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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 532
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 324
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 313
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 549
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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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 393
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 668
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 642
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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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 546
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 580
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 602
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 739
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 1385
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 526
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 1227
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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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 1385
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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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 379
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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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 602
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 665
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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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 1948
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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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 925
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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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 1576
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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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 3415
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)
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 563
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 646
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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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 881
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 694
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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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 1232
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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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 988
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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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 1084
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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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 1235
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 1234
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 4386
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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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 1162
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 967
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 1047
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 933
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 867
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 1055
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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42 pages, 830 KB  
Review
Gut–Brain Inflammatory Pathways in Attention-Deficit/Hyperactivity Disorder: The Role and Therapeutic Potential of Diet
by Naomi Lewis, Jim Lagopoulos and Anthony Villani
Metabolites 2025, 15(5), 335; https://doi.org/10.3390/metabo15050335 - 19 May 2025
Cited by 1 | Viewed by 3780
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder that often persists into adulthood, leading to various adverse outcomes. Its underlying pathology is multifactorial, involving neurotransmitter imbalances, gut microbiota alterations, and oxidative and inflammatory dysregulation. Diet, a key environmental modifier of gut ecology, [...] Read more.
Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder that often persists into adulthood, leading to various adverse outcomes. Its underlying pathology is multifactorial, involving neurotransmitter imbalances, gut microbiota alterations, and oxidative and inflammatory dysregulation. Diet, a key environmental modifier of gut ecology, is consistently poorer in individuals with ADHD, with multiple nutrients implicated in its pathophysiology. This review examines the role of specific nutrients such as omega-3 fatty acids, key micronutrients, and potentially harmful dietary components, as well as broader dietary patterns, particularly the Western diet and Mediterranean diet (MedDiet), in relation to ADHD symptoms. It also evaluates both whole-diet and supplement-based clinical interventions, supporting the growing recognition of nutrition as a safe and relatively affordable modifiable factor in ADHD management. Additionally, the biological mechanisms linking diet to ADHD are reviewed, highlighting strong evidence for the involvement of gut dysbiosis and inflammatory processes. Despite the well-documented antioxidant, anti-inflammatory, and microbiome benefits of the MedDiet, direct research investigating its role in ADHD remains limited. Most whole-diet approaches to date have focused on elimination diets, leaving a significant gap in understanding the potential role of the MedDiet in ADHD management. Therefore, this review outlines preliminary evidence supporting the MedDiet and its key components as modulators of ADHD-related biological pathways, indicating its potential as a therapeutic approach. However, further research is required to rigorously evaluate its clinical efficacy. Finally, the limitations of observational and interventional nutritional research in ADHD are discussed, along with recommendations for future research directions. Full article
(This article belongs to the Special Issue The Roles of Diet, Gut Microbiome and Microbial Metabolome in Precision Nutrition)
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23 pages, 3896 KB  
Article
Storage Profiling: Evaluating the Effect of Modified Atmosphere Packaging on Metabolomic Changes of Strawberries (Fragaria × ananassa)
by Johannes Brockelt, Robin Dammann, Jennifer Griese, Agnes Weiss, Markus Fischer and Marina Creydt
Metabolites 2025, 15(5), 330; https://doi.org/10.3390/metabo15050330 - 15 May 2025
Viewed by 877
Abstract
Background/Objectives: Strawberries (Fragaria × ananassa) are among the most commonly consumed fruits due to their taste and nutritional benefits. However, their high rate of spoilage poses a major problem during the period from harvest and transport to further processing or marketing. [...] Read more.
Background/Objectives: Strawberries (Fragaria × ananassa) are among the most commonly consumed fruits due to their taste and nutritional benefits. However, their high rate of spoilage poses a major problem during the period from harvest and transport to further processing or marketing. The aim of this study was, therefore, to investigate the effects of passive modified atmosphere packaging on the metabolome and shelf life of strawberries as a more sustainable alternative compared to standard market storage conditions. Methods: A total of 99 strawberry samples were analyzed for microbial viable counts, water content, and metabolomic changes using non-targeted low-resolution near-infrared spectroscopy, high-resolution mass spectrometry, and microbial culture-based methods. Results: Using near-infrared spectroscopy as a rapid screening method, the linear regression model indicated that strawberries stored under modified atmosphere packaging conditions had a longer shelf life. Furthermore, lipidomic analysis using mass spectrometry showed that the levels of spoilage biomarkers, such as oxidized phosphatidylcholines and lysophosphatidylcholines, were increased under common market storage conditions without a controlled atmosphere. In contrast, the levels of these metabolites were reduced when strawberries were stored in modified atmosphere packaging. Moreover, the strawberries stored under modified atmosphere packaging had a lower number of bacteria, yeasts, and molds as well as a lower water loss throughout the entire storage period. Conclusions: Overall, the study highlights the potential of passive modified atmosphere packaging films to extend the shelf life and thus maintain the edibility of strawberries over a longer period. Full article
(This article belongs to the Special Issue Metabolomic Technology in Quality and Safety of Agricultural Products and Foods)
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27 pages, 2350 KB  
Article
Exploring Postharvest Metabolic Shifts and NOX2 Inhibitory Potential in Strawberry Fruits and Leaves via Untargeted LC-MS/MS and Chemometric Analysis
by Georgia Ladika, Paris Christodoulou, Eftichia Kritsi, Thalia Tsiaka, Georgios Sotiroudis, Dionisis Cavouras and Vassilia J. Sinanoglou
Metabolites 2025, 15(5), 321; https://doi.org/10.3390/metabo15050321 - 13 May 2025
Viewed by 650
Abstract
Background/Objectives: Strawberries are highly appreciated for their rich phytochemical composition, but rapid postharvest deterioration limits their shelf life and nutritional quality. This study aimed to investigate the metabolic changes occurring in both strawberry fruits and leaves during storage and to evaluate the NADPH [...] Read more.
Background/Objectives: Strawberries are highly appreciated for their rich phytochemical composition, but rapid postharvest deterioration limits their shelf life and nutritional quality. This study aimed to investigate the metabolic changes occurring in both strawberry fruits and leaves during storage and to evaluate the NADPH oxidase 2 (NOX2) inhibitory potential of strawberry-derived metabolites. Methods: Untargeted LC-MS/MS analysis was conducted on fruit and leaf tissues stored at 8 ± 0.5 °C. A total of 37 metabolites were identified, including organic acids, phenolic acids, flavonoids, and hydroxycinnamic acid derivatives. Multivariate statistical analyses (ANOVA, PLS-DA, and volcano plots) were used to assess temporal and tissue-specific metabolic shifts. Additionally, a machine learning-based predictive model was applied to evaluate the NOX2 inhibitory potential of 24 structurally characterized metabolites. Results: Storage induced significant and tissue-specific metabolic changes. In fruits, malic acid, caffeic acid, and quercetin-3-glucuronide showed notable variations, while ellagic acid aglycone and galloylquinic acid emerged as prominent markers in leaves. The predictive model identified 21 out of 24 metabolites as likely NOX2 inhibitors, suggesting potential antioxidant and anti-inflammatory bioactivity. Conclusions: These findings provide new insights into postharvest biochemical dynamics in both strawberry fruits and leaves. The results highlight the value of leaves as a source of bioactive compounds and support their potential valorization in functional food and nutraceutical applications. Full article
(This article belongs to the Special Issue Metabolic Changes during Pre- and Post-harvest Fruit and Vegetable Decay, Ripening and Senescence)
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15 pages, 1440 KB  
Article
Plasma Metabolic Outliers Identified in Estonian Human Knockouts
by Ketian Yu, Estonian Biobank Research Team, Karol Estrada, Tõnu Esko, Mart Kals, Tiit Nikopensius, Jaanika Kronberg, Urmo Võsa, Arthur Wuster and Lorenzo Bomba
Metabolites 2025, 15(5), 323; https://doi.org/10.3390/metabo15050323 - 13 May 2025
Viewed by 717
Abstract
Background/Objectives: Metabolomics, in combination with genetic data, is a powerful approach to study the biochemical consequences of genetic variation. We assessed the impact of human gene knockouts (KOs) on the metabolite levels of Estonia Biobank (EstBB) participants and integrated the results with electronic [...] Read more.
Background/Objectives: Metabolomics, in combination with genetic data, is a powerful approach to study the biochemical consequences of genetic variation. We assessed the impact of human gene knockouts (KOs) on the metabolite levels of Estonia Biobank (EstBB) participants and integrated the results with electronic health record data. Methods: In 150,000 EstBB genotyped participants, we identified 723 KOs with 152 different predicted loss of function (pLoF) variants in 115 genes. For those KOs and 258 controls, 1387 metabolites were profiled using ultra-high-performance liquid chromatography–tandem mass spectrometry. Results: We identified 48 associations linking rare pLoF variants in 22 genes to 43 metabolites. Out of 48 associations, 27 (56%) were found in genes that cause inborn errors of metabolism. The top associations identified in our analysis included genes and metabolites involved in the degradation pathway of the pyrimidine bases uracil and thymine (DPYD and UPB1). We found DPYD gene KOs to be associated with elevated levels of Uracil, confirming that DPD-deficiency is a leading cause of severe 5-Fluorouracil toxicity. Overall, 54% of reported associations are gene targets of approved drugs or bioactive drug-like compounds. Conclusions: Our findings contribute to assessing the impact of human KOs on metabolite levels and offer insights into gene functions, disease mechanism, and drug target validation. Full article
(This article belongs to the Section Bioinformatics and Data Analysis)
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14 pages, 3108 KB  
Article
Comprehensive Analysis of Small RNA Modifications in Arabidopsis thaliana and Their Dynamics During Seed Germination
by Liu-Cheng Jiang, Meng Men, Xuan-Jun Cui, Ren-Jie Zeng, Shu-Yi Gu, Tian Feng, Chen Zeng, Tiantian Ye, Jun Xiong, Bi-Feng Yuan and Yu-Qi Feng
Metabolites 2025, 15(5), 319; https://doi.org/10.3390/metabo15050319 - 10 May 2025
Viewed by 602
Abstract
Background: Small RNA, defined as RNA molecules of less than 200 nucleotides in length, play pivotal regulatory roles in plant growth, development, and environmental stress responses. However, research on modifications in plant small RNA remains limited. Methods: In this study, we [...] Read more.
Background: Small RNA, defined as RNA molecules of less than 200 nucleotides in length, play pivotal regulatory roles in plant growth, development, and environmental stress responses. However, research on modifications in plant small RNA remains limited. Methods: In this study, we developed a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the simultaneous detection of 41 RNA modifications, facilitating the systematic qualification and quantification of modifications in plant small RNA. Results: We identified a total of nine modifications, among which N6,N6-dimethyladenosine (m6,6A) is a newly identified modification in plant small RNA. Furthermore, we conducted a quantitative analysis of these modifications in Arabidopsis thaliana during the germination process and observed significant dynamic changes in their abundance from 1 to 5 days post-germination. Notably, the trends in the contents of these modifications exhibited a strong correlation with the reported gene expression levels of the relevant modifying enzymes and demodifying enzymes, suggesting that these modifications may play essential roles during seed germination and are tightly regulated by the genes of the corresponding enzymes. Conclusions: The discovery of these modifications in plant small RNA, coupled with the dynamic changes in their levels during germination, holds great promise for a further understanding of the physiological functions of small RNA modifications and their associated regulatory mechanisms in plant seed germination. Full article
(This article belongs to the Special Issue LC-MS/MS Analysis for Plant Secondary Metabolites)
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20 pages, 3404 KB  
Article
A Data-Driven Approach to Link GC-MS and LC-MS with Sensory Attributes of Chicken Bouillon with Added Yeast-Derived Flavor Products in a Combined Prediction Model
by Simon Leygeber, Carmen Diez-Simon, Justus L. Großmann, Anne-Charlotte Dubbelman, Amy C. Harms, Johan A. Westerhuis, Doris M. Jacobs, Peter W. Lindenburg, Margriet M. W. B. Hendriks, Brenda C. H. Ammerlaan, Marco A. van den Berg, Rudi van Doorn, Roland Mumm, Age K. Smilde, Robert D. Hall and Thomas Hankemeier
Metabolites 2025, 15(5), 317; https://doi.org/10.3390/metabo15050317 - 8 May 2025
Viewed by 1020
Abstract
Background: There is a continuous demand to create new, superior sensory food experiences. In the food industry, yeast-derived flavor products (YPs) are often used as ingredients in foods to create new aromas and taste qualities that are appreciated by consumers. Methods: Chicken bouillon [...] Read more.
Background: There is a continuous demand to create new, superior sensory food experiences. In the food industry, yeast-derived flavor products (YPs) are often used as ingredients in foods to create new aromas and taste qualities that are appreciated by consumers. Methods: Chicken bouillon samples containing diverse YPs were chemically and sensorially characterized using statistical multivariate analyses. The sensory evaluation was performed using quantitative descriptive analysis (QDA) by trained panelists. Thirty-four sensory attributes were scored, including odor, flavor, mouthfeel, aftertaste and afterfeel. Untargeted metabolomic profiles were obtained using stir bar sorptive extraction (SBSE) coupled to GC-MS, RPLC-MS and targeted HILIC-MS. Results: In total, 261 volatiles were detected using GC-MS, from chemical groups of predominantly aldehydes, esters, pyrazines and ketones. Random Forest (RF) modeling revealed volatiles associated with roast odor (2-ethyl-5-methyl pyrazine, 2,3,5-trimethyl-6-isopentyl pyrazine) and chicken odor (2,4-nonadienal, 2,4-decadienal, 2-acetyl furan), which could be predicted by our combined model with R2 > 0.5. In total, 2305 non-volatiles were detected for RPLC-MS and 34 for targeted HILIC-MS, where fructose-isoleucine and cyclo-leucine-proline were found to correlate with roast flavor and odor. Furthermore, a list of metabolites (glutamate, monophosphates, methionyl-leucine) was linked to umami-related flavor. This study describes a straightforward data-driven approach for studying foods with added YPs to identify flavor-impacting correlations between molecular composition and sensory perception. It also highlights limitations and preconditions for good prediction models. Overall, this study emphasizes a matrix-based approach for the prediction of food taste, which can be used to analyze foods for targeted flavor design or quality control. Full article
(This article belongs to the Section Food Metabolomics)
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17 pages, 1679 KB  
Article
Peripheral Antinociception Induced by Carvacrol in the Formalin Test Involves the Opioid Receptor-NO-cGMP-K+ Channel Pathway
by Mario I. Ortiz, Raquel Cariño-Cortés, Eduardo Fernández-Martínez, Victor Manuel Muñoz-Pérez, Gilberto Castañeda-Hernández and Martha Patricia González-García
Metabolites 2025, 15(5), 314; https://doi.org/10.3390/metabo15050314 - 7 May 2025
Viewed by 648
Abstract
Background/Objectives: Carvacrol is a naturally occurring phenolic monoterpene that is one of the main constituents of the essential oils of oregano (Origanum vulgare) and other herbs. Carvacrol has anti-inflammatory and antinociceptive effects. Carvacrol can activate and inhibit several second messengers and [...] Read more.
Background/Objectives: Carvacrol is a naturally occurring phenolic monoterpene that is one of the main constituents of the essential oils of oregano (Origanum vulgare) and other herbs. Carvacrol has anti-inflammatory and antinociceptive effects. Carvacrol can activate and inhibit several second messengers and ionic channels at the systemic level. However, there is no evidence of the peripheral antinociception of carvacrol and its mechanism of action. This study was designed to determine whether the opioid receptor-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-K+ channel pathway is involved in the local antinociception of carvacrol. Methods: Wistar rats were injected with 1% formalin subcutaneously on the dorsal surface of the right hind paw with the vehicle or carvacrol (100–300 µg/paw). To determine whether the opioid receptor-NO-cGMP-K+ channel pathway and a biguanide-dependent mechanism are responsible for the local antinociception induced by carvacrol, the effect of the injection (10 min before the 1% formalin injection) with the corresponding vehicles, metformin, naltrexone, NG-L-nitro-arginine methyl ester (L-NAME), 1 H-(1,2,4)-oxadiazolo (4,2-a) quinoxalin-1-one (ODQ), and K+ channel blockers on the antinociception induced by local carvacrol (300 µg/paw) was determined. Results: In both phases of the formalin test, carvacrol produced antinociception. Naltrexone, metformin, L-NAME, ODQ, glibenclamide and glipizide (both ATP-sensitive K+ channel blockers), tetraethylammonium and 4-aminopyridine (voltage-gated K+ channel blockers), and apamin and charybdotoxin (Ca2+-activated K+ channel blockers) reversed the carvacrol-induced peripheral antinociception. Conclusions: The local peripheral administration of carvacrol produced significant antinociception and activated the opioid receptor-NO-cGMP-K+ channel pathway. Full article
(This article belongs to the Special Issue Exploring Innovations in Secondary Metabolites and Their Effects on Pain, Inflammation and Metabolic Syndrome)
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14 pages, 1467 KB  
Article
Propionyl Carnitine Metabolic Profile: Optimizing the Newborn Screening Strategy Through Customized Cut-Offs
by Maria Lucia Tommolini, Maria Concetta Cufaro, Silvia Valentinuzzi, Ilaria Cicalini, Mirco Zucchelli, Alberto Frisco, Simonetta Simonetti, Michela Perrone Donnorso, Sara Moccia, Ines Bucci, Maurizio Aricò, Vincenzo De Laurenzi, Luca Federici, Damiana Pieragostino and Claudia Rossi
Metabolites 2025, 15(5), 308; https://doi.org/10.3390/metabo15050308 - 6 May 2025
Cited by 1 | Viewed by 1218
Abstract
Background: The advent of tandem mass spectrometry (MS/MS) had an essential role in the expansion of newborn screening (NBS) for different inborn errors of metabolism (IEMs). Nowadays, almost 50 IEMs are screened in Italy. The use of second-tier tests (2-TTs) in NBS minimizes [...] Read more.
Background: The advent of tandem mass spectrometry (MS/MS) had an essential role in the expansion of newborn screening (NBS) for different inborn errors of metabolism (IEMs). Nowadays, almost 50 IEMs are screened in Italy. The use of second-tier tests (2-TTs) in NBS minimizes the false positive rate; nevertheless, the metabolic profile is influenced not only by the genome but also by environmental factors and clinical variables. We reviewed the MS/MS NBS data from over 37,000 newborns (of which 8% required 2-TTs) screened in the Italian Abruzzo region to evaluate the impact of neonatal and maternal variables on propionate-related primary biomarker levels. Methods: Expanded NBS and 2-TT analyses were performed using MS/MS and liquid chromatography–MS/MS methods. We set up layered cut-offs dividing all 37,000 newborns into categories. Statistical analysis was used to create alarm thresholds for NBS-positive samples. Statistically significant differences were found in both neonatal and maternal conditions based on the 2-TTs carried out. According to the stratified cut-offs, only 1.47% of the newborns would have required a 2-TT while still retaining the ability to recognize the true-positive case of methylmalonic acidemia with homocystinuria, which has been identified by NBS. To further support the clinical applicability, we performed an external evaluation considering nine positive cases from an extra-regional neonatal population, confirming the potential of our model. Interestingly, the setting of alarm thresholds and their application would allow for establishing the degree of priority/urgency for 2-TTs. Conclusions: Tailoring NBS by customized cut-offs may enhance the application of precision medicine, focusing on true-positive cases and also reducing analysis costs and times. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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18 pages, 1862 KB  
Review
SMARCB1 Deficiency as a Driver of the Hallmarks of Cancer in Rhabdoid Tumours: Novel Insights into Dysregulated Energy Metabolism, Emerging Targets, and Ongoing Clinical Trials
by Abdul L. Shakerdi and Graham P. Pidgeon
Metabolites 2025, 15(5), 304; https://doi.org/10.3390/metabo15050304 - 3 May 2025
Viewed by 1842
Abstract
Background: Rhabdoid tumours (RTs) are aggressive neoplasms most often characterised by biallelic loss of the SMARCB1 gene, encoding a core subunit of the SWI/SNF chromatin-remodelling complex. Despite their relative genetic stability, RTs exhibit a highly malignant phenotype and poor prognosis. Methods: This review [...] Read more.
Background: Rhabdoid tumours (RTs) are aggressive neoplasms most often characterised by biallelic loss of the SMARCB1 gene, encoding a core subunit of the SWI/SNF chromatin-remodelling complex. Despite their relative genetic stability, RTs exhibit a highly malignant phenotype and poor prognosis. Methods: This review explores the mechanisms underlying SMARCB1 aberrations, their role in driving hallmarks of cancer, and emerging therapeutic strategies for RTs. Ongoing clinical trials listed on ClinicalTrials were reviewed to evaluate the translational potential of targeted therapies in SMARCB1-deficient rhabdoid tumours. Results: Loss of SMARCB1 drives multiple cancer hallmarks by disrupting key regulatory pathways. It promotes unchecked cell proliferation through alterations in p16INK4a and Myc signalling. SMARCB1-deficient tumours possess immune-evading capabilities via PD-L1 overexpression and immune checkpoint activation. SMARCB1 deficiency also alters cellular energetics. The nucleotide biosynthesis pathway has been demonstrated to be upregulated in RT organoids, as shown by increased levels of pathway metabolites. Enzymes of the mevalonate pathway such as HMG-CoA reductase and mevalonate kinase are also dysregulated. Targeting glutathione metabolism with eprenetapopt may induce oxidative stress and apoptosis. Widespread epigenetic aberrations, including increased EZH2 activity, are being targeted with inhibitors such as tazemetostat. Conclusions: SMARCB1 loss is a central driver of cancer hallmarks in RTs, enabling proliferation, immune evasion, metabolic reprogramming, and epigenetic dysregulation. Future horizons in RT treatment include immunotherapies, epigenetic modifiers, and gene therapies. The synergy and optimal timing of targeted therapy with conventional treatment requires further characterisation for clinical translation. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2024)
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24 pages, 2280 KB  
Review
From Biomarker Discovery to Clinical Applications of Metabolomics in Glioblastoma
by Neja Šamec, Gloria Krapež, Cene Skubic, Ivana Jovčevska and Alja Videtič Paska
Metabolites 2025, 15(5), 295; https://doi.org/10.3390/metabo15050295 - 29 Apr 2025
Cited by 1 | Viewed by 1436
Abstract
Background/Objectives: In recent years, interest in studying changes in cancer metabolites has resulted in significant advances in the metabolomics field. Glioblastoma remains the most aggressive and lethal brain malignancy, which presents with notable metabolic reprogramming. Methods: We performed literature research from the PubMed [...] Read more.
Background/Objectives: In recent years, interest in studying changes in cancer metabolites has resulted in significant advances in the metabolomics field. Glioblastoma remains the most aggressive and lethal brain malignancy, which presents with notable metabolic reprogramming. Methods: We performed literature research from the PubMed database and considered research articles focused on the key metabolic pathways altered in glioblastoma (e.g., glycolysis, lipid metabolism, TCA cycle), the role of oncometabolites and metabolic plasticity, and the differential expression of metabolites in glioblastoma. Currently used metabolomics approaches can be either targeted, focusing on specific metabolites and pathways, or untargeted, which involves data-driven exploration of the metabolome and also results in the identification of new metabolites. Data processing and analysis is of great importance and can be improved with the integration of machine learning approaches for metabolite identification. Results: Changes in α/β-glucose, lactate, choline, and 2-hydroxyglutarate were detected in glioblastoma compared with non-tumor tissues. Different metabolites such as fumarate, tyrosine, and leucine, as well as citric acid, isocitric acid, shikimate, and GABA were detected in blood and CSF, respectively. Conclusions: Although promising new technological and bioinformatic approaches help us understand glioblastoma better, challenges associated with biomarker availability, tumor heterogeneity, interpatient variability, standardization, and reproducibility still remain. Metabolomics research, either alone or combined with genomics or proteomics (i.e., multiomics) in glioblastoma, can lead to biomarker identification, tracking of metabolic therapy response, discovery of novel metabolites and pathways, and identification of potential therapeutic targets. Full article
(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics in Health and Disease: Targeted Analysis and Its Trends)
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34 pages, 1818 KB  
Review
From Childhood Obesity to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Hyperlipidemia Through Oxidative Stress During Childhood
by Siham Accacha, Julia Barillas-Cerritos, Ankita Srivastava, Frances Ross, Wendy Drewes, Shelly Gulkarov, Joshua De Leon and Allison B. Reiss
Metabolites 2025, 15(5), 287; https://doi.org/10.3390/metabo15050287 - 24 Apr 2025
Cited by 2 | Viewed by 2625
Abstract
Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is rapidly becoming the most prevalent form of chronic liver disease in both pediatric and adult populations. It encompasses a wide spectrum of liver abnormalities, ranging from simple [...] Read more.
Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is rapidly becoming the most prevalent form of chronic liver disease in both pediatric and adult populations. It encompasses a wide spectrum of liver abnormalities, ranging from simple fat accumulation to severe conditions such as inflammation, fibrosis, cirrhosis, and liver cancer. Major risk factors for MASLD include obesity, insulin resistance, type 2 diabetes, and hypertriglyceridemia. Methods: This narrative review employed a comprehensive search of recent literature to identify the latest studies on the relationship between MAFLD and obesity, the health consequences and the latest treatment options to prevent long-term damage to the liver and other organs. Additionally, the article presents perspectives on diagnostic biomarkers. Results: Childhood obesity is linked to a multitude of comorbid conditions and remains a primary risk factor for adult obesity. This abnormal fat accumulation is known to have long-term detrimental effects into adulthood. Scientific evidence unequivocally demonstrates the role of obesity-related conditions, such as insulin resistance, dyslipidemia, and hyperglycemia, in the development and progression of MASLD. Oxidative stress, stemming from mitochondrial dysfunction, is a leading factor in MASLD. This review discusses the interconnections between oxidative stress, obesity, dyslipidemia, and MASLD. Conclusions: Atherogenic dyslipidemia, oxidative stress, inflammation, insulin resistance, endothelial dysfunction, and cytokines collectively contribute to the development of MASLD. Potential treatment targets for MASLD are focused on prevention and the use of drugs to address obesity and elevated blood lipid levels. Full article
(This article belongs to the Special Issue Metabolic Dysregulation in Fatty Liver Disease)
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