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Metabolites
Volume 15
Issue 6
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Metabolites, Volume 15, Issue 6 (June 2025) – 74 articles

Cover Story (view full-size image): Moderate exercise has anti-inflammatory effects, while intense exercise may cause inflammation. This study examined cytokine changes in 21 elite padel players (11 female, 10 male; 27.7 ± 6.3 y) before/after matches, focusing on court side (forehand/backhand) and sex differences. Pro-inflammatory (IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-12, TNF-α, IFN-γ) and anti-inflammatory (IL-5, IL-6, IL-10, IL-13) cytokines were measured. Results showed decreased IL-7 (p = 0.02) and increased IL-8 (p ≤ 0.001) and IL-10 (p = 0.001). Court side did not affect responses. Elite padel playing induces anti-inflammatory responses (increased IL-10, decreased pro-inflammatory cytokines), suggesting health benefits as a moderate-intensity sport. View this paper
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35 pages, 1811 KiB  
Review
Microbial Metabolites: A Sustainable Approach to Combat Plant Pests
by Somasundaram Prabhu, Rajendran Poorniammal and Laurent Dufossé
Metabolites 2025, 15(6), 418; https://doi.org/10.3390/metabo15060418 - 19 Jun 2025
Viewed by 512
Abstract
With the sustainable increase in agricultural productivity, the need for safer, environmentally friendly pesticide alternatives is also growing. Metabolites of microorganisms (bacteria, fungi, actinomycetes) are emerging as potential bioactive compounds for integrated pest and disease management. These compounds comprise amino acids, carbohydrates, lipids, [...] Read more.
With the sustainable increase in agricultural productivity, the need for safer, environmentally friendly pesticide alternatives is also growing. Metabolites of microorganisms (bacteria, fungi, actinomycetes) are emerging as potential bioactive compounds for integrated pest and disease management. These compounds comprise amino acids, carbohydrates, lipids, organic acids, phenolics, peptides, alkaloids, polyketides, and volatile organic compounds. The majority of them have insecticidal, fungicidal, and nematicidal activities. In this review, the classifications, biosynthetic pathways, and ecological functions of primary and secondary metabolites produced by microorganisms are discussed, including their mechanisms of action, ranging from competition to systemic acquired resistance in host plants. The article highlights the importance of microbial genera (viz., Bacillus sp., Pseudomonas sp., Trichoderma sp., Streptomyces sp., etc.) in making chemicals and biopesticides for crop defense. We present the possible applications of microbial biosynthesis strategies and synthetic biology tools in bioprocess development, covering recent innovations in formulation, delivery, and pathway engineering to enhance metabolite production. This review emphasizes the significance of microbial metabolites in improving the plant immunity, yield performance, reduction in pesticide application, and the sustainability of an ecological, sustainable, and resilient agricultural system. Full article
(This article belongs to the Special Issue Bioactive Metabolites from Natural Sources (2nd Edition))
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16 pages, 1791 KiB  
Article
Insomnia, Cognitive Impairment, or a Combination of Both, Alter Lipid Metabolism Due to Changes in Acylcarnitine Concentration in Older Persons
by Selma Karime Castillo-Vazquez, Berenice Palacios-González, Marcela Vela-Amieva, Isabel Ibarra-González, Ricardo Morales, Paola García-delaTorre, Sergio Sánchez-García, Carmen García-Peña, Ricardo Reyes-Chilpa, Raúl Hernán Medina-Campos, Jessica Hernández-Pineda, Juan Carlos Gomez-Verjan and Nadia Alejandra Rivero-Segura
Metabolites 2025, 15(6), 417; https://doi.org/10.3390/metabo15060417 - 19 Jun 2025
Viewed by 468
Abstract
Background/Objectives: Insomnia has been widely associated with cognitive impairment (CI). However, the relationship between the two entities (insomnia and CI) is poorly understood. In this context, adults with insomnia show metabolic changes, including alterations in the catabolism of branched-chain amino acids, glycerophospholipids, and [...] Read more.
Background/Objectives: Insomnia has been widely associated with cognitive impairment (CI). However, the relationship between the two entities (insomnia and CI) is poorly understood. In this context, adults with insomnia show metabolic changes, including alterations in the catabolism of branched-chain amino acids, glycerophospholipids, and glutathione and glutamate biosynthesis. Nevertheless, aging itself induces metabolic changes that may be amplified by chronic diseases that compromise the health of the elderly. Therefore, in the present study we aim to characterise metabolomic profiles of insomnia and CI alone in order to address a significant gap in current research regarding the pathways through which insomnia may lead to CI in older persons. Methods: In this study we perform a targeted metabolomics analysis (UPLC-MS) on 80 serum samples from the Cohort of Obesity, Sarcopenia, and Frailty of Older Mexican Adults (COSFOMA); these samples were classified into four groups (control, insomnia, CI, and insomnia + CI). Results: Our results show that insomnia increases the concentration of acylcarnitines (C10, C8, C14, C12:1, C18:1 and C18) as compared to CI group, while older persons with CI show a decrease the concentration of the acylcarnitines C16, C10 and C8. Finally, individuals with both conditions (insomnia + CI) show that only the concentration of the acylcarnitine C16 decreases compared to controls. Conclusions: Taken together, our results shed light on the relevance of insomnia on lipid metabolism in older persons. Full article
(This article belongs to the Special Issue Lipid Metabolism in Age-Related Diseases)
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24 pages, 1964 KiB  
Article
Metabolomic Profiling Reveals PGPR-Driven Drought Tolerance in Contrasting Brassica juncea Genotypes
by Asha Rani Sheoran, Nita Lakra, Baljeet Singh Saharan, Annu Luhach, Yogesh K. Ahlawat, Rosa Porcel, Jose M. Mulet and Prabhakar Singh
Metabolites 2025, 15(6), 416; https://doi.org/10.3390/metabo15060416 - 19 Jun 2025
Viewed by 545
Abstract
Background: Drought stress is a major abiotic factor limiting Brassica juncea productivity, resulting in significant yield reductions. Plant Growth-Promoting Rhizobacteria (PGPR) have shown potential in enhancing drought tolerance; however, the metabolomic changes associated with their effects remain largely unexplored. This study examines the [...] Read more.
Background: Drought stress is a major abiotic factor limiting Brassica juncea productivity, resulting in significant yield reductions. Plant Growth-Promoting Rhizobacteria (PGPR) have shown potential in enhancing drought tolerance; however, the metabolomic changes associated with their effects remain largely unexplored. This study examines the metabolic changes induced by a PGPR consortium (Enterobacter hormaechei, Pantoea dispersa, and Acinetobacter sp.) in two contrasting genotypes B. juncea (L.) Czern. ‘RH 725’ (drought tolerant) and B. juncea (L.) Czern. ‘RH-749’ (drought sensitive for drought tolerance, under both control and drought conditions. Methods: Metabolite profiling was conducted using gas chromatography-mass spectrometry (GC-MS) to identify compounds that accumulated differentially across treatments. We applied multivariate statistical methods, such as Partial Least Squares Discriminant Analysis (PLS-DA), hierarchical clustering, and pathway enrichment analysis, to explore metabolic reprogramming. Results: Drought stress induced significant changes in metabolite profile, particularly increasing the levels of osmoprotectants such as trehalose, glucose, sucrose, proline, and valine. Additionally, alterations in organic acids (malic acid and citric acid) and fatty acids (oleic acid and linoleic acid) were observed. PGPR inoculation further amplified these metabolic responses to enhance the osmotic regulation, reactive oxygen species (ROS) detoxification, and carbon-nitrogen metabolism, with RH-725 displaying a stronger adaptive response. Pathway enrichment analysis revealed that PGPR treatment significantly influenced metabolic pathways related to starch and sucrose metabolism, galactose metabolism, and amino acid biosynthesis, which play critical roles in drought adaptation. Conclusion: These findings provide insights into how PGPR contributes to stress resilience in B. juncea by modulating key biochemical pathways. This study provides new molecular insights into the known effect of PGPR for mitigating drought stress in oilseed crops. Full article
(This article belongs to the Section Plant Metabolism)
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23 pages, 1267 KiB  
Review
Gadolinium in the Environment: A Double-Edged Sword for Plant Growth and Ecosystem Stability
by Marlena Tomczuk, Beata Godlewska-Żyłkiewicz and Andrzej Bajguz
Metabolites 2025, 15(6), 415; https://doi.org/10.3390/metabo15060415 - 19 Jun 2025
Viewed by 439
Abstract
Gadolinium, a rare earth element, is increasingly released into the environment due to its widespread applications in medical imaging, industry, and agriculture. This review explores the dual role of gadolinium in plant systems, highlighting its potential benefits at subtoxic concentrations and detrimental effects [...] Read more.
Gadolinium, a rare earth element, is increasingly released into the environment due to its widespread applications in medical imaging, industry, and agriculture. This review explores the dual role of gadolinium in plant systems, highlighting its potential benefits at subtoxic concentrations and detrimental effects at higher levels. At subtoxic doses, gadolinium can enhance plant growth, metabolism, and stress tolerance by promoting enzymatic activity and nutrient absorption. However, elevated concentrations induce oxidative stress, disrupt nutrient uptake, and impair photosynthesis, leading to cellular damage and reduced growth. The bioaccumulation of gadolinium in plant tissues raises concerns about its trophic transfer within food chains and its broader ecological impact. Current evidence suggests that previously regarded as stable and inert gadolinium complexes can degrade under environmental conditions, increasing their bioavailability and toxicity. Despite its potential for agricultural applications, including improving crop resilience, the ecological risks associated with gadolinium remain poorly understood. Addressing these risks requires coordinated efforts to optimize gadolinium usage, develop advanced waste management strategies, and enhance monitoring of its environmental presence. This review emphasizes the need for in-depth research on gadolinium interactions with plants and ecosystems to balance its industrial benefits with environmental sustainability. Full article
(This article belongs to the Section Plant Metabolism)
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10 pages, 545 KiB  
Article
Periodontitis Frequently Exists in Patients with Colorectal Carcinoma and Causes Supplementary Impairment of Insulin Resistance
by Mario Zivkovic, Marko Boban, Domagoj Vrazic, Ivan Vulic, Ivan Budimir, Nina Blazevic, Aleksandar Vcev and Marko Nikolic
Metabolites 2025, 15(6), 414; https://doi.org/10.3390/metabo15060414 - 19 Jun 2025
Viewed by 426
Abstract
Background: There are known associations between periodontitis and colorectal cancer, but knowledge on the connections existing between the two are not fully understood. The aim of our study was to assess prevalence and clinical severity of periodontitis in patients with localized colorectal cancer. [...] Read more.
Background: There are known associations between periodontitis and colorectal cancer, but knowledge on the connections existing between the two are not fully understood. The aim of our study was to assess prevalence and clinical severity of periodontitis in patients with localized colorectal cancer. Secondly, the dynamics of metabolic derangements, particularly glucose metabolism, insulin resistance, and diabetes mellitus were studied as well. Methods: Diagnostic procedures included endoscopies with patohistology, laboratory exams, the insulin resistance homeostatic model assessment method (HOMA index), anthropometrics, and radiology imaging. Periodontal status was evaluated by full-mouth periodontal examination. Results: A total of 79 patients with localized colorectal carcinoma, with slight male predominance of 55.7%, and an age of 65.7 ± 12.4 years participated in this study. Three-quarters of patients (73.4%; 95% CI: 63.0–82.2%) were diagnosed with periodontitis. Patients with periodontitis and colorectal cancer had significantly increased glucose levels (fasting and after oral glucose challenge), (both p < 0.05). Also, increased values of the HOMA index were found in patients with periodontitis vs. controls (without periodontitis) and colorectal cancer; 6.38 ± 5.74 vs. 3.58 ± 2.6 (p = 0.012); Spearman’s Rho correlation coefficient = 0.271 (p = 0.039). There were significant differences in high-density cholesterol in patients with periodontitis vs. controls, 1.41 ± 0.28 vs. 1.23 ± 0.35 mmol/L (p = 0.016), but correlations were insignificant; Rho c.c. = 0.045 (p = 0.738). Conclusions: The most consorted connections between periodontitis and colorectal cancer were found among parameters of metabolic domain, especially glucose concentrations and insulin resistance. Further studies, which would include novel and emerging antidiabetic treatments and their effects on the prevention or control of both diseases, would be warranted. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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15 pages, 1477 KiB  
Article
Geopropolis from Melipona fasciculata Smith Accelerates Wound Healing in Diabetic Mice
by Aramys Silva Reis, Gabriel Carvalho de Souza, Guilherme Martins Gomes Fontoura, Luecya Alves de Carvalho Silva, Alberto Jorge Oliveira Lopes, Richard Pereira Dutra, Lucilene Amorim Silva, Rosane Nassar Meireles Guerra, Maria Nilce Sousa Ribeiro and Flávia Raquel Fernandes Nascimento
Metabolites 2025, 15(6), 413; https://doi.org/10.3390/metabo15060413 - 19 Jun 2025
Viewed by 682
Abstract
Background: Diabetic foot ulcers present a significant clinical challenge because of their high prevalence and severe complications. The need for innovative and accessible treatment options is critical. Owing to their medicinal properties, natural products, such as geopropolis, hold promise. However, the wound healing [...] Read more.
Background: Diabetic foot ulcers present a significant clinical challenge because of their high prevalence and severe complications. The need for innovative and accessible treatment options is critical. Owing to their medicinal properties, natural products, such as geopropolis, hold promise. However, the wound healing potential of the geopropolis of Melipona fasciculata, particularly in accelerating the healing of diabetic ulcers, remains unexplored. In this study, we evaluated the ability of the geopropolis of M. fasciculata to promote wound healing in diabetic mice. Methods: Geopropolis was collected, prepared as a hydroalcoholic extract, and formulated into a topical cream. Non-obese diabetic (NOD) mice with induced chronic wounds were treated with this cream daily, and wound healing was assessed through macroscopic measurements, histological analysis, cytokine quantification, and in silico molecular docking studies. Results: The results demonstrated that, compared with the control treatment, the geopropolis cream accelerated wound closure at all the analyzed time points (days 3, 7, and 14), reduced inflammatory infiltrates, and enhanced fibroblast proliferation and collagen deposition. These alterations were particularly pronounced in the final phase of healing, indicating an improvement in wound repair processes. These effects occurred without altering systemic cytokine levels, suggesting a localized treatment action. These results may be partially associated with the theoretical ability of beta-amyrin and cycloartenol to interact with human myeloperoxidase (MPO), as suggested by in silico docking analysis. Conclusions: Overall, the findings indicate that geopropolis cream could represent a viable alternative for managing diabetic ulcers, providing an effective means to enhance wound healing while remaining accessible to low-income populations. Full article
(This article belongs to the Special Issue Exploring and Expanding Horizons in Secondary Metabolites: Biosynthesis, Identification, Regulation and Biological Activity)
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12 pages, 732 KiB  
Systematic Review
Gut-Microbiome Signatures Predicting Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review
by Ielmina Domilescu, Bogdan Miutescu, Florin George Horhat, Alina Popescu, Camelia Nica, Ana Maria Ghiuchici, Eyad Gadour, Ioan Sîrbu and Delia Hutanu
Metabolites 2025, 15(6), 412; https://doi.org/10.3390/metabo15060412 - 18 Jun 2025
Viewed by 445
Abstract
Background and Objectives: Rectal cancer management increasingly relies on watch-and-wait strategies after neoadjuvant chemoradiotherapy (nCRT). Accurate, non-invasive prediction of pathological complete response (pCR) remains elusive. Emerging evidence suggests that gut-microbiome composition modulates radio-chemosensitivity. We systematically reviewed primary studies that correlated baseline or on-treatment [...] Read more.
Background and Objectives: Rectal cancer management increasingly relies on watch-and-wait strategies after neoadjuvant chemoradiotherapy (nCRT). Accurate, non-invasive prediction of pathological complete response (pCR) remains elusive. Emerging evidence suggests that gut-microbiome composition modulates radio-chemosensitivity. We systematically reviewed primary studies that correlated baseline or on-treatment gut-microbiome features with nCRT response in locally advanced rectal cancer (LARC). Methods: MEDLINE, Embase and PubMed were searched from inception to 30 April 2025. Eligibility required (i) prospective or retrospective human studies of LARC, (ii) faecal or mucosal microbiome profiling by 16S, metagenomics, or metatranscriptomics, and (iii) response assessment using tumour-regression grade or pCR. Narrative synthesis and random-effects proportion meta-analysis were performed where data were homogeneous. Results: Twelve studies (n = 1354 unique patients, median sample = 73, range 22–735) met inclusion. Four independent machine-learning models achieved an Area Under the Receiver Operating Characteristic curve AUROC ≥ 0.85 for pCR prediction. Consistently enriched taxa in responders included Lachnospiraceae bacterium, Blautia wexlerae, Roseburia spp., and Intestinimonas butyriciproducens. Non-responders showed over-representation of Fusobacterium nucleatum, Bacteroides fragilis, and Prevotella spp. Two studies linked butyrate-producing modules to radiosensitivity, whereas nucleotide-biosynthesis pathways conferred resistance. Pooled pCR rate in patients with a “butyrate-rich” baseline profile was 44% (95% CI 35–54) versus 21% (95% CI 15–29) in controls (I2 = 18%). Conclusions: Despite heterogeneity, convergent functional and taxonomic signals underpin a microbiome-based radiosensitivity axis in LARC. Multi-centre validation cohorts and intervention trials manipulating these taxa, such as prebiotics or live-biotherapeutics, are warranted before clinical deployment. Full article
(This article belongs to the Special Issue Advances in Gut Microbiome Metabolomics)
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20 pages, 3234 KiB  
Article
SGLT-2 Inhibitors and Metabolic Outcomes: A Primary Data Study Exploring the Microbiota–Diabetes Connection
by Nicoleta Mihaela Mindrescu, Cristian Guja, Viorel Jinga, Sorina Ispas, Antoanela Curici, Rucsandra Elena Danciulescu Miulescu, Andreea Nelson Twakor and Anca Mihaela Pantea Stoian
Metabolites 2025, 15(6), 411; https://doi.org/10.3390/metabo15060411 - 18 Jun 2025
Viewed by 447
Abstract
Background: The gut microbiota plays a critical role in metabolic health and type 2 diabetes mellitus (T2DM). Alterations in microbial composition may influence glycemic control and systemic inflammation. Materials and methods: In this single-center, randomized study, 60 adults with T2DM receiving metformin were [...] Read more.
Background: The gut microbiota plays a critical role in metabolic health and type 2 diabetes mellitus (T2DM). Alterations in microbial composition may influence glycemic control and systemic inflammation. Materials and methods: In this single-center, randomized study, 60 adults with T2DM receiving metformin were evaluated biologically and received either empagliflozin or sitagliptin. Demographic, metabolic, and lifestyle data were collected. Gut microbiota profiling was conducted at two timepoints to assess changes in bacterial and fungal taxa. Blood glucose, HbA1c, and inflammation markers were analyzed longitudinally. Results: Both treatment groups showed significant improvements in glycemic control. Median fasting glucose decreased from 132 to 123 mg/dL (p = 0.046) in the sitagliptin group and from 131 to 114 mg/dL (p = 0.025) in the empagliflozin group. Median HbA1c levels declined significantly in both groups, with a greater reduction in the empagliflozin group (p = 0.001 vs. p = 0.049). The microbiota analysis revealed an increase in beneficial bacteria (e.g., Bifidobacterium spp. and Lactobacillus spp.) and a decrease in pro-inflammatory taxa (Escherichia coli and Streptococcus spp.). Notably, empagliflozin was associated with a more pronounced microbiota rebalancing and a significant decline in fungal overgrowth (e.g., Candida spp.; p = 0.034). Conclusions: Treatment with sitagliptin and empagliflozin led to improved glycemic outcomes and partial restoration of gut microbial balance in T2DM patients. Empagliflozin showed superior efficacy in modulating both glycemia and dysbiosis. Full article
(This article belongs to the Special Issue Diet, Gut Microbiota and Metabolic Health)
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11 pages, 2431 KiB  
Article
Development of Sucrose-Utilizing Escherichia coli Nissle 1917 for Efficient Heparosan Biosynthesis
by Yaozong Chen, Zihua Wan and Zheng-Jun Li
Metabolites 2025, 15(6), 410; https://doi.org/10.3390/metabo15060410 - 18 Jun 2025
Viewed by 418
Abstract
Background/Objectives: Heparosan is a component of the capsular polysaccharide in Escherichia coli K5 and Pasteurella multocida Type D. It shares a similar glycan structure with heparin and can be enzymatically modified to produce bioactive heparin. Methods: In this study, the probiotic [...] Read more.
Background/Objectives: Heparosan is a component of the capsular polysaccharide in Escherichia coli K5 and Pasteurella multocida Type D. It shares a similar glycan structure with heparin and can be enzymatically modified to produce bioactive heparin. Methods: In this study, the probiotic strain E. coli Nissle 1917 (EcN), which naturally produces heparosan, was genetically engineered to utilize sucrose as a carbon source for growth while achieving high-yield heparosan biosynthesis. Results: By expressing the sucrose hydrolase genes sacA (from Bacillus subtilis) or spI (from Bifidobacterium adolescentis), EcN was enabled to utilize sucrose, achieving heparosan titers of 131 mg/L and 179 mg/L, respectively. Further metabolic engineering was performed to block the glycolytic and pentose phosphate pathways, thereby redirecting sucrose-derived glucose-6-phosphate and fructose-6-phosphate toward heparosan biosynthesis, while glycerol was supplemented as an auxiliary carbon source to support cell growth. Finally, the key biosynthesis genes galU, kfiD, and glmM were overexpressed, resulting in an engineered strain with a heparosan titer of 622 mg/L. Conclusions: This study represents the first successful engineering of EcN to utilize sucrose as the carbon source for growth, while achieving enhanced heparosan production through synergistic carbon source utilization. These findings establish a foundational strategy for employing this strain in the sucrose-based biosynthesis of other glycosaminoglycans. Full article
(This article belongs to the Special Issue Synthetic Biology Approaches for Expanding the Metabolic Capabilities of E. coli)
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18 pages, 2209 KiB  
Article
Impact of Dietary Carbohydrate Levels on Growth Performance, Feed Efficiency, and Immune Response in Litopenaeus vannamei Cultured in Biofloc Systems
by Yulong Sun, Shuailiang Zhang, Wenping Feng, Yunqi Zhang, Tao Han and Jiteng Wang
Metabolites 2025, 15(6), 409; https://doi.org/10.3390/metabo15060409 - 17 Jun 2025
Viewed by 444
Abstract
Background/Objective: Over an eight-week period, this study assessed the influence of dietary carbohydrate levels on growth, metabolism, and immunity in Pacific white shrimp (Litopenaeus vannamei) raised within a biofloc technology (BFT) system. Methods: Five isonitrogenous and isolipidic diets, spanning carbohydrate levels [...] Read more.
Background/Objective: Over an eight-week period, this study assessed the influence of dietary carbohydrate levels on growth, metabolism, and immunity in Pacific white shrimp (Litopenaeus vannamei) raised within a biofloc technology (BFT) system. Methods: Five isonitrogenous and isolipidic diets, spanning carbohydrate levels from 11% to 47%, were evaluated. Results: The results showed that dietary carbohydrate significantly impacted both growth performance and feed utilization. The diet containing 38% carbohydrate yielded the best outcomes, resulting in the highest weight gain, specific growth rate, and an optimal feed conversion ratio in the shrimp. Hepatopancreatic metabolic analysis revealed that the shrimp adapted to diets high in carbohydrates through the upregulation of glycolytic enzymes (PK, PFK) and downregulation of gluconeogenic enzymes (PEPCK, G6Pase). By optimizing the water quality and supplementing microbial nutrition, L. vannamei in the BFT system exhibited enhanced dietary carbohydrate utilization and strengthened innate immunity. Specifically, SOD and CAT activities remained largely unaffected by varying carbohydrate levels. However, excessive carbohydrate intake still induced oxidative stress. The high-sugar group (47%) exhibited a significant increase in hemolymph MDA content (p < 0.05), with corresponding metabolic alterations observed in glucose, triglyceride, and total protein levels. On the basis of the results of this study, the BFT system may mitigate the adverse effects of a high-carbohydrate diet by enhancing lysosomal enzyme activity (e.g., ACP) and increasing total protein levels. Conclusions: These findings suggest that the BFT system enhances shrimp immunity and mitigates the potential adverse effects of imbalanced dietary components. Piecewise regression analysis determined the optimal dietary carbohydrate level for shrimp within the BFT system to be 31.44–31.77%. Full article
(This article belongs to the Special Issue Nutrition, Metabolism and Physiology in Aquatic Animals)
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15 pages, 2016 KiB  
Article
Metabolomics Signatures of a Respiratory Tract Infection During an Altitude Training Camp in Elite Rowers
by Félix Boudry, Fabienne Durand and Corentine Goossens
Metabolites 2025, 15(6), 408; https://doi.org/10.3390/metabo15060408 - 17 Jun 2025
Viewed by 380
Abstract
Background: Respiratory pathologies, such as COVID-19 and bronchitis, pose significant challenges for high-level athletes, particularly during demanding altitude training camps. Metabolomics offers a promising approach for early detection of such pathologies, potentially minimizing their impact on performance. This study investigates the metabolic [...] Read more.
Background: Respiratory pathologies, such as COVID-19 and bronchitis, pose significant challenges for high-level athletes, particularly during demanding altitude training camps. Metabolomics offers a promising approach for early detection of such pathologies, potentially minimizing their impact on performance. This study investigates the metabolic differences between athletes with and without respiratory illnesses during an altitude training camp using urine samples and multivariate analysis. Methods: Twenty-seven elite rowers (15 males, 12 females) participated in a 12-day altitude training camp at 1850 m. Urine samples were collected daily, with nine athletes developing respiratory pathologies (8 COVID-19, 1 bronchitis). Nuclear Magnetic Resonance spectroscopy was used to analyze the samples, followed by data processing with Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA), allowing to use Variable Importance in Projection (VIP) scores to identify key metabolites contributing to group separation. Results: The PLS-DA model for respiratory illness showed good performance (R2 = 0.89, Q2 = 0.35, p < 0.05). Models for altitude training achieved higher predictive power (Q2 = 0.51 and 0.72, respectively). Metabolites kynurenine, N-methylnicotinamide, pyroglutamate, propionate, N-formyltryptophan, tryptophan and glucose were significantly highlighted in case of respiratory illness while trigonelline, 3-hydroxyphenylacetate, glutamate, creatine, citrate, urea, o-hydroxyhippurate, creatinine, hippurate and alanine were correlated to effort in altitude. This distinction confirms that respiratory illness induces a unique metabolic profile, clearly separable from hypoxia and training-induced adaptations. Conclusions: This study highlights the utility of metabolomics in identifying biomarkers of respiratory pathologies in athletes during altitude training, offering the potential for improved monitoring and intervention strategies. These findings could enhance athlete health management, reducing the impact of illness on performance during critical training periods. Further research with larger cohorts is warranted to confirm these results and explore targeted interventions. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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11 pages, 447 KiB  
Article
An LC-MS Method to Quantify Rhein and Its Metabolites in Plasma: Application to a Pharmacokinetic Study in Rats
by Nyma Siddiqui, Yuan Chen, Ting Du, Yang Wang, Charmeyce Buck and Song Gao
Metabolites 2025, 15(6), 407; https://doi.org/10.3390/metabo15060407 - 17 Jun 2025
Viewed by 348
Abstract
Background: Diacerein, a prodrug of Rhein, is commonly prescribed for the management of joint disorders, specifically osteoarthritis. This study aimed to develop and validate an LC-MS/MS method to quantify Rhein and its major metabolites, Rhein-G1 and Rhein-G2, in plasma samples. Method: An ACE [...] Read more.
Background: Diacerein, a prodrug of Rhein, is commonly prescribed for the management of joint disorders, specifically osteoarthritis. This study aimed to develop and validate an LC-MS/MS method to quantify Rhein and its major metabolites, Rhein-G1 and Rhein-G2, in plasma samples. Method: An ACE C18 column was used for chromatographic separation with a mobile phase comprising ammonium acetate at a concentration of 1.0 mM and acetonitrile. Detection was achieved using a Sciex 4000 Q-Trap LC-MS/MS, operated in negative ion mode with multiple reaction monitoring (MRM). Results: The analytical results indicated that the lower limit of quantification (LLOQ) for Rhein and its glucuronides was 7.81 nM. Precision was consistently below 9.14%, while accuracy remained within the acceptable range of 80.1–104.2%. We also verified the method’s matrix effect recovery and stability variance, which were less than 12.60% and 10.37%, respectively. The pharmacokinetic study demonstrated that diacerein is swiftly metabolized into Rhein, and then Rhein subsequently undergoes glucuronidation, forming detectable concentrations of Rhein-G1 and Rhein-G2 in plasma. Conclusions: This new LC-MS/MS method proved to be both sensitive and selective, allowing for pharmacokinetic studies in rats. Full article
(This article belongs to the Special Issue Novel Approaches for Metabolomics in Drugs and Biomarkers Discovery: 2nd Edition)
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29 pages, 876 KiB  
Review
SARS-CoV-2 in Asthmatic Children: Same Consequences in Different Endotypes?
by Alice Bosco, Vassilios Fanos, Serena Bosone, Valeria Incandela, Federica La Ciacera and Angelica Dessì
Metabolites 2025, 15(6), 406; https://doi.org/10.3390/metabo15060406 - 16 Jun 2025
Viewed by 511
Abstract
During the early stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, concerns arose regarding the susceptibility of asthmatic children, one of the most common chronic conditions in childhood and a major cause of hospitalization in pediatric settings. Unexpectedly, evidences showed [...] Read more.
During the early stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, concerns arose regarding the susceptibility of asthmatic children, one of the most common chronic conditions in childhood and a major cause of hospitalization in pediatric settings. Unexpectedly, evidences showed milder clinical courses and fewer asthma exacerbations in these patients, even if cases of critical and fatal infection, often related to specific clinical features of the patient, are not negligible. In this regard, obesity is considered not only an important comorbidity in patients with difficult-to-treat asthma but also a risk factor for more severe forms of COVID-19. These observations are of even greater concern in the context of an increase in childhood obesity that began even before the SARS-CoV-2 pandemic and has continued also as a consequence of it. Given asthma’s heterogeneity, especially in children, an endotype-based approach is crucial. This is possible through a detailed analysis of the complex metabolic pathways that correlate asthma, COVID-19 infection and obesity thanks to new high-through-put technologies, especially metabolomics, which with minimally invasive sampling, including on exhaled breath condensate (EBC), can provide precise and unbiased evidence in support of existing endotypes, making it possible to identify not only the most vulnerable individuals and thus risk stratification through specific biomarkers, but also new molecular and therapeutic targets. This review explores asthma endotypes by highlighting their shared immunometabolic pathways with COVID-19. Findings suggest that metabolomics could enable more accurate risk stratification and guide personalized interventions during viral pandemics, especially in the presence of relevant comorbidities such as obesity. Full article
(This article belongs to the Special Issue Risk Prediction and Novel Biomarker Discovery of Chronic Diseases by Advanced Methodologies in Lipidomics and Metabolomics)
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14 pages, 5828 KiB  
Article
Salivary Metabolite Variation After High-Intensity Rowing Training and Potential Biomarker Screening for Exercise-Induced Muscle Damage
by Yue Yi, Junjie Ding, Baoguo Wang, Yuxian Li, Liming Wang, Shumin Bo, Qiongqiong Ren and Aiqin Luo
Metabolites 2025, 15(6), 405; https://doi.org/10.3390/metabo15060405 - 16 Jun 2025
Viewed by 423
Abstract
Background: Exercise-induced muscle damage (EIMD) is the most common health risk in training. So far, EIMD diagnosis predominantly relies on blood biochemical analysis or medical imaging. EIMD prediction by using saliva shows great prospects in public fitness. Methods: A total of 18 participants [...] Read more.
Background: Exercise-induced muscle damage (EIMD) is the most common health risk in training. So far, EIMD diagnosis predominantly relies on blood biochemical analysis or medical imaging. EIMD prediction by using saliva shows great prospects in public fitness. Methods: A total of 18 participants performed high-intensity rowing training. Blood biochemical indicator and pain analyses indicated EIMD occurrence. Pseudo-targeted metabolomics techniques were utilized to analyze changes in salivary metabolites after exercise. Results: A total of 43 salivary metabolites significantly increased while 31 salivary metabolites significantly decreased after exercise. The upregulated metabolites were related to hormone secretion, antioxidation, and muscle repair. A partial least squares discriminant analysis model was established, and three potential salivary biomarkers for EIMD prediction were screened. The sensitivity and specificity of single biomarkers achieved more than 88.9% and 94.4% in classification of EIMD occurrence, respectively. The accuracy of classification increased to ~100% with multiple metabolites. Conclusion: Salivary metabolites significantly changed after high-intensity rowing training and EIMD occurrence. Some salivary metabolites exhibited similar trends with blood biochemical indicators. Salivary biomarkers have great prospects in EIMD prediction, and better performance was achieved with multiple salivary metabolites. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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24 pages, 1408 KiB  
Review
Biomolecular Basis of Life
by Janusz Wiesław Błaszczyk
Metabolites 2025, 15(6), 404; https://doi.org/10.3390/metabo15060404 - 16 Jun 2025
Viewed by 512
Abstract
Life is defined descriptively by the capacity for metabolism, homeostasis, self-organization, growth, adaptation, information metabolism, and reproduction. All these are achieved by a set of self-organizing and self-sustaining processes, among which energy and information metabolism play a dominant role. The energy metabolism of [...] Read more.
Life is defined descriptively by the capacity for metabolism, homeostasis, self-organization, growth, adaptation, information metabolism, and reproduction. All these are achieved by a set of self-organizing and self-sustaining processes, among which energy and information metabolism play a dominant role. The energy metabolism of the human body is based on glucose and lipid metabolism. All energy-dependent life processes are controlled by phosphate and calcium signaling. To maintain the optimal levels of energy metabolism, cells, tissues, and the nervous system communicate mutually, and as a result of this signaling, metabolism emerges with self-awareness, which allows for conscience social interactions, which are the most significant determinants of human life. Consequently, the brain representation of our body and the egocentric representation of the environment are built. The last determinant of life optimization is the limited life/death cycle, which exhibits the same pattern at cellular and social levels. This narrative review is my first attempt to systematize our knowledge of life phenomena. Due to the extreme magnitude of this challenge, in the current article, I tried to summarize the current knowledge about fundamental life processes, i.e., energy and information metabolism, and, thus, initiate a broader discussion about the life and future of our species. Full article
(This article belongs to the Section Thematic Reviews)
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16 pages, 1684 KiB  
Article
Development and Validation of a New LC-MS/MS Method for the Assay of Plasmatic Peripheral Short- and Medium-Chain Fatty Acids for Metabolomics Applications
by Lenard Farczadi, Laura Barcutean, Smaranda Maier, Rodica Balasa and Silvia Imre
Metabolites 2025, 15(6), 403; https://doi.org/10.3390/metabo15060403 - 16 Jun 2025
Viewed by 436
Abstract
Background: Short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) are human metabolites which are involved in various biochemical processes and can offer valuable insights and information on various pathological and metabolic issues of patients. Accurate, precise, high-performance bioanalytical methods are important tools [...] Read more.
Background: Short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) are human metabolites which are involved in various biochemical processes and can offer valuable insights and information on various pathological and metabolic issues of patients. Accurate, precise, high-performance bioanalytical methods are important tools in both research and diagnostics of many pathologies, with LC-MS being the most frequently used methodology in modern metabolomics studies. Methods: The current paper describes a complete LC-MS/MS methodology for the accurate quantification of total plasmatic SCFA concentrations in humans using high-resolution QTOF mass spectrometric detection, including sample cleanup, preparation, and derivatization. Results and Conclusions: The method was validated with regard to all relevant parameters (selectivity, sensitivity, accuracy, precision, linearity, recovery, carryover, and reproducibility of sample preparation) according to the current applicable guidelines and tested in an in vivo study to quantify peripheral SCFAs in human patients as biomarkers for gut–brain axis disruption. Full article
(This article belongs to the Special Issue Future Trends and Emerging Applications in Metabolomics)
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13 pages, 1293 KiB  
Article
Uric Acid Promotes Human Umbilical Vein Endothelial Cell Senescence In Vitro
by Katarzyna Lewandowska, Justyna Mikuła-Pietrasik, Krzysztof Książek, Andrzej Tykarski and Paweł Uruski
Metabolites 2025, 15(6), 402; https://doi.org/10.3390/metabo15060402 - 14 Jun 2025
Viewed by 456
Abstract
Background/Objectives: Uric acid can act as a prooxidant or an antioxidant; therefore, its effects on human umbilical vein endothelial cells (HUVECs) were investigated to better understand its role in promoting cellular senescence and vascular dysfunction. Methods: HUVECs were exposed to different concentrations of [...] Read more.
Background/Objectives: Uric acid can act as a prooxidant or an antioxidant; therefore, its effects on human umbilical vein endothelial cells (HUVECs) were investigated to better understand its role in promoting cellular senescence and vascular dysfunction. Methods: HUVECs were exposed to different concentrations of exogenous uric acid levels typically found in patients with cardiovascular conditions (5 mg/dL, 7.5 mg/dL, and 10 mg/dL) to assess cell viability, proliferation, and senescence markers including SA-β-Gal activity, γ-H2A.X and 53BP1 expression, as well as mitochondrial dysfunction parameters such as reactive oxygen species (ROS) production, mitochondrial mass, and mitochondrial membrane potential (ΔΨm). Additionally, the secretion of factors related to the senescence-associated secretory phenotype (SASP) was quantified. Results: Uric acid concentrations of 7.5 mg/dL and above significantly reduced HUVEC viability, enhanced proliferation, and increased markers of cellular senescence, including SA-β-Gal activity and γ-H2A.X/53BP1 expression. Higher uric acid levels also led to increased ROS production, increased mitochondrial mass, and reduced membrane potential. Uric acid also dose-dependently increased IL-6, IL-8, HGF, GRO-1, and TGF-β1 levels. Conclusions: High uric acid concentrations (≥7.5 mg/dL) promote HUVEC senescence, possibly due to ROS-induced DNA damage. In addition, uric acid triggers the production of pro-inflammatory cytokines and growth factors. Full article
(This article belongs to the Special Issue Exploring Uric Acid and Beyond)
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26 pages, 849 KiB  
Review
Bile Acids and Type 2 Diabetes: Roles in Glucose Homeostasis and Therapeutic Opportunities
by Yiting Lin, Chunyan Hu, Shuangyuan Wang and Hong Lin
Metabolites 2025, 15(6), 401; https://doi.org/10.3390/metabo15060401 - 13 Jun 2025
Viewed by 528
Abstract
Background: Type 2 diabetes mellitus (T2DM), characterized by impaired glucose homeostasis, represents a significant threat to public health. Bile acids (BAs), as key metabolic regulators, play an essential role in glucose metabolism. Recent advances in high-resolution metabolomics have revealed that various BA species [...] Read more.
Background: Type 2 diabetes mellitus (T2DM), characterized by impaired glucose homeostasis, represents a significant threat to public health. Bile acids (BAs), as key metabolic regulators, play an essential role in glucose metabolism. Recent advances in high-resolution metabolomics have revealed that various BA species are closely linked to T2DM pathogenesis and play a critical role in maintaining glucose homeostasis. Understanding the underlying mechanisms by which BAs modulate glucose metabolism provides valuable insights for the prevention and treatment of T2DM. Methods/Results: This review describes the roles of diverse BA species in regulating glucose metabolism and comprehensively summarizes the relationship of unconjugated and conjugated BAs with T2DM in population studies. Furthermore, we discuss BA-targeted therapeutic approaches for T2DM, highlighting the urgent need for developing tissue-restricted modulators of BA receptors and advancing the clinical translation of novel beneficial BAs. Conclusion: Deeply understanding the role of BAs played in the pathogenesis and progression of T2DM will facilitate the development of potential therapeutic agents. Full article
(This article belongs to the Special Issue New Analytical Techniques and Applications of Metabolomics and Lipidomics)
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19 pages, 586 KiB  
Article
In Vitro Antioxidant, Antithrombotic and Anti-Inflammatory Activities of Bioactive Metabolites Extracted from Kiwi and Its By-Products
by Anastasia Maria Moysidou, Konstantina Cheimpeloglou, Spyridoula Ioanna Koutra, Vasileios Manousakis, Anna Ofrydopoulou, Katie Shiels, Sushanta Kumar Saha and Alexandros Tsoupras
Metabolites 2025, 15(6), 400; https://doi.org/10.3390/metabo15060400 - 13 Jun 2025
Viewed by 526
Abstract
Background/Objectives: Growing interest in natural, health-promoting ingredients for functional foods, nutraceuticals, and cosmetics has increased the demand for bioactive compounds from kiwi (Actinidia deliciosa). This study aimed to assess the antioxidant, anti-inflammatory, and antithrombotic properties of amphiphilic bioactives extracted from kiwi fruit and [...] Read more.
Background/Objectives: Growing interest in natural, health-promoting ingredients for functional foods, nutraceuticals, and cosmetics has increased the demand for bioactive compounds from kiwi (Actinidia deliciosa). This study aimed to assess the antioxidant, anti-inflammatory, and antithrombotic properties of amphiphilic bioactives extracted from kiwi fruit and its by-products, including peel, seeds, and pulp. Methods: Bioactive compounds were extracted and analyzed using liquid chromatography–mass spectrometry (LC–MS) and attenuated total reflectance–Fourier transform infrared (ATR–FTIR) spectroscopy. Antioxidant activity was evaluated using DPPH and ABTS radical scavenging assays. Anti-inflammatory and antithrombotic effects were assessed through inhibition of platelet aggregation induced by platelet-activating factor (PAF) and adenosine diphosphate (ADP) in human platelets. Results: All extracts showed significant antioxidant activity. FTIR and LC–MS analyses confirmed the presence of phenolics, flavonoids, carotenoids, and polar lipids. Kiwi peel extract exhibited the strongest inhibition of PAF- and ADP-induced platelet aggregation, attributed to its higher content of phenolics and unsaturated polar lipids. LC–MS data indicated a favorable fatty acid profile with high omega-9 levels and a low omega-6/omega-3 ratio. Polar lipid structural analysis revealed a predominance of phospholipids with unsaturated fatty acids at the sn-2 position. Conclusions: Kiwi by-products are valuable sources of health-promoting bioactives with antioxidant and anti-inflammatory potential. These findings support their incorporation into nutraceutical, nutricosmetic, and cosmeceutical products and lay the groundwork for further studies on safety, efficacy, and practical application. Full article
(This article belongs to the Special Issue Phytochemicals and Pharmacological Significance of Plant Secondary Metabolites in Medicine)
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14 pages, 4541 KiB  
Article
A Systems Hypothesis of Lipopolysaccharide-Induced Vitamin Transport Suppression and Metabolic Reprogramming in Autism Spectrum Disorders: An Open Call for Validation and Therapeutic Translation
by Albion Dervishi
Metabolites 2025, 15(6), 399; https://doi.org/10.3390/metabo15060399 - 13 Jun 2025
Viewed by 913
Abstract
Background: Autism spectrum disorder (ASD) is increasingly linked to systemic metabolic dysfunction, potentially influenced by gut–brain axis dysregulation, but the underlying mechanisms remain unclear. Methods: We developed Personalized Metabolic Margin Mapping (PM3), a computational systems biology framework, to analyze RNA-seq data [...] Read more.
Background: Autism spectrum disorder (ASD) is increasingly linked to systemic metabolic dysfunction, potentially influenced by gut–brain axis dysregulation, but the underlying mechanisms remain unclear. Methods: We developed Personalized Metabolic Margin Mapping (PM3), a computational systems biology framework, to analyze RNA-seq data from 12 ASD and 12 control postmortem brain samples. The model focused on 158 curated metabolic genes selected for their roles in redox balance, mitochondrial function, neurodevelopment, and gut–brain interactions. Results: Using unsupervised machine learning (Isolation Forest) to detect outlier expression patterns, Euclidean distance, and percent expression difference metrics, PM3 revealed a consistent downregulation of glycolysis (e.g., −5.4% in PFKM) and mitochondrial enzymes (e.g., −12% in SUCLA2). By incorporating cofactor dependency and subcellular localization, PM3 identified a coordinated suppression of multivitamin transporters (e.g., −4.5% in SLC5A6, −3.5% in SLC19A2), potentially limiting cofactor availability and compounding energy deficits in ASD brains. Conclusions: These findings suggest a convergent metabolic dysregulation signature in ASD; wherein the subtle suppression of cofactor-dependent pathways may impair energy metabolism and neurodevelopment. We propose that chronic microbial lipopolysaccharide (LPS) exposure in ASD suppresses vitamin transporter function, initiating mitochondrial dysfunction and transcriptomic reprogramming. Validation in LPS-exposed systems using integrated transcriptomic–metabolomic analysis is warranted. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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13 pages, 228 KiB  
Article
Outcomes of Different Lifestyle Approaches in a Multicentre, Open-Label, Parallel-Group, Randomised Controlled Trial of the Effectiveness of Integrating a Pragmatic Pathway for Prescribing Liraglutide 3.0 mg in Weight Management Services (STRIVE Study)
by Werd Al-Najim, Babak Dehestani, Ahmed W. Al-Humadi, Danielle H. Bodicoat, Dimitris Papamargaritis, Michael Lean, Barbara McGowan, David R. Webb, John PH Wilding, Melanie J. Davies and Carel W. le Roux
Metabolites 2025, 15(6), 398; https://doi.org/10.3390/metabo15060398 - 13 Jun 2025
Viewed by 635
Abstract
Background/Objectives: The STRIVE study was a multicentre, open-label, real-world clinical trial evaluating the effectiveness of a targeted prescribing pathway for liraglutide 3.0 mg as an adjunct to standard care versus standard care alone in people with obesity attending Specialist Weight Management Services (SWMS) [...] Read more.
Background/Objectives: The STRIVE study was a multicentre, open-label, real-world clinical trial evaluating the effectiveness of a targeted prescribing pathway for liraglutide 3.0 mg as an adjunct to standard care versus standard care alone in people with obesity attending Specialist Weight Management Services (SWMS) in the UK and Ireland. This post hoc analysis focuses on the standard care arm to explore differences in outcomes between sites, particularly the potential impact of offering meal replacements as part of usual care. Methods: Participants included individuals with a BMI ≥ 35 kg/m² and at least one obesity-related complication who received standard care at five SWMS sites. All sites provided specialist nutrition and exercise counselling; however, only the Dublin site (n = 40) included meal replacements as part of routine care. Baseline characteristics and weight change data were compared between the Dublin and UK cohorts (n = 92) at 52 and 104 weeks. Statistical comparisons were made using appropriate parametric and non-parametric tests. Results: At baseline, the Dublin cohort was significantly older (p < 0.01), had a higher prevalence of hypertension (p < 0.05), and a lower reported incidence of depression/anxiety (p < 0.05) than the UK cohort. At week 52, the Dublin group achieved greater mean weight loss (−6.1%, SD ± 5.7%) compared to the UK cohort (−1.3%, SD ± 6.7%, n = 27, p < 0.01). By week 104, Dublin participants maintained a mean weight loss of −4.4% (SD ± 5.7%) while UK participants had a mean weight gain of 0.37% (SD ± 7.6%) (p < 0.05). Conclusions: The integration of meal replacements as part of usual care may have contributed to the greater and sustained weight loss observed in the Dublin cohort compared to other SWMS in the UK. Full article
(This article belongs to the Special Issue Diabetes and Metabolic Diseases: From Prevention to Clinical Management)
30 pages, 1219 KiB  
Review
Gut Microbiota Dysbiosis and Its Impact on Type 2 Diabetes: From Pathogenesis to Therapeutic Strategies
by Yonghua Yu, Yilan Ding, Shuangyuan Wang and Lei Jiang
Metabolites 2025, 15(6), 397; https://doi.org/10.3390/metabo15060397 - 12 Jun 2025
Viewed by 1106
Abstract
Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction. Emerging evidence indicates that gut microbiota dysbiosis may contribute to the development of T2DM. Individuals with T2DM exhibit notable changes in gut microbiota composition, including [...] Read more.
Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction. Emerging evidence indicates that gut microbiota dysbiosis may contribute to the development of T2DM. Individuals with T2DM exhibit notable changes in gut microbiota composition, including shifts in the balance between Firmicutes and Bacteroidetes, a reduction in butyrate-producing bacteria, and an increase in opportunistic pathogens. Gut microbiota-derived metabolites—such as short-chain fatty acids, bile acids, and amino acids—have been implicated in the pathogenesis of T2DM, highlighting the critical role of host-microbe interactions. In this overview, we discuss the gut microbiota dysbiosis associated with T2DM and explore the molecular links between microbiota-derived metabolites and the pathogenesis of diseases. Additionally, we explore potential therapeutic strategies, including probiotics and dietary interventions, to modulate the gut microbiota and its metabolites, providing insights for future clinical research and the development of novel treatments for T2DM. Full article
(This article belongs to the Special Issue Dysbiosis and Metabolic Disorders of the Microbiota)
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26 pages, 2650 KiB  
Article
Combining Metabolomics and Proteomics to Reveal Key Serum Compounds Related to Canine Intervertebral Disc Herniation
by Anita Horvatić, Josipa Kuleš, Andrea Gelemanović, Ozren Smolec, Boris Pirkić, Marko Pećin, Ivana Rubić, Vladimir Mrljak, Marko Samardžija and Marija Lipar
Metabolites 2025, 15(6), 396; https://doi.org/10.3390/metabo15060396 - 12 Jun 2025
Viewed by 595
Abstract
Background/Objectives: Canine intervertebral disc herniation (IVDH) is an important musculoskeletal pathology. Unlike in humans, IVDH mechanisms in dogs are underinvestigated from a system-level integrative omics point of view. The aim of this study was to identify key serum molecular players in canine [...] Read more.
Background/Objectives: Canine intervertebral disc herniation (IVDH) is an important musculoskeletal pathology. Unlike in humans, IVDH mechanisms in dogs are underinvestigated from a system-level integrative omics point of view. The aim of this study was to identify key serum molecular players in canine IVDH. Methods: An integrative multi-omics approach combining high-resolution LC-MS-based untargeted metabolomics and tandem mass tag (TMT)-based proteomics was applied. Additionally, serum zinc concentration was determined by spectrophotometry. Results: Nineteen serum metabolites were differentially abundant in IVDH dogs. Metabolite analysis highlighted dysregulation in lipoic acid and branched-chain amino acid (BCAA) metabolism, with elevated levels of valine, leucine, and isoleucine in IVDH. These findings suggest disrupted energy, nitrogen, and neurotransmitter metabolism, potentially contributing to the IVDH pathophysiology. Additionally, lower serum uridine, possibly influenced by BCAA accumulation, was observed, indicating altered neuroinflammatory responses. ELISA validation confirmed elevated serum levels of zinc-α2-glycoprotein (ZAG), alpha-1-microglobulin/bikunin precursor (AMBP), and vitronectin (VTN) in IVDH, supporting immune modulation and neuroprotective mechanisms. Serum prekallikrein (KLKB1) and Protein C inhibitor (SERPINA5), involved in fibrin cloth formation, were found to be lowered in IVDH patients. Pathway enrichment revealed disturbances in aromatic amino acid biosynthesis, with elevated phenylalanine, tyrosine, and tryptophan influencing neurotransmission and inflammation. In addition, elevated serum Zn concentration emphasized its antioxidant importance in immune response, wound healing, and neuropathic pain signaling. Conclusions: Integration with our prior CSF multi-omics data reinforced the relevance of identified molecules in IVDH-associated neurodegeneration, inflammation, and repair processes. This study offers insight into potential diagnostic biomarkers and therapeutic targets for canine IVDH through serum-based molecular profiling. Full article
(This article belongs to the Special Issue Mass Spectrometry-Based Technology for Metabolic Profiling)
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15 pages, 1216 KiB  
Article
Blood Metabolic Biomarkers of Diabetes Mellitus Type 2 in Aged Adults Determined by a UPLC-MS Metabolomic Approach
by Alba Simón, Daniel Bordonaba-Bosque, Olimpio Montero, Javier Solano-Castán and Irma Caro
Metabolites 2025, 15(6), 395; https://doi.org/10.3390/metabo15060395 - 12 Jun 2025
Viewed by 509
Abstract
Background/Objectives: Type 2 diabetes mellitus (T2DM) is a metabolic disease whose importance rises with aging, though it is also looming large in younger populations due to increasing obesity. Its effects may damage renal and heart functioning. Plasma biomarkers of T2DM have been shown [...] Read more.
Background/Objectives: Type 2 diabetes mellitus (T2DM) is a metabolic disease whose importance rises with aging, though it is also looming large in younger populations due to increasing obesity. Its effects may damage renal and heart functioning. Plasma biomarkers of T2DM have been shown through metabolomic studies under different conditions, mainly obesity, but untargeted metabolomic studies on T2DM are lacking for elderly people. Methods: A UPLC-MS-based metabolomic approach was conducted to ascertain potential plasma biomarkers in a cohort older than 65 years. Results: The dipeptide Gly-His, along with diverse lysophosphatidylcholines (LPCs), mainly LPC(14:0) and LPC(20:4), and three gangliosides were found to have different plasma content in T2DM subjects compared to control (non-diabetic) subjects (NT2DM). LPC(20:4) exhibited a gender dependence, with statistically significant differences only in females. Gly-His correlated with MEDAS-14, whereas LPC(14:0) correlated with sugar-rich food consumption. Conclusions: As previously demonstrated for other conditions, mainly obesity, altered lipid metabolism was shown in this study to be a hallmark of T2DM in elderly people also. Full article
(This article belongs to the Special Issue Advanced Metabolic Profiling via Gas Chromatography–Mass Spectrometry and Liquid Chromatography–Mass Spectrometry)
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20 pages, 4640 KiB  
Article
Metabolite Profile and Metabolic Network Analysis of Walnuts (Juglans regia L.) in Response to Chilling Stress
by Kai Liu, Yang Li, Yaxin Sang, Yaru Zhang, Xiuhong An, Hongxia Wang and Ruifen Zhang
Metabolites 2025, 15(6), 394; https://doi.org/10.3390/metabo15060394 - 12 Jun 2025
Viewed by 428
Abstract
Background: Walnut (Juglans regia L.) is a species of considerable ecological, social, and economic importance. However, comprehensive metabolomic investigations into walnut cultivars under chilling stress remain scarce. Methods: In this study, we utilized LC-MS/MS-based non-targeted metabolomics to analyze differential metabolites in two [...] Read more.
Background: Walnut (Juglans regia L.) is a species of considerable ecological, social, and economic importance. However, comprehensive metabolomic investigations into walnut cultivars under chilling stress remain scarce. Methods: In this study, we utilized LC-MS/MS-based non-targeted metabolomics to analyze differential metabolites in two walnut cultivars exposed to chilling stress at 0.5 °C for 0 and 48 h. Results: A total of 1504 metabolites were identified, including 871 in positive ion mode and 633 in negative ion mode. Specifically, 160 and 287 differential metabolites were detected in ‘Qingxiang’ and ‘Liaoning No.8’, respectively, under positive ion mode. In negative ion mode, 83 and 206 differential metabolites were identified in ‘Qingxiang’ and ‘Liaoning No.8’, respectively. These metabolites were primarily associated with α-linolenic acid metabolism, phenylpropanoid biosynthesis, flavonoid biosynthesis, and phenylalanine metabolism, and multiple candidate genes were obtained that exhibit significant correlations with metabolites, suggesting their critical roles in the walnut’s response to chilling stress. Conclusions: This study proposes a metabolic network for walnut leaves under chilling stress, enriching our understanding of the metabolic adaptation mechanisms of walnuts to low-temperature conditions. It lays a foundation for investigating the regulatory mechanisms of metabolite synthesis under cold stress and provides important theoretical insights for breeding cold-resistant walnut cultivars. Full article
(This article belongs to the Section Plant Metabolism)
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22 pages, 30677 KiB  
Article
Mitochondrial Translation Inhibition Uncovers a Critical Metabolic–Epigenetic Interface in Renal Cell Carcinoma
by Kazumi Eckenstein, Beyza Cengiz, Matthew E. K. Chang, Jessie May Cartier, Mark R. Flory and George V. Thomas
Metabolites 2025, 15(6), 393; https://doi.org/10.3390/metabo15060393 - 12 Jun 2025
Viewed by 502
Abstract
Background/Objectives: Renal cell carcinoma (RCC) exhibits distinctive metabolic vulnerabilities that may be therapeutically targeted. This study investigates how tigecycline, an FDA-approved antibiotic that inhibits mitochondrial translation, affects RCC cells and explores potential combinatorial approaches to enhance its efficacy. Methods: We employed comprehensive metabolomic [...] Read more.
Background/Objectives: Renal cell carcinoma (RCC) exhibits distinctive metabolic vulnerabilities that may be therapeutically targeted. This study investigates how tigecycline, an FDA-approved antibiotic that inhibits mitochondrial translation, affects RCC cells and explores potential combinatorial approaches to enhance its efficacy. Methods: We employed comprehensive metabolomic profiling, subcellular proteomics, and functional assays to characterize the effects of tigecycline on RCC cell lines, patient-derived organoids, and xenograft models. The synergistic potential of tigecycline with the histone deacetylase inhibitor entinostat was evaluated using combination index analysis. Results: Tigecycline selectively inhibited mitochondrial translation in RCC cells, reducing mitochondrially-encoded proteins while sparing nuclear-encoded components, profoundly disrupting mitochondrial bioenergetics and reducing tumor growth in xenograft models. Subcellular proteomic analyses revealed that tigecycline treatment triggered a significant accumulation of multiple histone variants concurrent with cell cycle arrest. Based on this discovery, combined treatment with tigecycline and entinostat demonstrated remarkable synergism across RCC cell lines and patient-derived. Conclusions: Our findings identify a promising therapeutic opportunity by targeting the crosstalk between mitochondrial function and epigenetic homeostasis in RCC, with the potential for rapid clinical translation given the established pharmacological profiles of both agents. Full article
(This article belongs to the Special Issue Metabolomics and Machine Learning for Improved Diagnostics and as a Tool to Accelerate Drug Development)
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15 pages, 1180 KiB  
Article
Differential Expression of Lipid Metabolism Genes, CROT and ABCG1, in Obese Patients with Comorbid Depressive Disorder and Risk of MASLD
by Joanna Michalina Jurek, Elena Cristina Rusu, Javier Camaron, Helena Clavero-Mestres, Carmen Aguilar, David Riesco, Belen Xifré, Javier U. Chicote, Salomé Martinez, Marga Vives, Fàtima Sabench and Teresa Auguet
Metabolites 2025, 15(6), 392; https://doi.org/10.3390/metabo15060392 - 11 Jun 2025
Viewed by 548
Abstract
Background: There is accumulating evidence supporting a bidirectional relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and depressive disorder (DD), with possible genetic factors related to hepatic lipid metabolism. Our aim was to analyse the prevalence of DD in patients with obesity at [...] Read more.
Background: There is accumulating evidence supporting a bidirectional relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and depressive disorder (DD), with possible genetic factors related to hepatic lipid metabolism. Our aim was to analyse the prevalence of DD in patients with obesity at risk of MASLD, and to evaluate the hepatic expression of genes involved in lipid metabolism, in patients with DD. Methods: In 152 patients with morbid obesity who underwent bariatric surgery, medical data, blood and liver samples were collected. Liver biopsies were scored for MASLD staging were used for gene expression analysis. Results: The DD prevalence in this cohort was 29.6%, and patients with DD had a significantly higher hepatic expression of the CROT and ABCG1 genes. Moreover, patients in the MASLD group showed significantly higher relative hepatic expression of SREBP1 and ABCG1 genes compared to the normal liver group. Some anthropometric and clinical measures (BMI and DBP) were positively correlated with the expression of SREBP2, ABCG1 and CROT genes, while the expression of CPT1α was negatively correlated with age, SBP and DBP. There was a positive relationship between GGT and ALP levels and the relative expression of ABCG1 and ACC1 genes. Conclusions: In this study, individuals with morbid obesity demonstrated an elevated prevalence of DD. Moreover, hepatic genetic dysregulation of lipid metabolism may influence the interplay between MASLD and DD in patients with morbid obesity. Full article
(This article belongs to the Section Lipid Metabolism)
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24 pages, 3424 KiB  
Article
Oxidative Stress, Energy Metabolism Disorder, Mitochondrial Damage, and miR-144 Participated in Molecular Mechanisms of 4-Octylphenol-Caused Cardiac Autophagic Damage in Common Carps (Cyprinus carpio L.)
by Minna Qiu, Chunyu Jiang, Jiatian Liang, Qin Zhou, Yuhao Liu, Zhiyu Hao, Yuhang Liu, Xiumei Liu, Xiaohua Teng, Wei Sun and You Tang
Metabolites 2025, 15(6), 391; https://doi.org/10.3390/metabo15060391 - 11 Jun 2025
Viewed by 490
Abstract
Background/Objectives: In 4-octylphenol (4-OP), a toxic environmental pollutant with endocrine disruptive effect, the use of 4-OP causes pollution in the freshwater environment and poses risks to aquatic organisms. Common carps (Cyprinus carpio L.) live in freshwater and are experimental animals for [...] Read more.
Background/Objectives: In 4-octylphenol (4-OP), a toxic environmental pollutant with endocrine disruptive effect, the use of 4-OP causes pollution in the freshwater environment and poses risks to aquatic organisms. Common carps (Cyprinus carpio L.) live in freshwater and are experimental animals for studying the toxic effects of environmental pollutants on fish. Its heart is susceptible to toxicants. However, whether 4-OP has a toxic effect on common carp heart remains unknown. Methods: Here, we conducted a common carp 4-OP exposure experiment (carp treated with 17 μg/L 4-OP for 45 days), aiming to investigate whether 4-OP has a toxic effect on common carp hearts. We observed the microstructure and ultrastructure of carp heart and detected autophagy genes, mitochondrial fission genes, mitochondrial fusion genes, glycolytic enzymes, AMPK, ATPase, and oxidative stress factors, to investigate the molecular mechanism of 4-OP induced damage in common carp hearts. Results: Our results showed that 4-OP exposure caused mitochondrial damage, autophagy, and damage in common carp hearts. 4-OP exposure increased the levels of miR-144, and eight autophagy factors (Beclin1, RB1CC1, ULK1, LC3-I, LC3-II, ATG5, ATG12, and ATG13), and decreased the levels of four autophagy factors (PI3K, AKT, mTOR, and SQSTM1). Furthermore, 4-OP exposure induced the imbalance between mitochondrial fission and fusion and mitochondrial dynamics imbalance, as demonstrated by the increase in three mitochondrial fission factors (Mff, Drp1, and Fis1) and the decrease in three mitochondrial fusion factors (Mfn1, Mfn2, and Opa1). Moreover, excess 4-OP treatment caused energy metabolism disorder, as demonstrated by the reduction in four ATPase (Na+K+-ATPase, Ca2+Mg2+-ATPase, Ca2+-ATPase, and Mg2+-ATPase), elevation in four glycolysis genes (HK1, HK2, LDHA, and PGK1), reduction in glycolysis gen (PGAM2), and the elevation in energy-sensing AMPK. Finally, 4-OP treatment induced the imbalance between antioxidant and oxidant and oxidative stress, as demonstrated by the increase in oxidant H2O2, and the decreases in five antioxidant factors (CAT, SOD, T-AOC, Nrf2, and HO-1). Conclusions: miR-144 mediated autophagy by targeting PI3K, mTOR, and SQSTM1, and the miR-144/PI3K-AKT-mTOR/ULK1 pathway was involved in 4-OP-induced autophagy. Mff-Drp1 axis took part in 4-OP-caused mitochondrial dynamics imbalance, and mitochondrial dynamics imbalance mediated autophagy via Mfn2-SQSTM1, Mfn2/Beclin1, and Mff-LC3-II axes. Energy metabolism disorder mediated mitochondrial dynamics imbalance through the AMPK-Mff-Drp1 pathway. Oxidative stress mediated energy metabolism disorder via the H2O2-AMPK axis. Taken together, oxidative stress triggered energy metabolism disorder, induced mitochondrial dynamics imbalance, and caused autophagy via the H2O2-AMPK-Mff-LC3-II pathway. Our study provided references for the toxic effects of endocrine disruptor on common carp hearts, and provided a basis for assessing environmental pollutant-induced damage in common carp heart. We only studied the toxic effects of 4-OP on common carp, and the toxic effects of 4-OP on other fish species need to be further studied. Full article
(This article belongs to the Section Cell Metabolism)
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15 pages, 1361 KiB  
Review
Gut Microbiome Dysbiosis and Its Impact on Reproductive Health: Mechanisms and Clinical Applications
by Efthalia Moustakli, Sofoklis Stavros, Periklis Katopodis, Anastasios Potiris, Peter Drakakis, Stefanos Dafopoulos, Athanasios Zachariou, Konstantinos Dafopoulos, Konstantinos Zikopoulos and Athanasios Zikopoulos
Metabolites 2025, 15(6), 390; https://doi.org/10.3390/metabo15060390 - 11 Jun 2025
Cited by 1 | Viewed by 706
Abstract
The human gut microbiome is integral to maintaining systemic physiological balance, with accumulating evidence emphasizing its critical role in reproductive health. This review investigates the bidirectional interactions between the gut microbiota and the female reproductive system, mediated by neuroendocrine, immune, and metabolic pathways, [...] Read more.
The human gut microbiome is integral to maintaining systemic physiological balance, with accumulating evidence emphasizing its critical role in reproductive health. This review investigates the bidirectional interactions between the gut microbiota and the female reproductive system, mediated by neuroendocrine, immune, and metabolic pathways, constituting the gut–reproductive axis. Dysbiosis, characterized by microbial imbalance, has been linked to reproductive disorders such as polycystic ovary syndrome (PCOS), endometriosis, infertility, impaired spermatogenesis, and pregnancy complications. These associations can be explained by immunological dysregulation, systemic inflammation, altered sex hormone metabolism, and hypothalamic–pituitary–gonadal (HPG) axis disturbances. This review aims to clarify the molecular and cellular mechanisms underpinning gut–reproductive interactions and to evaluate the feasibility of microbiome-targeted therapies as clinical interventions for improving reproductive outcomes. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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20 pages, 1113 KiB  
Systematic Review
Salivaomics: New Frontiers in Studying the Relationship Between Periodontal Disease and Alzheimer’s Disease
by Giuseppina Malcangi, Grazia Marinelli, Alessio Danilo Inchingolo, Irma Trilli, Laura Ferrante, Lucia Casamassima, Paola Nardelli, Francesco Inchingolo, Andrea Palermo, Angelo Michele Inchingolo and Gianna Dipalma
Metabolites 2025, 15(6), 389; https://doi.org/10.3390/metabo15060389 - 10 Jun 2025
Viewed by 531
Abstract
Background: This study explores the link between oral biofluids, microbial dysbiosis, and Alzheimer’s disease (AD), highlighting saliva and gingival crevicular fluid (GCF) as non-invasive diagnostic sources. AD onset and progression appear to be influenced not only by genetic and environmental factors but also [...] Read more.
Background: This study explores the link between oral biofluids, microbial dysbiosis, and Alzheimer’s disease (AD), highlighting saliva and gingival crevicular fluid (GCF) as non-invasive diagnostic sources. AD onset and progression appear to be influenced not only by genetic and environmental factors but also by changes in the oral microbiome and related inflammatory and metabolic alterations. As global populations age, the incidence of AD is projected to rise significantly. Emerging evidence implicates the oral microbiome and salivary metabolites in neurodegenerative pathways, suggesting that oral health may mirror or influence brain pathology. Materials and Methods: A systematic review of recent multi-omics studies was performed, focusing on salivary and GCF analysis in patients with AD, those with mild cognitive impairment (MCI), and cognitively healthy individuals. Databases searched included PubMed, Web of Science, and Scopus, following PRISMA guidelines. Results: Across the 11 included studies, significant alterations were reported in both the salivary microbiome and metabolome in AD patients. Notable microbial shifts involved increased abundance of Veillonella parvula and Porphyromonas gingivalis, while key metabolites such as L-tyrosine, galactinol, and mannitol were consistently dysregulated. These biomarkers correlated with cognitive performance and systemic inflammation. Conclusions: Oral biofluids represent promising, accessible sources of biomarkers for early AD detection. Multi-omics integration reveals the oral–brain axis as a potential target for diagnosis, monitoring, and therapeutic strategies. Full article
(This article belongs to the Special Issue Advancing Metabolite Biomarkers in Neurodegenerative Disease: Discovery, Integration, and Therapeutic Potential)
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