Metabolites

18 pages, 3602 KB

Open AccessArticle

Metabolomics and Cytokine Signatures in COVID-19: Uncovering Immunometabolism in Pathogenesis

by Mohammad Mehdi Banoei, Abdulrazagh Hashemi Shahraki, Kayo Santos, Gregory Holt and Mehdi Mirsaeidi

Metabolites 2025, 15(9), 608; https://doi.org/10.3390/metabo15090608 - 11 Sep 2025

Abstract

Background: This study aimed to analyze metabolic changes in blood samples from patients with confirmed COVID-19 to explore the correlation between metabolomics and cytokines in survivors and non-survivors of SARS-CoV-2 infection. Understanding the complex biochemical and immunometabolic mechanisms underlying SARS-CoV-2 infection is essential [...] Read more.

Background: This study aimed to analyze metabolic changes in blood samples from patients with confirmed COVID-19 to explore the correlation between metabolomics and cytokines in survivors and non-survivors of SARS-CoV-2 infection. Understanding the complex biochemical and immunometabolic mechanisms underlying SARS-CoV-2 infection is essential for elucidating the pathophysiology and virulence of COVID-19. Methods: This study included 40 hospitalized COVID-19 patients and 40 healthy controls. Serum metabolic profiles were analyzed using ultra-high-pressure liquid chromatography-mass spectrometry (UHPLC-MS), and cytokine levels were measured using ELISA. Results: Our study defined three clear metabolic phenotypes among survivors and non-survivors of COVID-19 compared with healthy controls, which might be related to mortality, severity, and disease burden. A strong relationship was observed between certain inflammatory markers, including IL-1β, IL-2, IFN-β, IFN-γ, IL-17, and GM-CSF, as well as several metabolites, particularly in COVID-19 non-survivors, such as LysoPCs, 3-hydroxykynurenine, and serotonin. Different metabolite-cytokine correlation patterns were observed according to patient outcomes, indicating unique correlations between metabolic and immune responses in survivors and non-survivors. Metabolic phenotypes were associated with clinical outcomes, comorbidities, and sex-related differences. Kynurenine and related metabolites of tryptophan metabolism were closely correlated with COVID-19 severity, age, and mortality. Compared with survivors and healthy controls, non-survivors displayed higher IL-6, together with distinct metabolic changes. These included increased kynurenine through the IDO1 pathway, elevated glucose and lactate reflecting hyperglycolysis and energy stress, and higher xanthosine from purine turnover. Stronger cytokine–metabolite correlations in this group point to tightly linked immunometabolic activation. Conclusions: Metabolomic profiling revealed distinct metabolic phenotypes that could be associated with the severity and inflammation levels of COVID-19. Correlation analysis between metabolites and cytokines demonstrated strong intercorrelations between specific metabolites and cytokines, indicating a strong interrelationship between inflammatory markers and metabolic alterations. Specific metabolic pathways associated with cytokines and their clinical relevance may serve as 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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18 pages, 1327 KB

Open AccessReview

NMR-Based Metabolomic Profiling for Brain Cancer Diagnosis and Treatment Guidance

by Julia R. Zickus, José S. Enriquez, Paytience Smith, Bill T. Sun, Muxin Wang, Aldo Morales, Pratip K. Bhattacharya and Shivanand Pudakalakatti

Metabolites 2025, 15(9), 607; https://doi.org/10.3390/metabo15090607 - 11 Sep 2025

Abstract

Nuclear magnetic resonance (NMR) spectroscopy is a routinely used analytical tool for studying chemical entities of varying molecular sizes, ranging from approximately 20 Da to ~45 kDa, and in some cases even larger. Over the past two decades, the use of NMR spectroscopy [...] Read more.

Nuclear magnetic resonance (NMR) spectroscopy is a routinely used analytical tool for studying chemical entities of varying molecular sizes, ranging from approximately 20 Da to ~45 kDa, and in some cases even larger. Over the past two decades, the use of NMR spectroscopy has significantly expanded to the study of metabolomics. In this medium-sized review, the application of NMR-based metabolomics in the diagnosis, therapeutic intervention, and guidance of therapy for various types of brain cancer is discussed. Full article

(This article belongs to the Special Issue Harnessing the Power of NMR Metabolomics in Unraveling Metabolic Diseases)

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15 pages, 1082 KB

Open AccessArticle

The Metabolic Vulnerability Index (MVX) in Subclinical Thyroid Disorders and Euthyroidism: A Cross-Sectional Exploratory Analysis from the ELSA-Brasil Study

by Carolina Castro Porto Silva Janovsky, Vandrize Meneghini, William Tebar, Joao Roberto Maciel Martins, José Augusto Sgarbi, Patrícia de Fatima dos Santos Teixeira, Itamar de Souza Santos, Steven R. Jones, Michael J. Blaha, Peter P. Toth, Marcio S. Bittencourt, Raul D. Santos, Paulo A. Lotufo, Layal Chaker and Isabela M. Bensenor

Metabolites 2025, 15(9), 606; https://doi.org/10.3390/metabo15090606 - 11 Sep 2025

Abstract

Background: Recently, a new biomarker index that reflects inflammation and protein energy malnutrition has emerged as a predictor of mortality in cardiovascular diseases. The metabolic vulnerability index (MVX) derives from blood-based inflammation (IVX) and malnutrition (MMX) markers measured by nuclear magnetic resonance (NMR) [...] Read more.

Background: Recently, a new biomarker index that reflects inflammation and protein energy malnutrition has emerged as a predictor of mortality in cardiovascular diseases. The metabolic vulnerability index (MVX) derives from blood-based inflammation (IVX) and malnutrition (MMX) markers measured by nuclear magnetic resonance (NMR) spectroscopy. We aimed to explore the association of subclinical hypothyroidism and thyroid-related parameters with IVX, MMX, and MVX scores. Methods: This cross-sectional study used the baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Individuals with normal thyroid function and subclinical hypothyroidism were included. Thyroid-related parameters—thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), the FT3–FT4 ratio, and antithyroperoxidase antibodies (TPOAb)—were the explanatory variables. The primary outcomes, MVX, MMX, and IVX scores, were analyzed as continuous variables. Linear regression analyses were performed for both univariate and multivariable models, with sensitivity and subgroup analyses applied to assess robustness. Findings: There were 3979 participants (51.4% female) with a mean age of 51.26 (SD: 9.02) years. After full adjustment for potential confounder variables, FT3 levels [B: −1.37 (−2.43;−0.31) p = 0.011] and the FT3–FT4 ratio [B: −0.90 (−1.79;−0.01) p = 0.047] were inversely associated with MVX scores. FT3 levels were also inversely associated with IVX [B: −1.32 (−2.39;−0.24) p = 0.017]. These results were consistent in euthyroid individuals and those with cardiometabolic diseases. In the sex-stratified analysis, FT3 levels were inversely associated with MVX, MMX, and IVX scores for men. Conclusion: Lower FT3 levels and the FT3–FT4 ratio were associated with a higher metabolic vulnerability in our cohort. Our study sheds light on the importance of metabolic surveillance in these patients, especially for men with cardiometabolic diseases. Full article

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

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18 pages, 680 KB

Open AccessArticle

Enzymatic Evolution and Longitudinal Recovery in Biotinidase Deficiency: Genotypic and Clinical Insights from the Follow-Up of a Newborn-Screened Cohort in Emilia-Romagna, Italy

by Rita Ortolano, Soara Menabò, Egidio Candela, Giacomo Biasucci, Elisa Bortolamedi, Giulia Montanari, Alessandro Zuccotti, Umberto Cattini, Marcello Lanari and Federico Baronio

Metabolites 2025, 15(9), 605; https://doi.org/10.3390/metabo15090605 - 10 Sep 2025

Abstract

Background/Objectives: Biotinidase deficiency (BD) is a treatable autosomal recessive disorder included in many newborn screening (NBS) programs. The importance of early diagnosis and treatment is now well established. However, recent studies are emerging on the possibility of increased enzyme activity with age, an [...] Read more.

Background/Objectives: Biotinidase deficiency (BD) is a treatable autosomal recessive disorder included in many newborn screening (NBS) programs. The importance of early diagnosis and treatment is now well established. However, recent studies are emerging on the possibility of increased enzyme activity with age, an observation that raises questions about the long-term validity of the initial classification of these patients. This study aimed to assess the incidence, genetic and clinical features, and, notably, the longitudinal enzymatic trajectory of BD in a cohort identified by NBS in Emilia-Romagna, Italy, with implications for diagnostic re-evaluation and therapeutic decisions. Methods: A retrospective and prospective analysis was conducted on 64 infants recalled after NBS for suspected BD between 2016 and 2020. Biochemical, molecular, and clinical data were collected, and biotinidase (BTD) activity was monitored longitudinally. Affected individuals were supplemented with biotin and followed clinically for at least 5 years. Results: Thirty-one patients were diagnosed with BD (30 partial, 1 profound; incidence 1:5448). A significant and sustained increase in BTD activity was observed from diagnosis through early childhood (p < 0.001 up to 60 months), particularly among patients carrying the p.Asp444His variant. This enzymatic trend suggests a potential remodulation of biochemical classification over time. Genotype–phenotype concordance was high (92%), and clinical outcomes were favorable across the cohort. Conclusions: This study provides new evidence that BTD activity in patients with BD increases progressively, supporting the concept of age-dependent enzyme recovery. Our results support the need for systematic re-evaluation of diagnosis and treatment, especially at 12 months of age, and particularly in patients with evidence of partial activity deficiency and the p.Asp444His mutation. Full article

(This article belongs to the Special Issue Research of Inborn Errors of Metabolism)

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16 pages, 3312 KB

Open AccessArticle

Organ-Specific Metabolome Reveals Potential Nutritional and Health Benefits of Ampelopsis grossedentata

by Yanna Li, Ran Ye, Ju Yang, Siting Deng, Dongqing Rong, Yinling Luo and Hui Huang

Metabolites 2025, 15(9), 604; https://doi.org/10.3390/metabo15090604 - 10 Sep 2025

Abstract

Background/Objectives: Ampelopsis grossedentata, a novel food resource (vine tea), is a therapeutically valuable species wherein all parts exhibit bioactive potential. The therapeutic value and health benefits of A. grossedentata are rooted in its metabolomic profile, yet the metabolites in its various parts [...] Read more.

Background/Objectives: Ampelopsis grossedentata, a novel food resource (vine tea), is a therapeutically valuable species wherein all parts exhibit bioactive potential. The therapeutic value and health benefits of A. grossedentata are rooted in its metabolomic profile, yet the metabolites in its various parts remain incompletely characterized. In this study, the tissue-specific biochemical properties and metabolic profiles of A. grossedentata were systematically characterized to identify the optimal tissue type for harvesting, with the goal of maximizing the production of bioactive compounds. Methods: The biochemical properties of various A. grossedentata tissues were assessed using a spectrophotometer, and their metabolic profiles were characterized through LC-MS/MS-based untargeted metabolomics. Results: The results demonstrate that, compared with the stems and roots, the tender leaves and floral tissues contained a higher TFC and TPC, correlating with superior antioxidant activity (DPPH, ABTS, and FRAP). A metabolic analysis revealed that the tender leaves accumulated multiple bioactive flavonoids beyond dihydromyricetin, including naringenin 7-O-beta-D-glucoside, (-)-epigallocatechin, tricetin, and cyanidin 3-O-sophoroside. The floral tissues displayed a comparable antioxidant capacity and dihydromyricetin level to the leaves, as well as unique compounds, such as leucodelphinidin, naringenin, epicatechin, dihydroquercetin, astilbin, and myricitrin. A metabolomic analysis further demonstrated a high accumulation of L-glutamine and L-glutamic acid in the floral tissues, potentially contributing to the characteristic umami flavor profile of vine tea made from A. grossedentata flowers. Conclusions:A. grossedentata flowers could be considered a promising raw material for developing novel functional foods and premium herbal tea products, as they possess superior antioxidant activity and abundant flavonoids and amino acids. Full article

(This article belongs to the Special Issue Advances in Food Metabolomics for Functional Food Development and Analysis)

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24 pages, 4186 KB

Open AccessArticle

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

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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18 pages, 747 KB

Open AccessReview

Impact of Dietary Interventions on the Human Plasma and Lipoprotein Lipidome

by Rosa Casas, Nancy D. Sánchez-García, Ramon Estruch and Anallely López-Yerena

Metabolites 2025, 15(9), 602; https://doi.org/10.3390/metabo15090602 - 9 Sep 2025

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Abstract

Lipids are structurally diverse biomolecules that play essential roles in cellular function, energy storage, and signaling. The human lipidome, a dynamic and complex subset of the metabolome, is shaped by both endogenous factors, such as genetics, sex, age, and metabolic health, and exogenous [...] Read more.

Lipids are structurally diverse biomolecules that play essential roles in cellular function, energy storage, and signaling. The human lipidome, a dynamic and complex subset of the metabolome, is shaped by both endogenous factors, such as genetics, sex, age, and metabolic health, and exogenous influences like lifestyle, diet, and microbiota. Among these, diet stands out as one of the most modifiable and impactful determinants, influencing lipid composition across plasma, serum, and lipoprotein fractions. While traditional lipid profiling provides limited insight, lipidomics enables comprehensive characterization of lipid species, revealing mechanistic links between lipid metabolism and diseases such as cardiovascular disease (CVD), metabolic syndrome (MetS), and inflammatory disorders. This review explores: (1) the relationship between lipid profiles and CVD risk, (2) the internal and external modulators of the lipidome, and (3) current evidence on how specific dietary patterns, including Mediterranean, Nordic, low glycemic, and vegetarian diets, and individual nutrients such as omega-3 fatty acids (FAs), plant sterols, and mycoprotein, influence lipidomic profiles. Advances in lipidomics highlight that dietary fat quality, food matrix, and eating patterns can significantly modulate lipid species such as triacylglycerols (TAGs), ceramides (Cers), and phospholipids, with implications for cardiometabolic health. Notably, distinct responses are observed across plasma High-Density Lipoprotein (HDL) and Low-Density Lipoprotein (LDL) lipidomes, emphasizing the need for compartment-specific analyses. Understanding these diet-lipidome interactions offers promising avenues for precision nutrition and the development of lipid-based biomarkers for disease prevention and management. Full article

(This article belongs to the Special Issue Food Intake and Bioactive Metabolism in Humans)

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21 pages, 3678 KB

Open AccessReview

Amino Acid Metabolism of the Skin: Control by Specific Enzymes and Contribution to Protective Functions

by Corina Dörner, Julia Steinbinder, Attila Placido Sachslehner, Supawadee Sukseree and Leopold Eckhart

Metabolites 2025, 15(9), 601; https://doi.org/10.3390/metabo15090601 - 9 Sep 2025

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Abstract

The skin protects the body from damaging external stressors. The function of its outermost compartment, the epidermis, depends on high rates of protein synthesis and the production of protective molecules, both requiring amino acids as precursors. Conversely, the degradation of the epidermal barrier [...] Read more.

The skin protects the body from damaging external stressors. The function of its outermost compartment, the epidermis, depends on high rates of protein synthesis and the production of protective molecules, both requiring amino acids as precursors. Conversely, the degradation of the epidermal barrier protein filaggrin releases free amino acids. Here, we review the epidermal amino acid metabolism, focusing on the metabolism of histidine, arginine and tyrosine, which are subjected to epidermal cell-specific control mechanisms. Histidine and arginine are metabolized by enzymes that are transcriptionally upregulated during terminal differentiation of keratinocytes, while tyrosine is specifically metabolized in melanocytes. Arginase converts arginine into ornithine and urea. While ornithine is decarboxylated to putrescine, a regulator of cellular proliferation, urea contributes to the moisturization of the skin surface. Histidase, also known as histidine ammonia lyase, converts histidine into urocanic acid (UCA) and ammonia. UCA is the main ultraviolet-absorbing molecule of the cornified layer of the epidermis, serving as a natural sunscreen of human skin. In melanocytes, tyrosinase initiates the polymerization of tyrosine to melanin, the main skin pigment that absorbs both visible light and ultraviolet radiation. The current evidence indicates that the metabolism of histidine, arginine, tyrosine and other amino acids critically influences normal and diseased skin. Full article

(This article belongs to the Section Cell Metabolism)

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16 pages, 3407 KB

Open AccessArticle

Time-Resolved Metabolomics Reveals Mitochondrial Protection in Septic Liver Injury

by Naoki Suzuki, Shoichiro Shibata, Masahiro Sugimoto, Eskil Elmer and Hiroyuki Uchino

Metabolites 2025, 15(9), 600; https://doi.org/10.3390/metabo15090600 - 9 Sep 2025

Viewed by 367

Abstract

Background/Objectives: Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated host response to infection. Mitochondrial dysfunction is considered a key contributor to the pathogenesis of sepsis, but its molecular mechanisms remain unclear. Methods: In this study, we [...] Read more.

Background/Objectives: Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated host response to infection. Mitochondrial dysfunction is considered a key contributor to the pathogenesis of sepsis, but its molecular mechanisms remain unclear. Methods: In this study, we used a cecal ligation and puncture (CLP) model to induce sepsis in wild-type (WT) and cyclophilin D knockout (CypD KO) mice. Liver tissues were collected at 0, 6, and 18 h post-CLP and analyzed using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results: Metabolomic profiling revealed that lactate levels significantly increased in the WT mice but remained stable in the KO mice. While AMP levels were preserved in the KO mice, these mice had significantly higher glutathione disulfide (GSSG) and spermidine concentrations than the WT mice at 18 h (p < 0.05). The levels of malondialdehyde (MDA), a marker of oxidative stress, were also significantly lower in the KO mice at 18 h (p < 0.05). These findings suggest that CypD deficiency preserves mitochondrial function, enhances resistance to oxidative stress, and mitigates septic liver injury. Conclusions: Our results highlight the potential of targeting mitochondrial permeability transition as a therapeutic strategy for sepsis. Full article

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

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22 pages, 2656 KB

Open AccessArticle

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

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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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13 pages, 1451 KB

Open AccessArticle

Glutamine and Albumin Levels in Cerebrospinal Fluid Are Correlated with Neurological Severity in an Experimental Model of Acute Hepatic Encephalopathy

by Pedro Arend Guazzelli, Felipe dos Santos Fachim, Anderson Santos Travassos, Caroline Casagrande Schaukoski, Pâmela Cristina Lukasewicz Ferreira, Fernanda Uruth Fontella, Marco Antônio de Bastiani, Adriano Martimbianco de Assis and Diogo Onofre Souza

Metabolites 2025, 15(9), 598; https://doi.org/10.3390/metabo15090598 - 8 Sep 2025

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Abstract

Background/Objectives: Hepatic encephalopathy (HE) is a severe neurological complication of acute liver failure (ALF) characterized by the accumulation of neurotoxic metabolites and impaired cerebral function. We aimed to examine the correlation between HE severity and cerebrospinal fluid (CSF) biomarker levels in a rat [...] Read more.

Background/Objectives: Hepatic encephalopathy (HE) is a severe neurological complication of acute liver failure (ALF) characterized by the accumulation of neurotoxic metabolites and impaired cerebral function. We aimed to examine the correlation between HE severity and cerebrospinal fluid (CSF) biomarker levels in a rat model of ALF induced by subtotal hepatectomy. Methods: Male Wistar rats underwent 92% hepatectomy and were monitored for neurological impairment via a standardized HE score. At twenty-four hours post surgery, CSF and blood were collected for biochemical analysis. Results: We found a significant positive correlation between neurological severity and CSF levels of glutamine (r = 0.929, p < 0.001) and albumin (r = 0.869, p < 0.001), both with HE grade I scores, highlighting their prominent role as HE biomarkers. Other amino acids, including aspartate (r = 0.790, p < 0.001), glutamate (r = 0.853, p < 0.001), isoleucine (r = 0.834, p < 0.001), leucine (r = 0.813, p < 0.001), lysine (r = 0.861, p < 0.001), methionine (r = 0.889, p < 0.001), phenylalanine (r = 0.916, p < 0.001), ornithine (r = 0.775, p < 0.001), tryptophan (r = 0.814, p < 0.001), and valine (r = 0.721, p < 0.001), also showed significant correlations with HE severity but not with HE grade I scores. Conclusions: These findings underscore the potential of glutamine and albumin in CSF as key biomarkers for assessing neurological severity in ALF patients. Full article

(This article belongs to the Special Issue Metabolic Profiling in Neurometabolisms)

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18 pages, 2326 KB

Open AccessArticle

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

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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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14 pages, 535 KB

Open AccessArticle

Effects of 12 Weeks of Calanus Oil Supplementation on Cardiac Diastolic Function in Obese and Prediabetic Women—A Pilot Study

by Felix Kerlikowsky, Fabian Spahiu, Eric J. Stöhr, Sina Junge, Wiebke Jonas, Edda van de Flierdt, Jan Philipp Schuchardt and Andreas Hahn

Metabolites 2025, 15(9), 596; https://doi.org/10.3390/metabo15090596 - 8 Sep 2025

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Abstract

Background/Objectives: In early-stage diabetes, diastolic dysfunction is an initial indicator of heart failure and is linked to altered glucose metabolism, including in prediabetes. Based on initial evidence that Calanus oil, derived from Calanus finmarchicus, which is rich in omega-3 polyunsaturated fatty acids [...] Read more.

Background/Objectives: In early-stage diabetes, diastolic dysfunction is an initial indicator of heart failure and is linked to altered glucose metabolism, including in prediabetes. Based on initial evidence that Calanus oil, derived from Calanus finmarchicus, which is rich in omega-3 polyunsaturated fatty acids and other bioactive compounds, benefits metabolic and cardiorespiratory health, this proof-of-principle study aimed to assess whether Calanus oil improves diastolic function in prediabetic women. Methods: Twenty middle-aged, obese women with prediabetes and no history of cardiac complications were enrolled and received 4 g/day of Calanus oil, providing 276 mg EPA + 256 mg DHA, for 12 weeks. Systolic and diastolic cardiac function, including the E/A ratio (E/A), was assessed by echocardiography. In addition, central blood pressure (BP) and pulse wave velocity (PWV) were analyzed by oscillometry. Metabolic health was evaluated using composite markers, including the metabolic syndrome severity score (Met-S score) and the triacylglycerol glucose–waist-to-height ratio (TyG-WHtR). Results: E/A was significantly improved (p = 0.023) following 12 weeks of Calanus oil supplementation. Furthermore, a significant improvement in metabolic health, indicated by a reduced Met-S score and a lower TyG-WHtR, was noticed (p < 0.001, respectively), reflecting decreased metabolic syndrome severity and enhanced insulin sensitivity. In addition, a significant reduction in diastolic BP, resting heart rate (p = 0.047), but not PWV or systolic BP (all p > 0.05) was observed. The improvement in E/A was associated with improved insulin sensitivity, as reflected by a decrease in the TyG-WHtR (p = 0.014). Conclusions: These exploratory findings suggest that Calanus oil supplementation in pre-diabetic women might improve central diastolic haemodynamics, accompanied by an overall improvement in metabolic health. However, the absence of a placebo control group limits definitive conclusions. Full article

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

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20 pages, 1114 KB

Open AccessReview

Fatty Acid Profile and Desaturase Activity in Obesity: Roles, Mechanisms, and Clinical Relevance

by Michalina Banaszak, Ilona Górna and Sławomira Drzymała-Czyż

Metabolites 2025, 15(9), 595; https://doi.org/10.3390/metabo15090595 - 8 Sep 2025

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Abstract

Background: Obesity is a complex metabolic disease associated with several health complications, including insulin resistance, hypertension, and type 2 diabetes mellitus. Growing evidence indicates that fatty acid profiles and the activity of desaturating enzymes—stearoyl-CoA desaturase-1 (SCD1), delta-5 desaturase (D5D), and delta-6 desaturase (D6D)—are [...] Read more.

Background: Obesity is a complex metabolic disease associated with several health complications, including insulin resistance, hypertension, and type 2 diabetes mellitus. Growing evidence indicates that fatty acid profiles and the activity of desaturating enzymes—stearoyl-CoA desaturase-1 (SCD1), delta-5 desaturase (D5D), and delta-6 desaturase (D6D)—are important factors in the pathophysiology of obesity. This review aims to summarise the current understanding of the alterations in lipid metabolism and desaturase activity in obesity, its complications, and potential therapeutic interventions. Methods: A literature review was performed using the PubMed, Scopus, and Web of Science databases. Systematic reviews, meta-analyses, clinical studies, cross-sectional studies, and animal studies that assessed fatty acid profiles and desaturase activity in the context of obesity were included. Results: Obesity is associated with significant changes in the profiles of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs), as well as altered desaturase activity. Increased activity of SCD1 and D6D and decreased activity of D5D are observed even in childhood and correlate with metabolic risk markers. Genetic variation in genes encoding fatty acid desaturases, such as fatty acid desaturase 1 (FADS1), fatty acid desaturase 2 (FADS2), and SCD1, influences lipid metabolism and susceptibility to metabolic disorders. Nutritional interventions, supplementation (e.g., omega-3 fatty acids, L-carnitine, and crocin), physical activity, and bariatric surgery positively influence the fatty acid profile and enzymatic activity, modifying the risk of obesity-related diseases. Conclusions: Fatty acid profile and desaturase activity are significantly altered in obesity and represent potential biomarkers and therapeutic targets for its treatment and the prevention of related complications. Their assessment may contribute to a more personalised approach to treating obesity and associated metabolic diseases. Full article

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

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15 pages, 2867 KB

Open AccessArticle

Phenolic-Rich Indian Almond (Terminalia catappa Linn) Leaf Extract Ameliorates Lipid Metabolism and Inflammation in High-Fat Diet (HFD)-Induced Obese Mice

by Opeyemi O. Deji-Oloruntoba, Ji Eun Kim, Hee Jin Song, Ayun Seol, Dae Youn Hwang and Miran Jang

Metabolites 2025, 15(9), 594; https://doi.org/10.3390/metabo15090594 - 8 Sep 2025

Viewed by 228

Abstract

Background: Obesity is a global health issue closely associated with dysregulated lipid metabolism and chronic inflammation. Effective strategies targeting both lipogenesis and inflammation are essential for managing obesity and its related metabolic disorders. Methods: This study evaluated the effects of Terminalia catappa Linn. [...] Read more.

Background: Obesity is a global health issue closely associated with dysregulated lipid metabolism and chronic inflammation. Effective strategies targeting both lipogenesis and inflammation are essential for managing obesity and its related metabolic disorders. Methods: This study evaluated the effects of Terminalia catappa Linn. leaf extract (TCE) on lipogenic and lipolytic pathways in high-fat diet (HFD)-induced obese mice. UPLC-QTOF-MS analysis was conducted to identify and quantify the major phenolic compounds in TCE. Mice were administered low and high doses of TCE, and various metabolic parameters, including lipid profiles, liver function markers, adipokine levels, and gene/protein expressions related to lipid metabolism and inflammation, were assessed. Results: UPLC-QTOF-MS analysis identified four major phenolic compounds in TCE—gallic acid, orientin, vitexin, and ellagic acid—with respective contents of 112.5, 163.3, 184.7, and 295.7 mg/g extract. TCE administration significantly reduced liver and adipose tissue weights, along with hepatic and adipose lipid accumulation. Both low and high doses of TCE markedly lowered serum lipid levels. Liver function was improved, as indicated by reduced levels of AST, ALT, and ALP, while BUN levels remained unchanged. On the molecular level, TCE downregulated adipogenic and lipogenic genes (PPARγ, PPARα, C/EBPα, aP2) and upregulated metabolic regulators, including leptin, adiponectin, p-HSL/HSL, and p-perilipin/perilipin, without affecting ATGL expression. TCE also suppressed pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, and TGFβ-1. Conclusions: These findings highlight the therapeutic potential of TCE in managing obesity by inhibiting lipogenesis, enhancing lipolysis, and reducing inflammation. Full article

(This article belongs to the Section Pharmacology and Drug Metabolism)

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15 pages, 2026 KB

Open AccessArticle

Multiparametric Evaluation of Drug-Induced Acute Kidney Injury Using Preclinical 7T Magnetic Resonance Imaging in Rat Models

by Tomohiro Natsuyama, Junpei Ueda, Isamu Yabata, Reika Sawaya, Koji Itagaki and Shigeyoshi Saito

Metabolites 2025, 15(9), 593; https://doi.org/10.3390/metabo15090593 - 7 Sep 2025

Viewed by 367

Abstract

Objectives: Acute kidney injury (AKI), characterized by a rapid decline in renal function, affects approximately 13 million new patients annually. Adverse drug reactions have increasingly contributed to renal injury, underscoring the need for methods to directly and quantitatively evaluate renal injury. Methods [...] Read more.

Objectives: Acute kidney injury (AKI), characterized by a rapid decline in renal function, affects approximately 13 million new patients annually. Adverse drug reactions have increasingly contributed to renal injury, underscoring the need for methods to directly and quantitatively evaluate renal injury. Methods: We utilized a drug-induced AKI model using gentamicin overdose, combining 7T magnetic resonance imaging (MRI) relaxation time measurements and blood tests to evaluate pathophysiological changes from multiple perspectives. Ten-week-old Wistar rats received intraperitoneal administration of gentamicin (80 mg/kg) for 7 days. Under respiratory synchronization, T₁, T_1rho, T₂, and T₂* maps were obtained in six control and five disease model rats. Relaxation times in the cortex and medulla were measured separately and compared between groups. Results: Blood tests evaluated Na, K, Cl, blood urea nitrogen, creatinine, and hematocrit levels. Renal tissue damage was evaluated via hematoxylin and eosin (HE) staining. Relaxation time showed significant changes in the cortex, especially in the T₁ (control: 1156.7 ± 140.0, gentamicin: 1550.4 ± 162.1, p < 0.05) and T₂ (control: 42.9 ± 3.4, gentamicin: 53.4 ± 4.8, p < 0.05) maps. Blood tests revealed significant increases in Na, blood urea nitrogen, creatinine, and hematocrit levels in the disease model. A correlation was observed between the T1 map of the renal cortex and each substance. HE staining revealed tissue damage due to renal injury. Conclusions: Multiparametric MRI facilitates quantitative and multidimensional evaluation of renal pathological changes caused by drug-induced AKI. Full article

(This article belongs to the Special Issue Integration of Emerging Technologies in Metabolite Analysis)

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16 pages, 3103 KB

Open AccessArticle

Plasma Lipidomic Alterations in Fontan Circulation Reflect Cardiovascular Functional Reserve

by Arun Surendran, Amir Ravandi and Ashish H. Shah

Metabolites 2025, 15(9), 592; https://doi.org/10.3390/metabo15090592 - 7 Sep 2025

Viewed by 307

Abstract

Background: Fontan circulation is associated with impaired cardiac output, reduced exercise capacity, and systemic metabolic stress. However, the underlying lipidomic alterations remain poorly defined. Methods: Using targeted mass spectrometry, we analyzed 291 lipid species in fasting plasma samples from 20 adults with Fontan [...] Read more.

Background: Fontan circulation is associated with impaired cardiac output, reduced exercise capacity, and systemic metabolic stress. However, the underlying lipidomic alterations remain poorly defined. Methods: Using targeted mass spectrometry, we analyzed 291 lipid species in fasting plasma samples from 20 adults with Fontan circulation and 20 age- and sex-matched healthy controls. Results: Forty-eight lipids were significantly altered between groups (p < 0.05), including reductions in total lysophosphatidylcholines (LPC) and total ether-linked LPC [LPC(O)] and elevations in total phosphatidylserines (PS). Notably, LPC(O-22:1) and LPC(O-20:0) were decreased, while PS 40:5 was elevated, with several of these species demonstrating strong correlations (|r| > 0.5, p < 0.001) with the stroke index, cardiac index, and VO₂max. These three lipid species also showed excellent capability in discriminating Fontan patients from healthy controls (AUC > 0.78). Correlation network and pathway enrichment analyses revealed tightly coordinated lipid clusters containing LPC/LPC(O), PE, and PS species as central features of dysregulated Fontan metabolism. Conclusions: These exploratory findings highlight coordinated lipid alterations associated with impaired cardiovascular reserve in Fontan patients. While based on unadjusted p-values and therefore being hypothesis-generating, they provide novel insight into the metabolic landscape of Fontan physiology and warrant validation in larger, independent cohorts. Full article

(This article belongs to the Special Issue Lipid Metabolism Dysregulation in Metabolic Disorders: Unraveling the Molecular Complexity)

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24 pages, 4858 KB

Open AccessArticle

A Holistic Approach to Metabolic Health Assessment—Analysis of Bioimpedance, Blood, and Saliva Biochemistry in Population Studies—A Pilot Study

by Aleksandra Stawiarska, Renata Francik, Anna Mikulec, Marek Zborowski, Urszula Cisoń-Apanasewicz, Ryszard Gajdosz, Iwona Zaczyk, Halina Potok, Agnieszka Radom, Dorota Ogonowska and Elżbieta Rafa

Metabolites 2025, 15(9), 591; https://doi.org/10.3390/metabo15090591 - 7 Sep 2025

Viewed by 239

Abstract

Background: Metabolic syndrome is a multifaceted condition involving lipid and carbohydrate metabolism disorders and hypertension, increasing the risk of cardiovascular disease and type 2 diabetes. Accurate diagnosis and prevention require an interdisciplinary approach that includes both traditional lab tests and modern, non-invasive health [...] Read more.

Background: Metabolic syndrome is a multifaceted condition involving lipid and carbohydrate metabolism disorders and hypertension, increasing the risk of cardiovascular disease and type 2 diabetes. Accurate diagnosis and prevention require an interdisciplinary approach that includes both traditional lab tests and modern, non-invasive health assessments. Methods: This study aimed to evaluate metabolic health in adults from the Małopolska Voivodeship by analyzing the relationships between obesity indicators (BMI, waist circumference) and anthropometric, blood, and salivary biomarkers. Sixty-three participants (36 women, 27 men) aged 40–71 underwent body composition analysis (InBody 770), anthropometric measurements, and biochemical tests of blood and saliva. Assessed parameters included body composition (BMI, BFM, FFM, SMM, PBF, VFA, PA), blood pressure, blood biomarkers (glucose, TG, LDL, HDL, HbA1c, insulin, cortisol), and salivary markers (FRAP, DPPH, urea, amylase activity, protein content, pH, buffering capacity). Results: The results showed a strong correlation between body composition and biochemical markers, but the results of the analyzed salivary biomarkers were inconclusive and, in some cases, contradictory to the findings of other authors. Conclusions: Fat mass, cell integrity, and diastolic pressure were key determinants of waist circumference. Our research confirms the validity of using combined diagnostics, bioimpedance, and blood analysis for a comprehensive assessment of metabolic health and indicates the direction for further research using salivary biomarkers. A holistic approach improves risk assessment and strengthens preventive and therapeutic strategies. However, our pilot study showed that the research requires a larger sample size, especially in order to draw representative conclusions regarding salivary biomarkers and their relationship to metabolic health. Full article

(This article belongs to the Special Issue Metabolic Changes in Diet-Mediated Inflammatory Diseases)

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12 pages, 757 KB

Open AccessArticle

The Role of Visfatin/NAMPT in the Pathogenesis of Psoriasis

by Mateusz Matwiejuk, Agnieszka Kulczyńska-Przybik, Bartłomiej Łukaszuk, Hanna Myśliwiec, Piotr Myśliwiec, Adrian Chabowski, Barbara Mroczko and Iwona Flisiak

Metabolites 2025, 15(9), 590; https://doi.org/10.3390/metabo15090590 - 6 Sep 2025

Viewed by 423

Abstract

Introdcution: Psoriasis is a complex, chronic, immunologically, inflammatory, and environmentally mediated disease which may affect not only the skin, but also nails, and joints. This dermatosis is known for hyperproliferation, parakeratosis, dysregulated differentiation of keratinocytes, lack of granular layer of the skin and [...] Read more.

Introdcution: Psoriasis is a complex, chronic, immunologically, inflammatory, and environmentally mediated disease which may affect not only the skin, but also nails, and joints. This dermatosis is known for hyperproliferation, parakeratosis, dysregulated differentiation of keratinocytes, lack of granular layer of the skin and impaired apoptosis of keratinocytes. Methods Fifty patients with psoriasis and twenty-eight healthy individuals were enrolled in the study. Serum samples were collected both from the psoriatic patients and patients with an inguinal hernia, who served as the control group. Visfatin levels were measured by enzyme-linked immunosorbent assay. Various proteins have been well described as key contributors to the complex pathogenesis of psoriasis. Results: In our study, we found that serum visfatin levels were significantly higher in the psoriatic group compared to the control group. Interestingly, we observed a positive and statistically significant correlation between serum visfatin levels and HDL-C concentrations in patients with psoriasis. Discussion: An elevated HDL-C level in psoriatic serum might be a sign of a compensatory response to systemic inflammation, or a marker of metabolic dysfunction, or an early prognostic signal in disease progression. However, no significant correlations were found between visfatin levels and the Psoriasis Area and Severity Index (PASI) score. Conclusions: In summary, our findings indicate that visfatin levels are significantly altered in the serum of patients with psoriasis compared to the control group and it could be a pivotal point of understanding the pathogenesis of psoriasis and a new way of implementing therapeutic procedures. Full article

(This article belongs to the Special Issue Psoriasis and Metabolic Syndrome)

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53 pages, 3155 KB

Open AccessReview

The Power of Lignans: Plant Compounds with Multifaceted Health-Promoting Effects

by Marta Burgberger, Justyna Mierziak, Beata Augustyniak, Wioleta Wojtasik and Anna Kulma

Metabolites 2025, 15(9), 589; https://doi.org/10.3390/metabo15090589 - 4 Sep 2025

Viewed by 589

Abstract

Lignans are plant-derived biphenolic compounds with multiple hydroxyl groups, which, upon ingestion, are metabolized by gut microbiota into enterolignans—enterolactone and enterodiol. These mammalian metabolites exhibit structural similarity to estradiol, enabling lignans to modulate hormonal balance and exert estrogen-like effects. A growing body of [...] Read more.

Lignans are plant-derived biphenolic compounds with multiple hydroxyl groups, which, upon ingestion, are metabolized by gut microbiota into enterolignans—enterolactone and enterodiol. These mammalian metabolites exhibit structural similarity to estradiol, enabling lignans to modulate hormonal balance and exert estrogen-like effects. A growing body of evidence highlights their broad spectrum of health-promoting properties, including antioxidant, anti-inflammatory, and hormone-regulating effects. Lignans have shown potential in alleviating menopausal symptoms, preventing estrogen-dependent cancers, and mitigating conditions such as cardiovascular disease, diabetes, and metabolic syndrome. Additionally, their antimicrobial activity against bacteria, fungi, and viruses is being increasingly recognized. This review provides a comprehensive and up-to-date synthesis of current knowledge. It uniquely integrates the latest insights into lignan biosynthesis, gut microbiota-mediated metabolism, and clinically relevant outcomes. Importantly, this review incorporates recent findings from prospective cohort studies and meta-analyses and sheds light on emerging therapeutic applications, including antifungal activity—an area rarely covered in earlier literature. By presenting a holistic perspective, this review advances our understanding of lignans as multifaceted compounds with significant potential in preventive and therapeutic health strategies. Full article

(This article belongs to the Section Plant Metabolism)

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22 pages, 1349 KB

Open AccessArticle

Fruit Quality Characterization and Comprehensive Evaluation of 30 Chionanthus retusus Accessions

by Muge Niu, Jinnan Wang, Baoqiang Huang, Hui Tian, Maotong Sun, Jihong Li, Jing Ren and Cuishuang Liu

Metabolites 2025, 15(9), 588; https://doi.org/10.3390/metabo15090588 - 3 Sep 2025

Viewed by 404

Abstract

Objectives: Research on kernel oil content and secondary metabolites in Chionanthus retusus was conducted to evaluate its potential as an oil crop. Methods: Fruits from 30 individual trees were collected to analyze morphological traits, oil content, and the composition of fatty acids, phytosterols, [...] Read more.

Objectives: Research on kernel oil content and secondary metabolites in Chionanthus retusus was conducted to evaluate its potential as an oil crop. Methods: Fruits from 30 individual trees were collected to analyze morphological traits, oil content, and the composition of fatty acids, phytosterols, and tocopherols. Correlation, cluster, and principal component analyses were performed on the resulting data. Results: The mean fresh fruit weight, dry fruit weight, dry kernel weight, and kernel percentage were 77.02 g, 24.33 g, 12.22 g, and 51.14%, respectively. Kernel oil content averaged 35.83%, comprising seven fatty acids with oleic acid as the predominant component. Total phytosterol content reached 279.58 mg/100 g oil, with β-sitosterol being the major constituent among seven detected sterols. Total tocopherols were 571.13 μg/g oil, dominated by γ-tocopherol, indicating a potential antioxidant capacity. These components may reduce the demand for synthetic antioxidant food additives. A significant positive correlation was observed between kernel dry weight and oil content (r = 0.760, p < 0.01), supporting kernel dry weight as a key phenotypic indicator for high-oil breeding. Fruit quality traits did not cluster by geographic origin, whereas secondary metabolite profiles showed origin-based clustering. For breeding oil-producing C. retusus, select seeds with superior provenances based on secondary metabolites and cultivate them under optimal conditions to develop varieties with plump fruit, thereby boosting yield. Accessions WS-4 and WS-3 were identified as promising germplasm resources for oil production. Conclusions: The abundant oleic acid, β-sitosterol, and γ-tocopherol in C. retusus kernels highlight its potential as a woody oilseed crop. Full article

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

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21 pages, 1109 KB

Open AccessArticle

Herbal Weight Loss Supplements Induce Metabolomic In Vitro Changes Indicative of Oxidative Stress

by Emily C. Davies, Garth L. Maker, Ian F. Musgrave and Samantha Lodge

Metabolites 2025, 15(9), 587; https://doi.org/10.3390/metabo15090587 - 1 Sep 2025

Viewed by 542

Abstract

Background/Objectives: The prevalence of obesity continues to rise globally, and with this an increase in the use of herbal weight loss supplements (WLS). At present, there is limited evidence to support the efficacy and safety of WLS, and there have been growing [...] Read more.

Background/Objectives: The prevalence of obesity continues to rise globally, and with this an increase in the use of herbal weight loss supplements (WLS). At present, there is limited evidence to support the efficacy and safety of WLS, and there have been growing reports of adverse events associated with their use. We aimed to determine those WLS that caused toxicity in vitro and to use ¹H nuclear magnetic spectroscopy (NMR) to examine the metabolomic changes induced by these WLS in human hepatic and intestinal cells. Materials and Methods: This study used in vitro methods and ¹H NMR spectroscopy to analyse the metabolomic changes in vitro of WLS available for purchase in Australia. Ten WLS were selected, nine WLS caused significant toxicity in HepG2 human liver cells, and of these, six met the criteria for ¹H NMR analysis, which was based on a 25–50% reduction in cell viability. Results: All 10 WLS caused a significant reduction in viability of Caco-2 human intestinal cells, with seven selected for metabolic profiling. Orthogonal partial least squares discriminant analysis (O-PLS-DA) of ¹H NMR spectral data was used to characterise the metabolites that differed between the untreated and treated cells and the fold changes of the metabolites were determined. The results showed alterations to key metabolites such as amino acids, glucose, carboxylic acids, and amines in all treatment groups compared to untreated controls across both cell lines. Conclusions: Collectively, these biochemical changes represent disturbances to intracellular proteins, energy metabolism, and membrane lipids suggestive of oxidative stress. This study highlights the need for further investigations into the actions of these WLS in vivo, and, as these products were regulated by the Therapeutic Goods Administration (TGA) at the time of purchase, this study suggests improved pre-market screening to ensure consumer health is protected. Full article

(This article belongs to the Special Issue Metabolic Signatures in Human Health and Disease)

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12 pages, 424 KB

Open AccessReview

Investigating the Utility of Dopamine in Agricultural Practices: A Review

by Wael M. Semida, Kareem Khalafallah Abdeltawab, Ashraf Sh. Osman and Mohamed H. H. Roby

Metabolites 2025, 15(9), 586; https://doi.org/10.3390/metabo15090586 - 31 Aug 2025

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Abstract

Background/Objectives: Dopamine (DA), a chemical commonly associated with neuroscience and human physiology, has been the subject of growing interest in the field of agriculture due to its potential applications. Methods: This comprehensive review examines the multifaceted role of dopamine in agricultural [...] Read more.

Background/Objectives: Dopamine (DA), a chemical commonly associated with neuroscience and human physiology, has been the subject of growing interest in the field of agriculture due to its potential applications. Methods: This comprehensive review examines the multifaceted role of dopamine in agricultural practices, elucidating its chemical characteristics, biological activities, and diverse applications. The review examines the chemical properties and physiological functions of dopamine in plants, highlighting the unique characteristics that make it suitable for agricultural applications. A significant portion of the review is dedicated to analyzing the biological activities of dopamine, particularly its antioxidant properties, and exploring the underlying mechanisms. The review also delves into the potential of dopamine to enhance crop growth, yield, and quality and investigates the influence of dopamine on plant physiology and metabolism. Results: Furthermore, the review provides a forward-looking perspective on the prospects of dopamine in agriculture, identifying emerging trends and areas of innovation that hold promise for sustainable and resilient farming systems. Conclusions: In summary, this review consolidates the current knowledge surrounding dopamine’s potential in agriculture, underscoring its versatility as a natural tool for growth enhancement and environmental sustainability, and offering valuable insights for researchers, practitioners, and policymakers seeking innovative approaches to address the challenges of modern agriculture. Full article

(This article belongs to the Section Plant Metabolism)

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40 pages, 14652 KB

Open AccessArticle

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 491

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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17 pages, 3479 KB

Open AccessArticle

Selective Knockdown of Ceramide Synthases Reveals Opposite Roles of Different Ceramide Species in Cardiac Homeostasis

by Alexandra M. Wiley, Melissa A. Krueger, Jessica O. Becker, Matthew Karasu, Nona Sotoodehnia, Jason G. Umans, Andrew N. Hoofnagle, Sina A. Gharib, Rheem A. Totah and Rozenn N. Lemaitre

Metabolites 2025, 15(9), 584; https://doi.org/10.3390/metabo15090584 - 31 Aug 2025

Viewed by 495

Abstract

Background/Objectives: Sphingolipids are a class of lipids that play important structural and functional roles in the cell. Specific ceramide species are distinguishable through the fatty acid that is acylated to the sphingosine backbone, leading to distinct biological activities. Generally, long-chain (LC) ceramides (16:0 [...] Read more.

Background/Objectives: Sphingolipids are a class of lipids that play important structural and functional roles in the cell. Specific ceramide species are distinguishable through the fatty acid that is acylated to the sphingosine backbone, leading to distinct biological activities. Generally, long-chain (LC) ceramides (16:0 and 18:0) drive metabolic dysfunction resulting in the progression of different disease states, while very long-chain (VLC) ceramides (22:0 and 24:0) are thought to be either beneficial against disease progression or benign. In this study, we sought to alter the cellular composition of LC and VLC ceramides in ventricular HCMs to investigate how alterations in these lipids can affect the transcriptome of otherwise healthy HCMs. Methods: Here, we used specific siRNA to knockdown the ceramide synthases responsible for the production of LC and VLC ceramides in ventricular HCMs and investigated the changes in the transcriptome of HCMs with CERS2 or CERS5/6 silenced compared to control conditions. Results: Knocking down CERS2 led to an increase in cell death as well as widespread reductions in cellular VLC sphingolipids. Additionally, we demonstrated that VLC sphingolipid species may play a protective role in maintaining cardiovascular function and that reducing these lipids may contribute to cardiac dysfunction. Similarly, knocking down CERS5 and CERS6 led to reduced LC ceramides and also resulted in profound changes in gene transcription. Interestingly, multiple genes and pathways were affected in the opposite direction when compared to the changes observed with the CERS2 knockdown. Conclusions: Taken together, our results suggest pathways through which VLC ceramides may contribute to cardiac protection, and pathways where LC ceramides may promote HCM stress and the development of cardiac disease. Full article

(This article belongs to the Special Issue Lipid Biomarkers and Cardiometabolic Diseases—2nd Edition)

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13 pages, 671 KB

Open AccessReview

Metabolic Signatures in Lean MASLD: Current Insights and Future Directions

by Ambrin Farizah Babu

Metabolites 2025, 15(9), 583; https://doi.org/10.3390/metabo15090583 - 31 Aug 2025

Viewed by 610

Abstract

Lean metabolic dysfunction-associated steatotic liver disease (lean MASLD) challenges longstanding views that link hepatic steatosis primarily to obesity. Emerging as a distinct and under-recognized clinical entity, lean MASLD affects individuals with a normal body mass index (BMI), yet carries risks of cardiovascular disease, [...] Read more.

Lean metabolic dysfunction-associated steatotic liver disease (lean MASLD) challenges longstanding views that link hepatic steatosis primarily to obesity. Emerging as a distinct and under-recognized clinical entity, lean MASLD affects individuals with a normal body mass index (BMI), yet carries risks of cardiovascular disease, hepatocellular carcinoma, and liver-related mortality comparable to obesity-associated MASLD. The absence of overt metabolic dysfunction complicates diagnosis, revealing critical limitations in current screening frameworks centered on BMI. This review synthesizes evolving clinical insights and epidemiological trends in lean MASLD, and delineates its unique pathophysiological mechanisms. Recent advances in metabolomics have uncovered disease-specific disruptions in lipid and amino acid metabolism, bile acid signaling, and gut microbiota-derived metabolites. By integrating evidence from metabolic, genetic, and epigenetic domains, we identified promising biomarkers, and therapeutic targets that may support earlier detection and precision-guided treatment strategies. Full article

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

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18 pages, 1532 KB

Open AccessArticle

Metabolomic Signatures and Predictive Utility of LOXL1-Associated Genetic Risk Scores for Exfoliation Syndrome/Glaucoma in US Cohorts

by Namuunaa Juramt, Oana A. Zeleznik, Louis R. Pasquale, Janey L. Wiggs and Jae H. Kang

Metabolites 2025, 15(9), 582; https://doi.org/10.3390/metabo15090582 - 30 Aug 2025

Viewed by 478

Abstract

Background: Exfoliation syndrome (XFS) is a form of deleterious ocular aging mediated by genetic and environmental factors that frequently produces glaucoma (XFG). We aimed to develop a genetic risk score (GRS), assess its clinical utility, and identify metabolites/metabolite classes associated with a high [...] Read more.

Background: Exfoliation syndrome (XFS) is a form of deleterious ocular aging mediated by genetic and environmental factors that frequently produces glaucoma (XFG). We aimed to develop a genetic risk score (GRS), assess its clinical utility, and identify metabolites/metabolite classes associated with a high GRS. Methods: For 39,472 Nurses’ Health Studies (NHS, 1980–2018; NHS2, 1989–2019) and Health Professionals Follow-up Study (1986–2018) participants aged ≥ 40 years reporting eye exams and no baseline glaucoma, we formed an eight-single nucleotide polymorphism Genetic Risk Score (GRS8) using loci with genome-wide associations with XFS. We estimated relative risks (RR) for incident XFG suspect (XFGS)/XFG (n = 118 cases) and Harrell’s C statistics. Among 7547 participants with plasma metabolites measured via liquid chromatography-mass spectrometry, we evaluated the relation between GRS8 and 427 individual metabolites and 20 metabolite classes, adjusting for multiple comparisons. Results: Higher GRS8 was associated with XFGS/XFG (GRS8 RR_{Quintile(Q)5vs.Q1} = 3.82, 95% CI: 1.76, 8.29). GRS8 significantly (p = 0.04) improved model prediction from C-index of 88% (95% CI: 0.84, 0.92) to 93% (95% CI: 0.91, 0.95) when added to a basic risk model including age, sex, period at risk, intraocular pressure, and glaucoma family history. Metabolite class analyses revealed positive associations of bile acids and inverse associations of fatty acyls with GRS8 (adjusted p < 0.001). Conclusions: XFS GRS8 improved XFGS/XFG prediction, and a higher XFS GRS8 was associated with altered levels of fatty acyl and bile acid metabolite classes. Full article

(This article belongs to the Special Issue Metabolomics of the Eye and Adnexa)

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41 pages, 2467 KB

Open AccessReview

Crosstalk Between Skeletal Muscle and Proximal Connective Tissues in Lipid Dysregulation in Obesity and Type 2 Diabetes

by Nataša Pollak, Efua Gyakye Janežič, Žiga Šink and Chiedozie Kenneth Ugwoke

Metabolites 2025, 15(9), 581; https://doi.org/10.3390/metabo15090581 - 30 Aug 2025

Viewed by 707

Abstract

Background/Objectives: Obesity and type 2 diabetes mellitus (T2DM) profoundly disrupt lipid metabolism within local microenvironments of skeletal muscle and its associated connective tissues, including adipose tissue, bone, and fascia. However, the role of local communication between skeletal muscle and its proximal connective tissues [...] Read more.

Background/Objectives: Obesity and type 2 diabetes mellitus (T2DM) profoundly disrupt lipid metabolism within local microenvironments of skeletal muscle and its associated connective tissues, including adipose tissue, bone, and fascia. However, the role of local communication between skeletal muscle and its proximal connective tissues in propagating metabolic dysfunction is incompletely understood. This narrative review synthesizes current evidence on these local metabolic interactions, highlighting novel insights and existing gaps. Methods: We conducted a comprehensive literature analysis of primary research published in the last decade, sourced from PubMed, Web of Science, and ScienceDirect. Studies were selected for relevance to skeletal muscle, adipose tissue, fascia, and bone lipid metabolism in the context of obesity and T2DM, with emphasis on molecular, cellular, and paracrine mechanisms of local crosstalk. Findings were organized into thematic sections addressing physiological regulation, pathological remodeling, and inter-organ signaling pathways. Results: Our synthesis reveals that local lipid dysregulation in obesity and T2DM involves altered fatty acid transporter dynamics, mitochondrial overload, fibro-adipogenic remodeling, and compartment-specific adipose tissue dysfunction. Crosstalk via myokines, adipokines, osteokines, bioactive lipids, and exosomal miRNAs integrates metabolic responses across these tissues, amplifying insulin resistance and lipotoxic stress. Emerging evidence highlights the underappreciated roles of fascia and marrow adipocytes in regional lipid handling. Conclusions: Collectively, these insights underscore the pivotal role of inter-tissue crosstalk among skeletal muscle, adipose tissue, bone, and fascia in orchestrating lipid-induced insulin resistance, and highlight the need for integrative strategies that target this multicompartmental network to mitigate metabolic dysfunction in obesity and T2DM. Full article

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

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17 pages, 2407 KB

Open AccessArticle

Urine Metabolomics of Gout Reveals the Dynamic Reprogramming and Non-Invasive Biomarkers of Disease Progression

by Guizhen Zhu, Yuan Luo, Nan Su, Xiangyi Zheng, Zhusong Mei, Qiao Ye, Jie Peng, Peiyu An, Yangqian Song, Weina Luo, Hongxia Li, Guangyun Wang and Haitao Zhang

Metabolites 2025, 15(9), 580; https://doi.org/10.3390/metabo15090580 - 29 Aug 2025

Viewed by 418

Abstract

Background/Objectives: Gout, a complex metabolic disorder of increasing global incidence, remains incompletely understood in its pathogenesis. Current diagnostic approaches exhibit significant limitations, including insufficient specificity and the requirement for invasive joint aspiration, highlighting the need for non-invasive, sensitive biomarkers for early detection. Methods: [...] Read more.

Background/Objectives: Gout, a complex metabolic disorder of increasing global incidence, remains incompletely understood in its pathogenesis. Current diagnostic approaches exhibit significant limitations, including insufficient specificity and the requirement for invasive joint aspiration, highlighting the need for non-invasive, sensitive biomarkers for early detection. Methods: Urine metabolites were extracted from 28 healthy controls, 13 asymptomatic hyperuricemia (HUA) patients, and 29 acute gouty arthritis (AGA) patients. The extracted metabolites were analyzed by UHPLC-MS/MS for untargeted metabolomics. Differential metabolites were screened by partial least squares discriminant analysis (PLS-DA) and volcano plot analysis. Pathway analysis determined the core disorder pathway of gout progression. Results: A total of 278 differential metabolites associated with gout progression were identified. The most pronounced metabolic alterations were observed between the AGA and control groups, indicative of substantial metabolic reprogramming during disease transition. Metabolic pathway analysis revealed four significantly dysregulated pathways: histidine metabolism, nicotinate and nicotinamide metabolism, phenylalanine metabolism, and tyrosine metabolism. Receiver operating characteristic (ROC) curve analysis revealed that three urine markers with high diagnostic efficacy—oxoamide, 3-methylindole, and palmitic acid—exhibited progressive alterations across the disease continuum. Conclusions: This metabolomics study identified core regulatory metabolites and newly discovered metabolic pathways underlying gout pathogenesis, along with novel urinary biomarkers capable of predicting HUA-to-AGA progression. The aberrant levels of key metabolites in the disordered pathway implicate neuroimmune dysregulation, energy metabolism disruption, and oxidative stress in gout pathogenesis. These findings provide new foundations and strategies for the daily monitoring and prevention of gout. Full article

(This article belongs to the Special Issue Metabolomics in Clinical Research: Advancing Precision Medicine Through the Analysis of Biological Samples)

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Open AccessArticle

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

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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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Metabolites, Volume 15, Issue 9 (September 2025) – 47 articles

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