Metabolites

20 pages, 1864 KiB

Open AccessArticle

Serum Metabolomic Signatures in Nonhuman Primates Treated with a Countermeasure and Exposed to Partial- or Total-Body Radiation

by Alana D. Carpenter, Yaoxiang Li, Benjamin E. Packer, Oluseyi O. Fatanmi, Stephen Y. Wise, Sarah A. Petrus, Martin Hauer-Jensen, Amrita K. Cheema and Vijay K. Singh

Metabolites 2025, 15(8), 546; https://doi.org/10.3390/metabo15080546 (registering DOI) - 12 Aug 2025

Abstract

Background: Irradiation-induced injury is a common fallout of radiological/nuclear accidents or therapeutic exposures to high doses of radiation at high dose rates. Currently, there are no prophylactic drugs available to mitigate radiation injury as a result of exposure to lethal doses of ionizing [...] Read more.

Background: Irradiation-induced injury is a common fallout of radiological/nuclear accidents or therapeutic exposures to high doses of radiation at high dose rates. Currently, there are no prophylactic drugs available to mitigate radiation injury as a result of exposure to lethal doses of ionizing radiation. Gamma-tocotrienol (GT3) of vitamin E is a promising radioprotector under advanced development which has been tested for efficacy in both murine and nonhuman primate (NHP) models. Previously, we have demonstrated that GT3 has radioprotective efficacy in intestinal epithelial and crypt cells, and restores transcriptomic changes in NHPs with a supralethal dose of 12 Gy total-body irradiation (TBI). Methods: In this study, we evaluated the effect of 12 Gy partial-body irradiation (PBI) or TBI on metabolomic changes in serum samples and the extent to which GT3 was able to modulate these irradiation-induced changes. A total of 32 nonhuman primates were used for this study, and blood sample were collected 3 days (d) prior to irradiation, and 4 hours (h), 8 h, 12 h, 1 d, 2, and 6 d post-irradiation. Results: Our results demonstrate that exposure to a supralethal dose of radiation induces a complex range of metabolomic shifts with similar degrees of dysregulation in both partial- and total-body irradiated animals. The C21-steroid hormone biosynthesis and metabolism pathway was significantly dysregulated in both PBI and TBI groups, with minimal protection afforded by GT3 administration. Conclusions: GT3 offered a differential response in terms of protected metabolites and pathways in either group that was most effective at the early post-irradiation time points. Full article

(This article belongs to the Section Advances in Metabolomics)

4 pages, 147 KiB

Open AccessEditorial

Salivary Fingerprint in the Metabolomics Era: Potential and Challenges

by Tatiana Kelly da Silva Fidalgo and Ana Paula Valente

Metabolites 2025, 15(8), 545; https://doi.org/10.3390/metabo15080545 - 12 Aug 2025

Abstract

In recent years, the field of metabolomics has significantly advanced our understanding of human health and disease by providing a comprehensive snapshot of metabolic alterations [...] Full article

(This article belongs to the Special Issue Salivary Fingerprint in Metabolomics Era: Potential and Challenges)

2 pages, 136 KiB

Open AccessRetraction

RETRACTED: El-Garawani et al. In Vitro Induction of Apoptosis in Isolated Acute Myeloid Leukemia Cells: The Role of Anastatica hierochuntica Methanolic Extract. Metabolites 2022, 12, 878

by Islam M. El-Garawani, Amira S. Abd El-Gaber, Noura A. Algamdi, Aamer Saeed, Chao Zhao, Omar M. Khattab, Mohamed F. AlAjmi, Zhiming Guo, Shaden A. M. Khalifa and Hesham R. El-Seedi

Metabolites 2025, 15(8), 544; https://doi.org/10.3390/metabo15080544 - 12 Aug 2025

Abstract

The journal Metabolites retracts the article “In Vitro Induction of Apoptosis in Isolated Acute Myeloid Leukemia Cells: The Role of Anastatica hierochuntica Methanolic Extract” [...] Full article

16 pages, 1520 KiB

Open AccessArticle

Preoperative Tyrosine Levels as Predictive Biomarkers for Excessive Fat-Free Mass Loss Following Laparoscopic Sleeve Gastrectomy in Patients with Morbid Obesity

by Inyoung Lee, Eunhye Seo, Yeongkeun Kwon, Chang Min Lee, Nam Hoon Kim, Jong-Han Kim, Sung Il Choi and Sungsoo Park

Metabolites 2025, 15(8), 543; https://doi.org/10.3390/metabo15080543 - 11 Aug 2025

Abstract

Background/Objectives: Fat-free mass (FFM) loss after metabolic and bariatric surgery (MBS) is associated with adverse long-term outcomes, including osteoporosis. Identifying biomarkers that predict excessive FFM loss can improve perioperative patient management and postoperative risk stratification. This study investigated whether preoperative amino acid [...] Read more.

Background/Objectives: Fat-free mass (FFM) loss after metabolic and bariatric surgery (MBS) is associated with adverse long-term outcomes, including osteoporosis. Identifying biomarkers that predict excessive FFM loss can improve perioperative patient management and postoperative risk stratification. This study investigated whether preoperative amino acid metabolite (AAM) levels could predict excessive FFM loss after laparoscopic sleeve gastrectomy (LSG). Methods: Forty patients with morbid obesity who underwent LSG between 2019 and 2020 were retrospectively analyzed. Based on the FFM loss to body weight loss ratio (%FFML/BWL) at 3 months postoperatively, patients were categorized into excessive (>25%) and non-excessive (≤25%) FFM loss groups. Anthropometric measurements and serum sampling were performed preoperatively and at 3, 6, and 12 months postoperatively. AAM profiles were collected before surgery. Statistical analyses, including logistic regression and receiver operating characteristic curves, were performed. Results: Twenty-five patients showed excessive FFM loss 3 months after surgery. They had significantly lower preoperative tyrosine (Tyr) levels (p = 0.025). Logistic regression revealed that higher Tyr levels were significantly associated with lower odds of being male, suggesting a potential protective effect (odds ratio (OR) =0.019, p = 0.010). Tyr profiling demonstrated acceptable predictive performance (area under the curve =0.715, p = 0.025). Despite nonsignificant p-values, trends showed lower FFM and muscle mass and higher fat mass in the excessive FFM loss group throughout follow-up. Conclusions: Preoperative Tyr profiling may help identify patients at risk for excessive FFM loss. These findings support prioritizing metabolic health alongside total weight loss in the evaluation of MBS outcomes. Full article

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

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16 pages, 1716 KiB

Open AccessArticle

Flavonoids and Sesquiterpene Lactones from Lychnophora ericoides (Arnica-Do-Cerrado) and Their In Vitro Effects on Multiple Myeloma and Acute Myeloid Leukemia

by Calisto Moreno Cardenas, Ren Ove Kratzert, Sofie Hanifle, Elida Cleyse Gomes da Mata Kanzaki, Isamu Kanzaki, Brigitte Kircher and Serhat Sezai Çiçek

Metabolites 2025, 15(8), 542; https://doi.org/10.3390/metabo15080542 - 9 Aug 2025

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Abstract

Objectives: Multiple myeloma and acute myeloid leukemia are severe forms of blood cancer, which lack effective therapies for treatment. In our search for new chemical lead structures from nature, we were investigating the Brazilian medicinal plant arnica-do-cerrado (Lychnophora ericoides). Methods: Repeated [...] Read more.

Objectives: Multiple myeloma and acute myeloid leukemia are severe forms of blood cancer, which lack effective therapies for treatment. In our search for new chemical lead structures from nature, we were investigating the Brazilian medicinal plant arnica-do-cerrado (Lychnophora ericoides). Methods: Repeated chromatography led to the isolation of four flavonoids and three sesquiterpenoids, which were evaluated for their cytostatic and cytotoxic properties against HL-60, MOLM-13, AMO-1, and KMS-12 PE cancer cells as well as the non-malignant HS-5 cell line. Results: Whereas the isolated flavonoids displayed only moderate activity, the three sesquiterpene lactones goyazensolide, centratherin, and lychnopholide exhibited pronounced effects against all four tested cell lines. Goyazensolide was the most effective compound, inhibiting proliferation and metabolic activity with IC₅₀ values between 1.0 and 1.6 µM, as well as 1.0 to 2.0 µM, respectively. Centratherin and lychnopholide were somewhat less active but showed higher selectivity towards malignant cell lines, which was most pronounced for MOLM-13 cells. Conclusion: The results of this study revealed interesting natural products that will be further evaluated for their potential as new lead compounds for the treatment of acute myeloid leukemia and multiple myeloma. Full article

(This article belongs to the Special Issue Effects of Secondary Plant Metabolites on Human Health)

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16 pages, 2274 KiB

Open AccessArticle

Molybdenum-Induced Oxidative and Inflammatory Injury and Metabolic Pathway Disruption in Goat Pancreas

by Longfei Li, Yang Ran and Xiaoyun Shen

Metabolites 2025, 15(8), 541; https://doi.org/10.3390/metabo15080541 - 9 Aug 2025

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Abstract

Background: Molybdenum (Mo) is an essential trace element for animals, but too much intake can cause adverse effects. Due to the metabolic characteristics of goats and other ruminants, they are more susceptible to the cumulative effects of Mo toxicity. A high Mo [...] Read more.

Background: Molybdenum (Mo) is an essential trace element for animals, but too much intake can cause adverse effects. Due to the metabolic characteristics of goats and other ruminants, they are more susceptible to the cumulative effects of Mo toxicity. A high Mo intake can cause multi-organ toxicity in ruminants, but the mechanism of damage to the pancreas is still unclear. The aim of this study was to systematically analyze the key regulatory pathways of pancreatic injury induced by Mo in goats using a metabolomics approach. Methods: Twenty male Yudong Black goats (22.34 ± 1.87 kg, six months) were randomly divided into a control group (fed a basal diet) and the Mo group (fed a basal diet supplemented with 50 mg·kg⁻¹ Na₂MoO₄·2H₂O). After 60 days of continuous feeding, their pancreatic tissues were collected and the mineral elements, antioxidant capacity, and inflammatory factors were examined. Untargeted metabolomics based on HILIC UHPLC-Q-EXACTIVE MS was used to analyze changes in metabolites. The core regulatory mechanisms were revealed by KEGG enrichment analysis. Results: The results demonstrated that goats in the Mo group showed obvious clinical signs, such as lethargy, loss of appetite, and unsteady gait. The pancreatic tissue of goats in the Mo group exhibited significantly elevated levels of Mo and copper, accompanied by a marked reduction in antioxidant capacity and concurrent increases in inflammatory cytokine levels. Between the Mo group and control group, 167 differentially expressed metabolites were identified. KEGG enrichment analysis showed that it disrupted multiple metabolic pathways, including glycine, serine, and threonine metabolism, cysteine and methionine metabolism, and butanoate metabolism. Conclusions: This study mainly revealed, at the metabolomics level, that Mo exposure would disrupt the metabolic pathways related to antioxidant capacity in goat pancreata. It provides new insights into the molecular mechanisms of Mo-induced pancreatic injury in goats. Full article

(This article belongs to the Section Animal Metabolism)

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20 pages, 1995 KiB

Open AccessSystematic Review

MALDI-TOF MS Biomarkers for Methicillin-Resistant Staphylococcus aureus Detection: A Systematic Review

by Pedro Santos, Irina Alho and Edna Ribeiro

Metabolites 2025, 15(8), 540; https://doi.org/10.3390/metabo15080540 - 8 Aug 2025

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Abstract

Background/Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) infections remain a significant challenge in healthcare. Conventional and molecular techniques used for MRSA identification are either time-consuming or costly. Alternatively, Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF MS) offers a rapid method for microbial identification and has [...] Read more.

Background/Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) infections remain a significant challenge in healthcare. Conventional and molecular techniques used for MRSA identification are either time-consuming or costly. Alternatively, Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF MS) offers a rapid method for microbial identification and has the potential to detect biomarkers that distinguish methicillin resistance in S. aureus isolates. The aim of this study was to identify methicillin-resistant discriminative biomarkers for S. aureus obtained using MALDI-TOF MS. Methods: A systematic review was conducted by searching databases such as PubMed and Web of Science for studies that focused on MRSA detection with biomarkers by MALDI-TOF MS, including all relevant studies published up to July 2024. The review protocol was registered in PROSPERO registry. Results: A total of 15 studies were selected for analysis. Data were extracted on study location, sample size, MALDI-TOF MS analyzer, sample preparation, methicillin resistance and sensitivity biomarkers, and the use of Artificial Intelligence (AI) models. Notably, PSM-mec and delta toxin were frequently reported as informative biomarkers, detectable at 2414 ± 2 Da and 3006 ± 2 Da, respectively. Additionally, eight studies used AI models to identify specific biomarkers differentiating methicillin-resistant and methicillin-sensitive strains, based on differences in peak intensities or the exclusive presence of certain peaks. Moreover, two studies employed detection of MRSA in low concentrations from biological samples and others employed an optimized matrix solution for improved analysis. Conclusions: Overall, MALDI-TOF MS is not only a powerful tool for the identification of bacterial isolates but also shows strong potential for rapid, cost-effective detection of methicillin resistance in S. aureus through biomarker analysis. Given that it is already implemented in several clinical laboratories, this approach could be adopted without significant additional cost. Full article

(This article belongs to the Special Issue Novel Approaches for Metabolomics in Drugs and Biomarkers Discovery: 2nd Edition)

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27 pages, 1703 KiB

Open AccessReview

Spatially Resolved Plant Metabolomics

by Ronald J. Myers, Jr., Zachary M. Tretter, Abigail G. Daffron, Eric X. Fritschi, William Thives Santos, Maiya L. Foster, Matthew Klotz, Kristin M. Stafford, Christina Kasch, Thomas J. Taylor, Lillian C. Tellefson, Tyler Hartman, Dru Hackler, Preston Stephen and Lloyd W. Sumner

Metabolites 2025, 15(8), 539; https://doi.org/10.3390/metabo15080539 - 8 Aug 2025

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Abstract

Research and innovation in metabolomics tools to measure metabolite accumulation within plants have led to important discoveries with respect to the improvement of plant stress tolerance, development, and crop yield. Traditional metabolomics analyses have commonly utilized gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry, [...] Read more.

Research and innovation in metabolomics tools to measure metabolite accumulation within plants have led to important discoveries with respect to the improvement of plant stress tolerance, development, and crop yield. Traditional metabolomics analyses have commonly utilized gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry, but these methods are often performed without regard for the spatial locations of metabolites within tissues. Methods for mass spectral imaging (MSI) have recently been developed to detect and spatially resolve metabolite accumulation and are rapidly being adopted on a wider scale. Since 2010, the number of publications incorporating mass spectral imaging has grown from approximately 80 articles to over 378 on a yearly basis, constituting an increase of at least 350% during this time frame. Spatially resolved metabolite accumulation data provides unique insights into the function and regulation of plant biochemical pathways. Mass spectral imaging is commonly paired with desorption ionization technologies, including matrix-assisted laser desorption ionization (MALDI) and desorption electrospray ionization (DESI), to generate accurate, spatially resolved metabolomics data from prepared tissue segments. Here, we describe the most recent advancements in sample preparation methods, mass spectral imaging technologies, and data processing tools that have been developed to address the limits of MSI technology. Additionally, we summarize recent applications of MSI technologies in plant metabolomics and discuss potential avenues for future research advancements within the plant biology community through the use of these technologies. Full article

(This article belongs to the Special Issue Mass Spectrometry Imaging and Spatial Metabolomics)

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2 pages, 132 KiB

Open AccessCorrection

Correction: Lloyd et al. Chemical Diversity of UK-Grown Tea Explored Using Metabolomics and Machine Learning. Metabolites 2025, 15, 52

by Amanda J. Lloyd, Alina Warren-Walker, Jasen Finch, Jo Harper, Kathryn Bennet, Alison Watson, Laura Lyons, Pilar Martinez Martin, Thomas Wilson and Manfred Beckmann

Metabolites 2025, 15(8), 538; https://doi.org/10.3390/metabo15080538 - 8 Aug 2025

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Abstract

There was a provenance issue with the seed varieties in the original publication [...] Full article

11 pages, 330 KiB

Open AccessArticle

Triglyceride–Glucose Index and New-Onset Type 2 Diabetes Mellitus in Middle-Aged Men

by Lanfranco D’Elia, Domenico Rendina, Roberto Iacone, Pasquale Strazzullo and Ferruccio Galletti

Metabolites 2025, 15(8), 537; https://doi.org/10.3390/metabo15080537 - 8 Aug 2025

Viewed by 199

Abstract

Background: Type 2 diabetes mellitus (T2DM) is a major contributor to cardiovascular disease worldwide, with insulin resistance (IR) being a central pathophysiological mechanism. The triglyceride–glucose (TyG) index, derived from routine fasting measures, has emerged as a simple yet reliable proxy for IR and [...] Read more.

Background: Type 2 diabetes mellitus (T2DM) is a major contributor to cardiovascular disease worldwide, with insulin resistance (IR) being a central pathophysiological mechanism. The triglyceride–glucose (TyG) index, derived from routine fasting measures, has emerged as a simple yet reliable proxy for IR and is increasingly recognised for its prognostic value in metabolic disorders. Despite growing interest, longitudinal evidence on TyG and incident T2DM, especially within European cohorts, remains limited and inconsistent. Therefore, we aimed to estimate the predictive role of TyG on the development of T2DM in an 8-year follow-up observation of a sample of adult men. Methods: We analysed data from 789 adult men without baseline T2DM, enrolled in the Olivetti Heart Study. Receiver operating characteristic curve analysis was used to determine the optimal TyG threshold for predicting new-onset T2DM. Results: Baseline TyG exhibited a strong, linear association with the subsequent development of T2DM. A TyG value above 4.88 was associated with an approximately twofold increase in risk, both before and after adjustment for confounding factors. Conclusions: The principal findings of this study indicate a significant predictive value of the TyG index in the development of new-onset T2DM. These observations suggest that the TyG index may serve as a low-cost, simple, and non-invasive tool for early cardio-metabolic risk assessment. Full article

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

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15 pages, 2691 KiB

Open AccessReview

SGLT2 Inhibitors: Multifaceted Therapeutic Agents in Cardiometabolic and Renal Diseases

by Ana Checa-Ros, Owahabanun-Joshua Okojie and Luis D’Marco

Metabolites 2025, 15(8), 536; https://doi.org/10.3390/metabo15080536 - 7 Aug 2025

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Abstract

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2is), initially developed as antihyperglycemic agents, have emerged as multifunctional therapeutics with profound cardiorenal and metabolic benefits. Their unique insulin-independent mechanism, targeting renal glucose reabsorption, distinguishes them from conventional antidiabetic drugs. Mechanisms and Clinical Evidence: SGLT2is induce [...] Read more.

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2is), initially developed as antihyperglycemic agents, have emerged as multifunctional therapeutics with profound cardiorenal and metabolic benefits. Their unique insulin-independent mechanism, targeting renal glucose reabsorption, distinguishes them from conventional antidiabetic drugs. Mechanisms and Clinical Evidence: SGLT2is induce glycosuria, reduce hyperglycemia, and promote weight loss through increased caloric excretion. Beyond glycemic control, they modulate tubuloglomerular feedback, attenuate glomerular hyperfiltration, and exert systemic effects via natriuresis, ketone utilization, and anti-inflammatory pathways. Landmark trials (DAPA-HF, EMPEROR-Reduced, CREDENCE, DAPA-CKD) demonstrate robust reductions in heart failure (HF) hospitalizations, cardiovascular mortality, and chronic kidney disease (CKD) progression, irrespective of diabetes status. Adipose Tissue and Metabolic Effects: SGLT2is mitigate obesity-associated adiposopathy by shifting macrophage polarization (M1 to M2), reducing proinflammatory cytokines (TNF-α, IL-6), and enhancing adipose tissue browning (UCP1 upregulation) and mitochondrial biogenesis (via PGC-1α/PPARα). Modest weight loss (~2–4 kg) occurs, though compensatory hyperphagia may limit long-term effects. Emerging Applications: Potential roles in non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and neurodegenerative disorders are under investigation, driven by pleiotropic effects on metabolism and inflammation. Conclusions: SGLT2is represent a paradigm shift in managing T2DM, HF, and CKD, with expanding implications for metabolic syndrome. Future research should address interindividual variability, combination therapies, and non-glycemic indications to optimize their therapeutic potential. Full article

(This article belongs to the Special Issue Metabolic Modulators in Cardiovascular Disease Management)

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12 pages, 264 KiB

Open AccessArticle

Discriminative Capacity of Visceral Adiposity and Triglyceride Glucose-Waist Circumference Indices for Metabolic Syndrome in Spanish Adolescents: A Cross-Sectional Study

by Ángel Fernández-Aparicio, Miriam Mohatar-Barba, Javier S. Perona, Jacqueline Schmidt-RioValle, Carmen Flores Navarro-Pérez and Emilio González-Jiménez

Metabolites 2025, 15(8), 535; https://doi.org/10.3390/metabo15080535 - 7 Aug 2025

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Abstract

Background/Objectives: Adolescence is a critical period for the early detection of metabolic syndrome (MetS), a condition that increases the risk of cardiometabolic diseases in adulthood. Timely identification of at-risk adolescents enables targeted prevention strategies. This study aimed to analyze the discriminative capacity and [...] Read more.

Background/Objectives: Adolescence is a critical period for the early detection of metabolic syndrome (MetS), a condition that increases the risk of cardiometabolic diseases in adulthood. Timely identification of at-risk adolescents enables targeted prevention strategies. This study aimed to analyze the discriminative capacity and accuracy of six biochemical and/or anthropometric indices related to lipid metabolism and adiposity for the early detection of MetS in a sample of Spanish adolescents. Methods: A cross-sectional study carried out according to the STROBE guidelines. A sample of 981 adolescents aged 11–16 years old were randomly recruited from schools in Southeastern Spain. The presence or absence of MetS was determined according to the International Diabetes Federation criteria. The following biochemical and/or anthropometric indices were evaluated: triglyceride glucose index, visceral adiposity index, logarithm children’s lipid accumulation product, triglyceride glucose-body mass index, triglyceride glucose-waist circumference, and triglyceride glucose-waist-to-hip ratio. Results: The triglyceride glucose-waist-to-hip ratio and triglyceride glucose-body mass index parameters were the strongest indicators associated with MetS in boys and girls, respectively, after adjusting for several factors. Moreover, all evaluated indices showed optimal AUC values, with the visceral adiposity index and triglyceride glucose-waist circumference index exhibiting the highest discriminative capacity in both genders. Conclusions: The evaluated biochemical and anthropometric indices—particularly visceral adiposity index and triglyceride-glucose-waist circumference—show promise as accessible biomarkers for identifying adolescents at metabolic risk. These indices may serve as practical tools in preventive health strategies aimed at improving metabolic health by screening adolescents at risk of MetS, thereby helping to reduce the future burden of non-communicable diseases. Full article

(This article belongs to the Special Issue Effects of Diet on Metabolic Health of Obese People)

18 pages, 2516 KiB

Open AccessArticle

Joint Metabolomics and Transcriptomics Reveal Rewired Glycerophospholipid and Arginine Metabolism as Components of BRCA1-Induced Metabolic Reprogramming in Breast Cancer Cells

by Thomas Lucaora and Daniel Morvan

Metabolites 2025, 15(8), 534; https://doi.org/10.3390/metabo15080534 - 7 Aug 2025

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Abstract

Background/Objectives: The breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene whose mutations are associated with increased susceptibility to develop breast or ovarian cancer. BRCA1 mainly exerts its protective effects through DNA double-strand break repair. Although not itself [...] Read more.

Background/Objectives: The breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene whose mutations are associated with increased susceptibility to develop breast or ovarian cancer. BRCA1 mainly exerts its protective effects through DNA double-strand break repair. Although not itself a transcriptional factor, BRCA1, through its multiple protein interaction domains, exerts transcriptional coregulation. In addition, BRCA1 expression alters cellular metabolism including inhibition of de novo fatty acid synthesis, changes in cellular bioenergetics, and activation of antioxidant defenses. Some of these actions may contribute to its global oncosuppressive effects. However, the breadth of metabolic pathways reprogrammed by BRCA1 is not fully elucidated. Methods: Breast cancer cells expressing BRCA1 were investigated by multiplatform metabolomics, metabolism-related transcriptomics, and joint metabolomics/transcriptomics data processing techniques, namely two-way orthogonal partial least squares and pathway analysis. Results: Joint analyses revealed the most important metabolites, genes, and pathways of metabolic reprogramming in BRCA1-expressing breast cancer cells. The breadth of metabolic reprogramming included fatty acid synthesis, bioenergetics, HIF-1 signaling pathway, antioxidation, nucleic acid synthesis, and other pathways. Among them, rewiring of glycerophospholipid (including phosphatidylcholine, -serine and -inositol) metabolism and increased arginine metabolism have not been reported yet. Conclusions: Rewired glycerophospholipid and arginine metabolism were identified as components of BRCA1-induced metabolic reprogramming in breast cancer cells. The study helps to identify metabolites that are candidate biomarkers of the BRCA1 genotype and metabolic pathways that can be exploited in targeted therapies. Full article

(This article belongs to the Section Cell Metabolism)

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31 pages, 3977 KiB

Open AccessArticle

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

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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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2 pages, 140 KiB

Open AccessCorrection

Correction: Mahnashi et al. In-Vitro, In-Vivo, Molecular Docking and ADMET Studies of 2-Substituted 3,7-Dihydroxy-4H-chromen-4-one for Oxidative Stress, Inflammation and Alzheimer’s Disease. Metabolites 2022, 12, 1055

by Mater H. Mahnashi, Mohammed Abdulrahman Alshahrani, Mohammed H. Nahari, Syed Shams ul Hassan, Muhammad Saeed Jan, Muhammad Ayaz, Farhat Ullah, Osama M. Alshehri, Mohammad Ali Alshehri, Umer Rashid and Abdul Sadiq

Metabolites 2025, 15(8), 532; https://doi.org/10.3390/metabo15080532 - 6 Aug 2025

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Abstract

There was an error in the original publication [...] Full article

(This article belongs to the Special Issue Identification and Therapeutic Properties of Secondary Metabolites of Medicinal Plants)

16 pages, 4074 KiB

Open AccessArticle

Exploring 6-aza-2-Thiothymine as a MALDI-MSI Matrix for Spatial Lipidomics of Formalin-Fixed Paraffin-Embedded Clinical Samples

by Natalia Shelly Porto, Simone Serrao, Greta Bindi, Nicole Monza, Claudia Fumagalli, Vanna Denti, Isabella Piga and Andrew Smith

Metabolites 2025, 15(8), 531; https://doi.org/10.3390/metabo15080531 - 5 Aug 2025

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Abstract

Background/Objectives: In recent years, lipids have emerged as critical regulators of different disease processes, being involved in cancer pathogenesis, progression, and outcome. Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) has significantly expanded the technology’s reach, enabling spatially resolved profiling of lipids directly [...] Read more.

Background/Objectives: In recent years, lipids have emerged as critical regulators of different disease processes, being involved in cancer pathogenesis, progression, and outcome. Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) has significantly expanded the technology’s reach, enabling spatially resolved profiling of lipids directly from tissue, including formalin-fixed paraffin-embedded (FFPE) specimens. In this context, MALDI matrix selection is crucial for lipid extraction and ionization, influencing key aspects such as molecular coverage and sensitivity, especially in such specimens with already depleted lipid content. Thus, in this work, we aim to explore the feasibility of mapping lipid species in FFPE clinical samples with MALDI-MSI using 6-aza-2-thiothymine (ATT) as a matrix of choice. Methods: To do so, ATT performances were first compared to those two other matrices commonly used for lipidomic analyses, 2′,5′-dihydroxybenzoic acid (DHB) and Norharmane (NOR), on lipid standards. Results: As a proof-of-concept, we then assessed ATT’s performance for the MALDI-MSI analysis of lipids in FFPE brain sections, both in positive and negative ion modes, comparing results with those obtained from other commonly used dual-polarity matrices. In this context, ATT enabled the putative annotation of 98 lipids while maintaining a well-balanced detection of glycerophospholipids (60.2%) and sphingolipids (32.7%) in positive ion mode. It outperformed both DHB and NOR in the identification of glycolipids (3%) and fatty acids (4%). Additionally, ATT exceeded DHB in terms of total lipid count (62 vs. 21) and class diversity and demonstrated performance comparable to NOR in negative ion mode. Moreover, ATT was applied to a FFPE glioblastoma tissue microarray (TMA) evaluating the ability of this matrix to reveal biologically relevant lipid features capable of distinguishing normal brain tissue from glioblastoma regions. Conclusions: Altogether, the results presented in this work suggest that ATT is a suitable matrix for pathology imaging applications, even at higher lateral resolutions of 20 μm, not only for proteomic but also for lipidomic analysis. This could enable the use of the same matrix type for the analysis of both lipids and peptides on the same tissue section, offering a unique strategic advantage for multi-omics studies, while also supporting acquisition in both positive and negative ionization modes. Full article

(This article belongs to the Special Issue Expanding Boundaries in Spatial Metabolomics and Lipidomics: Advances in Mass Spectrometry Imaging)

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15 pages, 2361 KiB

Open AccessArticle

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

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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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16 pages, 3202 KiB

Open AccessArticle

Gut Microbiota Composition in Rats Consuming Sucralose or Rebaudioside A at Recommended Doses Under Two Dietary Interventions

by Meztli Ramos-García, Alma Delia Genis-Mendoza, Carlos García-Vázquez, José Jaime Martínez-Magaña, Viridiana Olvera-Hernández, Mirian Carolina Martínez-López, Juan Cuauhtémoc Díaz-Zagoya, Carina Shianya Alvarez-Villagomez, Isela Esther Juárez-Rojop, Humberto Nicolini and Jorge Luis Ble-Castillo

Metabolites 2025, 15(8), 529; https://doi.org/10.3390/metabo15080529 - 4 Aug 2025

Viewed by 320

Abstract

Background: Artificial non-nutritive sweeteners (NNSs), such as sucralose, have been associated with gut microbiota (GM) alterations. However, the impact of rebaudioside A (reb A), a natural NNS, on GM has received limited scrutiny. Objective: The objective of this study was to examine [...] Read more.

Background: Artificial non-nutritive sweeteners (NNSs), such as sucralose, have been associated with gut microbiota (GM) alterations. However, the impact of rebaudioside A (reb A), a natural NNS, on GM has received limited scrutiny. Objective: The objective of this study was to examine the response of GM composition to sucralose and reb A in rats under two dietary conditions. Methods: Male Wistar rats (150–200 g) fed with a normal diet (ND) or a high-fat diet (HFD) were randomly assigned to receive sucralose (SCL), reb A (REB), glucose (GLU, control), or sucrose (SUC). The NNS interventions were administered in water at doses equivalent to the acceptable daily intake (ADI). After eight weeks, the GM composition in fecal samples was analyzed through 16S ribosomal RNA gene sequencing. Results: The NNSs did not modify the diversity, structure, phylum-level composition, or Firmicutes/Bacteroidetes (F/B) ratio of the GM in rats under ND or HFD. However, REB with HFD decreased Bacilli and increased Faecalibacterium abundance at the class level. SCL and REB in rats receiving ND reduced the genera Romboutsia and Lactobacillus. Conclusions: Our study suggests that when sucralose or reb A is consumed at recommended doses, there is no alteration in the diversity or the composition of the GM at the phylum level. The clinical relevance of these findings lies in the potential modifications of the GM at specific taxonomic levels by the consumption of these NNSs. Further research involving humans and including a broader range of microbial analyses is warranted. Full article

(This article belongs to the Section Nutrition and Metabolism)

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20 pages, 346 KiB

Open AccessReview

Dietary Strategies in the Prevention of MASLD: A Comprehensive Review of Dietary Patterns Against Fatty Liver

by Barbara Janota, Karolina Janion, Aneta Buzek and Ewa Janczewska

Metabolites 2025, 15(8), 528; https://doi.org/10.3390/metabo15080528 - 4 Aug 2025

Viewed by 671

Abstract

Understanding the components of the diet, food groups, and nutritional strategies that help prevent MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease) is essential for identifying dietary behaviors that can stop the progression of this condition, which currently affects over one-quarter of the global population. [...] Read more.

Understanding the components of the diet, food groups, and nutritional strategies that help prevent MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease) is essential for identifying dietary behaviors that can stop the progression of this condition, which currently affects over one-quarter of the global population. This review highlights the importance of including antioxidant nutrients in the diet, such as vitamins C and E, CoQ10, and polyphenolic compounds. It also emphasizes substances that support lipid metabolism, including choline, alpha-lipoic acid, and berberine. Among food groups, it is crucial to choose those that help prevent metabolic disturbances. Among carbohydrate-rich foods, vegetables, fruits, and high-fiber products are recommended. For protein sources, eggs, fish, and white meat are preferred. Among fat sources, plant oils and fatty fish are advised due to their content of omega-3 and omega-6 fatty acids. Various dietary strategies aimed at preventing MASLD should include elements of the Mediterranean diet or be personalized to provide anti-inflammatory compounds and substances that inhibit fat accumulation in liver cells. Other recommended dietary models include the DASH diet, the flexitarian diet, intermittent fasting, and diets that limit fructose and simple sugars. Additionally, supplementing the diet with spirulina or chlorella, berberine, probiotics, or omega-3 fatty acids, as well as drinking several cups of coffee per day, may be beneficial. Full article

(This article belongs to the Special Issue Metabolic Dysregulation in Fatty Liver Disease)

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22 pages, 2692 KiB

Open AccessArticle

Differences in the Profile of Aromatic Metabolites in the Corresponding Blood Serum and Cerebrospinal Fluid Samples of Patients with Secondary Bacterial Meningitis

by Alisa K. Pautova, Peter A. Meinarovich, Vladislav E. Zakharchenko, Pavel D. Sobolev, Natalia A. Burnakova and Natalia V. Beloborodova

Metabolites 2025, 15(8), 527; https://doi.org/10.3390/metabo15080527 - 3 Aug 2025

Viewed by 277

Abstract

Background: Secondary (nosocomial) bacterial meningitis remains a serious problem in patients with severe brain damage. The aim of this study was to assess the differences in the aromatic metabolites of tryptophan, phenylalanine, and tyrosine, in serum and cerebrospinal fluid (CSF) samples collected simultaneously [...] Read more.

Background: Secondary (nosocomial) bacterial meningitis remains a serious problem in patients with severe brain damage. The aim of this study was to assess the differences in the aromatic metabolites of tryptophan, phenylalanine, and tyrosine, in serum and cerebrospinal fluid (CSF) samples collected simultaneously from patients with long-term sequelae of severe brain damage with suspected secondary bacterial meningitis. Methods: Group I included 16 paired serum and CSF samples from patients (N = 11) without secondary bacterial meningitis; group II included 13 paired serum and CSF samples from patients (N = 4) with secondary bacterial meningitis. Results: The median concentrations of serum 5-hydroxyindole-3-acetic, CSF 4-hydroxyphenyllactic (p-HPhLA), CSF 4-hydroxyphenylacetic, CSF phenyllactic, and indole-3-lactic acids in serum and CSF were statistically higher in group II compared to group I (p-value ≤ 0.03), while 4-hydroxyphenylpropionic and indole-3-acetic in serum were lower in group II compared to group I (p-value = 0.04). In group I, p-HPhLA serum concentrations were greater than or equal to its CSF concentrations in 14 paired samples; in group II, p-HPhLA concentrations in serum were lower than in CSF in all paired samples. Conclusions: The obtained results demonstrate the differences in the profile of aromatic metabolites in serum and CSF and may confirm the hypothesis of the p-HPhLA microbial origin in the CSF of patients with secondary bacterial meningitis. Full article

(This article belongs to the Special Issue Advances in Metabolomics for Precision Medicine: From Biomarker Discovery to Clinical Applications)

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16 pages, 2968 KiB

Open AccessArticle

Dissecting Organ-Specific Aroma-Active Volatile Profiles in Two Endemic Phoebe Species by Integrated GC-MS Metabolomics

by Ming Xu, Yu Chen and Guoming Wang

Metabolites 2025, 15(8), 526; https://doi.org/10.3390/metabo15080526 - 3 Aug 2025

Viewed by 231

Abstract

Background: Phoebe zhennan and Phoebe chekiangensis are valuable evergreen trees recognized for their unique aromas and ecological significance, yet the organ-related distribution and functional implications of aroma-active volatiles remain insufficiently characterized. Methods: In this study, we applied an integrated GC-MS-based volatile metabolomics [...] Read more.

Background: Phoebe zhennan and Phoebe chekiangensis are valuable evergreen trees recognized for their unique aromas and ecological significance, yet the organ-related distribution and functional implications of aroma-active volatiles remain insufficiently characterized. Methods: In this study, we applied an integrated GC-MS-based volatile metabolomics approach combined with a relative odor activity value (rOAV) analysis to comprehensively profile and compare the volatile metabolite landscape in the seeds and leaves of both species. Results: In total, 1666 volatile compounds were putatively identified, of which 540 were inferred as key aroma-active contributors based on the rOAV analysis. A multivariate statistical analysis revealed clear tissue-related separation: the seeds were enriched in sweet, floral, and fruity volatiles, whereas the leaves contained higher levels of green leaf volatiles and terpenoids associated with ecological defense. KEGG pathway enrichment indicated that terpenoid backbone and phenylpropanoid biosynthesis pathways played major roles in shaping these divergent profiles. A Venn diagram analysis further uncovered core and unique volatiles underlying species and tissue specificity. Conclusions: These insights provide an integrated reference for understanding tissue-divergent volatile profiles in Phoebe species and offer a basis for fragrance-oriented selection, ecological trait evaluation, and the sustainable utilization of organ-related metabolic characteristics in breeding and conservation programs. Full article

(This article belongs to the Section Plant Metabolism)

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22 pages, 1641 KiB

Open AccessArticle

Site-Specific Trafficking of Lipid and Polar Metabolites in Adipose and Muscle Tissue Reveals the Impact of Bariatric Surgery-Induced Weight Loss: A 6-Month Follow-Up Study

by Aidan Joblin-Mills, Zhanxuan E. Wu, Garth J. S. Cooper, Ivana R. Sequeira-Bisson, Jennifer L. Miles-Chan, Anne-Thea McGill, Sally D. Poppitt and Karl Fraser

Metabolites 2025, 15(8), 525; https://doi.org/10.3390/metabo15080525 - 2 Aug 2025

Viewed by 405

Abstract

Background: The causation of type 2 diabetes remains under debate, but evidence supports both abdominal lipid and ectopic lipid overspill into tissues including muscle as key. How these depots differentially alter cardiometabolic profile and change during body weight and fat loss is not [...] Read more.

Background: The causation of type 2 diabetes remains under debate, but evidence supports both abdominal lipid and ectopic lipid overspill into tissues including muscle as key. How these depots differentially alter cardiometabolic profile and change during body weight and fat loss is not known. Methods: Women with obesity scheduled to undergo bariatric surgery were assessed at baseline (BL, n = 28) and at 6-month follow-up (6m_FU, n = 26) after weight loss. Fasting plasma (Pla), subcutaneous thigh adipose (STA), subcutaneous abdominal adipose, (SAA), and thigh vastus lateralis muscle (VLM) samples were collected at BL through surgery and at 6m_FU using needle biopsy. An untargeted liquid chromatography mass spectrometry metabolomics platform was used. Pla and tissue-specific lipid and polar metabolite profiles were modelled as changes from BL and 6m_FU. Results: There was significant body weight (−24.5 kg) loss at 6m_FU (p < 0.05). BL vs. 6m_FU tissue metabolomics profiles showed the largest difference in lipid profiles in SAA tissue in response to surgery. Conversely, polar metabolites were more susceptible to change in STA and VLM. In Pla samples, both lipid and polar metabolite profiles showed significant differences between timepoints. Jaccard–Tanimoto coefficient t-tests identified a sub-group of gut microbiome and dietary-derived omega-3-fatty-acid-containing lipid species and core energy metabolism and adipose catabolism-associated polar metabolites that are trafficked between sample types in response to bariatric surgery. Conclusions: In this first report on channelling of lipids and polar metabolites to alternative tissues in bariatric-induced weight loss, adaptive shuttling of small molecules was identified, further promoting adipose processing and highlighting the dynamic and coordinated nature of post-surgical metabolic regulation. Full article

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

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10 pages, 503 KiB

Open AccessBrief Report

RAGE Knockout Mitigates Diet-Induced Obesity and Metabolic Disruption

by Isabelle L. Palmer, Genevieve Parker, Alden T. Chiu, Colson G. Beus, Ethan P. Evans, Jack H. Radford, Cameron R. Braithwaite, Ryan D. van Slooten, Elijah T. Cooper-Leavitt, Zachary E. Moore, Derek M. Clarke, R. Ryley Parrish, Juan A. Arroyo, Paul R. Reynolds and Benjamin T. Bikman

Metabolites 2025, 15(8), 524; https://doi.org/10.3390/metabo15080524 - 2 Aug 2025

Viewed by 333

Abstract

Background/Objectives: The receptor for advanced glycation end products (RAGEs) has been implicated in obesity and metabolic dysfunction. However, its precise role in diet-induced obesity remains unclear. Methods: In this study, we investigated the metabolic consequences of RAGE knockout (RAGE KO) in mice subjected [...] Read more.

Background/Objectives: The receptor for advanced glycation end products (RAGEs) has been implicated in obesity and metabolic dysfunction. However, its precise role in diet-induced obesity remains unclear. Methods: In this study, we investigated the metabolic consequences of RAGE knockout (RAGE KO) in mice subjected to a Western diet (WD). Results: Our findings demonstrate that RAGE KO mice remained significantly leaner than their wild-type (WT) counterparts when fed a WD, exhibiting reduced body weight gain and smaller adipocyte size. Indirect calorimetry revealed that RAGE KO mice had increased oxygen consumption and locomotor activity compared to WT mice, indicating enhanced energy expenditure. Mitochondrial respiration assays indicated significantly greater oxygen consumption in RAGE KO animals. Additionally, systemic inflammation markers, such as TNF-α, were significantly lower in RAGE KO mice when fed a WD, indicating a reduction in diet-induced inflammatory responses. Conclusions: These findings suggest that RAGE plays a key role in metabolic homeostasis, and its deletion confers resistance to obesity and metabolic disruption induced by a Western diet. Targeting RAGE may provide a novel therapeutic approach for combating obesity and related metabolic disorders. Full article

(This article belongs to the Special Issue Fat and Glucose Metabolism)

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18 pages, 5815 KiB

Open AccessArticle

Novel Lipid Biomarkers of Chronic Kidney Disease of Unknown Etiology Based on Urinary Small Extracellular Vesicles: A Pilot Study of Sugar Cane Workers

by Jie Zhou, Kevin J. Kroll, Jaime Butler-Dawson, Lyndsay Krisher, Abdel A. Alli, Chris Vulpe and Nancy D. Denslow

Metabolites 2025, 15(8), 523; https://doi.org/10.3390/metabo15080523 - 2 Aug 2025

Viewed by 339

Abstract

Background/Objectives: Chronic kidney disease of unknown etiology (CKDu) disproportionately affects young male agricultural workers who are otherwise healthy. There is a scarcity of biomarkers for early detection of this type of kidney disease. We hypothesized that small extracellular vesicles (sEVs) released into urine [...] Read more.

Background/Objectives: Chronic kidney disease of unknown etiology (CKDu) disproportionately affects young male agricultural workers who are otherwise healthy. There is a scarcity of biomarkers for early detection of this type of kidney disease. We hypothesized that small extracellular vesicles (sEVs) released into urine may provide novel biomarkers. Methods: We obtained two urine samples at the start and the end of a workday in the fields from a limited set of workers with and without kidney impairment. Isolated sEVs were characterized for size, surface marker expression, and purity and, subsequently, their lipid composition was determined by mass spectrometry. Results: The number of particles per ml of urine normalized to osmolality and the size variance were larger in workers with possible CKDu than in control workers. Surface markers CD9, CD63, and CD81 are characteristic of sEVs and a second set of surface markers suggested the kidney as the origin. Differential expression of CD25 and CD45 suggested early inflammation in CKDu workers. Of the twenty-one lipids differentially expressed, several were bioactive, suggesting that they may have essential functions. Remarkably, fourteen of the lipids showed intermediate expression values in sEVs from healthy individuals with acute creatinine increases after a day of work. Conclusions: We identified twenty-one possible lipid biomarkers in sEVs isolated from urine that may be able to distinguish agricultural workers with early onset of CKDu. Differentially expressed surface proteins in these sEVs suggested early-stage inflammation. This pilot study was limited in the number of workers evaluated, but the approach should be further evaluated in a larger population. Full article

(This article belongs to the Special Issue The Molecular Cargo of Extracellular Vesicles: A Key to Understanding Their Biological Role)

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29 pages, 3012 KiB

Open AccessArticle

Investigating Multi-Omic Signatures of Ethnicity and Dysglycaemia in Asian Chinese and European Caucasian Adults: Cross-Sectional Analysis of the TOFI_Asia Study at 4-Year Follow-Up

by Saif Faraj, Aidan Joblin-Mills, Ivana R. Sequeira-Bisson, Kok Hong Leiu, Tommy Tung, Jessica A. Wallbank, Karl Fraser, Jennifer L. Miles-Chan, Sally D. Poppitt and Michael W. Taylor

Metabolites 2025, 15(8), 522; https://doi.org/10.3390/metabo15080522 - 1 Aug 2025

Viewed by 437

Abstract

Background: Type 2 diabetes (T2D) is a global health epidemic with rising prevalence within Asian populations, particularly amongst individuals with high visceral adiposity and ectopic organ fat, the so-called Thin-Outside, Fat-Inside phenotype. Metabolomic and microbiome shifts may herald T2D onset, presenting potential biomarkers [...] Read more.

Background: Type 2 diabetes (T2D) is a global health epidemic with rising prevalence within Asian populations, particularly amongst individuals with high visceral adiposity and ectopic organ fat, the so-called Thin-Outside, Fat-Inside phenotype. Metabolomic and microbiome shifts may herald T2D onset, presenting potential biomarkers and mechanistic insight into metabolic dysregulation. However, multi-omics datasets across ethnicities remain limited. Methods: We performed cross-sectional multi-omics analyses on 171 adults (99 Asian Chinese, 72 European Caucasian) from the New Zealand-based TOFI_Asia cohort at 4-years follow-up. Paired plasma and faecal samples were analysed using untargeted metabolomic profiling (polar/lipid fractions) and shotgun metagenomic sequencing, respectively. Sparse multi-block partial least squares regression and discriminant analysis (DIABLO) unveiled signatures associated with ethnicity, glycaemic status, and sex. Results: Ethnicity-based DIABLO modelling achieved a balanced error rate of 0.22, correctly classifying 76.54% of test samples. Polar metabolites had the highest discriminatory power (AUC = 0.96), with trigonelline enriched in European Caucasians and carnitine in Asian Chinese. Lipid profiles highlighted ethnicity-specific signatures: Asian Chinese showed enrichment of polyunsaturated triglycerides (TG.16:0_18:2_22:6, TG.18:1_18:2_22:6) and ether-linked phospholipids, while European Caucasians exhibited higher levels of saturated species (TG.16:0_16:0_14:1, TG.15:0_15:0_17:1). The bacteria Bifidobacterium pseudocatenulatum, Erysipelatoclostridium ramosum, and Enterocloster bolteae characterised Asian Chinese participants, while Oscillibacter sp. and Clostridium innocuum characterised European Caucasians. Cross-omic correlations highlighted negative correlations of Phocaeicola vulgatus with amino acids (r = −0.84 to −0.76), while E. ramosum and C. innocuum positively correlated with long-chain triglycerides (r = 0.55–0.62). Conclusions: Ethnicity drove robust multi-omic differentiation, revealing distinctive metabolic and microbial profiles potentially underlying the differential T2D risk between Asian Chinese and European Caucasians. Full article

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

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13 pages, 1192 KiB

Open AccessArticle

Serum Endocan Levels Correlate with Metabolic Syndrome Severity and Endothelial Dysfunction: A Cross-Sectional Study Using the MetS-Z Score

by Mehmet Vatansever, Selçuk Yaman, Ahmet Cimbek, Yılmaz Sezgin and Serap Ozer Yaman

Metabolites 2025, 15(8), 521; https://doi.org/10.3390/metabo15080521 - 1 Aug 2025

Viewed by 219

Abstract

Background: Metabolic syndrome (MetS) is a complex clinical condition characterized by the coexistence of interrelated metabolic abnormalities that significantly increase the risk of cardiovascular diseases and type 2 diabetes mellitus. Endocan—an endothelial cell-specific molecule—is considered a biomarker of endothelial dysfunction and inflammation. This [...] Read more.

Background: Metabolic syndrome (MetS) is a complex clinical condition characterized by the coexistence of interrelated metabolic abnormalities that significantly increase the risk of cardiovascular diseases and type 2 diabetes mellitus. Endocan—an endothelial cell-specific molecule—is considered a biomarker of endothelial dysfunction and inflammation. This study aimed to evaluate the relationship between serum endocan levels and the severity of MetS, assessed using the MetS-Z score. Methods: This study included 120 patients with MetS and 50 healthy controls. MetS was diagnosed according to the NCEP-ATP III criteria. MetS-Z scores were calculated using the MetS Severity Calculator. Serum levels of endocan, sICAM-1, and sVCAM-1 were measured using the ELISA method. Results: Serum levels of endocan, sICAM-1, and sVCAM-1 were significantly higher in the MetS group compared to the control group (all p < 0.001). When the MetS group was divided into tertiles based on MetS-Z scores, stepwise and statistically significant increases were observed in the levels of endocan and other endothelial markers from the lowest to highest tertile (p < 0.0001). Correlation analysis revealed a strong positive association between the MetS-Z score and serum endocan levels (r = 0.584, p < 0.0001). ROC curve analysis showed that endocan has high diagnostic accuracy for identifying MetS (AUC = 0.967, p = 0.0001), with a cutoff value of >88.0 ng/L. Conclusions: Circulating levels of endocan were significantly increased in MetS and were associated with the severity of MetS, suggesting that endocan may play a role in the cellular response to endothelial dysfunction-related injury in patients with MetS. Full article

(This article belongs to the Special Issue Lipid Metabolism Disorders in Obesity)

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13 pages, 994 KiB

Open AccessArticle

Evaluation of the Metabolomics Profile in Charcot–Marie–Tooth (CMT) Patients: Novel Potential Biomarkers

by Federica Murgia, Martina Cadeddu, Jessica Frau, Giancarlo Coghe, Lorefice Lorena, Alessandro Vannelli, Maria Rita Murru, Martina Spada, Antonio Noto, Luigi Atzori and Eleonora Cocco

Metabolites 2025, 15(8), 520; https://doi.org/10.3390/metabo15080520 - 1 Aug 2025

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Abstract

Background: Charcot–Marie–Tooth (CMT) is a group of inherited diseases impairing the peripheral nervous system. CMT originates from genetic variants that affect proteins fundamental for the myelination of peripheral nerves and survival. Moreover, environmental and humoral factors can impact disease development and evolution. Currently, [...] Read more.

Background: Charcot–Marie–Tooth (CMT) is a group of inherited diseases impairing the peripheral nervous system. CMT originates from genetic variants that affect proteins fundamental for the myelination of peripheral nerves and survival. Moreover, environmental and humoral factors can impact disease development and evolution. Currently, no therapy is available. Metabolomics is an emerging field of biomedical research that enables the development of novel biomarkers for neurodegenerative diseases by targeting metabolic pathways or metabolites. This study aimed to evaluate the metabolomics profile of CMT disease by comparing patients with healthy individuals. Methods: A total of 22 CMT patients (CMT) were included in this study and were demographically matched with 26 healthy individuals (C). Serum samples were analyzed through Nuclear Magnetic Resonance spectroscopy, and multivariate and univariate statistical analyses were subsequently applied. Results: A supervised model showed a clear separation (R²X = 0.3; R²Y = 0.7; Q² = 0.4; p-value = 0.0004) between the two classes of subjects, and nine metabolites were found to be significantly different (2-hydroxybutyrate, 3-hydroxybutyrate, 3-methyl-2-oxovalerate, choline, citrate, glutamate, isoleucine, lysine, and methyl succinate). The combined ROC curve showed an AUC of 0.94 (CI: 0.9–1). Additional altered metabolic pathways were also identified within the disease context. Conclusion: This study represents a promising starting point, demonstrating the efficacy of metabolomics in evaluating CMT patients and identifying novel potential disease biomarkers. Full article

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

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14 pages, 31608 KiB

Open AccessArticle

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 266

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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13 pages, 688 KiB

Open AccessArticle

Metabolomic Patterns at Birth of Preterm Newborns with Extrauterine Growth Restriction: Towards Putative Markers of Nutritional Status

by Marta Meneghelli, Giovanna Verlato, Matteo Stocchero, Anna Righetto, Elena Priante, Lorenzo Zanetto, Paola Pirillo, Giuseppe Giordano and Eugenio Baraldi

Metabolites 2025, 15(8), 518; https://doi.org/10.3390/metabo15080518 - 1 Aug 2025

Viewed by 306

Abstract

Background: Nutrition is of paramount importance during early development, since suboptimal growth in this period of life is linked to adverse long- and mid-term outcomes. This is particularly relevant for preterm infants, who fail to thrive during the first weeks of life and [...] Read more.

Background: Nutrition is of paramount importance during early development, since suboptimal growth in this period of life is linked to adverse long- and mid-term outcomes. This is particularly relevant for preterm infants, who fail to thrive during the first weeks of life and develop extrauterine growth restriction (EUGR). This group of premature babies represents an interesting population to investigate using a metabolomic approach to optimize nutritional intake. Aims: To analyse and compare the urinary metabolomic pattern at birth of preterm infants with and without growth restriction at 36 weeks of postmenstrual age or at discharge, searching for putative markers of growth failure. Methods: We enrolled preterm infants between 23 and 32 weeks of gestational age (GA) and/or with a birth weight <1500 g, admitted to the Neonatal Intensive Care Unit (NICU) at the Department of Women’s and Children’s Health of Padova University Hospital. We collected urinary samples within 48 h of life and performed untargeted metabolomic analysis using mass spectrometry. Results: Sixteen EUGR infants were matched with sixteen non-EUGR controls. The EUGR group showed lower levels of L-cystathionine, kynurenic acid, L-carnosine, N-acetylglutamine, xanthurenic acid, aspartylglucosamine, DL5-hydroxylysine-hydrocloride, homocitrulline, and L-aminoadipic acid, suggesting a lower anti-inflammatory and antioxidant status with respect to the non-EUGR group. Conclusions: Metabolomic analysis suggests a basal predisposition to growth restriction, the identification of which could be useful for tailoring nutritional approaches. Full article

(This article belongs to the Special Issue Metabolomics-Based Biomarkers for Nutrition and Health)

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15 pages, 2737 KiB

Open AccessArticle

Thermogenic Activation of Adipose Tissue by Caffeine During Strenuous Exercising and Recovery: A Double-Blind Crossover Study

by Dany Alexis Sobarzo Soto, Diego Ignácio Valenzuela Pérez, Mateus Rossow de Souza, Milena Leite Garcia Reis, Naiara Ribeiro Almeida, Bianca Miarka, Esteban Aedo-Muñoz, Armin Isael Alvarado Oyarzo, Manuel Sillero-Quintana, Andreia Cristiane Carrenho Queiroz and Ciro José Brito

Metabolites 2025, 15(8), 517; https://doi.org/10.3390/metabo15080517 - 1 Aug 2025

Viewed by 422

Abstract

Background/Objectives: To investigate acute caffeine (CAF: 375 mg, ≈4.8 mg/kg body mass) effects on energy expenditure (EE) and substrate kinetics during high-intensity interval exercise in individuals with high (HBAT) versus low (LBAT) brown adipose tissue activity using time-trend polynomial modeling. Methods: This [...] Read more.

Background/Objectives: To investigate acute caffeine (CAF: 375 mg, ≈4.8 mg/kg body mass) effects on energy expenditure (EE) and substrate kinetics during high-intensity interval exercise in individuals with high (HBAT) versus low (LBAT) brown adipose tissue activity using time-trend polynomial modeling. Methods: This is a randomized, double-blind crossover study in which 35 highly-trained males [HBAT-CAF, HBAT-PLA (Placebo), LBAT-CAF, LBAT-PLA] performed 30-min treadmill HIIE. Infrared thermography (IRT) assessed BAT activity by measuring supraclavicular skin temperature (SST). Breath-by-breath ergospirometry measured EE (kcal/min) and carbohydrate (CHO), lipid (LIP), and protein (PTN) oxidation. We applied second- and third-order polynomial regression models to depict the temporal trajectories of metabolic responses. Results: HBAT groups showed 25% higher sustained EE versus LBAT (p < 0.001), amplified by CAF. CHO oxidation exhibited biphasic kinetics: HBAT had 40% higher initial rates (0.75 ± 0.05 vs. 0.45 ± 0.04 g/min; p < 0.001) with accelerated decline (k = −0.21 vs. −0.15/min; p = 0.01). LIP oxidation peaked later in LBAT (40 vs. 20 min in HBAT), with CAF increasing oxidation by 18% in LBAT (p = 0.01). HBAT-CAF uniquely showed transient PTN catabolism (peak: 0.045 g/min at 10 min; k = −0.0033/min; p < 0.001). Conclusions: BAT status determines EE magnitude and substrate-specific kinetic patterns, while CAF exerts divergent modulation, potentiating early glycogenolysis in HBAT and lipolysis in LBAT. The HBAT-CAF synergy triggers acute proteolysis, revealing BAT-mediated metabolic switching. Full article

(This article belongs to the Special Issue Energy Metabolism in Brown Adipose Tissue)

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Metabolites, Volume 15, Issue 8 (August 2025) – 55 articles

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