex role that processing plays in shaping tea quality. It provides valuable insights into the metabolic pathways that influence tea production and emphasises how these factors determine the final chemical profile and sensory characteristics of tea. Full article
(This article belongs to the Section Food Metabolomics)
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22 pages, 867 KB  
Article
A Major Update and Improved Validation Functionality in the mwtab Python Library and the Metabolomics Workbench File Status Website
by P. Travis Thompson and Hunter N. B. Moseley
Metabolites 2026, 16(1), 76; https://doi.org/10.3390/metabo16010076 - 15 Jan 2026
Cited by 1 | Viewed by 628
Abstract
Background: The Metabolomics Workbench (MW) is a public scientific data repository consisting of experimental data and metadata from metabolomics studies collected with mass spectroscopy (MS) and nuclear magnetic resonance (NMR) analyses. Although not as rapidly as in the past, MW has steadily evolved, [...] Read more.
Background: The Metabolomics Workbench (MW) is a public scientific data repository consisting of experimental data and metadata from metabolomics studies collected with mass spectroscopy (MS) and nuclear magnetic resonance (NMR) analyses. Although not as rapidly as in the past, MW has steadily evolved, updating its mwTab and JSON deposition text file formats and its web-based infrastructure. However, the growth of MW has been exponential since its inception in 2013 and continues to be exponential, with the number of datasets hosted on the repository increasing by 50% since April 2024. As part of regular maintenance to keep up with changes to the mwTab file format and an earnest effort to use MW datasets in meta-analyses, the mwtab Python package has been updated. Methods: Updates include better error handling for batch processing, better parsing to read more files without error, and extensive improvements to the validation capabilities of the package. These updates also required our mwFileStatusWebsite to be updated and improved. Results: We used the enhanced validation features of the mwtab package to evaluate all available datasets in MW to facilitate improved curation, FAIRness of the repository, and reuse for meta-analyses. Conclusions: Version 2.0.0 of the mwtab Python package is now officially released and freely available on GitHub and the Python Package Index (PyPI) under a Clear Berkeley Software Distribution (BSD) license, with documentation available on GitHub. The updated mwFileStatusWebsite is also officially in its 2.0.0 version. Full article
(This article belongs to the Section Bioinformatics and Data Analysis)
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20 pages, 5995 KB  
Article
Co-Metabolic Network Reveals the Metabolic Mechanism of Host–Microbiota Interplay in Colorectal Cancer
by Han-Wen Wang, Wang Li, Qi-Jun Ma, Hong-Yu Zhang, Yuan Quan and Qiang Zhu
Metabolites 2026, 16(1), 64; https://doi.org/10.3390/metabo16010064 - 11 Jan 2026
Cited by 1 | Viewed by 1029
Abstract
Background: Colorectal cancer (CRC) is a malignancy that ranks among the top three in terms of both global mortality and incidence. Although numerous studies have demonstrated that gut microbes are implicated in CRC pathogenesis, the precise mechanisms underlying host–microbiota metabolic crosstalk remain poorly [...] Read more.
Background: Colorectal cancer (CRC) is a malignancy that ranks among the top three in terms of both global mortality and incidence. Although numerous studies have demonstrated that gut microbes are implicated in CRC pathogenesis, the precise mechanisms underlying host–microbiota metabolic crosstalk remain poorly understood. Objective: This study aims to identify and delineate key co-metabolites and their associated metabolic pathways that modulate the biomass of CRC-related gut bacteria within healthy individuals, through the construction of host–gut microbiota co-metabolic network models. We seek to elucidate the underlying mechanisms of metabolic interplay between the host and CRC-related gut microbiota, thereby offering novel perspectives on the microbial involvement in the initiation and progression of CRC. Methods: We coupled a colon tissue-specific host Genome-Scale Metabolic Model (GEM), which utilized transcriptomic data from healthy human colon tissues, with 12 CRC-associated pro-/anti-carcinogenic gut bacterial GEMs to construct a co-metabolic network. Through a comparative analysis of the network structure and systemic methods (including Flux Sampling and metabolic difference analysis), we simulated scenarios of constrained host co-metabolite supply. Finally, metabolic subsystem enrichment analysis was employed to elucidate the specific molecular mechanisms by which key co-metabolites affect microbial function. Results: The 17 key co-metabolites identified include chloride ions, zinc ions, and acetate. Among these, thirteen metabolites (e.g., ferric iron, succinate, and acetate) were confirmed by literature to be associated with CRC. All 17 key co-metabolites were found to significantly modulate the biomass of CRC-associated gut bacteria. These regulatory effects primarily influence microbial function through core pathways such as glycerophospholipid metabolism and folate metabolism. Conclusion: This research provides a systemic perspective for elucidating the mechanisms of host–gut microbiota metabolic interplay in CRC, thereby complementing the existing theoretical framework concerning microbial regulation by the host genetic background. Full article
(This article belongs to the Section Bioinformatics and Data Analysis)
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12 pages, 1698 KB  
Article
Enhancing Caffeic Acid Production in Escherichia coli Through Heterologous Enzyme Combinations and Semi-Rational Design
by Qing Luo, Weihao Wang, Qingjing Huang, Chuan Wang, Lixiu Yan, Jun Kang, Jiamin Zhang and Jie Cheng
Metabolites 2026, 16(1), 62; https://doi.org/10.3390/metabo16010062 - 9 Jan 2026
Cited by 1 | Viewed by 732
Abstract
Background/Objectives: Caffeic acid is a hydroxycinnamic acid that has a wide range of applications in the medical field. The synthesis of caffeic acid using microbial fermentation technology is an environmentally friendly method. Methods: By engaging various enzymes, specifically 4-hydroxyphenylacetate 3-monooxygenase (HpaB), sourced from [...] Read more.
Background/Objectives: Caffeic acid is a hydroxycinnamic acid that has a wide range of applications in the medical field. The synthesis of caffeic acid using microbial fermentation technology is an environmentally friendly method. Methods: By engaging various enzymes, specifically 4-hydroxyphenylacetate 3-monooxygenase (HpaB), sourced from diverse bacterial strains, we successfully engineered a functional version of this enzyme within Escherichia coli, enabling the production of caffeic acid. In addition to the two common tyrosine ammonia lyases (TAL) and HpaC, different combinations of HpaB demonstrated varying abilities in converting the substrate L-tyrosine into the desired product, caffeic acid. Results: Under shake-flask culture conditions, the highest yield of caffeic acid was achieved with an enzyme mixture containing HpaB from Escherichia coli, reaching 75.88 mg/L. Enhancing the activity of the rate-limiting enzyme through engineering could potentially increase caffeic acid titer. This study aims to conduct a semi-rational design of HpaB through structure-based approaches to screen for mutants that can enhance the production of caffeic acid. Initially, the predicted three-dimensional structure of HpaB was generated using AlphaFold2, and subsequent analysis was conducted to pinpoint the critical mutation sites within the substrate-binding pocket. Five key amino acid residues (R113, Y117, H155, S210 and Y461) located in the vicinity of the flavin adenine dinucleotide binding domain in HpaB from Escherichia coli could be instrumental in modulating enzyme activity. Subsequently, the mutant S210G/Y117A was obtained by iterative saturation mutagenesis, which increased the titer of caffeic acid by 1.68-fold. The caffeic acid titer was further improved to 2335.48 mg/L in a 5 L fermenter. The findings show that the yield of caffeic acid was significantly enhanced through the integration of semi-rational design and fermentation process optimization. Full article
(This article belongs to the Special Issue SynBio-Driven Metabolic Engineering: From Novel Tools to Real-World Applications)
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26 pages, 3472 KB  
Article
Changes in the Metabolome of Different Tissues in Response to Streptozotocin Diabetes and Mildronate Exposure: A Metabolomic Assessment
by David Hauton, Dragana Savic, John Walsby-Tickle, Damian Tyler and James S. O. McCullagh
Metabolites 2026, 16(1), 61; https://doi.org/10.3390/metabo16010061 - 9 Jan 2026
Viewed by 856
Abstract
Background: Uncontrolled diabetes is characterised by a loss of blood glucose control and increased oxidation of fatty acids to produce ATP. Use of metabolic inhibitors to blunt fatty acid oxidation and restore glucose metabolism is a poorly studied intervention for diabetes. Methods: [...] Read more.
Background: Uncontrolled diabetes is characterised by a loss of blood glucose control and increased oxidation of fatty acids to produce ATP. Use of metabolic inhibitors to blunt fatty acid oxidation and restore glucose metabolism is a poorly studied intervention for diabetes. Methods: Steptozotocin-induced diabetes was developed in Wistar male rats. A subset was supplemented with mildronate (100 mg/kg—14 days). Exploiting liquid chromatography-mass spectrometry for workflows including ion exchange-, C18-reverse phase- and HILIC-based chromatography methods, metabolite levels were quantified in plasma liver and brain tissue. Using both untargeted and targeted metabolomic analysis changes to the global tissue metabolome and individual metabolic pathways were estimated. Results: We document that an inhibitor of carnitine synthesis, mildronate, decreased plasma (50% p < 0.01) carnitine abundance and decreased plasma glucose concentration by one-third compared to streptozotocin (STZ)-treated rats (p < 0.001). Targeted metabolomic analysis of the liver showed decreased alpha-ketoglutarate abundance (35% p < 0.05) by STZ diabetes that was further decreased following mildronate treatment (50% p < 0.05). For both beta-hydroxybutyrate and succinate levels, STZ diabetes increased hepatic abundance by 50% (p < 0.05 for both), which was restored to control levels by mildronate (p < 0.05 for both). In contrast, brain TCA intermediate abundances were unaffected by either STZ diabetes or mildronate (NS for all). STZ diabetes also decreased abundance of pentose phosphate pathway (PPP) metabolites in the liver (glucose-6-phosphate, 6-phosphogluconolactone, 6-phosphogluconate 50% for all; p < 0.05), which was not restored by mildronate treatment. However, brain PPP metabolite abundance was unchanged by STZ diabetes or mildronate (NS for all). However, mildronate treatment did not affect the increased abundance of brain sorbitol, sorbitol-6-phosphate and glucose-6-phosphate as a result of STZ diabetes. Conclusions: Together, these observations highlight the potential role that metabolic inhibitors, like mildronate, may play in restoring blood glucose for diabetic patients, without a direct effect of tissues that represent obligate consumers of glucose (e.g., brain) whilst manipulating fat oxidation in tissues such as the liver. Full article
(This article belongs to the Section Cell Metabolism)
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23 pages, 2381 KB  
Review
Neurotrophic Factors: Emerging Biology and Therapeutic Applications for Cardiovascular Diseases
by Yu Liu, Huijie Zhang, Fengzhi Yu, Tiemin Liu, Dandan Jia and Ruwen Wang
Metabolites 2026, 16(1), 58; https://doi.org/10.3390/metabo16010058 - 9 Jan 2026
Cited by 1 | Viewed by 1161
Abstract
Cardiovascular diseases (CVDs) have emerged as a common health problem. However, despite their prevalence, little progress has been made in their treatment. In recent years, neurotrophic factors (NTFs) have been discovered to exert cardioprotective functions for CVDs. NTFs can modulate vascular integrity, myocardial [...] Read more.
Cardiovascular diseases (CVDs) have emerged as a common health problem. However, despite their prevalence, little progress has been made in their treatment. In recent years, neurotrophic factors (NTFs) have been discovered to exert cardioprotective functions for CVDs. NTFs can modulate vascular integrity, myocardial remodeling, angiogenesis, and autonomic regulation, playing the roles of maintaining cardiovascular homeostasis and influencing disease progression. Under pathological conditions, the supplement of NTFs can induce substantial adaptations to mitigate adverse cardiac responses. Several NTFs have been investigated in this regard. This review briefly elaborates on present insights into the expression, signaling pathways, and regulatory effects of NTFs on the development of CVDs, and also discusses emerging therapeutic strategies based on NTFs, ranging from exercise to advanced modalities including stem cell therapy, gene transfer, recombinant protein therapy and NTF mimetics, among which the mimetics and exercise interventions emerge as the most promising avenues for clinical translation. Full article
(This article belongs to the Special Issue Diabetes and Metabolic Diseases: From Prevention to Clinical Management, 2nd Edition)
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38 pages, 4718 KB  
Review
Mass Spectrometry-Based Metabolomics in Pediatric Health and Disease
by Debasis Sahu, Andrei M. Matusa, Alicia DiBattista, Bradley L. Urquhart and Douglas D. Fraser
Metabolites 2026, 16(1), 49; https://doi.org/10.3390/metabo16010049 - 6 Jan 2026
Viewed by 1595
Abstract
Mass spectrometry-based metabolomics is a valuable tool for advancing pediatric health research. Along with nuclear magnetic resonance, it enables detailed biochemical analysis from minimal sample volumes, a critical feature for pediatric diagnosis. Metabolomics supports early detection of inherited metabolic disorders, monitors metabolic changes [...] Read more.
Mass spectrometry-based metabolomics is a valuable tool for advancing pediatric health research. Along with nuclear magnetic resonance, it enables detailed biochemical analysis from minimal sample volumes, a critical feature for pediatric diagnosis. Metabolomics supports early detection of inherited metabolic disorders, monitors metabolic changes during growth, and identifies disease markers for a range of conditions, including metabolic, neurodevelopmental, oncological, and infectious diseases. Integrating metabolomic data with genomic, proteomic (i.e., multi-omics approaches), and clinical information enables more precise and preventive care by enhancing risk assessment and informing targeted treatments. However, routine clinical use faces several challenges, including establishing age- and sex-specific reference ranges, standardizing sample collection and processing, ensuring consistency across platforms and laboratories, expanding reference databases, and improving data comparability. Ethical and regulatory issues, including informed consent, data privacy, and equitable access, also require careful consideration. Advances in high-resolution and single-cell metabolomics, artificial intelligence for data analysis, and cost-effective testing are expected to address these barriers and support broader clinical adoption. As standards and data-sharing initiatives grow, metabolomics will play an increasingly important role in pediatric diagnostics and personalized care, enabling earlier disease detection, improved treatment monitoring, and better long-term outcomes for children. Full article
(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics in Health and Disease: Targeted Analysis and Its Trends)
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16 pages, 24942 KB  
Article
Characterization of Volatile Organic Compounds Released by Penicillium expansum and Penicillium polonicum
by Guohua Yin, Kayla K. Pennerman, Wenpin Chen, Tao Wu and Joan W. Bennett
Metabolites 2026, 16(1), 37; https://doi.org/10.3390/metabo16010037 - 1 Jan 2026
Cited by 1 | Viewed by 1034
Abstract
Background/Objectives: Fungi produce a diverse array of metabolites, including various volatile organic compounds (VOCs) with known physiological functions and other biological activities. These metabolites hold significant potential for medical and industrial applications. Within the fungal domain, Penicillium species represent a particularly important group. [...] Read more.
Background/Objectives: Fungi produce a diverse array of metabolites, including various volatile organic compounds (VOCs) with known physiological functions and other biological activities. These metabolites hold significant potential for medical and industrial applications. Within the fungal domain, Penicillium species represent a particularly important group. Methods: This study characterized the VOC profiles of four Penicillium expansum strains (R11, R19, R21, and R27) and one Penicillium polonicum strain (RS1) using the solid-phase microextraction–gas chromatography–mass spectrometry technique. Results: The analysis revealed that the only compound in common among the five strains of Penicillium was phenyl ethanol. The high toxicity of P. polonicum RS1 to Drosophila larvae correlated with its diverse and abundant alkene production. Specifically, alkenes constituted 31.28% of its total VOCs, followed by alcohols at 29.13%. GC-MS analyses detected 22, 17, 22, and 18 specific VOCs from R11, R19, R21, and R27, respectively. Overall, alkenes dominated the R11 profile (17.03%), alcohols were most abundant in R19 (28.82%), and R21 showed the highest combined release of alcohols (23.2%) and alkenes (11.7%), while R27 produced a moderate abundance of alcohols (9.16%) and alkenes (4.19%). Among the P. expansum strains, R11, R21, and R27 exhibited substantially higher toxicity than R19 strain in our previous assessment; these findings are consistent with their respective VOC profiles. Conclusions: The distinct VOC compositions across Penicillium strains significantly influence their biological characteristics and ecological functions. These findings provide a basis for follow-up research into the mechanisms of fungal volatile-mediated toxicity and support the development of biocontrol strategies. Full article
(This article belongs to the Special Issue Mycotoxins and Fungal Secondary Metabolism)
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20 pages, 3309 KB  
Article
From Ornamental Value to Antioxidant Activity: Comparative Phytochemistry of Lavandula Species and Cultivars
by Andrea Baptista, Cecilia Brunetti, Dalila Pasquini, Luana Beatriz dos Santos Nascimento, Cassandra Detti, Francesco Ferrini, Sara Beltrami and Antonella Gori
Metabolites 2026, 16(1), 34; https://doi.org/10.3390/metabo16010034 - 30 Dec 2025
Viewed by 760
Abstract
Background: Lavandula (Lamiaceae) includes numerous species, cultivars, and hybrids widely cultivated for both their ornamental traits and for functional uses in perfumery, nutrition, medicinal, and cosmetic applications. Objectives: This study characterized the phytochemical profiles of three species (Lavandula stoechas L., Lavandula [...] Read more.
Background: Lavandula (Lamiaceae) includes numerous species, cultivars, and hybrids widely cultivated for both their ornamental traits and for functional uses in perfumery, nutrition, medicinal, and cosmetic applications. Objectives: This study characterized the phytochemical profiles of three species (Lavandula stoechas L., Lavandula latifolia Medik., and Lavandula angustifolia Mill.), two cultivars (L. stoechas ‘Alba’ L. and L. angustifolia ‘Krajova’ Mill.), and the interspecific hybrid Lavandula × intermedia ‘Alba’ Emeric ex Loisel. Methods: All grown species and cultivars were maintained under uniform environmental and harvested simultaneously, to provide a comparative assessment of their terpene and polyphenol profiles and content, as well as their associated antioxidant activity. Results: HPLC-DAD/QTOF-MS analysis revealed differences in flavonoid and hydroxycinnamic acid content among species and cultivars. The main compounds identified were glycosylated derivatives of coumaric, caffeic, and ferulic acids, along with luteolin and apigenin derivatives. L. latifolia Medik. exhibited the highest hydroxycinnamic acid content (5.306 ± 1.265 mg/g FW), whereas L. stoechas ‘Alba’ L. showed the highest flavonoid concentration (2.537 ± 0.192 mg/g FW). GC-MS analysis indicated that hydrocarbon and oxygenated monoterpenes were the predominant terpene classes, with the highest levels recorded in L. stoechas L. (1922.09 ± 144.12 ng/g FW oxygenated; 945.89 ± 159.26 ng/g FW hydrocarbon monoterpenes). Antioxidant activity, assessed via DPPH and FRAP assays, was significantly correlated with flavonoid content across species, cultivars, and the hybrid. Conclusions: Intraspecific and interspecific variability within the Lavandula genus influences antioxidant activity and determines its suitability for different applications. Full article
(This article belongs to the Special Issue Identification of Plant Metabolites: Characterization and Biological Activities, 2nd Edition)
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15 pages, 7128 KB  
Article
Norm-SVR for the Enhancement of Single-Cell Metabolomic Stability in ToF-SIMS
by Mingru Liu, Hongzhe Ma, Xiang Fang, Yanhua Chen, Zhaoying Wang and Xiaoxiao Ma
Metabolites 2026, 16(1), 36; https://doi.org/10.3390/metabo16010036 - 30 Dec 2025
Cited by 2 | Viewed by 755
Abstract
Purpose: Data stability is a critical factor in Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) single-cell analysis. However, various factors, such as sample processing, instrument condition, and data acquisition, can introduce uncertainties into ToF-SIMS data. Correcting this data is vital, yet current methods mainly [...] Read more.
Purpose: Data stability is a critical factor in Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) single-cell analysis. However, various factors, such as sample processing, instrument condition, and data acquisition, can introduce uncertainties into ToF-SIMS data. Correcting this data is vital, yet current methods mainly focus on total ion intensity normalization or using consistent substrates. No specific correction method exists for ToF-SIMS single-cell metabolomics. Methods: This study utilizes the Normalized Support Vector Regression (Norm-SVR), commonly used methods for correcting large-scale metabolomics data, for the correction of ToF-SIMS single-cell metabolomic analysis and assesses its performance in comparison to traditional total ion intensity normalization. Results and Conclusions: The results suggest that Norm-SVR effectively diminishes batch effects and reduces variability, thereby underscoring the method’s efficacy and practicality. This approach is expected to improve data quality assurance in extensive ToF-SIMS analytical datasets. Full article
(This article belongs to the Section Advances in Metabolomics)
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21 pages, 940 KB  
Article
Exploration of Key Flavor Compounds in Five Grilled Salmonid Species by Integrating Volatile Profiling and Sensory Evaluation
by Yuka Mori, Akimasa Hatanaka and Eiichiro Fukusaki
Metabolites 2026, 16(1), 30; https://doi.org/10.3390/metabo16010030 - 26 Dec 2025
Viewed by 891
Abstract
Background/Objectives: Salmonid species are globally popular and widely consumed in Japan, especially when grilled. Understanding their flavor characteristics from sensory and compositional perspectives is essential to improve the quality of processed salmonid products. However, scientific knowledge in this area remains limited. This [...] Read more.
Background/Objectives: Salmonid species are globally popular and widely consumed in Japan, especially when grilled. Understanding their flavor characteristics from sensory and compositional perspectives is essential to improve the quality of processed salmonid products. However, scientific knowledge in this area remains limited. This study aimed to explore compounds contributing delicious flavor of grilled salmon by performing correlation analysis between sensory evaluation and volatile profiles of five grilled salmonid species. Methods: To characterize each sample, sensory evaluation using paired comparisons and comprehensive analysis of volatile compounds by gas chromatography/mass spectrometry (GC/MS) were conducted. To select compounds strongly associated with the “delicious flavor of grilled salmon”, orthogonal partial least squares regression (OPLSR) and gas chromatography/olfactometry (GC/O) were performed. A subset of the selected candidate compounds was quantified, and additive tests on the samples were carried out based on their concentrations. Results: Sensory evaluation revealed clear differences in flavor profiles among the five salmonid species. A total of 344 peaks were detected in all samples, and principal component analysis (PCA) of these data showed grouping trends consistent with those obtained from sensory evaluation. OPLSR using sensory and volatile data as variables, and GC/O analysis identified 23 compounds, including trimethylamine, dimethyl sulfide, and 1-heptanol, as candidates contributing to the characteristic flavor of grilled salmonid species. Sensory evaluation of samples supplemented with a subset of these candidates showed that, particularly at the higher addition level, aroma and flavor tended to approach those of the highly preferred samples. Conclusions: These findings suggest that some of the selected candidate compounds contribute to the formation of delicious flavor of grilled salmon and may be useful for flavor design and quality improvement of processed products made from salmonid species. Full article
(This article belongs to the Section Food Metabolomics)
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21 pages, 1688 KB  
Article
Maternal Vitamin D Status, Oxidative Stress, and Implications for Neonatal Development: A Cross-Sectional Study
by Tania Flores-Bazán, Jacqueline Scarlett Barreto-González, José Pedraza-Chaverri, Omar Noel Medina-Campos, Araceli Castañeda-Ovando, Jeannett Alejandra Izquierdo-Vega, Diego Estrada-Luna, Martha Eunice Rodríguez-Arellano and Angélica Saraí Jiménez-Osorio
Metabolites 2026, 16(1), 19; https://doi.org/10.3390/metabo16010019 - 24 Dec 2025
Viewed by 2018
Abstract
Background: Vitamin D (VD) plays a central role in calcium homeostasis during pregnancy and has been implicated in redox-related biological processes. While VD deficiency (VDD) has been consistently associated with adverse pregnancy outcomes, the relationships between VD insufficiency (VDI), maternal antioxidant-related biomarkers, [...] Read more.
Background: Vitamin D (VD) plays a central role in calcium homeostasis during pregnancy and has been implicated in redox-related biological processes. While VD deficiency (VDD) has been consistently associated with adverse pregnancy outcomes, the relationships between VD insufficiency (VDI), maternal antioxidant-related biomarkers, and neonatal outcomes remain incompletely characterized, particularly during the third trimester. Objective: To determines the prevalence of VDI in third-trimester pregnant women and to examine its associations with antioxidant-related markers and selected neonatal outcomes. Methods: A cross-sectional study was conducted among pregnant women in the third trimester attending a tertiary referral hospital in Mexico City. Maternal serum 25-hydroxyvitamin D (25-OHD) concentrations were measured, along with a panel of redox-related markers, including 2,2-diphenyl-2-2picrylhydrazyl (DPPH) radical scavenging activity, reduced glutathione (GSH), glutathione S-transferase (GST), glutathione peroxidase (GPx), and oxygen radical absorbance capacity (ORAC). Neonatal anthropometric parameters were recorded at birth. Associations between maternal VD status, redox-related markers, environmental factors, and neonatal outcomes were evaluated using appropriate statistical analyses. Results: A high prevalence of VDI was observed in the study population. Maternal VDI was associated with lower activities of GSH, GST, and GPx. Passive exposure to tobacco smoke and season of sampling were also associated with lower VD concentrations. Neonates born to women with VDI had higher birth weight compared with those born to women with sufficient VD concentrations. Maternal serum 25-OHD concentrations correlated positively with selected antioxidant enzyme activities. Conclusions: In this cohort of third-trimester pregnant women, VDI co-occurred with environmental factors, differences in maternal redox-related markers, and selected neonatal outcomes. These findings support an associative framework in which suboptimal VD status during the third trimester is accompanied by variations in redox-related markers. Longitudinal and mechanistic studies are needed to clarify the temporal sequence and biological relevance of these associations. Full article
(This article belongs to the Special Issue Obesity, Hormones, and Metabolic Complications in Pregnancy)
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17 pages, 3103 KB  
Article
Multi-Analytical Insight into the Non-Volatile Phytochemical Composition of Coleus aromaticus (Roxb.) Benth.
by Chiara Toniolo, Martina Bortolami, Adriano Patriarca, Daniela De Vita, Fabio Sciubba and Luca Santi
Metabolites 2026, 16(1), 15; https://doi.org/10.3390/metabo16010015 - 23 Dec 2025
Viewed by 696
Abstract
Background/Objectives: Coleus aromaticus (Lamiaceae), also known as Cuban oregano or Indian borage, is a semi-succulent perennial species widely used in traditional medicine for its therapeutic and nutritional properties. While its essential oils and aromatic fraction have been extensively investigated, the characterization of [...] Read more.
Background/Objectives: Coleus aromaticus (Lamiaceae), also known as Cuban oregano or Indian borage, is a semi-succulent perennial species widely used in traditional medicine for its therapeutic and nutritional properties. While its essential oils and aromatic fraction have been extensively investigated, the characterization of its non-volatile metabolites remains limited. The aim of this study was to explore the chemical composition of fresh leaves with a focus on the non-volatile fraction. Methods: Fresh leaves of C. aromaticus were cryogenically treated with liquid nitrogen, ground, and subjected to three different extraction procedures: hydroalcoholic maceration, ethyl acetate maceration, and liquid–liquid partitioning to obtain a dichloromethane organic phase and a hydroalcoholic phase. Extracts and fractions were analyzed by HPTLC and HPLC for metabolic profiling. In addition, the Bligh–Dyer method was applied to separate polar and non-polar metabolites, which were subsequently characterized using NMR spectroscopy. Results: Chromatographic analyses highlighted the occurrence and distribution of organic acids, polyphenols (notably flavonoids), and proteinogenic amino acids. Spectroscopic data confirmed the presence of diverse polar and non-polar metabolites, providing a more detailed chemical fingerprint of C. aromaticus. This integrated approach broadened the phytochemical profile of the species beyond the well-documented essential oils. Conclusions: The results contribute to a better understanding of the non-volatile metabolites of C. aromaticus, offering novel insights into its chemical diversity. These findings highlight the potential of this plant as a valuable source of bioactive compounds, supporting its future application in nutraceutical and pharmaceutical research. Full article
(This article belongs to the Special Issue Advances in Secondary Metabolites: Phytochemical Analysis and Bioactivity Assays—2nd Edition)
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19 pages, 7490 KB  
Article
Bioactive Ingredient Profiling of Dendrobium officinale: Plant-Part-Specific Distribution of Key Metabolites and Their Multi-Disease Therapeutic Potential
by Yue Yang, Yongxin Guan, Shasha Li and Yingchao Xu
Metabolites 2026, 16(1), 10; https://doi.org/10.3390/metabo16010010 - 22 Dec 2025
Cited by 1 | Viewed by 1748
Abstract
Background/Objectives: Dendrobium officinale is a valuable medicinal orchid. However, the metabolic profiles of its leaves and flowers remain poorly characterized. This highlights the need for comprehensive analysis of stems, leaves, and flowers to reveal plant-part-specific bioactive compounds and expand whole-plant utilization. Methods: [...] Read more.
Background/Objectives: Dendrobium officinale is a valuable medicinal orchid. However, the metabolic profiles of its leaves and flowers remain poorly characterized. This highlights the need for comprehensive analysis of stems, leaves, and flowers to reveal plant-part-specific bioactive compounds and expand whole-plant utilization. Methods: An integrative metabolomic approach based on UHPLC–MS/MS was employed to systematically characterize secondary metabolite profiles in different parts of D. officinale, including stems (DOS), leaves (DOL), and flowers (DOF). Results: A total of 761 metabolites, predominantly flavonoids (30.6%), alkaloids (20.2%), phenolic acids (12.2%), and terpenoids (9.3%), were identified. The most abundant metabolites were detected in DOF (634), followed by DOL (598) and DOS (586). Total flavonoid and alkaloid contents were the highest in DOF, reaching 0.86 and 0.62 mg·g−1 DW, respectively. Screening identified 74 key active ingredients (KAI) and 83 active pharmaceutical ingredients (API) and demonstrated potential efficacy against six major human diseases. Among these, gardenoside and phloroglucinol were uniquely present in leaves, whereas 12 KAIs and 16 APIs were specific to DOF. Quercetin, a compound associated with more than 90 disease-related entries, was exclusively detected in DOF. Multivariate analyses revealed clear separation among the three plant parts. Furthermore, 15 metabolites with VIP > 1, including pinobanksin and naringenin, exhibited distinct plant-part-specific accumulation patterns. Additionally, potential plant-part-specific biomarkers were identified. Conclusions: This study presents a comprehensive plant-part-specific metabolomic profile of D. officinale, revealing that its flowers and leaves are particularly enriched in bioactive flavonoids and alkaloids. The findings reveal the remarkable metabolic diversity and functional potential of D. officinale, providing essential chemical insights that support the whole plant’s broader medicinal and biotechnological applications. Full article
(This article belongs to the Section Pharmacology and Drug Metabolism)
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21 pages, 1155 KB  
Systematic Review
Benchtop NMR in Biomedicine: An Updated Literature Overview
by Linda Fantato, Maria Salobehaj, Jacopo Patrussi, Gaia Meoni, Alessia Vignoli and Leonardo Tenori
Metabolites 2026, 16(1), 3; https://doi.org/10.3390/metabo16010003 - 22 Dec 2025
Cited by 1 | Viewed by 1439
Abstract
Background: Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful analytical tool in metabolomics, but it is often hindered by the high cost and technical complexity of the machines, limiting its clinical and point-of-care applications. Recent advances in benchtop NMR technology have sought [...] Read more.
Background: Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful analytical tool in metabolomics, but it is often hindered by the high cost and technical complexity of the machines, limiting its clinical and point-of-care applications. Recent advances in benchtop NMR technology have sought to overcome these barriers by providing more compact, affordable, and user-friendly instruments. This systematic review aims to assess the potential of benchtop NMR in clinical metabolomics, highlighting its practical advantages, current applications, and technological challenges relative to high-field systems. Methods: For this systematic review we searched Web of Science and PubMed databases to identify studies employing benchtop NMR spectroscopy in clinical and biomedical applications. The review focuses on works that evaluated metabolic profiling in human and animal disease contexts, compared benchtop and high-field performance, and utilized advanced data analysis methods, including multivariate and machine learning approaches. Results: Among the 74 records identified, 15 research articles were eligible, including 11 studies involving human biospecimens and 4 studies concerning animal samples. The selected works were published between 2018 and 2025. These studies demonstrated the potential clinical utility of low-field NMR in differentiating disease states such as tuberculosis, type 2 diabetes, neonatal sepsis, and chronic kidney disease, achieving diagnostic accuracies comparable to high-field instruments. Conclusions: Although limited by lower sensitivity and spectral resolution, benchtop NMR represents a significant step toward the democratization of NMR-based metabolomics. Continued hardware development, improved pulse sequences, and the integration of artificial intelligence for spectral processing and modeling are expected to enhance its analytical power and accelerate its clinical adoption. Full article
(This article belongs to the Collection Advances in Metabolomics)
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16 pages, 3473 KB  
Article
Study on Stability of Remifentanil, Sufentanil, and Their Metabolites in Human Whole Blood and Urine
by Zhuoyi Wang, Huan Gao, Yingwen Xu, Di Liang, Xian Ju, Kaili Du, Xiaoxi Mu, Xi Zhang, Ziyang Dong, Tao Wang, Dan Zhang, Zhiwen Wei, Jianguo Li, Keming Yun and Zhe Chen
Metabolites 2025, 15(12), 804; https://doi.org/10.3390/metabo15120804 - 18 Dec 2025
Viewed by 759
Abstract
Background: The accurate detection of remifentanil and sufentanil in biological samples is challenged by their rapid metabolism and instability, complicating clinical and forensic toxicology analysis. This study aimed to evaluate the stability of remifentanil, sufentanil, and their primary metabolites—remifentanil acid and norsufentanil—in human [...] Read more.
Background: The accurate detection of remifentanil and sufentanil in biological samples is challenged by their rapid metabolism and instability, complicating clinical and forensic toxicology analysis. This study aimed to evaluate the stability of remifentanil, sufentanil, and their primary metabolites—remifentanil acid and norsufentanil—in human whole blood and urine. Methods: A high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) method was developed and validated for simultaneous quantification, demonstrating satisfactory linearity (0.10–200 ng/mL, r2 > 0.99), detection limits (0.01–0.20 ng/mL), and recovery rates (85.06–119.42%). Stability was assessed under varying temperatures (4 °C, −20 °C, −80 °C) and anticoagulant conditions (EDTA-K2, sodium heparin, sodium citrate) over 35 days. Results: Remifentanil exhibited significant instability in whole blood, degrading over 50% within 6 h at 4 °C, whereas stability was markedly improved at −80 °C and in sodium citrate-containing samples. Remifentanil acid remained stable for up to 35 days at −80 °C. Sufentanil was generally more stable, particularly at −80 °C in both blood and urine, while norsufentanil remained stable for 7 days at −20 °C in citrate-anticoagulated blood but degraded rapidly at 4 °C. These findings support specific recommendations for sample preservation, including storage at −80 °C and the use of sodium citrate as an anticoagulant, to enhance detection reliability in toxicological and pharmacokinetic studies. Full article
(This article belongs to the Section Pharmacology and Drug Metabolism)
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21 pages, 1189 KB  
Review
Ultra-Processed Foods and Metabolic Dysfunction: A Narrative Review of Dietary Processing, Behavioral Drivers and Chronic Disease Risk
by Tyler J. Godsey, Travis Eden and Sam R. Emerson
Metabolites 2025, 15(12), 784; https://doi.org/10.3390/metabo15120784 - 5 Dec 2025
Cited by 5 | Viewed by 3949
Abstract
Background/Objectives: Ultra-processed foods (UPFs) have become a dominant component of the modern diet, paralleling the rise in obesity and chronic disease prevalence worldwide. This narrative review aims to synthesize evidence on how dietary processing and UPF consumption interacts with dietary quality, energy balance, [...] Read more.
Background/Objectives: Ultra-processed foods (UPFs) have become a dominant component of the modern diet, paralleling the rise in obesity and chronic disease prevalence worldwide. This narrative review aims to synthesize evidence on how dietary processing and UPF consumption interacts with dietary quality, energy balance, and biological pathways to influence metabolic health. Methods: We performed a targeted literature search of peer-reviewed articles and authoritative reports examining UPF definition (via the NOVA classification), global consumption patterns, behavioral drivers of overconsumption, nutrient composition, and mechanistic links to metabolic dysfunction. Emphasis was placed on recent human and animal research relating UPFs to obesity, cardiometabolic outcomes, inflammation and gut microbiome alterations. Results: High UPF intake is consistently associated with reduced diet quality (higher saturated fat, sugar, sodium; lower fiber and micronutrients), increased energy density, faster eating rates and activation of reward pathways. These factors facilitate excessive energy intake and adiposity, promoting metabolic dysregulation, chronic low-grade inflammation, hormonal disturbances and gut microbiome shifts. While cross-sectional and cohort evidence is extensive, causal intervention trials and mechanistic human work remain limited. Conclusions: The accumulated evidence suggests that UPFs may influence chronic disease risk through their unbalanced nutrient profiles and through additional effects introduced by industrial processing. To translate these insights into public health strategies, future work should prioritize real-world intervention studies to reduce UPF consumption and examine resulting effects on energy balance, inflammation and gut health. Full article
(This article belongs to the Special Issue Effects of Nutrition and Exercise on Cardiometabolic Health)
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20 pages, 2742 KB  
Article
Untargeted Metabolomics Reveals Distinct Soil Metabolic Profiles Across Land Management Practices
by Zane A. Vickery, Hector F. Castro, Stephen P. Dearth, Eric D. Tague, Aimée T. Classen, Jessica A. Moore, Michael S. Strickland and Shawn R. Campagna
Metabolites 2025, 15(12), 783; https://doi.org/10.3390/metabo15120783 - 4 Dec 2025
Cited by 1 | Viewed by 1271
Abstract
Background/Objectives: Land management practices strongly influence soil biochemical processes, yet conventional soil measurements often overlook dynamic small-molecule variation underlying nutrient cycling and microbial activity. This study aimed to evaluate whether MS1-based untargeted metabolomics can resolve meaningful biochemical differences among soil systems [...] Read more.
Background/Objectives: Land management practices strongly influence soil biochemical processes, yet conventional soil measurements often overlook dynamic small-molecule variation underlying nutrient cycling and microbial activity. This study aimed to evaluate whether MS1-based untargeted metabolomics can resolve meaningful biochemical differences among soil systems under distinct land management practices. Methods: Soils from six land-use types—conventional cultivation, organic cultivation, pasture, white pine, tulip poplar, and hardwood forest—were analyzed using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). Multivariate analyses, including PLS-DA, were performed to evaluate metabolic variation across systems. Both identified metabolites and unknown spectral features (MSI Level 4) were assessed, and biosynthetic class assignment of unknown features was performed using NPClassifier. Results: Metabolic features revealed clear separation between land management systems, demonstrating distinct chemical fingerprints across ecosystems. While conventional elemental ratios (e.g., C/N) showed minimal differentiation, phosphorus-related stoichiometric ratios (C/P and N/P) displayed strong land-use-dependent differences. NPClassifier superclasses highlighted unique chemical patterns, with forest soils enriched in diverse secondary metabolites, cultivated soils characterized by simplified profiles, and pasture soils dominated by microbial membrane lipids and alkaloids. Conclusions: Untargeted MS1-based metabolomics effectively distinguished soil systems under different land-use practices and revealed ecologically meaningful variation even without complete structural identification. This study demonstrates that an MS1-only workflow leveraging unknown spectral features can robustly distinguish soil systems, underscoring their value in untargeted metabolomics analyses. Full article
(This article belongs to the Section Environmental Metabolomics)
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34 pages, 8371 KB  
Article
Rumen Fluid Metabolomics and Microbiome Profiling of Dairy Cows Fed Combinations of Prebiotics, Essential Oil Blend, and Onion Peel Using the RUSITEC System
by Joel O. Alabi, Ahmed E. Kholif, Kelechi A. Ike, Deborah O. Okedoyin, Oludotun O. Adelusi, Michael Wuaku, Chika C. Anotaenwere, James M. Enikuomehin, Olatunde A. Oderinwale, John O. Adebayo, Andrea R. Gentry-Apple and Uchenna Y. Anele
Metabolites 2025, 15(12), 762; https://doi.org/10.3390/metabo15120762 - 25 Nov 2025
Viewed by 1783
Abstract
Background and Objectives: Dairy products provide vital energy, high-quality protein, and micronutrients for over six billion people worldwide, with dairy cows contributing nearly 81% of global milk production. Sustainable strategies to enhance productivity are therefore critical. Feed additives such as essential oil blends [...] Read more.
Background and Objectives: Dairy products provide vital energy, high-quality protein, and micronutrients for over six billion people worldwide, with dairy cows contributing nearly 81% of global milk production. Sustainable strategies to enhance productivity are therefore critical. Feed additives such as essential oil blends (EOB), onion peel (OPE), and prebiotics including mannan oligosaccharides (MOS) and galacto-oligosaccharides (GOS) have been proposed to improve rumen fermentation, modulate microbial ecology, and mitigate greenhouse gas emissions. This study evaluated the combined effects of EOB, OPE, MOS, and GOS on rumen metabolism using the rumen simulation technique (RUSITEC). Materials and Methods: Rumen inoculum from three cannulated Holstein Friesian cows was incubated across 16 vessels (four treatments × four replicates) for nine days. Treatments included a control (CON; TMR only), GEO (TMR + GOS + EOB + OPE), MEO (TMR + MOS + EOB + OPE), and OLEO (TMR + a 1:1 mixture of GOS and MOS + EOB + OPE). Additives were included at 3 µL/g TMR for EOB and 30 mg/g TMR (3% w/w) for OPE, GOS, MOS, or OLG. Rumen effluents were collected for untargeted metabolomic profiling by liquid chromatography–mass spectrometry, identifying 661 metabolites. Results: Partial least squares-discriminant analysis revealed clear separation between CON and additive groups, confirming distinct metabolic shifts. GEO primarily enhanced tryptophan, tyrosine, and purine metabolism; MEO stimulated phosphonate and pyrimidine pathways and bile acid biosynthesis; OLEO promoted phosphonate, nicotinamide, and taurine metabolism. Microbial analysis showed enrichment of taxa such as Lachnospira, Succinivibrionaceae, Macellibacteroides, Lysinibacillus, and Christensenellaceae, indicating complementary effects on fermentation and microbial stability. Conclusions: These results demonstrate that dietary supplementation with GEO, MEO, or OLEO modulates rumen metabolism and microbial ecology without impairing fermentation, supporting improved nutrient utilization, antioxidant defenses, and metabolic resilience in dairy cows, with potential benefits for productivity and sustainability. Full article
(This article belongs to the Special Issue Dysbiosis and Metabolic Disorders of the Microbiota)
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16 pages, 2826 KB  
Article
Integrative Genomic and Metabolomic Analysis Identifies mQTLs Associated with Genetic Selection for Tenderness in Nellore Cattle
by Joao Marcos Bovetto de Campos Valim, Vinicius Laerte Silva Herreira, Ana Laura dos Santos Munhoz Gôngora, Lauro César Ferreira Beltrão, Eduardo Solano Pina dos Santos, Brenda Santos de Oliveira, Guilherme Pugliesi, Miguel Henrique de Almeida Santana, Guilherme Henrique Gebim Polizel, Luiz Alberto Colnago, Fernanda Maria Marins Ocampos, Germán Dário Ramírez-Zamudio, Saulo Luz Silva and Nara Regina Brandão Cônsolo
Metabolites 2025, 15(12), 760; https://doi.org/10.3390/metabo15120760 - 25 Nov 2025
Viewed by 893
Abstract
Background: Beef tenderness is a key quality attribute that significantly influences consumer satisfaction; however, it exhibits considerable variability due to both genetic and environmental factors. While genomic selection based on Expected Progeny Differences (EPDs) has improved the accuracy of predictions, a substantial portion [...] Read more.
Background: Beef tenderness is a key quality attribute that significantly influences consumer satisfaction; however, it exhibits considerable variability due to both genetic and environmental factors. While genomic selection based on Expected Progeny Differences (EPDs) has improved the accuracy of predictions, a substantial portion of tenderness variability remains unexplained. Metabolomics has emerged as a valuable approach to address this gap, as metabolites reflect gene–environment interactions and may serve as biomarkers for complex traits such as meat tenderness. Objectives: This study aimed to integrate genomic and metabolomic data to identify genetic loci associated with serum metabolites in Nellore calves, offspring of sires with contrasting EPDs for meat tenderness. Methods: Ninety-five male calves were evaluated and divided into two groups according to the sires’ genetic merit: FA-T (favorable EPD for tenderness, n = 45) and UN-T (unfavorable EPD for tenderness, n = 46). Blood serum samples were analyzed by 1H NMR spectroscopy to quantify 40 metabolites, and genotyping was performed using a medium-density SNP panel. Metabolite quantitative trait loci (mQTL) were identified using the MatrixEQTL package, and metabolic enrichment analysis was performed in MetaboAnalyst 6.0. Results: In the FA-T group, SNPs were associated with metabolites such as phenylalanine, tyrosine, and succinate, suggesting enhanced oxidative metabolism and preservation of proteolysis. In the UN-T group, associations of pyruvate, creatinine, and glutamine with distinct SNPs indicated greater reliance on anaerobic glycolysis and early ATP consumption, potentially impairing phosphorylation and postmortem proteolytic activity. Conclusions: These findings suggest that genetic selection for tenderness may induce early divergent metabolic profiles, likely leading to persistent differences in postmortem biochemical pathways, with important implications for meat tenderness. Full article
(This article belongs to the Special Issue Metabolomic Technology in Quality and Safety of Agricultural Products and Foods, 2nd Edition)
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15 pages, 714 KB  
Article
Serum Calprotectin is Associated with Overweight and Laboratory Markers of Glucose Metabolism in Apparently Healthy Young Adults—A Cross-Sectional Descriptive Study
by Katarzyna Bergmann, Anna Stefańska, Magdalena Kuligowska-Prusińska and Magdalena Krintus
Metabolites 2025, 15(12), 756; https://doi.org/10.3390/metabo15120756 - 21 Nov 2025
Cited by 1 | Viewed by 971
Abstract
Background: Recent studies have indicated that serum calprotectin, a marker of inflammation, is associated with obesity and disorders of glucose and lipid metabolism. The aim of this study was to evaluate the relationship between serum calprotectin and cardiometabolic risk factors in presumably [...] Read more.
Background: Recent studies have indicated that serum calprotectin, a marker of inflammation, is associated with obesity and disorders of glucose and lipid metabolism. The aim of this study was to evaluate the relationship between serum calprotectin and cardiometabolic risk factors in presumably healthy young adults. Methods: The study enrolled 118 (61 females, 57 males) non-obese, normoglycemic, subjects aged 25–40 years, selected from the general population among participants of the diabetes preventive screening program in 2014–2015. Basic anthropometric measurements and the following laboratory tests were performed on all participants: glucose, glycated hemoglobin (HbA1c), lipid profile, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), high sensitivity C-reactive protein (hs-CRP), calprotectin and adiponectin. Results: The serum calprotectin concentration was significantly higher in men compared to women (p = 0.016), and in overweight subjects (p < 0.001) and those with abdominal obesity (p < 0.001), compared to lean individuals. Serum calprotectin was positively correlated with body mass index (BMI), waist circumference, HbA1c, hs-CRP, insulin, HOMA-IR and triglycerides, and negatively with HDL-cholesterol and adiponectin. In the univariable logistic regression analysis, overweight (OR = 2.529; p = 0.015), abdominal obesity (OR = 3.217; p = 0.006), hs-CRP > 1 mg/L (OR = 5.00; p < 0.001), HOMA-IR > 2.0 (OR = 4.394; p < 0.001), and HbA1c > 32 mmol/mol (OR = 2.166; p = 0.021) were significant predictors of increased calprotectin concentration (≥540.8 ng/mL; ≥median). However, in models adjusted for sex, BMI and hs-CRP, the significant association remained only for increased HbA1c and HOMA-IR values. Conclusions: Association of serum calprotectin with overweight, hs-CRP and laboratory indicators of glucose metabolism and insulin resistance suggest its significance as a laboratory biomarker of initial metabolic impairment. Full article
(This article belongs to the Special Issue Current Research in Metabolic Syndrome and Cardiometabolic Disorders)
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18 pages, 1086 KB  
Article
FADS1 and FADS2 Gene Polymorphisms Affect Omega-3 and Omega-6 Erythrocyte Fatty Acid Composition and Influence the Association Between Dietary Fatty Acid Intake and Lipid Profile in Brazilian Adults
by Lais Duarte Batista, Marcelo Macedo Rogero, Flávia Mori Sarti, Marcela Larissa Costa, Jaqueline Lopes Pereira França, João Valentini Neto and Regina Mara Fisberg
Metabolites 2025, 15(12), 758; https://doi.org/10.3390/metabo15120758 - 21 Nov 2025
Viewed by 1943
Abstract
Background: Polymorphisms in the FADS1 and FADS2 genes influence fatty acid metabolism. However, evidence of gene–diet interactions in population-based studies from Brazil remains limited. The objective of this study was to examine associations between FADS1–FADS2 single-nucleotide polymorphisms (SNPs) and erythrocyte fatty acid composition [...] Read more.
Background: Polymorphisms in the FADS1 and FADS2 genes influence fatty acid metabolism. However, evidence of gene–diet interactions in population-based studies from Brazil remains limited. The objective of this study was to examine associations between FADS1–FADS2 single-nucleotide polymorphisms (SNPs) and erythrocyte fatty acid composition and serum lipid concentrations, as well as to explore potential gene–diet interactions. Methods: Data were analyzed from 294 adults (20–93 years) enrolled in the 2015 ISA-Nutrition study. Erythrocyte fatty acid composition and serum lipids were measured using standard enzymatic methods. Dietary intake was assessed by 24 h recalls, and participants were classified into tertiles according to fatty acid intake. Five SNPs were genotyped; FADS1 rs174546 and FADS2 rs174570 were prioritized based on linkage disequilibrium. Associations and interactions were assessed using generalized linear models, adjusting for confounders. Results: Carriers of the minor alleles for rs174546 and rs174570 had significantly lower erythrocyte levels of long-chain polyunsaturated fatty acids, particularly along the ω-6 pathway, suggesting reduced desaturase activity. The rs174546 TT genotype was associated with higher total, very-low-density lipoprotein cholesterol (VLDL), and non–high-density lipoprotein (non-HDL) cholesterolconcentrations. Higher dietary intakes of docosahexaenoic acid (DHA) or a higher linoleic acid to alpha-linolenic acid ratio(LA/ALA ratio) among these carriers were linked to lower serum lipid levels, indicating gene–diet interactions that attenuate adverse genotype effects. In addition, rs174570 TT carriers showed elevated VLDL concentrations, with a significant dietary interaction observed with the LA/ALA ratio. Conclusions: FADS1 and FADS2 polymorphisms influence fatty acid metabolism and interact with diet to shape lipid profiles. These findings highlight the importance of considering gene-diet interactions in cardiometabolic risk. Full article
(This article belongs to the Special Issue Role of Lipid Metabolism in Cardiovascular Health)
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16 pages, 3806 KB  
Article
Isolation and Characterization of Two Monoterpene Synthases and a Sesquiterpene Synthase from Asarum heterotropoides
by Jiayi Li, Qianhua Shen, Yongze Zhang, Hanshu Tao, Bingyi Xu, Xiaoyan Min, Haiyang Liu, Na Han and Xin Fang
Metabolites 2025, 15(11), 753; https://doi.org/10.3390/metabo15110753 - 20 Nov 2025
Cited by 1 | Viewed by 1001
Abstract
Background: Asarum heterotropoides, a prominent medicinal plant in China, is well known for producing an abundance of monoterpenes and sesquiterpenes, which constitute the primary components of its essential oil and serve as the principal active compounds of the species. However, the [...] Read more.
Background: Asarum heterotropoides, a prominent medicinal plant in China, is well known for producing an abundance of monoterpenes and sesquiterpenes, which constitute the primary components of its essential oil and serve as the principal active compounds of the species. However, the biosynthetic pathways for these terpenoids remain largely unelucidated. Methods: Gas chromatography–mass spectrometry analysis, in vitro enzyme assay, subcellular localization experiment and molecular docking were used to characterize the function of terpene synthase from A. heterotropoides. Results: In this study, we isolated and characterized two monoterpene synthases and one sesquiterpene synthase from A. heterotropoides. These enzymes exhibit promiscuous activities, accepting geranyl pyrophosphate and farnesyl pyrophosphate as substrates to yield a variety of monoterpene and sesquiterpene products in in vitro enzymatic assays. All three enzymes possess a conserved RRx8W motif, a hallmark typically associated with TPS-b and TPS-d monoterpene synthases involved in cyclic monoterpene formation. However, these two monoterpene synthases yield linear instead of cyclic products. The sesquiterpene synthase (AhTPS3) is a second example of TPS-a terpene synthase harboring such motif. Conclusions: Our findings significantly expand our understanding of terpene biosynthesis, especially the role of RRx8W motif. Full article
(This article belongs to the Special Issue Metabolomics in Plant Natural Products Research, 2nd Edition)
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15 pages, 943 KB  
Article
LC-MS/MS Detection of Tryptophan, Kynurenine, Kynurenic Acid, and Quinolinic Acid in Urine Samples from Drug-Positive and Illicit Drug-Negative Patients with a Known History of Substance Use Disorder
by Lindsey Contella, Christopher L. Farrell, Luigi Boccuto, Alain H. Litwin, Hunter Flanagan, Stacy E. F. Melanson, Nicole V. Tolan, Marion L. Snyder and Dina N. Greene
Metabolites 2025, 15(11), 749; https://doi.org/10.3390/metabo15110749 - 18 Nov 2025
Cited by 5 | Viewed by 1395
Abstract
Introduction: Currently, there are few tools for monitoring recovery in substance use disorder. As substance use has increased in prevalence, tools for measuring recovery are needed to improve therapeutic outcomes. Measuring the kynurenine pathway for imbalances in metabolites could be a possible solution [...] Read more.
Introduction: Currently, there are few tools for monitoring recovery in substance use disorder. As substance use has increased in prevalence, tools for measuring recovery are needed to improve therapeutic outcomes. Measuring the kynurenine pathway for imbalances in metabolites could be a possible solution to monitor recovery. Methods: We developed a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method to quantify tryptophan, kynurenine, kynurenic acid, and quinolinic acid in urine. Metabolites were separated using a stepwise gradient and detected with an Agilent 6460 triple quadrupole mass analyzer. The samples were extracted using a simple protein precipitation protocol. Method validation was performed using routine toxicology urine samples and laboratory contrived samples. The performance characteristics assessed included precision, linearity, stability, interference, and matrix effects. Additionally, urine samples from two cohorts (illicit drug-negative and drug-positive; n = 120 per cohort) were analyzed for significant concentration differences in the four metabolites using Mann–Whitney, PCA, and Area Under the Receiver Operating Characteristic Curve statistical analysis. Results: The LC-MS/MS assay was linear from 195 to 100,000 ng/mL for tryptophan, 6 to 3000 ng/mL for kynurenine, 14 to 7200 ng/mL for kynurenic acid, and 125 to 64,000 ng/mL for quinolinic acid using an 8-point calibration curve. Imprecision ranged from 1.17% to 12.46% CV using two controls that spanned the analytical measurement range. Matrix effects were observed; however, the use of labeled internal standards matching the metabolites of interest minimized the impact on quantification. The extraction recovery efficiency was acceptable for the analytical validation. Ambient stability extended to 10 days, resulting in individual sample biases of up to 22%. A statistically significant increase in TRP, KYN, and QA was observed in drug-positive urine compared to illicit drug-negative urine (p < 0.01). Conclusion: We developed a rapid and sensitive LC-MS/MS method for quantifying tryptophan, kynurenine, kynurenic acid, and quinolinic acid in urine that can aid in future research elucidating the relationship between substance use disorders and tryptophan metabolism. Full article
(This article belongs to the Section Metabolomic Profiling Technology)
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28 pages, 3483 KB  
Review
Metabolomics and Pharmacometabolomics: Advancing Precision Medicine in Drug Discovery and Development
by Eleni V. Stolaki, Konstantina Psatha and Michalis Aivaliotis
Metabolites 2025, 15(11), 750; https://doi.org/10.3390/metabo15110750 - 18 Nov 2025
Cited by 3 | Viewed by 2754
Abstract
Metabolomics and pharmacometabolomics are at the forefront of precision medicine, serving as powerful tools in drug discovery and development. These approaches help address critical challenges in the field, including high clinical trial failure rates, adverse drug reactions, and interindividual variability in drug response. [...] Read more.
Metabolomics and pharmacometabolomics are at the forefront of precision medicine, serving as powerful tools in drug discovery and development. These approaches help address critical challenges in the field, including high clinical trial failure rates, adverse drug reactions, and interindividual variability in drug response. Comprehensive metabolome profiling enables the elucidation of disease mechanisms, identification of drug targets, optimization of therapeutic strategies, and assessment of drug safety and efficacy. It also supports more informed clinical trial design. This review highlights the pivotal role of metabolomics in advancing precision medicine and aims to broaden the perspectives of emerging scientists entering this complex field. Key analytical techniques–namely mass spectrometry and nuclear magnetic resonance spectroscopy–are discussed for their respective strengths and limitations in metabolite identification, quantitation, and structural elucidation. Additionally, analytical separation technologies such as liquid and gas chromatography, ion mobility spectrometry, capillary electrophoresis, and supercritical fluid chromatography are explored for their potential to enhance metabolome coverage, improve analytical efficiency, and reduce costs. Ongoing advancements in instrumentation and computational tools are helping to overcome major challenges in metabolomics, including metabolome complexity, data analysis and integration, and biomarker validation. These developments continue to expand the applications of metabolomics and pharmacometabolomics in both preclinical and clinical research. Ultimately, this review underscores their translational potential in facilitating drug discovery, mitigating risks in clinical trials, and shaping the future of precision medicine. Full article
(This article belongs to the Special Issue Advances in Metabolomics for Precision Medicine: From Biomarker Discovery to Clinical Applications)
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21 pages, 1599 KB  
Review
Personalized Delivery of Probiotics and Prebiotics via 3D Food Printing
by Jiyoung Yu
Metabolites 2025, 15(11), 744; https://doi.org/10.3390/metabo15110744 - 17 Nov 2025
Cited by 7 | Viewed by 2241
Abstract
Personalized nutrition aims to optimize health by addressing interindividual differences in metabolism, microbiota composition, and dietary responses. Modulating the gut microbiota through probiotics, prebiotics, and synbiotics is promising, yet conventional systems such as capsules or fermented foods offer limited control over dosage, release [...] Read more.
Personalized nutrition aims to optimize health by addressing interindividual differences in metabolism, microbiota composition, and dietary responses. Modulating the gut microbiota through probiotics, prebiotics, and synbiotics is promising, yet conventional systems such as capsules or fermented foods offer limited control over dosage, release kinetics, and microbial viability. These formats often cause 2–4 log reductions in viable counts during processing and gastrointestinal transit, underscoring the need for advanced delivery technologies. Three-dimensional (3D) food printing enables digital design of edible matrices with programmable geometry and composition to enhance microbial protection and controlled release. Coaxial and gel-in-gel architectures have retained over 90–96% of probiotic cells after printing and 80–85% after simulated digestion. Synbiotic formulations combining probiotics with fructooligosaccharides or whey protein achieve 98–99% survival and stability for 35 days. This review summarizes advances in formulation, encapsulation, and printing strategies, highlighting how 3D food printing uniquely overcomes challenges of viability, release control, and personalized dosage in microbiota-based nutrition. Full article
(This article belongs to the Special Issue Modulating Gut Microbiota and Host Interactions: The Role of Diet, Probiotics, and Circadian Rhythms)
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67 pages, 2775 KB  
Review
Differentiation of Therapeutic and Illicit Drug Use via Metabolite Profiling
by Stanila Stoeva-Grigorova, Nadezhda Hvarchanova, Silvia Gancheva, Miroslav Eftimov, Kaloyan D. Georgiev and Maya Radeva-Ilieva
Metabolites 2025, 15(11), 745; https://doi.org/10.3390/metabo15110745 - 17 Nov 2025
Cited by 3 | Viewed by 3669
Abstract
Objectives: The therapeutic use of controlled substances, particularly opioids, stimulants, and benzodiazepines, has significantly increased in recent decades. This is often accompanied by non-medical use and diversion, posing challenges for healthcare professionals and forensic experts monitoring potential misuse. As a result, the [...] Read more.
Objectives: The therapeutic use of controlled substances, particularly opioids, stimulants, and benzodiazepines, has significantly increased in recent decades. This is often accompanied by non-medical use and diversion, posing challenges for healthcare professionals and forensic experts monitoring potential misuse. As a result, the blurred boundary between legitimate therapy and substance abuse complicates the interpretation of toxicological results in clinical, legal, and occupational contexts. Methods: This review summarizes recent strategies for distinguishing therapeutic from illicit drug use through the analysis of substances and their metabolites in biological samples using sensitive and specific analytical methods. Results: Traditional drug abuse testing methods, based on parent substance detection, often lack the specificity needed to differentiate therapeutic use from illicit intake. Therefore, advanced analytical methods are required to accurately differentiate the source, route, and adherence to therapy. Therapeutic and illicit forms of the same substance can exhibit distinct metabolic profiles, with certain metabolites serving as biomarkers for illicit drug use. In some cases, chiral analysis may also aid in determining the drug source. Other studies have shown that the ratio of the parent compound to its metabolites (or between different metabolites) may reflect the pattern of use, such as chronic versus acute use or the route of administration. Illicit drugs may also contain synthesis by-products or cutting agents, detectable through advanced techniques. Conclusions: Metabolite profiling offers a robust approach for differentiating therapeutic from illicit drug use and is expected to be increasingly applied in clinical toxicology, forensic investigations, workplace testing, and/or doping control. Full article
(This article belongs to the Special Issue Drug Metabolism: Latest Advances and Prospects)
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50 pages, 3695 KB  
Review
Multiclass Assays for Measuring Environmental Chemical Mixture Exposure: Analytical Methodologies and Applications in Exposomics Research
by Ravikumar Jagani, Jasmin Chovatiya, Divya Pulivarthi, Anil K. Meher, Dhavalkumar Patel, Hiraj Patel, Sandipkumar Teraiya and Syam S. Andra
Metabolites 2025, 15(11), 742; https://doi.org/10.3390/metabo15110742 - 16 Nov 2025
Cited by 3 | Viewed by 1361
Abstract
Background/Objectives: The exposome includes all environmental exposures throughout a lifetime and profoundly influences health and disease, reflecting the totality of environmental chemical exposures throughout an individual’s life, encompassing both natural and anthropogenic chemicals from external sources. Conventional methods for environmental chemical analysis have [...] Read more.
Background/Objectives: The exposome includes all environmental exposures throughout a lifetime and profoundly influences health and disease, reflecting the totality of environmental chemical exposures throughout an individual’s life, encompassing both natural and anthropogenic chemicals from external sources. Conventional methods for environmental chemical analysis have generally concentrated on individual representatives or substance classes; however, single analyte/class techniques are impractical for extensive epidemiological studies that require the analysis of thousands of samples, as anticipated for forthcoming exposome-wide association studies. This narrative review analyzes the evolution and implementation of multiclass assays for measuring ambient chemical exposure, emphasizing analytical techniques that provide the concurrent quantification of various chemical classes. Methods: This narrative review consolidates existing literature on multiclass analytical methodologies for measuring exposure to environmental chemical mixtures, encompassing mass spectrometry platforms, sample preparation techniques, chromatographic separation methods, and validation strategies for thorough exposure assessment in human biomonitoring research. The review includes liquid chromatography–mass spectrometry techniques, solid-phase extraction methods, and data analysis strategies for both targeted and non-targeted study. Results: Multi-class methodologies provide the concurrent quantification of compounds from many classes without the necessity for distinct conventional procedures, thus minimizing time, expense, and sample volume. The robustness of the method indicates appropriate extraction recovery and matrix effects between 60 and 130%, inter-/intra-day precision under 30%, and remarkable sensitivity with detection limits from 0.015 to 50 pg/mL for 60–80% of analytes in the examined human matrices. The methodology facilitates the concurrent identification of the endogenous metabolome, food-associated metabolites, medicines, home chemicals, environmental contaminants, and microbiota derivatives, including over 1000 chemicals and metabolites in total. Conclusions: These thorough analytical methods deliver the requisite performance for extensive exposome-wide association studies, yielding quantitative results and uncovering unforeseen exposures, thereby augmenting our comprehension of the chemical exposome, which is essential for advancing disease prevention in public health and personalized medicine. Full article
(This article belongs to the Special Issue Targeted and Non-Targeted LC- and GC-HRMS Workflows for the Analysis of Emerging Contaminants and the Environmental Exposome)
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11 pages, 344 KB  
Article
Associations of S-Adenosylmethionine and S-Adenosylhomocysteine with Hepatocellular Carcinoma
by Naana N. Yalley, Sebastian M. Armasu, Winnie Z. Fan, Irene K. Yan, Fowsiyo Y. Ahmed, Per Stål, Lewis R. Roberts, Tushar Patel and Samuel O. Antwi
Metabolites 2025, 15(11), 740; https://doi.org/10.3390/metabo15110740 - 13 Nov 2025
Cited by 2 | Viewed by 1402
Abstract
Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, increasingly arising in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Epigenetic dysregulation, particularly DNA methylation, has been implicated in MASLD-HCC development, yet the roles that the principal DNA methylation precursor [...] Read more.
Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, increasingly arising in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Epigenetic dysregulation, particularly DNA methylation, has been implicated in MASLD-HCC development, yet the roles that the principal DNA methylation precursor metabolites, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), play in this association are unclear. Objective: We investigated associations of circulating SAM, SAH, the SAM/SAH ratio, with MASLD-HCC. Methods: In a multi-center pilot case–control study, we evaluated 69 MASLD-HCC cases and 136 cancer-free MASLD controls. Plasma SAM and SAH levels were quantified by liquid chromatography–tandem mass spectrometry. Metabolite levels were categorized as greater than or less than the median based on distribution in controls. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, body mass index, smoking status, and type 2 diabetes. Results: MASLD-HCC cases had significantly higher plasma SAM levels (mean 121 vs. 96 nmol/L; p = 0.001) and SAM/SAH ratios (2.09 vs. 1.48; p = 6.42 × 10−7) than MASLD controls. In multivariable-adjusted models, elevated SAM levels (OR≥median vs. <median = 2.76; 95% CI: 1.38–5.72) and higher SAM/SAH ratio (OR≥median vs. <median = 2.30; 95% CI: 1.15–4.73) were associated with higher odds of MASLD-HCC. SAH alone was associated with MASLD-HCC. Conclusions: Higher plasma SAM levels and SAM/SAH ratios are independently linked to MASLD-HCC development. These metabolites might serve as noninvasive markers for HCC risk stratification in patients with MASLD and improve early detection efforts for MASLD-HCC. Full article
(This article belongs to the Section Cell Metabolism)
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13 pages, 2322 KB  
Article
Gaucher Disease—Correlation of Lyso-Gb1 with Haematology and Biochemical Parameters
by Simona D’Amore, Sneha Patel, Juniebel Cooke and Uma Ramaswami
Metabolites 2025, 15(11), 731; https://doi.org/10.3390/metabo15110731 - 7 Nov 2025
Cited by 2 | Viewed by 1091
Abstract
Background/Objectives: Gaucher disease (GD) is a lysosomal disorder caused by a deficiency of β-glucosidase. Disease-modifying therapies (DMTs) include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Glucosylsphingosine (lyso-Gb1) is a biomarker with high sensitivity and specificity in GD. Methods: In [...] Read more.
Background/Objectives: Gaucher disease (GD) is a lysosomal disorder caused by a deficiency of β-glucosidase. Disease-modifying therapies (DMTs) include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Glucosylsphingosine (lyso-Gb1) is a biomarker with high sensitivity and specificity in GD. Methods: In GD patients attending a specialist centre, we evaluated dried blood spot lyso-Gb1 levels (normal values ≤ 6.8 ng/mL) by treatment status, sex, GD type and genotype, ERT dose, DMT type and duration, spleen status, and association with other GD biomarkers. Results: A total of 111 patients were screened; 100 (54M:46F; 93 GD1 and 7 GD3; median age 45.2 years, IQR 34.2–57.2; 7 naive and 93 patients on DMTs for a median of 10.4 years, IQR 5.7–21.2) had at least one lyso-Gb1 measurement. Median lyso-Gb1 values were higher in naïve (195, IQR 48.6–388) patients than treated patients (47.1, IQR 23.1–89.7), p = 0.015; higher in those treated ≥ 15 years (62.9, IQR 36.6–103) than in those treated < 15 years (35.1, IQR 20.3–73.9), p = 0.006; and higher in splenectomised (83.4, IQR 34.7–224.5) patients than non-splenectomised patients (40.7, IQR 21.4–77.1), p = 0.044. ERT dose > 60 U/kg had high median lyso-Gb1 values (87.3, IQR 19.7–126), reflecting greater disease burden, and this high dose was only used in patients with GD3. Lyso-Gb1 correlated with chitotriosidase (r = 0.495; p < 0.001) and haemoglobin (r = −0.231; p = 0.022). In a subset of 50 patients with paired values, lyso-Gb1 decreased from baseline (median −1.7 ng/mL, IQR −24.5–14.8). Conclusions: Whilst there was a modest decrease in lyso-Gb1 over time on DMTs, the values remained significantly above the normal range, which may be driven by underlying mechanisms such as inflammation. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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14 pages, 1051 KB  
Article
Comprehensive GC/MS Profiling of Volatile Organic Compounds in Whole and Glandular Saliva Using MonoTrap Micro-Extraction
by Asuka Mori, Masae Kuboniwa and Eiichiro Fukusaki
Metabolites 2025, 15(11), 726; https://doi.org/10.3390/metabo15110726 - 6 Nov 2025
Cited by 1 | Viewed by 1182
Abstract
Background/Objectives: Salivary volatile organic compounds (VOCs) are promising noninvasive biomarkers for a wide range of diseases. While glandular saliva, secreted by salivary glands, is a relatively pure biofluid, whole saliva is a complex mixture containing oral microbiota, food debris, and desquamated epithelial cells. [...] Read more.
Background/Objectives: Salivary volatile organic compounds (VOCs) are promising noninvasive biomarkers for a wide range of diseases. While glandular saliva, secreted by salivary glands, is a relatively pure biofluid, whole saliva is a complex mixture containing oral microbiota, food debris, and desquamated epithelial cells. Therefore, a comprehensive comparison of the VOC profiles of these two types of saliva is essential to identify biologically relevant compounds. In this study, we aimed to establish a reliable method for VOC profiling from small saliva volumes and identify VOCs that reflect the biological differences between glandular and whole saliva. Methods: We developed a protocol combining MonoTrap extraction with dichloromethane, allowing the analysis of VOCs from just 100 µL of saliva. To address the issue of sampling-derived artifacts, we implemented a two-step blank analysis to systematically exclude compounds originating from the collection device. Results: Our analysis successfully identified a total of 72 VOCs. Following blank analysis, we systematically excluded 15 artifacts originating from the sampling device. Subsequent orthogonal partial least squares discriminant analysis (OPLS-DA) and Wilcoxon signed-rank test (using variable importance for prediction (VIP) > 1.0 and q < 0.05) identified 10 key VOCs that were significantly higher in whole saliva than in glandular saliva. These compounds included isobutyric acid, isovaleric acid, 4-methylvaleric acid, 3-phenylpropionic acid, indole, skatole, methyl mercaptan, 1-propanol, δ-valerolactam, and acetaldehyde. Most of these compounds originate from the metabolic activities of the oral microbiome, suggesting that the distinct VOC profile of whole saliva is predominantly influenced by microbial activity. Conclusions: Our findings demonstrated the effectiveness of this method for identifying biologically relevant VOCs from relatively small sample volumes. The identified VOC profiles highlight the contribution to the discovery of non-invasive biomarkers for oral health and serve as a solid foundation for future research into clinical applications. Full article
(This article belongs to the Section Advances in Metabolomics)
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19 pages, 3542 KB  
Article
Regional Variation in Mulberry Leaf Metabolites: A Combined Metabolomic and Environmental Analysis of Biosynthetic Drivers
by Yao Zhou, Meiqi Li, Jinpeng Zhao, Lixia Yang, Fengxia Li, Jingtian Xu, Jingtian Chen, Yinyin Chen, Dongbei Xu, Dongju Feng, Wei Wu and Kai Hou
Metabolites 2025, 15(11), 728; https://doi.org/10.3390/metabo15110728 - 6 Nov 2025
Cited by 3 | Viewed by 1116
Abstract
Background: Morus alba L. (family Moraceae) is widely cultivated across the world and is well-known for its medicinal and nutritional value, especially its leaves. This study investigates the regional variation in mulberry leaf metabolites, focusing on alkaloids and flavonoids, and explores the [...] Read more.
Background: Morus alba L. (family Moraceae) is widely cultivated across the world and is well-known for its medicinal and nutritional value, especially its leaves. This study investigates the regional variation in mulberry leaf metabolites, focusing on alkaloids and flavonoids, and explores the influence of climatic and environmental factors on their biosynthesis using an integrated metabolomic and environmental analysis. Mulberry leaves, known for their medicinal and nutritional value, were collected from six regions across China, including Sichuan, Xinjiang, and Tibet. Methods: Untargeted metabolomics via UHPLC-MS was conducted. Differential metabolites were identified through multivariate analysis and annotated using the KEGG database. Redundancy analysis was used to link metabolite profiles with climatic data. Results: Mulberry leaves from six Chinese regions showed significant variation in total flavonoid content (TFC), total polyphenol content (TPC), and 1-Deoxynojirmycin (DNJ), with Tibet having the highest TFC and TPC, and Panzhihua the highest DNJ. Metabolomic analysis identified 3794 metabolites, revealing distinct regional clustering. A total of 79 differential metabolites were identified, which are enriched in pathways such as galactose metabolism and phenylalanine biosynthesis. Environmental factors, especially bio3, bio10, bio2, bio5, and bio20, strongly influenced metabolite profiles. Conclusions: The biosynthesis and accumulation of secondary metabolites in mulberry leaves are significantly influenced by region-specific environmental factors, particularly temperature, precipitation, and light. The identified differential metabolites are mainly enriched in galactose metabolism, arginine, and proline metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis. These pathways are closely associated with plant stress responses and the synthesis of secondary metabolites. The pronounced regional differences in metabolite profiles underscore the critical role of environmental factors in determining the chemical composition of mulberry leaves. This research provides valuable insights into the influence of climatic factors affecting the chemical composition of plants. It lays a theoretical foundation for the quality assessment and grading of mulberry leaves, providing scientific guidance for their targeted cultivation and utilization. Full article
(This article belongs to the Section Plant Metabolism)
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25 pages, 6660 KB  
Article
Delivery and Metabolic Fate of Doxorubicin and Betulin Nanoformulations In Vivo: A Metabolomics Approach
by Mihai Adrian Socaciu, Remus Moldovan, Carmen Socaciu, Flaviu Alexandru Tăbăran and Simona Clichici
Metabolites 2025, 15(11), 723; https://doi.org/10.3390/metabo15110723 - 5 Nov 2025
Viewed by 888
Abstract
Background: Betulins (betulin, betulinic acid and lupeol) demonstrated antitumor and chemopreventive activity but showed low bioavailability due to their self-aggregation in hydrophilic environments. To overcome these disadvantages, their incorporation into lipid nanoformulations (PEGylated liposomes and Lipid Nanostructured Carriers (NLCs)) has proven to [...] Read more.
Background: Betulins (betulin, betulinic acid and lupeol) demonstrated antitumor and chemopreventive activity but showed low bioavailability due to their self-aggregation in hydrophilic environments. To overcome these disadvantages, their incorporation into lipid nanoformulations (PEGylated liposomes and Lipid Nanostructured Carriers (NLCs)) has proven to represent a viable solution. Objectives: The purpose of this study is to evaluate the size and incorporation rate of these molecules in nanoformulations, as well as their delivery and metabolic fate (pure betulinic acid versus a standardized extract, TT) relative to Doxorubicin using an in vivo protocol. The investigation extended our previous in vitro investigations towards an in vivo evaluation of antitumor activity, metabolic fate and toxicity in Wistar rats bearing Walker 256 carcinoma tumors over 21 days. Since previous studies used oral or intratumor administration, this exploratory study applied intravenous administration via microbubble-assisted sonoporation, considering its higher relevance for translational studies. Methods: The delivery and metabolic fate of the parent molecules, the identification of their fragments and metabolites using UHPLC-QTOF-ESI+MS were investigated, along with the identification of some toxicity biomarkers in rat plasma, tumor tissues and urine. Results: Preferential accumulation of Doxorubicin in tumors was observed compared to betulinic acid and TT components, as well as their persistence in plasma or elimination in urine. Compared to PEGylated liposomes, NLC formulations (especially NLC Doxo) induced a lower survival rate, a decreased bioavailability and increased toxicity by around 20%. Conclusions: These data are a starting point and complement the contrast-enhanced imaging and histology evaluations, which may contribute to the actual knowledge about the in vivo fate of betulins. Full article
(This article belongs to the Special Issue Drug Metabolism, Interactions and Toxicity: Advances in Metabolomics Approaches)
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30 pages, 3344 KB  
Article
From Micronutrients to Potentially Toxic Elements: Physiological Responses of Canavalia ensiformis to Copper and Iron
by Nayane Cristina Pires Bomfim, Tassia Caroline Ferreira, Jailson Vieira Aguilar, Maiara Luzia Grigoli Olivio, Beatriz Silvério dos Santos, Isabella Fiorini Carvalho, Aline Renee Coscione, Lucas Anjos Souza and Liliane Santos Camargos
Metabolites 2025, 15(11), 706; https://doi.org/10.3390/metabo15110706 - 29 Oct 2025
Cited by 1 | Viewed by 1050
Abstract
Background: The increase in potentially toxic elements (PTEs) in the soil is worrying, especially in agricultural soils due to the bioaccumulation factor. Copper (Cu) and iron (Fe) are micronutrients, responsible for important functions in the plant body, but the high availability of [...] Read more.
Background: The increase in potentially toxic elements (PTEs) in the soil is worrying, especially in agricultural soils due to the bioaccumulation factor. Copper (Cu) and iron (Fe) are micronutrients, responsible for important functions in the plant body, but the high availability of these elements in the soil can cause soil contamination and toxicity in plants; consequently, they can be considered PTEs. Objectives: The focus of this study is to understand the physiological responses (pigments, gas exchange, growth, biomass, accumulation) of Canavalia ensiformis to high levels of Cu and Fe in the soil, in isolation, and to identify which PTE is most harmful to its development. Methods: Two experiments (Cu and Fe) were conducted simultaneously in a greenhouse. Treatments of 50, 150, 250, and 350 mg dm−3 of soil for each element (CuSO4*5H2O and FeSO4*7H2O) were incorporated into the soil (Oxisol) of each experimental unit (4 dm3 pot), in addition to the control. C. ensiformis seeds were sown directly in soil enriched with Cu and Fe, respectively, and after emergence they were cultivated for 90 days. Results: Changes in chlorophyll levels caused direct effects on gas exchange, shoot biomass, root development, nodulation, and total plant biomass. The tolerance of the species is dependent on chlorophyll levels and gas exchange. There was accumulation of both PTEs in the roots and low translocation to the shoot. Conclusions: The plants were tolerant to Fe treatments; however, they were not tolerant to Cu treatments (T150–T350). Excess Cu was more detrimental to plant development. Full article
(This article belongs to the Section Plant Metabolism)
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16 pages, 1706 KB  
Article
Metabolomics Analysis Uncovers Distinct Profiles of Liver Post-Transplant Patients by Immunosuppression Regimen
by Cristina Baciu, Bima J. Hasjim, Saba Maleki, Elisa Pasini, Meera Kennedybhai Patel, Maryam Shojaee, Amirhossein Azhie, Giovanna Saracino, Sumeet K. Asrani and Mamatha Bhat
Metabolites 2025, 15(11), 700; https://doi.org/10.3390/metabo15110700 - 29 Oct 2025
Viewed by 1089
Abstract
Background/Objectives: Long-term survival among liver transplant (LT) recipients who live beyond one year has remained relatively stable over recent decades. However, reducing long-term morbidity is increasingly important, and metabolomics may enable risk-based, personalized immunosuppression. We aimed to evaluate and compare the serum metabolomic [...] Read more.
Background/Objectives: Long-term survival among liver transplant (LT) recipients who live beyond one year has remained relatively stable over recent decades. However, reducing long-term morbidity is increasingly important, and metabolomics may enable risk-based, personalized immunosuppression. We aimed to evaluate and compare the serum metabolomic profiles of LT recipients treated with tacrolimus (TAC) versus sirolimus (SIR), to elucidate metabolic pathways associated with these regimens. Methods: Targeted metabolomic profiling of 894 metabolites was conducted on serum samples from 128 LT recipients using the Biocrates MxP® Quant 500 kit. Data were analyzed with MetaboAnalyst 6.0, and multivariate analysis was performed using Partial Least Squares-Discriminant Analysis (PLS-DA). Metabolites with Variable Importance in Projection (VIP) scores > 1.5 underwent pathway enrichment in OmicsNet, incorporating Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG)-based network analysis. Results: Eighty-seven metabolites were significantly altered between groups. Phosphatidylcholines (PCs) and ceramides were elevated in TAC-treated patients, while di- and triacylglycerols were higher in the SIR group. Pathway enrichment implicated lipid metabolism, particularly glycerophospholipid, ether lipid, and sphingolipid pathways. Network analysis identified enriched modules related to metabolic regulation and immune response. Conclusions: Divergent metabolomic profiles distinguish TAC- and SIR-treated recipients, suggesting regimen-specific impacts on lipid metabolism with potential relevance to post-transplant complications. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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18 pages, 2599 KB  
Article
Rapid FTIR Spectral Fingerprinting of Kidney Allograft Perfusion Fluids Distinguishes DCD from DBD Donors: A Pilot Machine Learning Study
by Luis Ramalhete, Rúben Araújo, Miguel Bigotte Vieira, Emanuel Vigia, Ana Pena, Sofia Carrelha, Anibal Ferreira and Cecília R. C. Calado
Metabolites 2025, 15(11), 702; https://doi.org/10.3390/metabo15110702 - 29 Oct 2025
Cited by 2 | Viewed by 896
Abstract
Background/Objectives: Rapid, objective phenotyping of donor kidneys is needed to support peri-implant decisions. Label-free Fourier-transform infrared (FTIR) spectroscopy of static cold-storage Celsior® perfusion fluid can discriminate kidneys recovered from donation after circulatory death (DCD) versus donation after brain death (DBD). Methods: Preservation [...] Read more.
Background/Objectives: Rapid, objective phenotyping of donor kidneys is needed to support peri-implant decisions. Label-free Fourier-transform infrared (FTIR) spectroscopy of static cold-storage Celsior® perfusion fluid can discriminate kidneys recovered from donation after circulatory death (DCD) versus donation after brain death (DBD). Methods: Preservation solution from isolated kidney allografts (n = 10; 5 DCD/5 DBD) matched on demographics was analyzed in the Amide I and fingerprint regions. Several spectral preprocessing steps were applied, and feature extraction was based on the Fast Correlation-Based Filter. Support vector machines and Naïve Bayes were evaluated. Unsupervised structure was assessed based on cosine distance, multidimensional scaling, and hierarchical clustering. Two-dimensional correlation spectroscopy (2D-COS) was used to examine band co-variation. Results: Donor cohorts were well balanced, except for higher terminal serum creatinine in DCD. Quality metrics were comparable, indicating no systematic technical bias. In Amide I, derivatives improved classification, but performance remained modest (e.g., second derivative with feature selection yielded an area under the curve (AUC) of 0.88 and an accuracy of 0.90 for support vector machines; Naïve Bayes reached an AUC of 0.92 with an accuracy of 0.70). The fingerprint window was most informative. Naïve Bayes with second derivative plus feature selection identified bands at ~1202, ~1203, ~1342, and ~1413 cm−1 and achieved an AUC of 1.00 and an accuracy of 1.00. Unsupervised analyses showed coherent grouping in the fingerprint region, and 2D correlation maps indicated coordinated multi-band changes. Conclusions: Performance in this 10-sample pilot should be interpreted cautiously, as perfect leave-one-out cross-validation (LOOCV) estimates are vulnerable to overfitting. The findings are preliminary and hypothesis-generating, and they require confirmation in larger, multicenter cohorts with a pre-registered analysis pipeline and external validation. Full article
(This article belongs to the Special Issue Novel Approaches for Metabolomics in Drugs and Biomarkers Discovery: 2nd Edition)
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17 pages, 1032 KB  
Review
Endothelial Arginine Metabolism in Angiogenesis: Mechanistic Insights from Tissue Repair to Tumor Progression
by Cristina Arce-Recatala and Roxana Elena Oberkersch
Metabolites 2025, 15(11), 694; https://doi.org/10.3390/metabo15110694 - 25 Oct 2025
Cited by 3 | Viewed by 1717
Abstract
Angiogenesis, the process of forming new blood vessels from pre-existing vasculature, is essential both during development and in adulthood under physiological and pathological conditions. Therefore, understanding the molecular mechanisms that control angiogenesis has far-reaching implications in developmental biology and the treatment of human [...] Read more.
Angiogenesis, the process of forming new blood vessels from pre-existing vasculature, is essential both during development and in adulthood under physiological and pathological conditions. Therefore, understanding the molecular mechanisms that control angiogenesis has far-reaching implications in developmental biology and the treatment of human diseases. In this context, amino acid metabolism has emerged as a key driver of blood vessel formation. While the role of L-arginine (L-arg) in the cardiovascular system has been extensively described, whether L-arg could serve as a potential metabolite to target during tumor angiogenesis or be exploited to promote tissue regeneration remains unclear. Here, we will describe L-arg metabolism in the vascular context and its crosstalk with angiogenic metabolic pathways. We will also review the main findings regarding the role of L-arg in tissue regeneration and tumor progression, situating L-arg at the center of the discussion on regenerative and preventive vascular medicine. Full article
(This article belongs to the Special Issue Amino Acid Metabolism in Angiogenesis)
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20 pages, 8426 KB  
Article
Metabolomic Profile of Weight Gain of People Living with HIV Treated with Integrase Strand Transfer Inhibitor Regimens Reveals Dysregulated Lipid Metabolism and Mitochondrial Dysfunction
by Ana Miriam Ascencio-Anastacio, Violeta Larios-Serrato, José Antonio Mata-Marín, Mara Rodríguez Evaristo, Mireya Núñez-Armendáriz, Ana Luz Cano-Díaz, Alberto Chaparro-Sánchez, Gloria Elizabeth Salinas-Velázquez, Angélica Maldonado-Rodríguez, Javier Torres, María Martha García-Flores, Zuriel Eduardo Martínez-Valencia, Beatriz Irene Arroyo-Sánchez, Viridiana Olin-Sandoval, Fernando Minauro, Jesus Enrique Gaytán-Martínez and Ericka Nelly Pompa-Mera
Metabolites 2025, 15(11), 695; https://doi.org/10.3390/metabo15110695 - 25 Oct 2025
Cited by 2 | Viewed by 2534
Abstract
Background/Objectives: Excessive weight gain is a growing concern among people living with HIV (PWH) receiving integrase strand transfer inhibitor (INSTI)-based regimens as first-line antiretroviral therapy (ART), as it may contribute to multimorbidity. The mechanisms driving weight gain in INSTI users are not [...] Read more.
Background/Objectives: Excessive weight gain is a growing concern among people living with HIV (PWH) receiving integrase strand transfer inhibitor (INSTI)-based regimens as first-line antiretroviral therapy (ART), as it may contribute to multimorbidity. The mechanisms driving weight gain in INSTI users are not fully understood but are thought to be multifactorial. This study examines the plasma metabolome associated with weight gain in PWH on INSTI-based regimens. Methods: We conducted a nested case–control study within the randomized clinical trial MICTLAN (NCT06629480). Sixty-six participants were randomized to receive INSTI-based regimens, either bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) or dolutegravir/abacavir/lamivudine (DTG/ABC/3TC), and followed for 18 months. Weight gain >10% relative to baseline was considered a primary endpoint and used as a criterium to categorize cases (n = 28) and controls (n = 38). Anthropometric and clinical measurements, plasma insulin, and metabolomic profiles were assessed at baseline and 18 months post-ART. Plasma untargeted metabolomics was performed using liquid chromatography–mass spectrometry (LC-MS/MS) to identify metabolomic changes linked to weight gain. Bioinformatic tools, including Partial Least Squares Discriminant Analysis (PLS-DA), volcano plots, and KEGG pathway enrichment analysis, were used to analyze plasma metabolomes and identify significant differential metabolites. Results: Weight gain at 18 months in PWH on INSTI-based ART was associated with insulin resistance, as measured by HOMA-IR (OR 3.23; 95% CI 1.14–9.10; p = 0.023), and visceral adipose tissue thickness > 4 cm (OR 4.50; 95% CI 1.60–13.03; 9.10; p = 0.004), and hypertriglyceridemia (OR 3.9; 95% CI 1.38–10.94; p = 0.008). Baseline HIV RNA viral load >50,000 copies/mL (OR 8.05; 95% CI 2.65–24.43; p = 0.0002) was identified as a baseline predictor of weight gain (aOR 6.58 (1.83–23.58); p = 0.004). In addition, accumulation of circulating medium-chain acylcarnitines, indicative of mitochondrial dysfunction, and insulin resistance were linked to weight gain in PWH on INSTI-based regimens after 18 months of therapy. Conclusions: This metabolomic study identified metabolites reflecting mitochondrial dysfunction, dysregulated lipid metabolism, and altered amino acid metabolism as key mechanisms underlying insulin resistance and weight gain in PWH on INSTI-based ART. Full article
(This article belongs to the Special Issue Lipid Metabolism Dysregulation in Metabolic Disorders: Unraveling the Molecular Complexity)
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18 pages, 2322 KB  
Article
Iron Stress Reprograms Enterocyte Metabolism
by Shya E. Navazesh and Peng Ji
Metabolites 2025, 15(11), 691; https://doi.org/10.3390/metabo15110691 - 24 Oct 2025
Cited by 2 | Viewed by 1242
Abstract
Objectives: This study utilized IPEC-J2, a neonatal pig jejunum-derived cell line, to assess how iron deficiency (ID) and excess (IE) alter enterocyte metabolism and the transcription of inflammatory markers. Methods: Cells were treated with deferiprone (DFP) or ferric ammonium citrate (FAC) [...] Read more.
Objectives: This study utilized IPEC-J2, a neonatal pig jejunum-derived cell line, to assess how iron deficiency (ID) and excess (IE) alter enterocyte metabolism and the transcription of inflammatory markers. Methods: Cells were treated with deferiprone (DFP) or ferric ammonium citrate (FAC) to induce ID or IE, respectively. The study evaluated: (1) transcriptional changes in iron-regulatory genes over 96 h under ID or IE; (2) the interaction between iron imbalance and lipopolysaccharide (LPS) exposure on mRNA expression of inflammation markers and iron transporters; and (3) cellular metabolic responses to ID, IE, and iron repletion using untargeted metabolomics. Results: ID triggered dynamic transcriptional changes in iron regulatory genes and suppressed cellular proliferation via impaired DNA replication. IE resulted in a persistent reduction in TFRC expression. LPS increased CYBRD1 (p < 0.001) and IL8 (p = 0.004) and tended to elevate TLR4 and TNF expression (p ≤ 0.07), while iron deficiency upregulated IL8 expression (p < 0.001). ID disrupted the TCA cycle, reduced glucuronic acid synthesis, and elevated glycolysis for energy production, whereas IE increased cholesterol biosynthesis and decreased alpha-tocopherol levels. Repletion of iron partially reversed ID-induced metabolic changes. Conclusions: ID impaired enterocyte proliferation and profoundly disrupted cellular metabolism, whereas IE enhanced cholesterol synthesis and depleted alpha-tocopherol levels. Restoration of cellular metabolism following iron repletion was observed, highlighting the resilience of enterocytes. Full article
(This article belongs to the Section Cell Metabolism)
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12 pages, 752 KB  
Article
Metabolomic Signatures of MASLD Identified by the Fatty Liver Index Reveal Gamma-Glutamyl Cycle Disruption and Lipid Remodeling
by Khaled Naja, Najeha Anwardeen and Mohamed A. Elrayess
Metabolites 2025, 15(11), 687; https://doi.org/10.3390/metabo15110687 - 23 Oct 2025
Cited by 2 | Viewed by 1472
Abstract
Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder worldwide and a key driver of cardiometabolic complications. Despite its growing burden, the underlying metabolic perturbations remain incompletely understood. The Fatty Liver Index (FLI) provides a validated non-invasive tool [...] Read more.
Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder worldwide and a key driver of cardiometabolic complications. Despite its growing burden, the underlying metabolic perturbations remain incompletely understood. The Fatty Liver Index (FLI) provides a validated non-invasive tool for stratifying MASLD in large-scale and clinical studies. Methods: This study utilized data from the Qatar Biobank, applying strict exclusion criteria and propensity score matching, to select 110 adults stratified by FLI into the MASLD group (≥60, n = 55) and the control group (<30, n = 55) with balanced age, sex, and BMI. Untargeted serum metabolomics was performed. Differential metabolite profiles were identified using linear regression adjusted for covariates and validated by multivariate modeling. Functional enrichment analyses were conducted to highlight perturbed metabolic pathways. Results: Metabolomic profiling revealed distinct metabolic signatures: the MASLD group was characterized by elevated glutamate and phospholipids, while the control group showed enrichment of gamma-glutamyl amino acids, plasmalogens, and sphingomyelins. Conclusions: This contrasting pattern reflects disruption of the gamma-glutamyl cycle and consistent depletion of antioxidant plasmalogen species, suggesting impaired redox homeostasis and lipid remodeling as hallmarks of MASLD pathogenesis. These findings provide a foundation for future research into targeted metabolic biomarkers and therapeutic strategies. Longitudinal and mechanistic studies are warranted to determine causal relationships and clinical utility. Full article
(This article belongs to the Special Issue Metabolomics and Lipidomics in MASLD and Related Liver Disorders)
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20 pages, 5998 KB  
Article
Land Use Shapes the Rhizosphere Microbiome and Metabolome of Naturally Growing Barbarea vulgaris
by Emoke Dalma Kovacs and Melinda Haydee Kovacs
Metabolites 2025, 15(11), 684; https://doi.org/10.3390/metabo15110684 - 22 Oct 2025
Cited by 1 | Viewed by 1176
Abstract
Background: Land use change fundamentally alters soil microbial communities and biochemical processes, yet the integrated effects on rhizosphere microbiome–metabolome networks remained poorly understood. Objective: This study investigated land uses as forest, grassland and intermediary edge shape the rhizosphere biochemical networks of naturally grown [...] Read more.
Background: Land use change fundamentally alters soil microbial communities and biochemical processes, yet the integrated effects on rhizosphere microbiome–metabolome networks remained poorly understood. Objective: This study investigated land uses as forest, grassland and intermediary edge shape the rhizosphere biochemical networks of naturally grown Barbarea vulgaris. Methods: Rhizosphere soils of Barbarea vulgaris were analysed for microbial community structure abundance, and metabolomic profile applying phospholipid fatty acid (PLFA) profiling and mass spectrometric untargeted metabolomics (GC–MS/MS and MALDI–TOF/TOF MS). These were coupled with co–inertia analysis to assess microbiome–metabolome interactions. Results: Microbial community analysis revealed significant effects of land use on bacterial community structure (G+/G−, p < 0.001). Untargeted metabolomics identified 248 metabolites, of which 161 were mapped to KEGG pathways. Amino acids and derivatives (21.1%) followed by organic acids (16.8%) were the most representative among identified metabolites. Pathway enrichment analysis revealed coordinated reprogramming of central carbon and nitrogen metabolism across land use gradients, particularly in the amino acid metabolism, TCA cycle, and glycolysis/gluconeogenesis pathways. Microbiome–metabolome coupling analysis revealed distinct correlation patterns between microbial phenotypes and metabolite classes, with forest environments showing the strongest biochemical network integration (RV = 0.91). Edge habitats presented intermediate signatures, supporting their role as transitional zones with unique biochemical properties. Conclusions: The environmental context fundamentally shapes rhizosphere biochemical network organization through coordinated shifts in bacterial community structure and metabolic pathway activity. These habitat-specific metabolic signatures suggest that land use change triggers adaptive biochemical responses that may influence plant performance and ecosystem functioning across environmental gradients. Full article
(This article belongs to the Special Issue Advanced Metabolic Profiling via Gas Chromatography–Mass Spectrometry and Liquid Chromatography–Mass Spectrometry)
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