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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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24 pages, 4186 KB  
Article
Seed Metabolomic Landscape Reflecting Key Differential Metabolic Profiles Among Different Wheat Cultivars
by Kgalaletso Othibeng, Lerato Nephali and Fidele Tugizimana
Metabolites 2025, 15(9), 603; https://doi.org/10.3390/metabo15090603 - 10 Sep 2025
Viewed by 619
Abstract
Background: Adverse environmental conditions and an ever-increasing world population require devising and designing a roadmap for the next generation of wheat crops for high productivity and resilience to climate change. As such, a fundamental understanding of wheat metabolism and molecular descriptors of [...] Read more.
Background: Adverse environmental conditions and an ever-increasing world population require devising and designing a roadmap for the next generation of wheat crops for high productivity and resilience to climate change. As such, a fundamental understanding of wheat metabolism and molecular descriptors of wheat seed potentials and quality is a sine qua non step. Objectives: In this study we investigated the seed metabolomes of five wheat cultivars to identify differential metabolic profiles and cultivar-related metabolic markers. Methods: Liquid chromatography-mass spectrometry (LC-MS) combined with computational strategies and functional analyses was applied. Metabolites were extracted using methanol, and samples were analysed on an LC-MS/MS system. Results: The results revealed that the extracted wheat cultivar seed metabolomes spanned a broad range of metabolite classes, including alkaloids, sugars, phenolics, amino acids, hormones, TCA compounds and lipids. Furthermore, the results also revealed key metabolic markers differentiating the wheat cultivars from one another, such as lipids (i.e., MGMG and 13-HODE) and flavonoids (i.e., rutin, tricin and vitexin), amongst many others. Conclusions: Such insights are important in assessing seed quality as well as in the selection of markers for seed nutrient and quality trait improvement in wheat breeding programmes. As such, this work generates novel actionable knowledge, a comprehensive metabolomic landscape of wheat seeds and potential markers for cultivar differentiation and quality assessment, which is essential for sustainable and improved wheat production. Thus, the study contributes towards the realisation of sustainable food security, an urgent call for action in a global partnership, as articulated in the United Nations Sustainable Development Goals, particularly zero hunger. Full article
(This article belongs to the Section Plant Metabolism)
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22 pages, 2656 KB  
Article
Dietary Intervention with Cottonseed and Olive Oil Differentially Affect the Circulating Lipidome and Immunoregulatory Compounds—A Randomized Clinical Trial
by Gwendolyn Cooper, Prabina Bhattarai, Brett Sather, Marguerite L. Bailey, Morgan Chamberlin, Mary Miles and Brian Bothner
Metabolites 2025, 15(9), 599; https://doi.org/10.3390/metabo15090599 - 8 Sep 2025
Viewed by 340
Abstract
Background/Objectives: Cottonseed oil (CSO) is a dietary oil especially high in the n-6 polyunsaturated fatty acid (PUFA), linoleic acid (FA 18:2), which is a precursor for many pro-inflammatory eicosanoids. Curiously, diets rich in CSO have not been shown to cause increases in [...] Read more.
Background/Objectives: Cottonseed oil (CSO) is a dietary oil especially high in the n-6 polyunsaturated fatty acid (PUFA), linoleic acid (FA 18:2), which is a precursor for many pro-inflammatory eicosanoids. Curiously, diets rich in CSO have not been shown to cause increases in inflammatory markers or other negative health outcomes in humans. To rigorously test this, we have compared the health impact of a diet rich in CSO to olive oil (OO), which is generally considered to be a healthy oil. Methods: Specifically, this study examines circulating metabolite and lipid profiles during a 4-week dietary intervention with CSO or OO on 47 healthy adults. Untargeted metabolomics, targeted bulk lipidomics, and targeted lipid mediator analyses were conducted on fasting plasma samples taken pre- and post-dietary intervention. Results: A high degree of similarity was observed in the global metabolomic profiles of CSO and OO participants, indicating that CSO may elicit metabolic responses comparable to those of OO, potentially supporting similar effects on metabolic health markers. Targeted bulk lipidomics revealed changes in acyl chain composition reflective of the dominant fatty acid consumed—either 18:2 in CSO or 18:1 in OO. Immunoregulatory lipids 15-deoxy-PGJ2 and prostaglandin F2 alpha (PGF2a) were both higher in abundance in high-CSO diets, demonstrating differential effects of CSO and OO on immunoregulatory compounds. A correlative network analysis revealed two clusters arising from the dietary intervention as drivers of the dietary and immune responses. Conclusions: This study shows that CSO and OO differentially impact the circulating lipidome and immunoregulatory compounds in healthy adults. Full article
(This article belongs to the Special Issue Advances in Food Metabolomics for Functional Food Development and Analysis)
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18 pages, 2326 KB  
Article
Methods for Untargeted Analysis of Milk Metabolites: Influence of Extraction Method and Optimization of Separation
by Daisy Wilkie, Brad White, Golnaz Heidari, Rafea Naffa, Gaile Peddie, Gareth J. Rowlands and Paul G. Plieger
Metabolites 2025, 15(9), 597; https://doi.org/10.3390/metabo15090597 - 8 Sep 2025
Viewed by 325
Abstract
Background/Objectives: Cow’s milk is a complex food, and research into its metabolome can provide information useful in the study of animal health, farming practices, food safety and the adulteration of milk. Comparative interlaboratory metabolic analysis is hampered by the lack of standardized methods—a [...] Read more.
Background/Objectives: Cow’s milk is a complex food, and research into its metabolome can provide information useful in the study of animal health, farming practices, food safety and the adulteration of milk. Comparative interlaboratory metabolic analysis is hampered by the lack of standardized methods—a requirement addressed in this study. Methods: We studied the influence of the chromatography column and extraction solvent on the metabolites isolated during untargeted metabolomics. Results: After studying fifteen columns and four extraction solvents, it was determined that an HILIC column offered the best compromise between retention time and separation of metabolites. Each extraction solvent covered a different area of the metabolome, only overlapping with previously annotated compounds. Extraction mixtures containing methanol tend to give better recovery. Conclusions: The choice of extraction solvent was crucial when looking at the difference between samples, but if interest lies only in previously annotated compounds, then there is little difference between the solvents. Full article
(This article belongs to the Section Food Metabolomics)
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40 pages, 14652 KB  
Article
Ecballium elaterium (L.) A. Rich. (Squirting Cucumber) Plants Cultured Under Different Temperatures: Anatomical and Biochemical Modifications of Their Leaves and the Bioactivity of Leaf Extracts
by Aikaterina L. Stefi, Maria Chalkiadaki, Emily Bashari, Konstantina Mitsigiorgi, Paweł Szczeblewski, Danae Papageorgiou, Dimitrios Gkikas, Dido Vassilacopoulou, Nikolaos S. Christodoulakis and Maria Halabalaki
Metabolites 2025, 15(9), 585; https://doi.org/10.3390/metabo15090585 - 31 Aug 2025
Viewed by 555
Abstract
Background/Objectives: Ecballium elaterium is a widely distributed species and is one of the earliest recorded in traditional medicine. With global temperatures rising, this study aimed to investigate the changes in E. elaterium plantlets subjected to thermal stress. The goal was to understand how [...] Read more.
Background/Objectives: Ecballium elaterium is a widely distributed species and is one of the earliest recorded in traditional medicine. With global temperatures rising, this study aimed to investigate the changes in E. elaterium plantlets subjected to thermal stress. The goal was to understand how thermal stress affects morphology, physiology, and bioactive metabolite production, both for ecological adaptation and potential therapeutic applications. Methods: Seedlings were cultivated under controlled conditions and subjected to either the control temperature (22 °C) or the heat stress temperature (35 °C) for one week. Morphological and anatomical traits were assessed, along with physiological parameters such as chlorophyll content, malondialdehyde (MDA), hydrogen peroxide (H2O2), L-proline, soluble sugars, and total phenolic content. Methanolic leaf extracts from both groups were analyzed via LC-HRMS/MS and examined in vitro for cytotoxic activity against three human cancer cell lines: MCF-7 (breast), DU-145 (prostate), and SH-SY5Y (neuroblastoma). Results: Heat stress reduced dry mass and stomatal density but increased the diameter of the root transition zone, indicating anatomical adaptation. Leaves exhibited elevated oxidative stress markers and altered metabolite accumulation, while the roots showed a more integrated stress response. LC-HRMS/MS profiling revealed significant shifts in Cucurbitacin composition. Extracts from heat-stressed plants displayed stronger cytotoxicity, particularly toward DU-145 and SH-SY5Y cells, correlating with higher levels of glycosylated Cucurbitacins. Conclusions: E. elaterium demonstrates organ-specific thermotolerance mechanisms, with heat stress enhancing the production of bioactive metabolites. These stress-induced phytochemicals, especially Cucurbitacins, hold promise for future cancer research and therapeutic applications. Full article
(This article belongs to the Section Plant Metabolism)
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12 pages, 1649 KB  
Article
Untargeted GC-MS Metabolic Profiling of Anaerobic Gut Fungi Reveals Putative Terpenoids and Strain-Specific Metabolites
by Lazarina V. Butkovich, Candice L. Swift, Chaevien S. Clendinen, Heather M. Olson, Samuel O. Purvine, Oliver B. Vining and Michelle A. O’Malley
Metabolites 2025, 15(9), 578; https://doi.org/10.3390/metabo15090578 - 29 Aug 2025
Viewed by 647
Abstract
Background/Objectives: Anaerobic gut fungi (Neocallimastigomycota) are biotechnologically relevant, lignocellulose-degrading microbes with under-explored biosynthetic potential for secondary metabolites. Untargeted metabolomic profiling with gas chromatography–mass spectrometry (GC-MS) was applied to two gut fungal strains, Anaeromyces robustus and Caecomyces churrovis, to establish a foundational [...] Read more.
Background/Objectives: Anaerobic gut fungi (Neocallimastigomycota) are biotechnologically relevant, lignocellulose-degrading microbes with under-explored biosynthetic potential for secondary metabolites. Untargeted metabolomic profiling with gas chromatography–mass spectrometry (GC-MS) was applied to two gut fungal strains, Anaeromyces robustus and Caecomyces churrovis, to establish a foundational metabolomic dataset to identify metabolites and provide insights into gut fungal metabolic capabilities. Methods: Gut fungi were cultured anaerobically in rumen-fluid-based media with a soluble substrate (cellobiose), and metabolites were extracted using the Metabolite, Protein, and Lipid Extraction (MPLEx) method, enabling metabolomic and proteomic analysis from the same cell samples. Samples were derivatized and analyzed via GC-MS, followed by compound identification by spectral matching to reference databases, molecular networking, and statistical analyses. Results: Distinct metabolites were identified between A. robustus and C. churrovis, including 2,3-dihydroxyisovaleric acid produced by A. robustus and maltotriitol, maltotriose, and melibiose produced by C. churrovis. C. churrovis may polymerize maltotriose to form an extracellular polysaccharide, like pullulan. GC-MS profiling potentially captured sufficiently volatile products of proteomically detected, putative non-ribosomal peptide synthetases and polyketide synthases of A. robustus and C. churrovis. The triterpene squalene and triterpenoid tetrahymanol were putatively identified in A. robustus and C. churrovis. Their conserved, predicted biosynthetic genes—squalene synthase and squalene tetrahymanol cyclase—were identified in A. robustus, C. churrovis, and other anaerobic gut fungal genera. Conclusions: This study provides a foundational, untargeted metabolomic dataset to unmask gut fungal metabolic pathways and biosynthetic potential and to prioritize future efforts for compound isolation and identification. Full article
(This article belongs to the Section Microbiology and Ecological Metabolomics)
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19 pages, 2480 KB  
Article
Application of Organic Nanofibers to Boost Specialized Metabolite Production and Antioxidant Potential in Stevia rebaudiana In Vitro Cultures
by Maria Geneva, Antoaneta Trendafilova, Kamelia Miladinova-Georgieva, Mariana Sichanova, Daniela Tsekova, Viktoria Ivanova, Elisaveta Kirova and Maria Petrova
Metabolites 2025, 15(9), 579; https://doi.org/10.3390/metabo15090579 - 29 Aug 2025
Viewed by 397
Abstract
Background: Potential advantages for improving plant growth, stress tolerance, and valuable metabolites generation are provided by the implementation of nanotechnology into plant biotechnology. A recently discovered technique with significant promise for agricultural practices is the use of biopolymer-based nanomaterials, like peptidomimetics, as insecticides, [...] Read more.
Background: Potential advantages for improving plant growth, stress tolerance, and valuable metabolites generation are provided by the implementation of nanotechnology into plant biotechnology. A recently discovered technique with significant promise for agricultural practices is the use of biopolymer-based nanomaterials, like peptidomimetics, as insecticides, growth regulators, and nutrient carriers. This study explores the impact of biopolymer-based organic nanofibers—specifically peptidomimetics formed through the self-assembly of L-valine and nicotinic acid (NA) (denoted as M6) on Stevia rebaudiana in vitro propagation and specialized metabolite production. The central hypothesis was that such nanofibers, particularly when used as hormone carriers, can beneficially influence plant morphology, physiology, and biochemistry, thereby promoting the synthesis of antioxidant compounds with therapeutic potential. Methods: The nanofibers were tested either alone (M6) or as carriers of the plant hormone indole-3-acetic acid (IAA) (M6+IAA), supplemented to the cultivation MS medium at variable concentrations (0, 1, 10, and 50 mg L−1). Results: The results revealed that treatment with 10 mg L−1 M6 significantly enhanced shoot growth parameters, including the highest fresh weight (0.249 g), mean shoot height (9.538 cm), shoot number (1.95), and micropropagation rate. Plants treated with M6 alone outperformed those treated with M6+IAA in terms of shoot growth, total soluble sugars, and steviol glycoside content. Conversely, M6+IAA treatment more effectively promoted root initiation, the increased accumulation of mono- and dicaffeoylquinic acids, and boosted antioxidant enzyme activity. Conclusions: These findings highlight the potential of organic nanofibers, both with and without hormone loading, as novel tools for optimizing micropropagation and metabolite enhancement in Stevia rebaudiana. Full article
(This article belongs to the Special Issue Bioactive Metabolites from Natural Sources (2nd Edition))
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24 pages, 4693 KB  
Article
Essence of Chicken Supplementation Alters Brain and Blood Metabolite Signatures in Sleep-Deprived Mice
by Yu Long, Zhaorong Wang, Xinyang Hu, Sisi Wang, Liujie Zheng, Zhengwei Fu and Yinhua Ni
Metabolites 2025, 15(9), 577; https://doi.org/10.3390/metabo15090577 - 29 Aug 2025
Viewed by 678
Abstract
Background: Essence of chicken (EC) has been found to improve brain function, increase short-term working memory, and reduce fatigue. However, the specific bioactives after EC consumption remain unknown, and the effect of EC on sleep deprivation (SD) is also elusive. The aim [...] Read more.
Background: Essence of chicken (EC) has been found to improve brain function, increase short-term working memory, and reduce fatigue. However, the specific bioactives after EC consumption remain unknown, and the effect of EC on sleep deprivation (SD) is also elusive. The aim of the present study is to clarify the metabolic changes induced by EC supplementation in the serum and brain and identify characteristic bioactive metabolites significantly altered after EC consumption. Methods: Firstly, a kinetic analysis of EC consumption was performed to determine the time-sequential change in serum and brain metabolites in mice using gas chromatography coupled with mass spectrometry (GC/MS). Next, the impact of EC on the metabolic signatures in an acute SD mouse model was assessed. Results: Based on the results of the kinetic study, myristoleic acid and L-tyrosine were significantly increased in the serum, whereas gentisic acid was significantly increased in the brain after the administration of EC. In addition, EC administration differentially modulated SD-induced alterations in gene expression across brain regions of acute sleep-deprived mice, ameliorated abnormal neurotransmitters, and increased several specific metabolites in the serum. Conclusions: These results suggest that EC might be an effective nutritional supplement to alleviate SD-induced physiological changes. Full article
(This article belongs to the Section Food Metabolomics)
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13 pages, 425 KB  
Article
Phytochemical Analysis and Appraisal of Antiproliferative Activity of Magnolia alejandrae
by José E. Caballero-Chávez, Alma D. Paz-González, Diana V. Navarrete-Carriola, Fabián E. Olazarán-Santibañez, María Miriam Estevez-Carmona, Benjamín Nogueda-Torres, Fernando Emiliano Jiménez-Mondragón, Melany X. Márquez-Aguilar, Carmen Michelle Pineda-Alcala, Diego Cisneros-Juárez, Álvaro Marín-Hernández, Debasish Bandyopadhyay and Gildardo Rivera
Metabolites 2025, 15(9), 567; https://doi.org/10.3390/metabo15090567 - 22 Aug 2025
Viewed by 645
Abstract
Background: Magnolia alejandrae is a tree endemic to Tamaulipas, Mexico, distributed in the forests of the Sierra Madre Oriental. Objective: Our objective was to analyze the secondary metabolite profile of different parts of M. alejandrae and evaluate their antiproliferative activity in vitro. [...] Read more.
Background: Magnolia alejandrae is a tree endemic to Tamaulipas, Mexico, distributed in the forests of the Sierra Madre Oriental. Objective: Our objective was to analyze the secondary metabolite profile of different parts of M. alejandrae and evaluate their antiproliferative activity in vitro. Methods: Different extracts of leaf, bark, and fruit were obtained using conventional and unconventional extraction methods with solvents of different polarity. The extracts were analyzed by Ultra-Performance Liquid Chromatography-Mass Spectra (UPLC-MS), and their antiproliferative activity against cancer cell lines was determined. Results: The primary yields of the extracts obtained from M. alejandrae ranged from 8.32% to 36.19%. Three hundred and twelve secondary metabolites previously reported from the Magnolia genus were detected. The most frequent were magnone A, pinoresinol, and yangambin. Honokiol and magnolol were not detected. Two of the extracts (FSW and BSW) had antiproliferative activity (IC50 < 140 µg/mL) against HeLa, MCF-7, A549, U373, and PC3 cancer cell lines. The higher activity was against the A549 cell line. Conclusions: M. alejandre extracts showed secondary metabolites previously reported and unreported in other species. Interestingly, some extracts had antiproliferative activity against cancer cell lines. Therefore, M. alejandrae is a source of molecules that could be explored to develop new drugs. Full article
(This article belongs to the Special Issue Advances in Secondary Metabolites: Phytochemical Analysis and Bioactivity Assays)
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26 pages, 2295 KB  
Article
Retrospective Urine Metabolomics of Clinical Toxicology Samples Reveals Features Associated with Cocaine Exposure
by Rachel K. Vanderschelden, Reya Kundu, Delaney Morrow, Simmi Patel and Kenichi Tamama
Metabolites 2025, 15(9), 563; https://doi.org/10.3390/metabo15090563 - 22 Aug 2025
Viewed by 547
Abstract
Background/Objectives: Cocaine is a widely used illicit stimulant with significant toxicity. Despite its clinical relevance, the broader metabolic alterations associated with cocaine use remain incompletely characterized. This study aims to identify novel biomarkers for cocaine exposure by applying untargeted metabolomics to retrospective urine [...] Read more.
Background/Objectives: Cocaine is a widely used illicit stimulant with significant toxicity. Despite its clinical relevance, the broader metabolic alterations associated with cocaine use remain incompletely characterized. This study aims to identify novel biomarkers for cocaine exposure by applying untargeted metabolomics to retrospective urine drug screening data. Methods: We conducted a retrospective analysis of a raw mass spectrometry (MS) dataset from urine comprehensive drug screening (UCDS) from 363 patients at the University of Pittsburgh Medical Center Clinical Toxicology Laboratory. The liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-qToF-MS) data were preprocessed with MS-DIAL and subjected to multiple statistical analyses to identify features significantly associated with cocaine-enzyme immunoassay (EIA) results. Significant features were further evaluated using MS-FINDER for feature annotation. Results: Among 14,883 features, 262 were significantly associated with cocaine-EIA results. A subset of 37 more significant features, including known cocaine metabolites and impurities, nicotine metabolites, norfentanyl, and a tryptophan-related metabolite (3-hydroxy-tryptophan), was annotated. Cluster analysis revealed co-varying features, including parent compounds, metabolites, and related ion species. Conclusions: Features associated with cocaine exposure, including previously underrecognized cocaine metabolites and impurities, co-exposure markers, and alterations in an endogenous metabolic pathway, were identified. Notably, norfentanyl was found to be significantly associated with cocaine -EIA, reflecting current trends in illicit drug use. This study highlights the potential of repurposing real-world clinical toxicology data for biomarker discovery, providing a valuable approach to identifying exposure biomarkers and expanding our understanding of drug-induced metabolic disturbances in clinical toxicology. Further validation and exploration using complementary analytical platforms are warranted. Full article
(This article belongs to the Special Issue Applications of Mass Spectrometry in Elucidating Human Drug Metabolism: From the Preclinical Phase to Real-World Studies)
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12 pages, 821 KB  
Article
Antiparasitic Effect of Polyphenols and Terpenes from Natural Products Against Trypanosoma cruzi and Leishmania mexicana
by Diana V. Navarrete-Carriola, Gildardo Rivera, Eyra Ortiz-Pérez, Alma D. Paz-González, Ana Verónica Martínez-Vázquez, Laura Victoria Aquino-González, Liliana Argueta-Figueroa, Michael P. Doyle and Adriana Moreno-Rodríguez
Metabolites 2025, 15(8), 560; https://doi.org/10.3390/metabo15080560 - 21 Aug 2025
Viewed by 555
Abstract
Background: Worldwide, the number of cases of parasitic diseases has been increasing; however, available treatments have variable adverse effects and low efficacy, mainly in Neglected Tropical Diseases such as Chagas disease and Leishmaniasis. Therefore, the development of new and more effective antiparasitic [...] Read more.
Background: Worldwide, the number of cases of parasitic diseases has been increasing; however, available treatments have variable adverse effects and low efficacy, mainly in Neglected Tropical Diseases such as Chagas disease and Leishmaniasis. Therefore, the development of new and more effective antiparasitic drugs is important. Natural products are the source of secondary metabolites with different biological activities, such as antibacterial, anticancer, anti-inflammatory, and antiparasitic. Objectives: In this work, secondary metabolites (phenols and terpenes) from natural products were selected to be evaluated against the epimastigotes of NINOA and A1 strains of Trypanosoma cruzi and the promastigotes of M379 strain and FCQEPS native isolate of Leishmania mexicana. Additionally, their cytotoxicity and selectivity index were determined. Methods: Eighteen secondary metabolites were evaluated in vitro against T. cruzi epimastigotes and L. mexicana promastigotes; additionally, their cytotoxicity on the J774.2 macrophage cell line was determined. Results: The compounds l-(-)-menthol (14, IC50 = 24.52 µM) and β-citronellol (11, IC50 = 21.54 µM) had higher trypanocidal activity than the reference drug (benznidazole) against NINOA and A1 strains of T. cruzi, respectively. On the other hand, para-anisyl alcohol (4, IC50 = 34.89 µM) had higher leishmanicidal activity than the reference drug (glucantime®) against M379 and the FCQEPS native isolate of L. mexicana. Finally, in silico, the determination of their pharmacokinetic and toxicological properties showed that they are promising candidates for oral and topical uses. Conclusions: This study opens the possibility of using secondary metabolites as scaffolds for access to the development of new molecules for the treatment of parasite diseases. Full article
(This article belongs to the Special Issue Advances in Secondary Metabolites: Phytochemical Analysis and Bioactivity Assays)
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13 pages, 2522 KB  
Article
Metabolomic Variation in Sugarcane Maturation Under a Temperate Climate
by Yasuhiro Date, Chiaki Ishikawa and Hiroshi Ono
Metabolites 2025, 15(8), 558; https://doi.org/10.3390/metabo15080558 - 20 Aug 2025
Viewed by 585
Abstract
Background: Metabolomics is a powerful tool used for the evaluation of sugarcane components which are key factors influencing its response to biotic and abiotic stresses. However, little is known about the compositional variability and diversity of the sugarcane juice metabolome under practical field [...] Read more.
Background: Metabolomics is a powerful tool used for the evaluation of sugarcane components which are key factors influencing its response to biotic and abiotic stresses. However, little is known about the compositional variability and diversity of the sugarcane juice metabolome under practical field conditions in temperate climates. Methods: In this study, we characterized metabolomic differences and variability in sugarcane juice components during the maturation stage of nine cultivars grown in a temperate climate in Japan using a nuclear magnetic resonance-based metabolomics approach, aiming to provide insights into genotype-dependent adaptability to environmental and climate changes. Results: Principal component analysis revealed distinct metabolic profiles based on cultivar and maturation level. Notably, sucrose levels increased from September to December accompanied by decreased glucose and fructose levels across all cultivars. Early-maturing cultivars had high sucrose content even with shorter growing periods, suggesting particular advantages for sugar production in temperate climates. Additionally, 4-aminobutyric acid accumulated in all cultivars as maturation progressed. On the other hand, trans-aconitic acid, choline, and branched-chain amino acids showed cultivar-dependent trends. In one example, choline concentrations increased significantly in specific cultivars during maturation. Conclusions: These findings support a deeper understanding of metabolic adaptation and may aid in identifying cultivars better suited to environmental fluctuations. Full article
(This article belongs to the Special Issue Metabolomic Technology in Quality and Safety of Agricultural Products and Foods)
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18 pages, 1585 KB  
Article
Modeling the Sensory Characteristics of Japanese Sake Using the Sake Metabolome Analysis Method
by Takuji Kobayashi, Yuko Komatsu-Hata, Ryota Saito, Hisashi Yazawa, Masayuki Takahashi, Ken Oda and Kazuhiro Iwashita
Metabolites 2025, 15(8), 559; https://doi.org/10.3390/metabo15080559 - 20 Aug 2025
Viewed by 611
Abstract
Background/Objectives: The components of food and beverages are important elements that determine their palatability. Although the components of sake, a traditional Japanese alcoholic beverage, have been studied for many years, their correlation with sensory characteristics is unclear. Methods: We investigate the correlation with [...] Read more.
Background/Objectives: The components of food and beverages are important elements that determine their palatability. Although the components of sake, a traditional Japanese alcoholic beverage, have been studied for many years, their correlation with sensory characteristics is unclear. Methods: We investigate the correlation with the sake metabolome analysis method developed by our group using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. We constructed orthogonal projections to latent structure models to predict sensory evaluation data obtained through the quantitative descriptive analysis method from the sake metabolome data. Results: For two years of study, 8 sensory evaluation models of the 2016 brewing year and 11 sensory evaluation models of the 2017 brewing year, including color, ethyl hexanoate, Hine-ka, Nama hine-ka, ethyl acetate, grainy/sweet aroma, sweetness, sourness, body, astringency, harsh taste/acrid taste, aftertaste, and overall quality, demonstrated a predictive performance with Q2 > 0.5. Liquid chromatography-based analytical data indicated that it is possible to predict not only taste but also aroma. Additionally, the generalization performance of the prediction models for sensory evaluation attributes common to both years was verified. Conclusions: These results provide a new option for explaining the sensory characteristics of sake from its components and contribute to a deeper understanding of them. Full article
(This article belongs to the Special Issue Advances in Food Sciences: Metabolomics to Unravel the Complexity of Food Metabolites)
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31 pages, 3977 KB  
Article
Exploring the Cytokinin Profile of Doliocarpus dentatus (Aubl.) Standl. From Guyana and Its Relationship with Secondary Metabolites: Insights into Potential Therapeutic Benefits
by Ewart A. Smith, Ainsely Lewis, Erin N. Morrison, Kimberly Molina-Bean, Suresh S. Narine and R. J. Neil Emery
Metabolites 2025, 15(8), 533; https://doi.org/10.3390/metabo15080533 - 6 Aug 2025
Viewed by 741
Abstract
Background/Objectives: Possessing red and white ecotypes, and utilized in traditional Guyanese medicine, Doliocarpus dentatus’ red ecotype is preferred locally for its purported superior therapeutic efficacy. Although therapeutic metabolites were detected in D. dentatus previously, phytohormones remain largely unexplored, until now. Cytokinins, [...] Read more.
Background/Objectives: Possessing red and white ecotypes, and utilized in traditional Guyanese medicine, Doliocarpus dentatus’ red ecotype is preferred locally for its purported superior therapeutic efficacy. Although therapeutic metabolites were detected in D. dentatus previously, phytohormones remain largely unexplored, until now. Cytokinins, phytohormones responsible for plant cell division, growth and differentiation, are gaining traction for their therapeutic potential in human health. This study screened and quantified endogenous cytokinins and correlated detected cytokinins with selected secondary metabolites. Methods: Liquid chromatography–mass spectrometry was used to acquire phytohormone and metabolite data. Bioinformatics tools were used to assess untargeted metabolomics datasets via statistical and pathway analyses, and chemical groupings of putative metabolites. Results: In total, 20 of the 35 phytohormones were detected and quantified in both ecotypes, with the red ecotype displaying higher free base and glucoside cytokinin concentrations and exhibited 6.2 times the total CK content when compared to the white ecotype. Pathway analysis revealed flavonoid and monoterpenoid biosynthesis in red and white ecotypes, respectively. Positive correlations between specific cytokinins and alkaloids, and between trans-Zeatin and isopentenyladenosine riboside with phenolic compounds were observed. Conclusions: These results suggest that the red ecotype’s elevated cytokinin levels coupled with flavonoid biosynthesis enrichment support its preference in Guyanese traditional medicine. Full article
(This article belongs to the Section Plant Metabolism)
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15 pages, 2361 KB  
Article
Galacto-Oligosaccharides Exert Bifidogenic Effects at Capsule-Compatible Ultra-Low Doses
by Lucien F. Harthoorn, Jasmine Heyse, Aurélien Baudot, Ingmar A. J. van Hengel and Pieter Van den Abbeele
Metabolites 2025, 15(8), 530; https://doi.org/10.3390/metabo15080530 - 5 Aug 2025
Viewed by 1398
Abstract
Background: Prebiotics are selectively used by host microorganisms to promote health. Because effective prebiotic doses (1.5–30 g/day) often require inconvenient delivery formats, this study aims to explore whether capsule-compatible doses of galacto-oligosaccharides (GOS) can effectively modulate the gut microbiome. Methods: The impact of [...] Read more.
Background: Prebiotics are selectively used by host microorganisms to promote health. Because effective prebiotic doses (1.5–30 g/day) often require inconvenient delivery formats, this study aims to explore whether capsule-compatible doses of galacto-oligosaccharides (GOS) can effectively modulate the gut microbiome. Methods: The impact of Bimuno® GOS (Reading, UK) at 0.5, 0.75, 1.83, and 3.65 g on the adult gut microbiome was assessed using the ex vivo SIFR® technology (n = 8), a clinically validated, bioreactor-based technology. Results: The GOS were rapidly fermented and significantly increased beneficial Bifidobacterium species (B. adolescentis, B. bifidum, and B. longum), even at the lowest tested dose. In doing so, GOS strongly promoted SCFA production, particularly acetate (significant from 0.5 g) and butyrate (significant from 0.75 g). Gas production only mildly increased, likely as Bifidobacterium species do not produce gases. Based on the ability of the SIFR® technology to cultivate strictly anaerobic, hard-to-culture gut microbes, unlike in past in vitro studies, we elucidated that GOS also enriched specific Lachnospiraceae species. Besides Anaerobutyricum hallii, this included Bariatricus comes, Blautia species (B. massiliensis, Blautia_A, B. faecis), Oliverpabstia intestinalis, Mediterraneibacter faecis, and Fusicatenibacter species. Finally, GOS also promoted propionate (significant from 0.75 g), linked to increases in Phocaeicola vulgatus. Conclusions: GOS displayed prebiotic potential at capsule-compatible doses, offering greater flexibility in nutritional product formulation and consumer convenience. Notably, the strong response at the lowest dose suggests effective microbiome modulation at lower levels than previously expected. Full article
(This article belongs to the Special Issue Targeting Microbiota and Metabolites for Prevention and Treatment of Human Diseases)
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14 pages, 31608 KB  
Article
Primary Metabolic Variations in Maize Plants Affected by Different Levels of Nitrogen Supply
by The Ngoc Phuong Nguyen, Rose Nimoh Serwaa and Jwakyung Sung
Metabolites 2025, 15(8), 519; https://doi.org/10.3390/metabo15080519 - 1 Aug 2025
Viewed by 528
Abstract
Background/Objectives: Nitrogen (N) is an essential macronutrient that strongly influences maize growth and metabolism. While many studies have focused on nitrogen responses during later developmental stages, early-stage physiological and metabolic responses remain less explored. This study investigated the effect of different nitrogen-deficient [...] Read more.
Background/Objectives: Nitrogen (N) is an essential macronutrient that strongly influences maize growth and metabolism. While many studies have focused on nitrogen responses during later developmental stages, early-stage physiological and metabolic responses remain less explored. This study investigated the effect of different nitrogen-deficient levels on maize seedling growth and primary metabolite profiles. Methods: Seedlings were treated with N-modified nutrient solution, which contained 0% to 120% of the standard nitrogen level (8.5 mM). Results: Nitrogen starvation (N0) significantly reduced plant height (by 11–14%), shoot fresh weight (over 30%) compared to the optimal N supply (N100). Total leaf nitrogen content under N0–N20 was less than half of that in N100, whereas moderate N deficiency resulted in moderate reductions in growth and nitrogen content. Metabolite analysis revealed that N deficiency induced the accumulation of soluble sugars and organic acids (up to threefold), while sufficient N promoted the synthesis of amino acids related to nitrogen assimilation and protein biosynthesis. Statistical analyses (PCA and ANOVA) showed that both genotypes (MB and TYC) and tissue type (upper vs. lower leaves) influenced the metabolic response to nitrogen, with MB displaying more consistent shifts and TYC exhibiting greater variability under moderate stress. Conclusions: These findings highlight the sensitivity of maize seedlings to early nitrogen deficiency, with severity influenced by nitrogen level, tissue-specific position, and genotype; thus underscore the close coordination between physiological growth and primary metabolic pathways in response to nitrogen availability. These findings expand current knowledge of nitrogen response mechanisms and offer practical insights for improving nitrogen use efficiency in maize cultivation. Full article
(This article belongs to the Special Issue Unlocking Nature's Toolbox: Advances in Plant Metabolites Identification)
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29 pages, 959 KB  
Review
Machine Learning-Driven Insights in Cancer Metabolomics: From Subtyping to Biomarker Discovery and Prognostic Modeling
by Amr Elguoshy, Hend Zedan and Suguru Saito
Metabolites 2025, 15(8), 514; https://doi.org/10.3390/metabo15080514 - 1 Aug 2025
Viewed by 1248
Abstract
Cancer metabolic reprogramming plays a critical role in tumor progression and therapeutic resistance, underscoring the need for advanced analytical strategies. Metabolomics, leveraging mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, offers a comprehensive and functional readout of tumor biochemistry. By enabling both targeted [...] Read more.
Cancer metabolic reprogramming plays a critical role in tumor progression and therapeutic resistance, underscoring the need for advanced analytical strategies. Metabolomics, leveraging mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, offers a comprehensive and functional readout of tumor biochemistry. By enabling both targeted metabolite quantification and untargeted profiling, metabolomics captures the dynamic metabolic alterations associated with cancer. The integration of metabolomics with machine learning (ML) approaches further enhances the interpretation of these complex, high-dimensional datasets, providing powerful insights into cancer biology from biomarker discovery to therapeutic targeting. This review systematically examines the transformative role of ML in cancer metabolomics. We discuss how various ML methodologies—including supervised algorithms (e.g., Support Vector Machine, Random Forest), unsupervised techniques (e.g., Principal Component Analysis, t-SNE), and deep learning frameworks—are advancing cancer research. Specifically, we highlight three major applications of ML–metabolomics integration: (1) cancer subtyping, exemplified by the use of Similarity Network Fusion (SNF) and LASSO regression to classify triple-negative breast cancer into subtypes with distinct survival outcomes; (2) biomarker discovery, where Random Forest and Partial Least Squares Discriminant Analysis (PLS-DA) models have achieved >90% accuracy in detecting breast and colorectal cancers through biofluid metabolomics; and (3) prognostic modeling, demonstrated by the identification of race-specific metabolic signatures in breast cancer and the prediction of clinical outcomes in lung and ovarian cancers. Beyond these areas, we explore applications across prostate, thyroid, and pancreatic cancers, where ML-driven metabolomics is contributing to earlier detection, improved risk stratification, and personalized treatment planning. We also address critical challenges, including issues of data quality (e.g., batch effects, missing values), model interpretability, and barriers to clinical translation. Emerging solutions, such as explainable artificial intelligence (XAI) approaches and standardized multi-omics integration pipelines, are discussed as pathways to overcome these hurdles. By synthesizing recent advances, this review illustrates how ML-enhanced metabolomics bridges the gap between fundamental cancer metabolism research and clinical application, offering new avenues for precision oncology through improved diagnosis, prognosis, and tailored therapeutic strategies. Full article
(This article belongs to the Special Issue Nutritional Metabolomics in Cancer)
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19 pages, 2222 KB  
Article
Low Metabolic Variation in Environmentally Diverse Natural Populations of Temperate Lime Trees (Tilia cordata)
by Carl Barker, Paul Ashton and Matthew P. Davey
Metabolites 2025, 15(8), 509; https://doi.org/10.3390/metabo15080509 - 31 Jul 2025
Viewed by 381
Abstract
Background: Population persistence for organisms to survive in a world with a rapidly changing climate will require either dispersal to suitable areas, evolutionary adaptation to altered conditions and/or sufficient phenotypic plasticity to withstand it. Given the slow growth and geographically isolated populations [...] Read more.
Background: Population persistence for organisms to survive in a world with a rapidly changing climate will require either dispersal to suitable areas, evolutionary adaptation to altered conditions and/or sufficient phenotypic plasticity to withstand it. Given the slow growth and geographically isolated populations of many tree species, there is a high likelihood of local adaption or the acclimation of functional traits in these populations across the UK. Objectives: Given the slow growth and often isolated populations of Tilia cordata (lime tree), we hypothesised that there is a high likelihood of local adaptation or the acclimation of metabolic traits in these populations across the UK. Our aim was to test if the functional metabolomic traits of Tilia cordata (lime tree), collected in situ from natural populations, varied within and between populations and to compare this to neutral allele variation in the population. Methods: We used a metabolic fingerprinting approach to obtain a snapshot of the metabolic status of leaves collected from T. cordata from six populations across the UK. Environmental metadata, longer-term functional traits (specific leaf area) and neutral allelic variation in the population were also measured to assess the plastic capacity and local adaptation of the species. Results: The metabolic fingerprints derived from leaf material collected and fixed in situ from individuals in six populations of T. cordata across its UK range were similar, despite contrasting environmental conditions during sampling. Neutral allele frequencies showed almost no significant group structure, indicating low differentiation between populations. The specific leaf area did vary between sites. Conclusions: The low metabolic variation between UK populations of T. cordata despite contrasting environmental conditions during sampling indicates high levels of phenotypic plasticity. Full article
(This article belongs to the Special Issue Metabolomics and Plant Defence, 2nd Edition)
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30 pages, 2433 KB  
Review
Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential
by Marta Pawłowska, Joanna Kruszka, Marta Porzych, Jakub Garbarek and Jarosław Nuszkiewicz
Metabolites 2025, 15(8), 508; https://doi.org/10.3390/metabo15080508 - 31 Jul 2025
Viewed by 1409
Abstract
Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and share key pathological features such as oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Recent research has highlighted the potential of ketogenic metabolism, particularly the use [...] Read more.
Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and share key pathological features such as oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Recent research has highlighted the potential of ketogenic metabolism, particularly the use of ketone bodies like β-hydroxybutyrate, as a therapeutic approach targeting these shared mechanisms. This review provides a comprehensive synthesis of current knowledge on the neuroprotective effects of ketogenic interventions, including both dietary strategies and exogenous ketone supplementation. We discuss how ketone bodies improve mitochondrial function, reduce reactive oxygen species, modulate inflammatory pathways, and influence neurotransmission and synaptic plasticity. Additionally, we examine experimental and clinical evidence supporting the application of ketogenic therapies in neurodegenerative diseases, highlighting disease-specific findings, benefits, and limitations. While preclinical data are robust and suggest meaningful therapeutic potential, clinical studies remain limited and heterogeneous, with challenges related to adherence, safety, and patient selection. The review also addresses the translational relevance of ketogenic strategies, considering their feasibility, combination with other therapies, and the need for personalized approaches based on genetic and metabolic profiles. By critically evaluating existing data, this article aims to clarify the mechanisms through which ketogenic metabolism may exert neuroprotective effects and to outline future directions for research and clinical application in the context of neurodegenerative disorders. Full article
(This article belongs to the Special Issue Brain Metabolic Alterations in Neurodegenerative Diseases)
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14 pages, 1512 KB  
Article
Postharvest NMR Metabolomic Profiling of Pomegranates Stored Under Low-Pressure Conditions: A Pilot Study
by Keeton H. Montgomery, Aya Elhabashy, Brendon M. Anthony, Yong-Ki Kim and Viswanathan V. Krishnan
Metabolites 2025, 15(8), 507; https://doi.org/10.3390/metabo15080507 - 30 Jul 2025
Viewed by 603
Abstract
Background: There is a high demand for long-term postharvest storage of valuable perishables with high-quality preservation and minimal product loss due to decay and physiological disorders. Postharvest low-pressure storage (LPS) provides a viable option for many fruits. While recent studies have presented the [...] Read more.
Background: There is a high demand for long-term postharvest storage of valuable perishables with high-quality preservation and minimal product loss due to decay and physiological disorders. Postharvest low-pressure storage (LPS) provides a viable option for many fruits. While recent studies have presented the details of technology, this pilot study presents the metabolomics changes due to the hypobaric storage of pomegranates as a model system. Methods: Nuclear magnetic resonance (NMR)-based metabolomics studies were performed on pomegranate fruit tissues, comparing fruit stored under LPS conditions versus the traditional storage system, with modified atmosphere packaging (MAP) as the control. The metabolomic changes in the exocarp, mesocarp, and arils were measured using 1H NMR spectroscopy, and the results were analyzed using multivariate statistics. Results: Distinguishable differences were noted between the MAP and LPS conditions in fruit quality attributes and metabolite profiles. Sucrose levels in the aril, mesocarp, and exocarp samples were higher under LPS, while sucrose levels were reduced in MAP. In addition, alanine levels were more abundant in the mesocarp and exocarp samples, and ethanol concentration decreased in the exocarp samples, albeit less significantly. Conclusions: This pilot investigation shows the potential for using NMR as a valuable assessment tool for monitoring the performance of viable long-term storage conditions in horticultural commodities. 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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17 pages, 7610 KB  
Article
Metabolomic Profiling of Hepatitis B-Associated Liver Disease Progression: Chronic Hepatitis B, Cirrhosis, and Hepatocellular Carcinoma
by Junsang Oh, Kei-Anne Garcia Baritugo, Jayoung Kim, Gyubin Park, Ki Jun Han, Sangheun Lee and Gi-Ho Sung
Metabolites 2025, 15(8), 504; https://doi.org/10.3390/metabo15080504 - 29 Jul 2025
Viewed by 675
Abstract
Background/Objective: The hepatitis B virus (HBV) can cause chronic hepatitis B (CHB), which can rapidly progress into fatal liver cirrhosis (CHB-LC) and hepatocellular carcinoma (CHB-HCC). Methods: In this study, we investigated metabolites associated with distinct clinical stages of HBV infection for the identification [...] Read more.
Background/Objective: The hepatitis B virus (HBV) can cause chronic hepatitis B (CHB), which can rapidly progress into fatal liver cirrhosis (CHB-LC) and hepatocellular carcinoma (CHB-HCC). Methods: In this study, we investigated metabolites associated with distinct clinical stages of HBV infection for the identification of stage-specific serum metabolite biomarkers using 1H-NMR-based metabolomics. Results: A total of 64 serum metabolites were identified, among which six core discriminatory metabolites, namely isoleucine, tryptophan, histamine (for CHB), and pyruvate, TMAO, lactate (for CHB-HCC), were consistently significant across univariate and multivariate statistical analyses, including ANOVA with FDR, OPLS-DA, and VIP scoring. These metabolites were closely linked to key metabolic pathways, such as propanoate metabolism, pyruvate metabolism, and the Warburg effect. Conclusions: The findings suggest that these six core metabolites serve as potential stage-specific biomarkers for CHB, CHB-LC, and CHB-HCC, respectively, and offer a foundation for the future development of metabolomics-based diagnostic and therapeutic strategies. Full article
(This article belongs to the Special Issue Harnessing the Power of NMR Metabolomics in Unraveling Metabolic Diseases)
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18 pages, 2513 KB  
Article
Decoding Fish Origins: How Metals and Metabolites Differentiate Wild, Cultured, and Escaped Specimens
by Warda Badaoui, Kilian Toledo-Guedes, Juan Manuel Valero-Rodriguez, Adrian Villar-Montalt and Frutos C. Marhuenda-Egea
Metabolites 2025, 15(7), 490; https://doi.org/10.3390/metabo15070490 - 21 Jul 2025
Viewed by 588
Abstract
Background: Fish escape events from aquaculture facilities are increasing and pose significant ecological, economic, and traceability concerns. Accurate methods to differentiate between wild, cultured, and escaped fish are essential for fishery management and seafood authentication. Methods: This study analyzed muscle tissue from Sparus [...] Read more.
Background: Fish escape events from aquaculture facilities are increasing and pose significant ecological, economic, and traceability concerns. Accurate methods to differentiate between wild, cultured, and escaped fish are essential for fishery management and seafood authentication. Methods: This study analyzed muscle tissue from Sparus aurata, Dicentrarchus labrax, and Argyrosomus regius using a multiomics approach. Heavy metals were quantified by ICP-MS, fatty acid profiles were assessed via GC-MS, and metabolomic and lipidomic signatures were identified using 1H NMR spectroscopy. Multivariate statistical models (MDS and PLS-LDA) were applied to classify fish origins. Results: Wild seabream showed significantly higher levels of arsenic (9.5-fold), selenium (3.5-fold), and DHA and ARA fatty acids (3.2-fold), while cultured fish exhibited increased linoleic and linolenic acids (6.5-fold). TMAO concentrations were up to 5.3-fold higher in wild fish, serving as a robust metabolic biomarker. Escaped fish displayed intermediate biochemical profiles. Multivariate models achieved a 100% classification accuracy across species and analytical techniques. Conclusions: The integration of heavy metal analysis, fatty acid profiling, and NMR-based metabolomics enables the accurate differentiation of fish origin. While muscle tissue provides reliable biomarkers relevant to human exposure, future studies should explore additional tissues such as liver and gills to improve the resolution of traceability. These methods support seafood authentication, enhance aquaculture traceability, and aid in managing the ecological impacts of escape events. Full article
(This article belongs to the Collection Feature Papers in Assessing Environmental Health and Function)
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28 pages, 8123 KB  
Article
Human Metabolism of Sirolimus Revisited
by Baharak Davari, Touraj Shokati, Alexandra M. Ward, Vu Nguyen, Jost Klawitter, Jelena Klawitter and Uwe Christians
Metabolites 2025, 15(7), 489; https://doi.org/10.3390/metabo15070489 - 20 Jul 2025
Viewed by 991
Abstract
Background: Sirolimus (SRL, rapamycin) is a clinically important mTOR inhibitor used in immunosuppression, oncology, and cardiovascular drug-eluting devices. Despite its long-standing FDA approval, the human metabolic profile of SRL remains incompletely characterized. SRL is primarily metabolized by CYP3A enzymes in the liver and [...] Read more.
Background: Sirolimus (SRL, rapamycin) is a clinically important mTOR inhibitor used in immunosuppression, oncology, and cardiovascular drug-eluting devices. Despite its long-standing FDA approval, the human metabolic profile of SRL remains incompletely characterized. SRL is primarily metabolized by CYP3A enzymes in the liver and intestine, but the diversity, pharmacokinetics, and biological activity of its metabolites have been poorly explored due to the lack of structurally identified standards. Methods: To investigate SRL metabolism, we incubated SRL with pooled human liver microsomes (HLM) and isolated the resulting metabolites. Structural characterization was performed using high-resolution mass spectrometry (HRMS) and ion trap MSn. We also applied Density Functional Theory (DFT) calculations to assess the energetic favorability of metabolic transformations and conducted molecular dynamics (MD) simulations to model metabolite interactions within the CYP3A4 active site. Results: We identified 21 unique SRL metabolites, classified into five major structural groups: O-demethylated, hydroxylated, didemethylated, di-hydroxylated, and mixed hydroxylated/demethylated derivatives. DFT analyses indicated that certain demethylation and hydroxylation reactions were energetically preferred, correlating with metabolite abundance. MD simulations further validated these findings by demonstrating the favorable orientation and accessibility of key sites within the CYP3A4 binding pocket. Conclusions: This study provides a comprehensive structural map of SRL metabolism, offering mechanistic insights into the formation of its metabolites. Our integrated approach of experimental and computational analyses lays the groundwork for future investigations into the pharmacodynamic and toxicodynamic effects of SRL metabolites on the mTOR pathway. Full article
(This article belongs to the Section Pharmacology and Drug Metabolism)
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20 pages, 1836 KB  
Article
Advancing Semiochemical Tools for Mountain Pine Beetle Management: Dendroctonus ponderosae Responses to Saprophytic Fungal Volatiles
by Leah Crandall, Rashaduz Zaman, Guncha Ishangulyyeva and Nadir Erbilgin
Metabolites 2025, 15(7), 488; https://doi.org/10.3390/metabo15070488 - 20 Jul 2025
Viewed by 597
Abstract
Background/Objectives: Within their host trees, mountain pine beetles (MPBs, Dendroctonus ponderosae) interact with many fungal species, each releasing a unique profile of volatile organic compounds (VOCs). The FVOCs released by the two primary symbionts of MPBs, Grosmannia clavigera and Ophiostoma montium, [...] Read more.
Background/Objectives: Within their host trees, mountain pine beetles (MPBs, Dendroctonus ponderosae) interact with many fungal species, each releasing a unique profile of volatile organic compounds (VOCs). The FVOCs released by the two primary symbionts of MPBs, Grosmannia clavigera and Ophiostoma montium, have been found to enhance MPB attraction in the field and laboratory studies. Opportunistic, saprophytic fungal species, such as Aspergillus sp. and Trichoderma atroviride, are also common in MPB galleries and can negatively impact MPB fitness. However, little is known about the FVOCs produced by these fungal species and how they may impact MPB feeding and attraction. Methods: To address this knowledge gap, we characterized the FVOC profile of T. atroviride, and performed bioassays to test the effects of its FVOCs on MPB attraction and feeding activity. Results: Our chemical analysis revealed several FVOCs from T. atroviride known to inhibit the growth of competing fungal species and impact subcortical-beetle attraction. Conclusions: From those FVOCs, we recommended four compounds—2-pentanone, 2-heptanone, 2-pentanol, and phenylethyl alcohol—for use in future field tests as anti-attraction lures for MPBs. In bioassays, we also observed strong MPB repellency from FVOCs released by T. atroviride, as well as the mild effects of FVOCs on MPB feeding activity. Our findings highlight the potential for these FVOCs to be utilized in the development of more effective MPB anti-attractant lures, which are crucial for the monitoring and management of low-density MPB populations. Full article
(This article belongs to the Special Issue Dysbiosis and Metabolic Disorders of the Microbiota)
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31 pages, 2163 KB  
Review
The Role of Probiotics, Prebiotics, Synbiotics, and Postbiotics in Livestock and Poultry Gut Health: A Review
by Taojing Yue, Yanan Lu, Wenli Ding, Bowen Xu, Cai Zhang, Lei Li, Fuchun Jian and Shucheng Huang
Metabolites 2025, 15(7), 478; https://doi.org/10.3390/metabo15070478 - 15 Jul 2025
Viewed by 1990
Abstract
Background: The gut health of livestock and poultry is of utmost importance as it significantly impacts their growth performance, disease resistance, and product quality. With the increasing restrictions on antibiotic use in animal husbandry, probiotics, prebiotics, synbiotics, and postbiotics (PPSP) have emerged as [...] Read more.
Background: The gut health of livestock and poultry is of utmost importance as it significantly impacts their growth performance, disease resistance, and product quality. With the increasing restrictions on antibiotic use in animal husbandry, probiotics, prebiotics, synbiotics, and postbiotics (PPSP) have emerged as promising alternatives. This review comprehensively summarizes the roles of PPSP in promoting gut health in livestock and poultry. Results: Probiotics, such as Lactobacillus, Bifidobacterium, and Saccharomyces, modulate the gut microbiota, enhance the gut barrier, and regulate the immune system. Prebiotics, including fructooligosaccharides, isomalto-oligosaccharides, galactooligosaccharides, and inulin, selectively stimulate the growth of beneficial bacteria and produce short-chain fatty acids, thereby improving gut health. Synbiotics, combinations of probiotics and prebiotics, have shown enhanced effects in improving gut microbiota and animal performance. Postbiotics, consisting of inanimate microorganisms and their constituents, restore the gut microbiota balance and have anti-inflammatory and antibacterial properties. Additionally, the review looks ahead to the future development of PPSP, emphasizing the importance of encapsulation technology and personalized strategies to maximize their efficacy. Conclusions: Our aim is to provide scientific insights for PPSP to improve the gut health of livestock and poultry. Full article
(This article belongs to the Special Issue Metabolomics Approaches to Nutrition, Intestine and Farm Animal)
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15 pages, 972 KB  
Article
Pharmacometabolomics Study of Sulfamethoxazole and Trimethoprim in Kidney Transplant Recipients: Real-World Metabolism and Urinary Excretion
by Marieke A. J. Hof, Hessel de Haan, Stepan Stepanovic, Stephan J. L. Bakker, Eelko Hak, Gérard Hopfgartner, Frank Klont and TransplantLines Investigators
Metabolites 2025, 15(7), 473; https://doi.org/10.3390/metabo15070473 - 11 Jul 2025
Viewed by 661
Abstract
Background/Objectives: The increased use of antibiotics is raising concerns about environmental contamination and antibiotic resistance, exemplified by the case of cotrimoxazole, a widely prescribed combination of sulfamethoxazole and trimethoprim. After oral administration and absorption, both drugs are excreted in their parent and [...] Read more.
Background/Objectives: The increased use of antibiotics is raising concerns about environmental contamination and antibiotic resistance, exemplified by the case of cotrimoxazole, a widely prescribed combination of sulfamethoxazole and trimethoprim. After oral administration and absorption, both drugs are excreted in their parent and metabolized forms, which is a factor that is commonly considered in environmental studies. Many studies, however, rely on pharmacokinetic data from drug developers, who mostly investigate drug metabolism in healthy male volunteers rather than in actual patient populations. Methods: We investigated the real-world metabolism and urinary excretion of cotrimoxazole in an LC-SWATH/MS-based pharmacometabolomics study of 149 kidney transplant recipients who took part in the TransplantLines Biobank and Cohort Study (NCT0327284). Results: Our study confirmed (as “putatively characterized compound classes”) the presence of all the expected metabolites, and we (putatively) identified several previously unreported metabolites, including glucuronide conjugates of both drugs and two isoxazole ring-opened variants of sulfamethoxazole. The relative metabolite profiles furthermore indicated that the active drug trimethoprim accounted for 75% of the total signal intensity. For sulfamethoxazole, its acetylated metabolite was the main metabolite (59%), followed by the active parent drug (17%) and its glucuronide (7%). Alongside trimethoprim, these substances could serve as analytical targets for environmental cotrimoxazole monitoring, given their abundance (all three substances), activity (parent drug), and/or back-transformation potential (both conjugated metabolites). The isoxazole ring-opened variants (2–3%) may also warrant attention, considering their (presumed) absolute excreted quantities and potential pharmacological activity. Conclusions: This study underscores the value of pharmacometabolomics in elucidating real-world metabolite profiles, and it provides novel insights into cotrimoxazole metabolism and excretion, with implications for environmental and clinical monitoring. Full article
(This article belongs to the Special Issue Drug Metabolism: Latest Advances and Prospects)
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21 pages, 2655 KB  
Article
Integrative Modeling of Urinary Metabolomics and Metal Exposure Reveals Systemic Impacts of Electronic Waste in Exposed Populations
by Fiona Hui, Zhiqiang Pang, Charles Viau, Gerd U. Balcke, Julius N. Fobil, Niladri Basu and Jianguo Xia
Metabolites 2025, 15(7), 456; https://doi.org/10.3390/metabo15070456 - 5 Jul 2025
Viewed by 929
Abstract
Background: Informal electronic waste (e-waste) recycling practices release a complex mixture of pollutants, particularly heavy metals, into the environment. Chronic exposure to these contaminants has been linked to a range of health risks, but the molecular underpinnings remain poorly understood. In this [...] Read more.
Background: Informal electronic waste (e-waste) recycling practices release a complex mixture of pollutants, particularly heavy metals, into the environment. Chronic exposure to these contaminants has been linked to a range of health risks, but the molecular underpinnings remain poorly understood. In this study, we investigated the alterations in metabolic profiles due to e-waste exposure and linked these metabolites to systemic biological effects. Methods: We applied untargeted high-resolution metabolomics using dual-column LC-MS/MS and a multi-step analysis workflow combining MS1 feature detection, MS2 annotation, and chemical ontology classification, to characterize urinary metabolic alterations in 91 e-waste workers and 51 community controls associated with the Agbogbloshie site (Accra, Ghana). The impacts of heavy metal exposure in e-waste workers were assessed by establishing linear regression and four-parameter logistic (4PL) models between heavy metal levels and metabolite concentrations. Results: Significant metal-associated metabolomic changes were identified. Both linear and nonlinear models revealed distinct sets of exposure-responsive compounds, highlighting diverse biological responses. Ontology-informed annotation revealed systemic effects on lipid metabolism, oxidative stress pathways, and xenobiotic biotransformation. This study demonstrates how integrating chemical ontology and nonlinear modeling facilitates exposome interpretation in complex environments and provides a scalable template for environmental biomarker discovery. Conclusions: Integrating dose–response modeling and chemical ontology analysis enables robust interpretation of exposomics datasets when direct compound identification is limited. Our findings indicate that e-waste exposure induces systemic metabolic alterations that can underlie health risks and diseases. Full article
(This article belongs to the Special Issue Method Development in Metabolomics and Exposomics)
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58 pages, 656 KB  
Review
Human Digestive Physiology and Evolutionary Diet: A Metabolomic Perspective on Carnivorous and Scavenger Adaptations
by Vicente Javier Clemente-Suárez, Laura Redondo-Flórez, Ana Isabel Beltrán-Velasco, Rodrigo Yáñez-Sepúlveda, Alejandro Rubio-Zarapuz, Alexandra Martín-Rodríguez, Eduardo Navarro-Jimenez and José Francisco Tornero-Aguilera
Metabolites 2025, 15(7), 453; https://doi.org/10.3390/metabo15070453 - 4 Jul 2025
Viewed by 3462
Abstract
This review examines human digestive physiology and metabolic adaptations in the context of evolutionary dietary patterns, particularly those emphasizing carnivorous and scavenging behaviors. By integrating metabolomic data with archaeological, anatomical, and microbiological evidence, the study explores how early hominins adapted to intermittent but [...] Read more.
This review examines human digestive physiology and metabolic adaptations in the context of evolutionary dietary patterns, particularly those emphasizing carnivorous and scavenging behaviors. By integrating metabolomic data with archaeological, anatomical, and microbiological evidence, the study explores how early hominins adapted to intermittent but energy-dense animal-based diets. The analysis highlights the development of hepatic insulin resistance, enhanced fat and protein metabolism, and shifts in gut microbiota diversity as physiological signatures of meat consumption. Comparative evaluations of digestive enzyme profiles, intestinal morphology, and salivary composition underscore humans’ omnivorous flexibility and partial carnivorous specialization. Additionally, biomarkers such as ketone bodies, branched-chain amino acids, and trimethylamine-N-oxide are identified as metabolic indicators of habitual meat intake. These adaptations, though once evolutionarily advantageous, are discussed in relation to current metabolic disorders in modern nutritional contexts. Overall, this review presents a metabolomic framework for understanding the evolutionary trajectory of human digestion and its implications for health and dietary recommendations. Full article
(This article belongs to the Section Advances in Metabolomics)
20 pages, 2548 KB  
Article
In Vitro Metabolism of Doping Agents (Stanozolol, LGD-4033, Anastrozole, GW1516, Trimetazidine) by Human Seminal Vesicle and Liver Fractions
by Johanna Sternberg, Insa Peters, Nana Naumann, Andreas Thomas and Mario Thevis
Metabolites 2025, 15(7), 452; https://doi.org/10.3390/metabo15070452 - 4 Jul 2025
Viewed by 1011
Abstract
Background: In order to address complex scenarios in anti-doping science, especially in cases where an unintentional exposure of athletes to prohibited substances and a corresponding contamination of doping control samples at the collection event are argued, an understanding of tissue-specific drug metabolism is [...] Read more.
Background: In order to address complex scenarios in anti-doping science, especially in cases where an unintentional exposure of athletes to prohibited substances and a corresponding contamination of doping control samples at the collection event are argued, an understanding of tissue-specific drug metabolism is essential. Hence, in this study, the metabolic capacity of the seminal vesicle using in vitro assays was investigated. Methods: The aim was to assess whether selected doping-relevant substances—stanozolol, LGD-4033, GW1516, trimetazidine, and anastrozole—are metabolised in seminal vesicle cellular fractions (SV-S9) and how that metabolism compares to biotransformations induced by human liver S9 fractions (HL-S9). Liquid chromatography coupled to high-resolution/accurate mass spectrometry (LC HRAM MS) enabled the sensitive detection and identification of metabolites, revealing a limited metabolic activity of SV-S9. Results: For LGD-4033, GW1516, and trimetazidine, minor metabolic transformations were observed, whereas no metabolites of stanozolol or anastrozole were detected. Gene expression analysis using digital polymerase chain reaction (dPCR) confirmed transcripts of CYP2D6, CYP2E1, and CYP2C9 in SV-S9, though no enzymatic activity was detected. Gene expression and enzymatic activity in CYP3A4 and CYP1A2—major hepatic enzymes—were absent in SV-S9. Conclusions: Overall, these pilot study results suggest that the seminal vesicle has only a low capacity for xenobiotic metabolism, which translates into a limited role in the biotransformation of drugs and, hence, the metabolic pattern. Full article
(This article belongs to the Section Pharmacology and Drug Metabolism)
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14 pages, 1035 KB  
Article
Interaction Between CYP1A2-Related Caffeine Metabolism and Vitamin B12/Folate Status in Patients with Metabolic Syndrome: A Novel Biomarker Axis
by Laura Claudia Popa, Ahmed Abu-Awwad, Simona Sorina Farcas, Simona-Alina Abu-Awwad and Nicoleta Ioana Andreescu
Metabolites 2025, 15(7), 450; https://doi.org/10.3390/metabo15070450 - 4 Jul 2025
Viewed by 1599
Abstract
Background/Objectives: The prevalence of metabolic syndrome (MetS) is steadily increasing worldwide, driven by complex genetic, nutritional, and environmental factors. Caffeine metabolism, primarily mediated by CYP1A2 (though other enzymes such as CYP1A1 may also be involved), and the status of micronutrients such as [...] Read more.
Background/Objectives: The prevalence of metabolic syndrome (MetS) is steadily increasing worldwide, driven by complex genetic, nutritional, and environmental factors. Caffeine metabolism, primarily mediated by CYP1A2 (though other enzymes such as CYP1A1 may also be involved), and the status of micronutrients such as vitamin B12 and folate have each been linked to MetS components. This study investigates the interaction between CYP1A2 genetic variants and vitamin B12/folate levels in patients with MetS, aiming to identify a novel biomarker axis with potential implications for personalized interventions. Methods: This cross-sectional observational study included 356 adults diagnosed with MetS, recruited from Western Romania. Genotyping for CYP1A2 rs762551 was performed using TaqMan PCR assays. Daily caffeine intake was assessed via validated dietary questionnaires. Serum levels of folate and vitamin B12 were measured using chemiluminescence immunoassays. Results: AA genotype patients with a moderate coffee intake (1–2 cups/day) had significantly higher folate and B12 levels than AC or CC carriers. These nutritional advantages were associated with more favorable BMI and triglyceride profiles. The interaction between CYP1A2 genotype and coffee intake was significant for both micronutrient levels and metabolic parameters, particularly in the AA group. No significant associations were found in high-coffee-intake subgroups (≥3 cups/day). Conclusions: The interplay between CYP1A2 polymorphisms and B-vitamin status may represent a clinically relevant biomarker axis in MetS. Moderate caffeine intake in slow metabolizers (AA genotype) may boost micronutrient status and metabolic health, supporting personalized nutrition. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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18 pages, 1475 KB  
Article
Metabolomic Prediction of Naphthalene Pneumo-Toxicity in the Snail Helix aspersa maxima
by Aude Devalckeneer, Marion Bouviez and Jean-Marie Colet
Metabolites 2025, 15(7), 448; https://doi.org/10.3390/metabo15070448 - 3 Jul 2025
Viewed by 785
Abstract
Background: Polluted soils represent a major problem in many industrialized countries that urgently requires appropriate health risk assessment. The One Health concept that considers a close relationship between human and animal health and ecosystems relies, among other techniques, on continuous monitoring through the [...] Read more.
Background: Polluted soils represent a major problem in many industrialized countries that urgently requires appropriate health risk assessment. The One Health concept that considers a close relationship between human and animal health and ecosystems relies, among other techniques, on continuous monitoring through the use of animal species as bioindicators. In this context, terrestrial gastropods, already recognized as relevant indicators due to their anatomo-physiology, provide a reliable model to study the pneumotoxic effects of pollutants. On the other hand, risk assessment is based on multi-biomarker studies. Therefore, omic approaches seem particularly useful since they can simultaneously detect numerous early biological changes. Methods: In this study, Helix aspersa maxima was exposed to naphthalene, a highly volatile aromatic hydrocarbon responsible for numerous respiratory disorders. Pulmonary membrane extracts and hemolymph samples were analyzed by 1H-NMR spectroscopy after single or repeated exposures to naphthalene. Results: Numerous metabolic changes were observed, which could be related to membrane lesions, energy, anti-inflammatory, and tumorigenesis pathways. Conclusions: Our findings highlight the potential of combining animal indicator and omics techniques to predict respiratory health risks in cases of exposure to polluted soils. Full article
(This article belongs to the Collection Feature Papers in Assessing Environmental Health and Function)
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14 pages, 1211 KB  
Article
Impact of Heavy Metals on the Antioxidant Activity of Vitamin D: A Metabolic Perspective
by Ji Seo Park, Mi-Ri Gwon, Jae Hwa Lee, Jin Ju Park, Hae Won Lee, Duk-Hee Lee, Sook Jin Seong and Young-Ran Yoon
Metabolites 2025, 15(7), 440; https://doi.org/10.3390/metabo15070440 - 1 Jul 2025
Viewed by 690
Abstract
Background/Objectives: Vitamin D (VD) is metabolized in the body and plays a crucial role in regulating the antioxidant system. While exposure to heavy metals (HMs) inhibits VD activity, HMs can also be absorbed following VD stimulation. Despite differing views on the interaction [...] Read more.
Background/Objectives: Vitamin D (VD) is metabolized in the body and plays a crucial role in regulating the antioxidant system. While exposure to heavy metals (HMs) inhibits VD activity, HMs can also be absorbed following VD stimulation. Despite differing views on the interaction between HM and VD activity, the effects of HM exposure on VD-related pathways have not been examined using metabolomics. This study aimed to investigate the impact of HM exposure on VD-related antioxidant activity under VD deficiency conditions using untargeted metabolic profiling. Methods: In this retrospective cohort study, 46 plasma samples were analyzed using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Metabolic profiling was performed on two groups: individuals with severe VD deficiency and low HM exposure (SVDD–LHM) and those with VD deficiency and high HM exposure (VDD–HHM). Results: As a compensatory response to oxidative stress induced by HMs, VD-related antioxidant pathways may be associated with elevated levels of antioxidants, including bilirubin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). In-creases in EPA and DHA were also linked to alterations in lipid metabolism, including diacylglycerol and phosphatidylcholine levels. DHA showed an area under the curve (AUC) of 0.850 (95% CI: 0.651–0.990), suggesting that DHA could serve as a potential biomarker for VD activity in response to HM exposure. Conclusions: The identified metabolites and metabolic pathways suggest that HM exposure may stimulate VD-related antioxidant activity, even under VD-deficient conditions. Full article
(This article belongs to the Section Environmental Metabolomics)
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14 pages, 13737 KB  
Article
Unravelling the Dynamic Physiological and Metabolome Responses of Wheat (Triticum aestivum L.) to Saline–Alkaline Stress at the Seedling Stage
by Wei Ren and Li Chen
Metabolites 2025, 15(7), 430; https://doi.org/10.3390/metabo15070430 - 23 Jun 2025
Cited by 1 | Viewed by 567
Abstract
Background/Objectives: Understanding metabolome adjustment under saline–alkaline conditions is crucial for enhancing crop tolerance capacity and ensuring food security. Although soil salinization impairs wheat seedlings’ growth, metabolome plasticity under saline–alkaline stress remains poorly understood. Here, we delved into dynamic physiological and metabolome shifts in [...] Read more.
Background/Objectives: Understanding metabolome adjustment under saline–alkaline conditions is crucial for enhancing crop tolerance capacity and ensuring food security. Although soil salinization impairs wheat seedlings’ growth, metabolome plasticity under saline–alkaline stress remains poorly understood. Here, we delved into dynamic physiological and metabolome shifts in wheat seedlings grown on SAS (saline–alkaline soil) on the 7th and 15th days post-germination (DPG). Methods: A self-developed and cultivated high-generation salt–alkali wheat variety (011) was grown on SAS and control soil, followed by comparative physiological, biochemical, and metabolomics analyses of seedlings. Results: The seedlings’ saline–alkaline stress responses were developmentally regulated with reduced growth, increasing accumulation of proline and soluble sugars, and differential antioxidant response. LC-MS-based global metabolomics analysis revealed significant metabolite profile differences, with 367 and 485 differential metabolites identified on the 7th and 15th DPG, respectively, between control and treatment. Upregulation of saccharides, flavonoids, organic acids (citrate cycle-related), phenolic acids, amino acids and derivatives, phytohormones, and sphingolipid metabolism was essential for seedlings’ growth on SAS. The key induced metabolites in seedlings grown on SAS include saccharic acid, trehalose, sucrose, glucose, L-citramalic acid, phellodendroside, scutellarin, anthranilate-1-O-sophoroside, lavandulifolioside, N-methyl-L-glutamate, etc. Up-regulated phytohormones include abscisic acid (3.8-fold, 7th DPG and 3.18-fold, 15th DPG), jasmonic acid (1.93-fold, 15th DPG), and jasmonoyl isoleucine (2.03-fold, 15th DPG). Conclusions: Our findings highlight the importance of ABA and jasmonic acid in regulating salt–alkali tolerance in wheat seedlings. Moreover, this study depicts key pathways involved in salt–alkali tolerance in wheat seedlings and unveils key DMs, offering resources for boosting wheat production on SAS. Full article
(This article belongs to the Section Plant Metabolism)
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19 pages, 4128 KB  
Article
Integrating Metabolomics and Machine Learning to Analyze Chemical Markers and Ecological Regulatory Mechanisms of Geographical Differentiation in Thesium chinense Turcz
by Cong Wang, Ke Che, Guanglei Zhang, Hao Yu and Junsong Wang
Metabolites 2025, 15(7), 423; https://doi.org/10.3390/metabo15070423 - 20 Jun 2025
Viewed by 592
Abstract
Background: The relationship between medicinal efficacy and the geographical environment in Thesium chinense Turcz. (T. chinense Turcz.), a traditional Chinese herb, remains systematically unexplored. This study integrates metabolomics, machine learning, and ecological factor analysis to elucidate the geographical variation patterns and regulatory [...] Read more.
Background: The relationship between medicinal efficacy and the geographical environment in Thesium chinense Turcz. (T. chinense Turcz.), a traditional Chinese herb, remains systematically unexplored. This study integrates metabolomics, machine learning, and ecological factor analysis to elucidate the geographical variation patterns and regulatory mechanisms of secondary metabolites in T. chinense Turcz. from Anhui, Henan, and Shanxi Provinces. Methods: Metabolomic profiling was conducted on T. chinense Turcz. samples collected from three geographical origins across Anhui, Henan, and Shanxi Provinces. Machine learning algorithms (Random Forest, LASSO regression) identified region-specific biomarkers through intersection analysis. Metabolic pathway enrichment employed MetaboAnalyst 5.0 with target prediction. Antioxidant activity (DPPH/hydroxyl radical scavenging) was quantified spectrophotometrically. Environmental correlation analysis incorporated 19 WorldClim variables using redundancy analysis, Mantel tests, and Pearson correlations. Results: We identified 43 geographical marker compounds (primarily flavonoids and alkaloids). Random forest and LASSO regression algorithms determined core markers for each production area: Anhui (4 markers), Henan (6 markers), and Shanxi (3 markers). Metabolic pathway enrichment analysis revealed these markers exert pharmacological effects through neuroactive ligand–receptor interaction and PI3K-Akt signaling pathways. Redundancy analysis demonstrated Anhui samples exhibited significantly higher antioxidant activity (DPPH and hydroxyl radical scavenging rates) than other regions, strongly correlating with stable low-temperature environments (annual mean temperature) and precipitation patterns. Conclusions: This study established the first geo-specific molecular marker system for T. chinense Turcz., demonstrating that the geographical environment critically influences metabolic profiles and bioactivity. Findings provide a scientific basis for quality control standards of geo-authentic herbs and offer insights into plant–environment interactions for sustainable cultivation practices. Full article
(This article belongs to the Special Issue Metabolomics in Plant Natural Products Research, 2nd Edition)
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23 pages, 1267 KB  
Review
Gadolinium in the Environment: A Double-Edged Sword for Plant Growth and Ecosystem Stability
by Marlena Tomczuk, Beata Godlewska-Żyłkiewicz and Andrzej Bajguz
Metabolites 2025, 15(6), 415; https://doi.org/10.3390/metabo15060415 - 19 Jun 2025
Viewed by 651
Abstract
Gadolinium, a rare earth element, is increasingly released into the environment due to its widespread applications in medical imaging, industry, and agriculture. This review explores the dual role of gadolinium in plant systems, highlighting its potential benefits at subtoxic concentrations and detrimental effects [...] Read more.
Gadolinium, a rare earth element, is increasingly released into the environment due to its widespread applications in medical imaging, industry, and agriculture. This review explores the dual role of gadolinium in plant systems, highlighting its potential benefits at subtoxic concentrations and detrimental effects at higher levels. At subtoxic doses, gadolinium can enhance plant growth, metabolism, and stress tolerance by promoting enzymatic activity and nutrient absorption. However, elevated concentrations induce oxidative stress, disrupt nutrient uptake, and impair photosynthesis, leading to cellular damage and reduced growth. The bioaccumulation of gadolinium in plant tissues raises concerns about its trophic transfer within food chains and its broader ecological impact. Current evidence suggests that previously regarded as stable and inert gadolinium complexes can degrade under environmental conditions, increasing their bioavailability and toxicity. Despite its potential for agricultural applications, including improving crop resilience, the ecological risks associated with gadolinium remain poorly understood. Addressing these risks requires coordinated efforts to optimize gadolinium usage, develop advanced waste management strategies, and enhance monitoring of its environmental presence. This review emphasizes the need for in-depth research on gadolinium interactions with plants and ecosystems to balance its industrial benefits with environmental sustainability. Full article
(This article belongs to the Section Plant Metabolism)
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11 pages, 2431 KB  
Article
Development of Sucrose-Utilizing Escherichia coli Nissle 1917 for Efficient Heparosan Biosynthesis
by Yaozong Chen, Zihua Wan and Zheng-Jun Li
Metabolites 2025, 15(6), 410; https://doi.org/10.3390/metabo15060410 - 18 Jun 2025
Cited by 1 | Viewed by 678
Abstract
Background/Objectives: Heparosan is a component of the capsular polysaccharide in Escherichia coli K5 and Pasteurella multocida Type D. It shares a similar glycan structure with heparin and can be enzymatically modified to produce bioactive heparin. Methods: In this study, the probiotic [...] Read more.
Background/Objectives: Heparosan is a component of the capsular polysaccharide in Escherichia coli K5 and Pasteurella multocida Type D. It shares a similar glycan structure with heparin and can be enzymatically modified to produce bioactive heparin. Methods: In this study, the probiotic strain E. coli Nissle 1917 (EcN), which naturally produces heparosan, was genetically engineered to utilize sucrose as a carbon source for growth while achieving high-yield heparosan biosynthesis. Results: By expressing the sucrose hydrolase genes sacA (from Bacillus subtilis) or spI (from Bifidobacterium adolescentis), EcN was enabled to utilize sucrose, achieving heparosan titers of 131 mg/L and 179 mg/L, respectively. Further metabolic engineering was performed to block the glycolytic and pentose phosphate pathways, thereby redirecting sucrose-derived glucose-6-phosphate and fructose-6-phosphate toward heparosan biosynthesis, while glycerol was supplemented as an auxiliary carbon source to support cell growth. Finally, the key biosynthesis genes galU, kfiD, and glmM were overexpressed, resulting in an engineered strain with a heparosan titer of 622 mg/L. Conclusions: This study represents the first successful engineering of EcN to utilize sucrose as the carbon source for growth, while achieving enhanced heparosan production through synergistic carbon source utilization. These findings establish a foundational strategy for employing this strain in the sucrose-based biosynthesis of other glycosaminoglycans. Full article
(This article belongs to the Special Issue Synthetic Biology Approaches for Expanding the Metabolic Capabilities of E. coli)
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19 pages, 586 KB  
Article
In Vitro Antioxidant, Antithrombotic and Anti-Inflammatory Activities of Bioactive Metabolites Extracted from Kiwi and Its By-Products
by Anastasia Maria Moysidou, Konstantina Cheimpeloglou, Spyridoula Ioanna Koutra, Vasileios Manousakis, Anna Ofrydopoulou, Katie Shiels, Sushanta Kumar Saha and Alexandros Tsoupras
Metabolites 2025, 15(6), 400; https://doi.org/10.3390/metabo15060400 - 13 Jun 2025
Viewed by 890
Abstract
Background/Objectives: Growing interest in natural, health-promoting ingredients for functional foods, nutraceuticals, and cosmetics has increased the demand for bioactive compounds from kiwi (Actinidia deliciosa). This study aimed to assess the antioxidant, anti-inflammatory, and antithrombotic properties of amphiphilic bioactives extracted from kiwi fruit and [...] Read more.
Background/Objectives: Growing interest in natural, health-promoting ingredients for functional foods, nutraceuticals, and cosmetics has increased the demand for bioactive compounds from kiwi (Actinidia deliciosa). This study aimed to assess the antioxidant, anti-inflammatory, and antithrombotic properties of amphiphilic bioactives extracted from kiwi fruit and its by-products, including peel, seeds, and pulp. Methods: Bioactive compounds were extracted and analyzed using liquid chromatography–mass spectrometry (LC–MS) and attenuated total reflectance–Fourier transform infrared (ATR–FTIR) spectroscopy. Antioxidant activity was evaluated using DPPH and ABTS radical scavenging assays. Anti-inflammatory and antithrombotic effects were assessed through inhibition of platelet aggregation induced by platelet-activating factor (PAF) and adenosine diphosphate (ADP) in human platelets. Results: All extracts showed significant antioxidant activity. FTIR and LC–MS analyses confirmed the presence of phenolics, flavonoids, carotenoids, and polar lipids. Kiwi peel extract exhibited the strongest inhibition of PAF- and ADP-induced platelet aggregation, attributed to its higher content of phenolics and unsaturated polar lipids. LC–MS data indicated a favorable fatty acid profile with high omega-9 levels and a low omega-6/omega-3 ratio. Polar lipid structural analysis revealed a predominance of phospholipids with unsaturated fatty acids at the sn-2 position. Conclusions: Kiwi by-products are valuable sources of health-promoting bioactives with antioxidant and anti-inflammatory potential. These findings support their incorporation into nutraceutical, nutricosmetic, and cosmeceutical products and lay the groundwork for further studies on safety, efficacy, and practical application. Full article
(This article belongs to the Special Issue Phytochemicals and Pharmacological Significance of Plant Secondary Metabolites in Medicine)
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14 pages, 3390 KB  
Article
The Potential of Aloe vera and Opuntia ficus-indica Extracts as Biobased Agents for the Conservation of Cultural Heritage Metals
by Çağdaş Özdemir, Lucia Emanuele, Marta Kotlar, Marina Brailo Šćepanović, Laura Scrano and Sabino Aurelio Bufo
Metabolites 2025, 15(6), 386; https://doi.org/10.3390/metabo15060386 - 10 Jun 2025
Viewed by 699
Abstract
Background/Objectives: Biocorrosion, driven by microbial colonization and biofilm formation, poses a significant threat to the integrity of metal artifacts, particularly those composed of copper and its alloys. Pseudomonas aeruginosa, a bacterial species that reduces nitrates, plays a key role in this process. [...] Read more.
Background/Objectives: Biocorrosion, driven by microbial colonization and biofilm formation, poses a significant threat to the integrity of metal artifacts, particularly those composed of copper and its alloys. Pseudomonas aeruginosa, a bacterial species that reduces nitrates, plays a key role in this process. This study explores the potential of two metabolite-rich plant extracts, Aloe vera and Opuntia ficus-indica, as sustainable biobased inhibitors of microbial-induced corrosion (MICOR). Methods: The antibacterial and antibiofilm activities of the extracts were evaluated using minimal inhibitory concentration (MIC) assays, time-kill kinetics, and biofilm prevention and removal tests on copper, bronze, and brass samples. Spectrophotometric and microbiological methods were used to quantify bacterial growth and biofilm density. Results: Both extracts exhibited significant antibacterial activity, with MIC values of 8.3% (v/v). A. vera demonstrated superior bactericidal effects, achieving reductions of ≥3 log10 in bacterial counts at lower concentrations. In antibiofilm assays, both extracts effectively prevented biofilm formation and reduced established biofilms, with A. vera exhibiting greater efficacy against them. The active metabolites—anthraquinones, phenolics, flavonoids, and tannins—likely contribute to these effects. Conclusions: These findings highlight the dual role of A. vera and O. ficus-indica extracts as both corrosion and biocorrosion inhibitors. The secondary metabolite profiles of these plants support their application as eco-friendly alternatives in the conservation of metal cultural heritage objects. Full article
(This article belongs to the Special Issue Bioactive Metabolites from Plants)
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20 pages, 746 KB  
Review
The Effect of Frailty on Body Composition and Its Impact on the Use of SGLT-2 Inhibitors and GLP-1RA in Older Persons with Diabetes
by Alan Sinclair, Izel Siqueira and Ahmed Abdelhafiz
Metabolites 2025, 15(6), 381; https://doi.org/10.3390/metabo15060381 - 9 Jun 2025
Viewed by 1091
Abstract
The association of frailty with body composition is complex. Frailty can be associated with significant anorexia and weight loss or overweight and obesity. In addition, the development of frailty leads to changes in muscle mass, muscle fibre type, and visceral fat. In older [...] Read more.
The association of frailty with body composition is complex. Frailty can be associated with significant anorexia and weight loss or overweight and obesity. In addition, the development of frailty leads to changes in muscle mass, muscle fibre type, and visceral fat. In older people with diabetes, frailty-induced body composition changes are clinically relevant as they may affect the metabolic profile of the frail person. The determinants of insulin resistance in frail older persons with diabetes include factors such as total body weight and the ratio of lean muscle mass to visceral fat mass. The predominant loss of insulin-resistant skeletal muscle fibres type II, in comparison to insulin-sensitive type I fibres, is another factor that modifies the overall insulin resistance of the individual. As a result, frailty appears to be a heterogeneous condition with variable insulin resistance across a metabolic spectrum. The spectrum spans from a sarcopenic obese frail phenotype at one end to an anorexic malnourished frail phenotype at the other end. The introduction of SGLT-2 inhibitors and GLP-1RA with novel anti-metabolic syndrome properties, not just glucose-lowering effect, should influence clinicians’ choice in frail older persons with diabetes. These agents are likely to be beneficial in patients at the sarcopenic obese end of the frailty spectrum, who should benefit most due to their high baseline risk of progression of metabolic syndrome, high insulin resistance, and the increased prevalence of cardiovascular risk factors. On the other hand, patients at the anorexic malnourished end of the frailty spectrum are likely not suitable for such therapy due to the regression of metabolic syndrome in this group of patients and the increased risk of further weight loss, dehydration, and hypotension. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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18 pages, 2481 KB  
Article
Alteration of Metabolic Profile in Patients with Narcolepsy Type 1
by Md Abdul Hakim, Waziha Purba, Akeem Sanni, Md Mostofa Al Amin Bhuiyan, Farid Talih, Giuseppe Lanza, Firas Kobeissy, Giuseppe Plazzi, Fabio Pizza, Raffaele Ferri and Yehia Mechref
Metabolites 2025, 15(6), 382; https://doi.org/10.3390/metabo15060382 - 9 Jun 2025
Viewed by 992
Abstract
Background: Narcolepsy type 1 (NT1) is a rare neurological sleep disorder characterized by excessive daytime sleepiness and cataplexy. NT1 is thought to be caused by the loss of hypocretin-producing neurons in the hypothalamus due to autoimmunity. Since cerebrospinal fluid hypocretin testing is invasive [...] Read more.
Background: Narcolepsy type 1 (NT1) is a rare neurological sleep disorder characterized by excessive daytime sleepiness and cataplexy. NT1 is thought to be caused by the loss of hypocretin-producing neurons in the hypothalamus due to autoimmunity. Since cerebrospinal fluid hypocretin testing is invasive and not always feasible in clinical practice, there is a critical need for less invasive biomarkers to improve diagnostic accuracy and accessibility. Very few studies have explored serum-based biomolecules that could serve as biomarkers for NT1. Methods: This study examines the differential abundance of serum metabolites in patients with NT1 using an LC-MS/MS-based comprehensive metabolomics approach. Results: An untargeted analysis identified a total of 1491 metabolites, 453 of which were differentially abundant compared to the control cohort. Ingenuity pathway analysis revealed that key pathways, such as the inflammatory response (p-value of 0.01, activation z-score of 0.5), generation and synthesis of reactive oxygen species (p-value of 0.0008, z-score of 1.3), and neuronal cell death (p-value of 0.04, z-score of 0.4), are predicted to be activated in NT1. A targeted analysis using parallel reaction monitoring validated 49 metabolites, including important downregulated metabolites such as uridine (fold change (FC) of 0.004), epinephrine (FC of 0.05), colchicine (FC of 0.2), corticosterone (FC of 0.3), and arginine (FC of 0.6), as well as upregulated metabolites such as p-cresol sulfate (FC of 2601.7), taurine (FC of 1315.4), inosine (FC of 429.7), and malic acid (FC of 7.9). Conclusions: Understanding the pathways identified in this study and further investigating the differentially abundant metabolites associated with them may pave the way for gaining insight into disease pathogenesis and developing novel therapeutic interventions. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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32 pages, 1153 KB  
Review
Unlocking Plant Resilience: Metabolomic Insights into Abiotic Stress Tolerance in Crops
by Agata Głuchowska, Bartłomiej Zieniuk and Magdalena Pawełkowicz
Metabolites 2025, 15(6), 384; https://doi.org/10.3390/metabo15060384 - 9 Jun 2025
Cited by 1 | Viewed by 1247
Abstract
Background/Objectives: In the context of accelerating climate change and growing food insecurity, improving crop resilience to abiotic stresses such as drought, salinity, heat, and cold is a critical agricultural and scientific challenge. Understanding the biochemical mechanisms that underlie plant stress responses is essential [...] Read more.
Background/Objectives: In the context of accelerating climate change and growing food insecurity, improving crop resilience to abiotic stresses such as drought, salinity, heat, and cold is a critical agricultural and scientific challenge. Understanding the biochemical mechanisms that underlie plant stress responses is essential for developing resilient crop varieties This review aims to provide an integrative overview of how metabolomics can elucidate biochemical mechanisms underlying stress tolerance and guide the development of stress-resilient crops. Methods: We reviewed the recent literature on metabolomic studies addressing abiotic stress responses in various crop species, focusing on both targeted and untargeted approaches using platforms such as nuclear magnetic resonance (NMR), liquid chromatography–mass spectrometry (LC-MS), and gas chromatography–mass spectrometry (GC-MS). We also included emerging techniques such as capillary electrophoresis–mass spectrometry (CE-MS), ion mobility spectrometry (IMS-MS), Fourier transform infrared spectroscopy (FT-IR), and data-independent acquisition (DIA). Additionally, we discuss the integration of metabolomics with transcriptomics and physiological data to support system-level insights. Results: The reviewed studies identify common stress-responsive metabolites, including osmoprotectants, antioxidants, and signaling compounds, which are consistently linked to enhanced tolerance. Novel metabolic biomarkers and putative regulatory hubs are highlighted as potential targets for molecular breeding and bioengineering. We also address ongoing challenges related to data standardization and reproducibility across analytical platforms. Conclusions: Metabolomics is a valuable tool for advancing our understanding of plant abiotic stress responses. Its integration with other omics approaches and phenotypic analyses offers promising avenues for improving crop resilience and developing climate-adaptive agricultural strategies. Full article
(This article belongs to the Special Issue Climate Change-Related Stresses and Plant Metabolism)
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19 pages, 1080 KB  
Review
Dietary and Lifestyle Interventions to Mitigate Oxidative Stress in Male and Female Fertility: Practical Insights for Infertility Management—A Narrative Review
by Efthalia Moustakli, Athanasios Zikopoulos, Periklis Katopodis, Stefanos Dafopoulos, Vasilis Sebastian Paraschos, Athanasios Zachariou and Konstantinos Dafopoulos
Metabolites 2025, 15(6), 379; https://doi.org/10.3390/metabo15060379 - 8 Jun 2025
Cited by 1 | Viewed by 1247
Abstract
Background/Objectives: Infertility in both men and women can be significantly influenced by oxidative stress (OS), which occurs due to an imbalance between reactive oxygen species (ROS) and the body’s antioxidant defenses. In women, OS disrupts oocyte maturation, implantation, and the viability of the [...] Read more.
Background/Objectives: Infertility in both men and women can be significantly influenced by oxidative stress (OS), which occurs due to an imbalance between reactive oxygen species (ROS) and the body’s antioxidant defenses. In women, OS disrupts oocyte maturation, implantation, and the viability of the embryo; in men, it impairs sperm quality, reduces motility, and damages DNA integrity. This review explores existing research on how dietary and lifestyle interventions can reduce OS and enhance reproductive health outcomes. Methods: We conducted a comprehensive review of clinical, translational, and molecular studies exploring the mechanisms by which OS affects fertility, as well as the efficacy of nutritional and behavioral strategies. The interventions evaluated include weight management, regular exercise, micronutrient supplementation, antioxidant-rich diets, smoking and alcohol cessation, and stress-reduction techniques. Results: Specific dietary components such as zinc, selenium, vitamins C and E, and polyphenols have been found to neutralize reactive oxygen species (ROS) and enhance gamete function. OS is additionally reduced through lifestyle modifications, including minimizing harmful exposures, managing stress, and participating in moderate physical activity. Biomarkers such as ROS levels, total antioxidant capacity, 8-OHdG, and DNA fragmentation index are essential for assessing the effectiveness of interventions. Conclusions: Fertility in both sexes can be improved, and oxidative stress significantly reduced, through a multimodal approach incorporating dietary and lifestyle changes. There are encouraging opportunities to improve reproductive health through customized approaches that are informed by biomarker profiles. To incorporate these treatments into regular fertility care, future studies should concentrate on standardized procedures and long-term results. Full article
(This article belongs to the Special Issue Interactions of Diet, Exercise, and Metabolism)
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12 pages, 1185 KB  
Article
High-Calorie Diet Consumption Induces Lac-Phe Changes in the Brain in a Time-of-Day Manner Independent of Exercise
by Jarne Jermei, Han Jiao, Ayano Shiba, Julia C. Goedhart, Roberta Tandari, Andries Kalsbeek, Eduard A. Struys and Chun-Xia Yi
Metabolites 2025, 15(6), 375; https://doi.org/10.3390/metabo15060375 - 6 Jun 2025
Viewed by 1251
Abstract
Background/Objectives: N-lactoyl-phenylalanine (Lac-Phe), an exercise-induced metabolite, has been shown to reduce food intake, decrease body weight and adiposity, and improve glucose homeostasis without affecting energy expenditure. Until now, Lac-Phe has mainly been investigated in blood plasma, showing its appetite-suppressing effects. Interestingly, these beneficial [...] Read more.
Background/Objectives: N-lactoyl-phenylalanine (Lac-Phe), an exercise-induced metabolite, has been shown to reduce food intake, decrease body weight and adiposity, and improve glucose homeostasis without affecting energy expenditure. Until now, Lac-Phe has mainly been investigated in blood plasma, showing its appetite-suppressing effects. Interestingly, these beneficial effects were caused by a temporary increase in Lac-Phe levels after exercise. Second, despite the central role of the central nervous system in the homeostatic control of energy metabolism, little is known about the presence and function of Lac-Phe in the brain. The goal of this study is to investigate how Lac-Phe concentrations in the brain change during the 24 h light/dark cycle. Methods: We conducted an experiment in rats in which time-restricted running was combined with time-restricted feeding (TRF) of a high-calorie diet, after which Lac-Phe levels were measured in the hypothalamus and cortex using stable isotope dilution LC-MS/MS. Microglia were isolated from rat brains to study Lac-Phe-related gene expression. Results: We found that Lac-Phe levels changed over time within the 24 h light/dark cycle in the hypothalamus and/or cortex, even without exercise. Our study indicates that brain Lac-Phe is not only induced by exercise but also by high-calorie diet intake independent of exercise. Finally, we showed that microglial cells are cytosolic nonspecific dipeptidase 2 (CNDP2) positive and therefore able to produce Lac-Phe. Hereby, we identified SLC16A1 in microglia as a possible key mediator of Lac-Phe production. Conclusions: We conclude that high-calorie diet consumption induces Lac-Phe changes in the brain in a time-of-day manner independent of exercise. This study provides new knowledge on the presence and production of Lac-Phe in the brain. Further research is needed to elucidate the potential mechanism by which Lac-Phe reduces food intake and body weight by targeting appetite-suppressing neurons. Full article
(This article belongs to the Section Bioinformatics and Data Analysis)
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29 pages, 1977 KB  
Review
Capsaicin as a Microbiome Modulator: Metabolic Interactions and Implications for Host Health
by Iván Artemio Corral-Guerrero, Angela Elena Martínez-Medina, Litzy Yazmin Alvarado-Mata, Ana Cristina Figueroa Chávez, Roberto Muñoz-García, Miriam Paulina Luévanos-Escareño, Jazel Doménica Sosa-Martínez, María José Castro-Alonso, Padma Nimmakayala, Umesh K. Reddy and Nagamani Balagurusamy
Metabolites 2025, 15(6), 372; https://doi.org/10.3390/metabo15060372 - 5 Jun 2025
Viewed by 4418
Abstract
Background/Objectives: Capsaicin is the principal pungent compound in chili peppers and is increasingly recognized as a multifunctional phytochemical with systemic effects beyond its sensory properties. It has been linked to metabolic regulation, neuroprotection, inflammation control, and cancer modulation. This review aims to provide [...] Read more.
Background/Objectives: Capsaicin is the principal pungent compound in chili peppers and is increasingly recognized as a multifunctional phytochemical with systemic effects beyond its sensory properties. It has been linked to metabolic regulation, neuroprotection, inflammation control, and cancer modulation. This review aims to provide an integrative synthesis of capsaicin’s metabolism, its interaction with the gut microbiome, and its physiological implications across organ systems. Methods: We conducted a critical literature review of recent in vivo and in vitro studies exploring capsaicin’s metabolic fate, biotransformation by host enzymes and gut microbes, tissue distribution, and molecular pathways. The literature was analyzed thematically to cover gastrointestinal absorption, hepatic metabolism, microbiota interactions, and systemic cellular responses. Results: Capsaicin undergoes extensive hepatic metabolism, producing hydroxylated and dehydrogenated metabolites that differ in transient receptor potential vanilloid type 1 (TRPV1) receptor affinity and tissue-specific bioactivity. It crosses the blood–brain barrier, alters neurotransmitter levels, and accumulates in brain regions involved in cognition. In addition to its systemic effects, capsaicin appears to undergo microbial transformation and influences gut microbial composition, favoring short-chain fatty acid producers and suppressing pro-inflammatory taxa. These changes contribute to anti-obesity, anti-inflammatory, and potentially anticancer effects. Dose-dependent adverse outcomes, such as epithelial damage or tumor promotion, have also been observed. Conclusions: Capsaicin represents a diet-derived bioactive molecule whose systemic impact is shaped by dynamic interactions between host metabolism and the gut microbiota. Clarifying its biotransformation pathways and context-specific effects is essential for its safe and effective use in metabolic and neurological health strategies. Full article
(This article belongs to the Special Issue Nutritional Metabolism in Model Organisms: Phytochemicals and Genetic Responses)
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15 pages, 1178 KB  
Article
Comparison of the Metabolic Profiles Associated with Protonitazene and Protonitazepyne in Two Severe Poisonings
by Romain Magny, Thomas Schiestel, Aymen M’Rad, Bertrand Lefrère, Jean-Herlé Raphalen, Stanislas Ledochowski, Laurence Labat, Bruno Mégarbane and Pascal Houzé
Metabolites 2025, 15(6), 371; https://doi.org/10.3390/metabo15060371 - 5 Jun 2025
Viewed by 916
Abstract
Nitazenes represent an emerging class of new synthetic opioids characterized by a high-potency μ-opioid receptor (MOR) agonist activity. Background: We report two 20-year-old males who presented with severe neurorespiratory depression with typical opioid syndrome, but no opioid identification based on routine blood [...] Read more.
Nitazenes represent an emerging class of new synthetic opioids characterized by a high-potency μ-opioid receptor (MOR) agonist activity. Background: We report two 20-year-old males who presented with severe neurorespiratory depression with typical opioid syndrome, but no opioid identification based on routine blood and urine screening tests. The first patient recovered with supportive care, mechanical ventilation, and naloxone infusion, whereas the second patient developed post-anoxic cardiac arrest and died from brain death. Methods: A complementary comprehensive toxicological screening using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) was performed, and data were processed using a dedicated molecular network strategy to profile the metabolites. Results: Protonitazene and protonitazepyne, two nitazenes differing in their ethylamine moieties (i.e., a diethyl versus a pyrrolidine substitution, respectively), were identified. We found an extensive metabolism of protonitazene, leading to the identification of multiple phase I (resulting from hydroxylation, N-desethylation, and O-despropylation) and phase II (resulting from glucuronidation) metabolites. By contrast, protonitazepyne metabolism appeared limited, with one metabolite annotated confidently, protonitazepyne acid, which resulted from the oxidative pyrrolidine ring cleavage. Concusions: To conclude, nitazene detection is highly challenging due to its extensive structural and metabolic diversity. Our findings highlight the contribution of the untargeted LC-HRMS screening approach and suggest that diagnostic product ions can serve as robust markers for nitazene identification. Full article
(This article belongs to the Special Issue Metabolite Profiling of Novel Psychoactive Substances)
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29 pages, 2657 KB  
Review
Bridging Ethnobotanical Knowledge and Multi-Omics Approaches for Plant-Derived Natural Product Discovery
by Kekeletso H. Chele, Lizelle A. Piater, Justin J. J. van der Hooft and Fidele Tugizimana
Metabolites 2025, 15(6), 362; https://doi.org/10.3390/metabo15060362 - 29 May 2025
Viewed by 1166
Abstract
For centuries, plant-derived natural products (NPs) have been fundamental to traditional medicine, providing essential therapeutic compounds. Ethnobotanical knowledge has historically guided NP discovery, leading to the identification of key pharmaceuticals such as aspirin, morphine, and artemisinin. However, conventional bioactivity-guided fractionation methods for NP [...] Read more.
For centuries, plant-derived natural products (NPs) have been fundamental to traditional medicine, providing essential therapeutic compounds. Ethnobotanical knowledge has historically guided NP discovery, leading to the identification of key pharmaceuticals such as aspirin, morphine, and artemisinin. However, conventional bioactivity-guided fractionation methods for NP isolation are labour-intensive and can result in the loss of bioactive properties due to the focus on a single compound. Advances in omics sciences—genomics, transcriptomics, proteomics, metabolomics, and phenomics—coupled with computational tools have altogether revolutionised NP research by enabling high-throughput screening and more precise compound identification. This review explores how integrating traditional medicinal knowledge with multi-omics strategies enhances NP discovery. We highlight emerging bioinformatics tools, mass spectrometry techniques, and metabologenomics approaches that accelerate the identification, annotation, and functional characterisation of plant-derived metabolites. Additionally, we discuss challenges in omics data integration and propose strategies to harness ethnobotanical knowledge for targeted NP discovery and drug development. By combining traditional wisdom with modern scientific advancements, this integrated approach paves the way for novel therapeutic discoveries and the sustainable utilisation of medicinal plants. Full article
(This article belongs to the Section Plant Metabolism)
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19 pages, 1871 KB  
Review
Thioredoxin-Interacting Protein (TXNIP) in Gestational Diabetes Mellitus
by Ioanna Kokkinopoulou and Anna Papadopoulou
Metabolites 2025, 15(6), 351; https://doi.org/10.3390/metabo15060351 - 26 May 2025
Viewed by 979
Abstract
Background: Thioredoxin-interacting protein (TXNIP) is a major inhibitor of the thioredoxin (TRX) antioxidant system and an important player in the development and aggravation of intracellular oxidative stress. Although first recognized as a metabolic regulator, recent studies have identified the multifaceted role of this [...] Read more.
Background: Thioredoxin-interacting protein (TXNIP) is a major inhibitor of the thioredoxin (TRX) antioxidant system and an important player in the development and aggravation of intracellular oxidative stress. Although first recognized as a metabolic regulator, recent studies have identified the multifaceted role of this protein in other molecular pathways involving inflammation, apoptosis, and glucose metabolism. Methods: This review aims to highlight the importance of TXNIP in diabetes-related pathophysiology and explore the existing evidence regarding TXNIP’s role in GDM-associated pathogenetic mechanisms, revealing common regulatory pathways. Results: Among other complex diseases, TXNIP has been found upregulated in diabetic pancreatic beta cells, thus contributing to diabetes pathogenesis and its related complications. In addition, depletion of TXNIP has been shown to decrease the negative consequences of excessive stress in various cellular systems and diseases, pointing towards a potential therapeutic target. In line with these findings, TXNIP has been investigated in the pathogenesis of Gestational Diabetes Mellitus (GDM), a common pregnancy complication affecting the mother and the neonate. Overexpression of TXNIP has been found in GDM placentas or trophoblast cell lines mimicking GDM conditions and has been associated with key dysregulated mechanisms of GDM pathophysiology, like oxidative stress, inflammation, apoptosis, impaired autophagy, altered trophoblast behavior, and placental morphology. Interestingly, TXNIP has been found upregulated in GDM maternal serum and downregulated in umbilical cord blood, indicating potential compensatory protective mechanisms to GDM-related oxidative stress. Conclusions: Due to its contribution to the regulation of critical cellular processes such as inflammation, metabolism, and apoptosis, TXNIP finds its place in the pathophysiology of gestational diabetes through a currently limited number of scientific reports. Full article
(This article belongs to the Special Issue Glucose Metabolism in Pregnancy)
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16 pages, 1210 KB  
Article
Effect of Thermal Processing by Spray Drying on Key Ginger Compounds
by Alina Warren-Walker, Manfred Beckmann, Alison Watson, Steffan McAllister and Amanda J. Lloyd
Metabolites 2025, 15(6), 350; https://doi.org/10.3390/metabo15060350 - 24 May 2025
Viewed by 1049
Abstract
Background/Objectives: Spray drying is a technique widely employed in the food and nutraceutical industries to convert liquid extracts into stable powders, preserving their functional properties. Ginger (Zingiber officinale) is rich in bioactive compounds such as gingerols, shogaols, and zingerone, which contribute [...] Read more.
Background/Objectives: Spray drying is a technique widely employed in the food and nutraceutical industries to convert liquid extracts into stable powders, preserving their functional properties. Ginger (Zingiber officinale) is rich in bioactive compounds such as gingerols, shogaols, and zingerone, which contribute to its health benefits. This study aimed to investigate the impact of spray drying on the chemical profile of ginger, particularly focusing on the transformation of gingerols into shogaols and related compounds. Methods: Fresh ginger juice was spray-dried using various carrier agents, including Clear Gum (CO03), pea protein, and inulin. Mass spectra of the resulting powders were acquired using High-Resolution Flow Infusion Electrospray Ionisation Mass Spectrometry (HR-FIE-MS) to obtain fingerprint data. Key bioactive compounds were tentatively identified to Level 2, and their relative intensities were assessed to evaluate the effects of different carriers on the chemical composition of the ginger powders. Results: Spray drying with the commercial carrier CO03 resulted in an increase in shogaol analogues ([10]-, [8]-, and cis-[8]-shogaol), gingerenone B, and oxidation products such as 6-hydroxyshogaol, 6-dehydroshogaol, and zingerone. In contrast, natural carriers like pea protein and inulin led to lower relative intensities of these bioactives, suggesting limited capacity for promoting thermal transformations. Spray drying without a carrier produced a shogaol-dominant profile but resulted in powders with poor handling properties, such as stickiness and agglomeration. Antioxidant and total polyphenol assays showed that spray drying reduced antioxidant capacity, while total polyphenol content was more preserved; natural carriers such as inulin better maintained bioactivity compared to modified starch or pea protein. Conclusions: Among the five formulations evaluated—ginger juice with no carrier, with CO03 (two dilutions), pea protein, or inulin—CO03-based samples showed the greatest chemical transformation, while inulin and pea protein better preserved antioxidant capacity but induced fewer metabolite changes. Thus, choice of carrier in the spray-drying process influences the chemical profile and functional characteristics of resultant ginger powders. While CO03 effectively enhances the formation of bioactive shogaols and related compounds, its ultra-processed nature may not align with clean-label product trends. Natural carriers, although more label-friendly, may not create the desired chemical transformations. Therefore, optimising carrier selection is important to balance bioactivity, product stability, and consumer acceptability in the development of ginger-based functional products. Full article
(This article belongs to the Special Issue Advances in Food Metabolomics for Functional Food Development and Analysis)
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16 pages, 289 KB  
Article
Dietary Black Soldier Fly Larvae Meal and Its Impact on the Growth Performance and Gut Health of Broilers Under an Intestinal Challenge
by Yuri Katagiri Dalmoro, Guilherme Librelotto de Godoy, Jessica Cristina Agilar, Glauco Anderson Raddatz, Fernanda de Candido de Oliveira, Natieli Witt and Catarina Stefanello
Metabolites 2025, 15(6), 347; https://doi.org/10.3390/metabo15060347 - 23 May 2025
Viewed by 944
Abstract
Background/Objectives: The use of black soldier fly (BSF) larvae meal in poultry nutrition is gaining attention as a sustainable protein source with a high nutritional value, an efficient bioconversion of organic waste, and potential functional benefits for intestinal health. This study evaluated the [...] Read more.
Background/Objectives: The use of black soldier fly (BSF) larvae meal in poultry nutrition is gaining attention as a sustainable protein source with a high nutritional value, an efficient bioconversion of organic waste, and potential functional benefits for intestinal health. This study evaluated the dietary effects of including 5% BSF larvae meal on the growth performance, nutrient digestibility, and energy utilization as well as on the intestinal integrity, gene expression, lipid profile, and short-chain fatty acid (SCFA) production of broilers under an intestinal challenge. Methods: Eight hundred one-day-old male broilers were assigned to four dietary treatments with eight replicates (25 birds/pen) and reared until day 40. Birds were fed either a Basal corn–soy diet or a BSF diet (5% BSF larvae meal replacing energy- and protein-yielding ingredients). Diets were provided to a non-challenged group and a challenged group, which was orally gavaged with Eimeria spp. on day 1 and Clostridium perfringens on days 11 and 14. The growth performance was evaluated up to day 40, while the nutrient digestibility, meat lipid profile, intestinal histomorphology, and gene expression were assessed at 21 days. The SCFAs were determined at both 21 and 40 days. Results: It was observed that the intestinal challenge induced dysbiosis and negatively affected growth performance, whereas the BSF meal inclusion partially mitigated these adverse effects. Broilers fed the BSF larvae meal showed increased cecal SCFA concentrations and a lower interleukin-6 gene expression, along with higher lauric and myristic acid levels in breast muscle (p ≤ 0.05). Conclusions: The inclusion of 5% BSF larvae meal improved performance without impairing nutrient digestibility or intestinal histomorphology, while increasing cecal concentrations of butyric and acetic acids and promoting a beneficial lipid deposition. Full article
(This article belongs to the Special Issue Nutrition and Metabolism in Poultry)
17 pages, 1366 KB  
Article
1H NMR-Based Analysis to Determine the Metabolomics Profile of Solanum nigrum L. (Black Nightshade) Grown in Greenhouse Versus Open-Field Conditions
by Lufuno Ethel Nemadodzi, Gudani Millicent Managa and Ndivho Nemukondeni
Metabolites 2025, 15(5), 344; https://doi.org/10.3390/metabo15050344 - 21 May 2025
Viewed by 872
Abstract
Background: Equally with other indigenous green leafy vegetables, Solunum nigrum L. has been widely consumed by the VhaVenda tribe found in the Limpopo Province of South Africa since ancient times as a source of food diversification due to its higher-quality nutritional value, sustainability, [...] Read more.
Background: Equally with other indigenous green leafy vegetables, Solunum nigrum L. has been widely consumed by the VhaVenda tribe found in the Limpopo Province of South Africa since ancient times as a source of food diversification due to its higher-quality nutritional value, sustainability, food security, and medicinal benefits. It is mostly cultivated from seeds in seedling trays and transplanted in the open field, and at the maturity stage, marketing and distribution are mainly conducting through informal markets (i.e., street vendors). However, recently, it can be found in selected supermarkets and commercial grocery stores in South Africa. The leaves and young shoots of S. nigrum are cooked solely and/or as a supplementary vegetable with Brassica rapa L. subsp. chinensis (Chinese cabbage), Spinacia oleracea L. (spinach), Amaranthus graecizans L. (green amaranth), Solanum lycopersicum L. (tomato), and/or cooking oil for flavor. Objective: Contrary to other green leafy vegetables, few studies have been conducted on the metabolites released by S. nigrum and the influence of growing conditions on the metabolites thereof. Method: A 1H-nuclear magnetic resonance tool was used to identify the untargeted metabolites released by S. nigrum, and spectra were phase-corrected and binned with MestReNova and statistically analyzed with SIMCA 18.0.2. Results: The findings showed that a total of 12 metabolites were detected between the growing conditions. Eleven similar metabolites, such as glycocholate, chlorogenate (human health benefits), caffeine for its bitter taste, choline, 3-Chlorotyrosine (antidiabetic, blood pressure), etc., and a few vital soluble sugars, were detected in S. nigrum samples grown in the open field and greenhouse-cultivated. Glucose was exclusively detected in the S. nigrum grown under greenhouse conditions. Full article
(This article belongs to the Special Issue Unlocking Nature's Toolbox: Advances in Plant Metabolites Identification)
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15 pages, 1429 KB  
Article
Characterizing Plasma-Based Metabolomic Signatures for Metastasis in Non-Small Cell Lung Cancer
by Manlu Liu, Yanlong Zhu, Sean J. McIlwain, Haotian Deng, Allan R. Brasier, Ying Ge, Michelle E. Kimple and Andrew M. Baschnagel
Metabolites 2025, 15(5), 340; https://doi.org/10.3390/metabo15050340 - 20 May 2025
Viewed by 1060
Abstract
Background/Objectives: The current staging of non-small cell lung cancer (NSCLC) relies on conventional imaging, which lacks the sensitivity to detect micrometastatic disease. The functional assessment of NSCLC progression may provide independent information to enhance the prediction of metastatic risk. The objective of [...] Read more.
Background/Objectives: The current staging of non-small cell lung cancer (NSCLC) relies on conventional imaging, which lacks the sensitivity to detect micrometastatic disease. The functional assessment of NSCLC progression may provide independent information to enhance the prediction of metastatic risk. The objective of this study was to determine if we could identify a metabolomic signature predictive of metastasis in patients with NSCLC treated with definitive radiation. Methods: Plasma samples were collected prospectively from patients enrolled in a clinical trial with non-metastatic NSCLC treated with definitive radiation. Metabolites were extracted, and mass spectrometry-based analysis was performed using a flow injection electrospray (FIE)–Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS) method. Early metastasis was defined as metastasis within 1 year of radiation treatment. Results: The study cohort included 28 patients. FIE-FITCR produced highly reproducible profiles in technical replicates. A total of 51 metabolic features were identified to be different in patients with early metastasis compared to patients without early metastasis (all adjusted p-values < 0.05, Welch’s t-test), including glycerophospholipids, sphingolipids, and fatty acyls. In the follow-up samples collected after the initiation of chemotherapy and radiation treatment, a total of 174 metabolic features were significantly altered in patients who developed early metastasis compared to those who did not. Conclusions: We identified several distinct changes in the metabolic profiles of patients with NSCLC who developed metastatic disease within 1 year of definitive radiation. These findings highlight the potential of metabolomic profiling as a predictive tool for assessing metastatic risk in NSCLC. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2024)
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