Metabolites

58 pages, 655 KiB

Open AccessReview

Human Digestive Physiology and Evolutionary Diet: A Metabolomic Perspective on Carnivorous and Scavenger Adaptations

by Vicente Javier Clemente-Suárez, Laura Redondo-Flórez, Ana Isabel Beltrán-Velasco, Rodrigo Yáñez-Sepúlveda, Alejandro Rubio-Zarapuz, Alexandra Martín-Rodríguez, Eduardo Navarro-Jimenez and José Francisco Tornero-Aguilera

Metabolites 2025, 15(7), 453; https://doi.org/10.3390/metabo15070453 (registering DOI) - 4 Jul 2025

Abstract

This review examines human digestive physiology and metabolic adaptations in the context of evolutionary dietary patterns, particularly those emphasizing carnivorous and scavenging behaviors. By integrating metabolomic data with archaeological, anatomical, and microbiological evidence, the study explores how early hominins adapted to intermittent but [...] Read more.

This review examines human digestive physiology and metabolic adaptations in the context of evolutionary dietary patterns, particularly those emphasizing carnivorous and scavenging behaviors. By integrating metabolomic data with archaeological, anatomical, and microbiological evidence, the study explores how early hominins adapted to intermittent but energy-dense animal-based diets. The analysis highlights the development of hepatic insulin resistance, enhanced fat and protein metabolism, and shifts in gut microbiota diversity as physiological signatures of meat consumption. Comparative evaluations of digestive enzyme profiles, intestinal morphology, and salivary composition underscore humans’ omnivorous flexibility and partial carnivorous specialization. Additionally, biomarkers such as ketone bodies, branched-chain amino acids, and trimethylamine-N-oxide are identified as metabolic indicators of habitual meat intake. These adaptations, though once evolutionarily advantageous, are discussed in relation to current metabolic disorders in modern nutritional contexts. Overall, this review presents a metabolomic framework for understanding the evolutionary trajectory of human digestion and its implications for health and dietary recommendations. Full article

(This article belongs to the Section Advances in Metabolomics)

20 pages, 2548 KiB

Open AccessArticle

In Vitro Metabolism of Doping Agents (Stanozolol, LGD-4033, Anastrozole, GW1516, Trimetazidine) by Human Seminal Vesicle and Liver Fractions

by Johanna Sternberg, Insa Peters, Nana Naumann, Andreas Thomas and Mario Thevis

Metabolites 2025, 15(7), 452; https://doi.org/10.3390/metabo15070452 (registering DOI) - 4 Jul 2025

Abstract

Background: In order to address complex scenarios in anti-doping science, especially in cases where an unintentional exposure of athletes to prohibited substances and a corresponding contamination of doping control samples at the collection event are argued, an understanding of tissue-specific drug metabolism is [...] Read more.

Background: In order to address complex scenarios in anti-doping science, especially in cases where an unintentional exposure of athletes to prohibited substances and a corresponding contamination of doping control samples at the collection event are argued, an understanding of tissue-specific drug metabolism is essential. Hence, in this study, the metabolic capacity of the seminal vesicle using in vitro assays was investigated. Methods: The aim was to assess whether selected doping-relevant substances—stanozolol, LGD-4033, GW1516, trimetazidine, and anastrozole—are metabolised in seminal vesicle cellular fractions (SV-S9) and how that metabolism compares to biotransformations induced by human liver S9 fractions (HL-S9). Liquid chromatography coupled to high-resolution/accurate mass spectrometry (LC HRAM MS) enabled the sensitive detection and identification of metabolites, revealing a limited metabolic activity of SV-S9. Results: For LGD-4033, GW1516, and trimetazidine, minor metabolic transformations were observed, whereas no metabolites of stanozolol or anastrozole were detected. Gene expression analysis using digital polymerase chain reaction (dPCR) confirmed transcripts of CYP2D6, CYP2E1, and CYP2C9 in SV-S9, though no enzymatic activity was detected. Gene expression and enzymatic activity in CYP3A4 and CYP1A2—major hepatic enzymes—were absent in SV-S9. Conclusions: Overall, these pilot study results suggest that the seminal vesicle has only a low capacity for xenobiotic metabolism, which translates into a limited role in the biotransformation of drugs and, hence, the metabolic pattern. Full article

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

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22 pages, 2428 KiB

Open AccessArticle

Assessment of Metabolic Alterations Induced by Halogenated Additives and Antifungal Activity of Extracts from the Endophytic Fungus Fusarium sp. Associated with Dizygostemon riparius (Plantaginaceae)

by Hilzimar de Jesus Freitas Sá, Anne Karoline Maiorana Santos, Adriano Souza Fonseca, Lourivaldo da Silva Santos, Josivan Regis Farias, Rosane Nassar Meireles Guerra, Edson Rodrigues-Filho, Gilmar Silverio da Silva, Cleydlenne Costa Vasconcelos, Alberto Jorge Oliveira Lopes and Antônio José Cantanhede Filho

Metabolites 2025, 15(7), 451; https://doi.org/10.3390/metabo15070451 - 4 Jul 2025

Abstract

Background/Objectives: Endophytic fungi are valuable sources of bioactive compounds with potential therapeutic applications. This study aimed to evaluate the antifungal activity of secondary metabolites produced by Fusarium sp. isolated from Dizygostemon riparius, with particular focus on the impact of culture medium [...] Read more.

Background/Objectives: Endophytic fungi are valuable sources of bioactive compounds with potential therapeutic applications. This study aimed to evaluate the antifungal activity of secondary metabolites produced by Fusarium sp. isolated from Dizygostemon riparius, with particular focus on the impact of culture medium supplementation with halogenated and metallic additives on metabolite production. Methods: The fungus was cultivated in standard Czapek medium and media supplemented with NH₄Br or MnCl₂. Methanolic extracts were obtained, fractionated, and chemically characterised via LC-ESI-HRMS. In vitro antifungal assays, including MIC and MFC determinations and biofilm inhibition tests, were performed against Candida albicans strains. In vivo toxicity and efficacy were assessed using Tenebrio molitor larvae. Results: Fifteen metabolites were annotated, including known antifungals such as fusaric acid and cyclosporin A. Fractions EMBr4 and EMC5 demonstrated fungicidal activity with MIC values close to fluconazole and significantly inhibited biofilm formation and maturation. In vivo, these fractions displayed low acute toxicity and improved survival in infected larvae, comparable to fluconazole treatment. Conclusions: The results indicate that culture medium modulation enhances the production of bioactive metabolites by Fusarium sp., leading to extracts with notable antifungal efficacy and safety. EMBr4 and EMC5 are promising candidates for further development as antifungal agents, particularly for targeting biofilm-associated Candida infections. These findings support the potential of endophytic fungi as sources of novel therapeutics and warrant further mechanistic and pharmacological investigations. Full article

(This article belongs to the Special Issue Secondary Metabolites and Their Activities: From the Identification to the Biological Investigation)

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14 pages, 1035 KiB

Open AccessArticle

Interaction Between CYP1A2-Related Caffeine Metabolism and Vitamin B12/Folate Status in Patients with Metabolic Syndrome: A Novel Biomarker Axis

by Laura Claudia Popa, Ahmed Abu-Awwad, Simona Sorina Farcas, Simona-Alina Abu-Awwad and Nicoleta Ioana Andreescu

Metabolites 2025, 15(7), 450; https://doi.org/10.3390/metabo15070450 - 4 Jul 2025

Abstract

Background/Objectives: The prevalence of metabolic syndrome (MetS) is steadily increasing worldwide, driven by complex genetic, nutritional, and environmental factors. Caffeine metabolism, primarily mediated by CYP1A2 (though other enzymes such as CYP1A1 may also be involved), and the status of micronutrients such as [...] Read more.

Background/Objectives: The prevalence of metabolic syndrome (MetS) is steadily increasing worldwide, driven by complex genetic, nutritional, and environmental factors. Caffeine metabolism, primarily mediated by CYP1A2 (though other enzymes such as CYP1A1 may also be involved), and the status of micronutrients such as vitamin B12 and folate have each been linked to MetS components. This study investigates the interaction between CYP1A2 genetic variants and vitamin B12/folate levels in patients with MetS, aiming to identify a novel biomarker axis with potential implications for personalized interventions. Methods: This cross-sectional observational study included 356 adults diagnosed with MetS, recruited from Western Romania. Genotyping for CYP1A2 rs762551 was performed using TaqMan PCR assays. Daily caffeine intake was assessed via validated dietary questionnaires. Serum levels of folate and vitamin B12 were measured using chemiluminescence immunoassays. Results: AA genotype patients with a moderate coffee intake (1–2 cups/day) had significantly higher folate and B12 levels than AC or CC carriers. These nutritional advantages were associated with more favorable BMI and triglyceride profiles. The interaction between CYP1A2 genotype and coffee intake was significant for both micronutrient levels and metabolic parameters, particularly in the AA group. No significant associations were found in high-coffee-intake subgroups (≥3 cups/day). Conclusions: The interplay between CYP1A2 polymorphisms and B-vitamin status may represent a clinically relevant biomarker axis in MetS. Moderate caffeine intake in slow metabolizers (AA genotype) may boost micronutrient status and metabolic health, supporting personalized nutrition. Full article

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

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13 pages, 7015 KiB

Open AccessArticle

Metabolic Changes in Zebrafish Larvae Infected with Mycobacterium marinum: A Widely Targeted Metabolomic Analysis

by Chongyuan Sima, Qifan Zhang, Xiaoli Yu, Bo Yan and Shulin Zhang

Metabolites 2025, 15(7), 449; https://doi.org/10.3390/metabo15070449 - 4 Jul 2025

Abstract

Objectives: To explore the metabolic changes in zebrafish larvae after infection with Mycobacterium marinum, this study adopted a widely targeted metabolomic approach to analyze the changes in the overall metabolic profiles of zebrafish larvae infected for 5 days. Methods: Data were collected [...] Read more.

Objectives: To explore the metabolic changes in zebrafish larvae after infection with Mycobacterium marinum, this study adopted a widely targeted metabolomic approach to analyze the changes in the overall metabolic profiles of zebrafish larvae infected for 5 days. Methods: Data were collected by liquid chromatography–tandem mass spectrometry (LC-MS/MS). Mass spectrometry data were processed using Analyst 1.6.3 and MultiQuant 3.0.3 software, and multivariate statistical analysis was carried out. The KEGG database, HMDB database, and CHEBI database were used to screen and identify differential metabolites, and metabolic pathway enrichment analysis was performed through KEGG pathways. Results: A total of 329 metabolites were detected, among which 61 differential metabolites were screened. Specifically, 41 metabolites, such as kynurenine, isoallolithocholic acid, 2′-deoxyguanosine, indole-3-carboxaldehyde, and L-lactic acid, were downregulated, while 20 metabolites, such as L-palmitoylcarnitine, myristoyl-L-carnitine, dodecanoylcarnitine, 2-isopropyl-malic acid, and 2-methylsuccinic acid, were upregulated. KEGG metabolic pathway enrichment analysis indicated that these differential metabolites were mainly involved in metabolic pathways such as pyrimidine metabolism, nucleotide metabolism, the pentose phosphate pathway, and purine metabolism. Conclusions: This study demonstrated that significant changes occurred in multiple metabolites and metabolic pathways in zebrafish larvae after infection with M. marinum. The research results have improved the understanding of zebrafish as a model organism in the field of Mycobacterium research and laid a solid foundation for subsequent metabolomic-related research using zebrafish. Full article

(This article belongs to the Section Advances in Metabolomics)

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18 pages, 1475 KiB

Open AccessArticle

Metabolomic Prediction of Naphthalene Pneumo-Toxicity in the Snail Helix aspersa maxima

by Aude Devalckeneer, Marion Bouviez and Jean-Marie Colet

Metabolites 2025, 15(7), 448; https://doi.org/10.3390/metabo15070448 - 3 Jul 2025

Abstract

Background: Polluted soils represent a major problem in many industrialized countries that urgently requires appropriate health risk assessment. The One Health concept that considers a close relationship between human and animal health and ecosystems relies, among other techniques, on continuous monitoring through the [...] Read more.

Background: Polluted soils represent a major problem in many industrialized countries that urgently requires appropriate health risk assessment. The One Health concept that considers a close relationship between human and animal health and ecosystems relies, among other techniques, on continuous monitoring through the use of animal species as bioindicators. In this context, terrestrial gastropods, already recognized as relevant indicators due to their anatomo-physiology, provide a reliable model to study the pneumotoxic effects of pollutants. On the other hand, risk assessment is based on multi-biomarker studies. Therefore, omic approaches seem particularly useful since they can simultaneously detect numerous early biological changes. Methods: In this study, Helix aspersa maxima was exposed to naphthalene, a highly volatile aromatic hydrocarbon responsible for numerous respiratory disorders. Pulmonary membrane extracts and hemolymph samples were analyzed by ¹H-NMR spectroscopy after single or repeated exposures to naphthalene. Results: Numerous metabolic changes were observed, which could be related to membrane lesions, energy, anti-inflammatory, and tumorigenesis pathways. Conclusions: Our findings highlight the potential of combining animal indicator and omics techniques to predict respiratory health risks in cases of exposure to polluted soils. Full article

(This article belongs to the Collection Feature Papers in Assessing Environmental Health and Function)

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18 pages, 2928 KiB

Open AccessArticle

Multi-Omics Analysis of Gut Microbiota and Sperm Quality in Tibetan Breeding Boars

by Mingxuan Zhao, Mengjia Han, Hongliang Zhang, Xiangdong Wang, Yikai Yin, Jian Zhang and Peng Shang

Metabolites 2025, 15(7), 447; https://doi.org/10.3390/metabo15070447 - 2 Jul 2025

Abstract

Background/Objectives: Reproductive efficiency in breeding boars critically impacts swine industry productivity, with sperm quality being multifactorially regulated by gut microbiota. This study aimed to elucidate the microbiota–metabolite interactions underlying sperm quality differences in Tibetan boars. Methods: Integrated 16S rRNA sequencing and untargeted metabolomics [...] Read more.

Background/Objectives: Reproductive efficiency in breeding boars critically impacts swine industry productivity, with sperm quality being multifactorially regulated by gut microbiota. This study aimed to elucidate the microbiota–metabolite interactions underlying sperm quality differences in Tibetan boars. Methods: Integrated 16S rRNA sequencing and untargeted metabolomics were performed on fecal and semen samples from eight healthy Tibetan boars (31–33 months old), stratified into low-semen (CJ) and high-semen utilization (HJ) groups. Analyses included sperm quality assessment, microbial profiling, and metabolic pathway enrichment. Results: The HJ group exhibited significantly enhanced sperm motility and semen utilization rates (p < 0.05). Gut microbiota composition differed markedly, with Firmicutes and Proteobacteria enriched in HJ boars. Metabolomics identified key metabolites positively correlated with sperm quality (e.g., butyrate, phenyllactic acid), while lithocholic acid showed negative associations. KEGG analysis revealed predominant involvement in butanoate metabolism and bile acid biosynthesis. Core microbiota (e.g., Ruminococcus) modulated sperm quality through short-chain fatty acid networks and bile acid homeostasis. Conclusions: Gut microbiota regulated the sperm microenvironment via a “metabolic-immune” dual pathway mediated by the gut–testis axis. These findings establish a theoretical basis for probiotic or metabolite-targeted strategies to improve boar reproductive performance. Full article

(This article belongs to the Section Animal Metabolism)

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21 pages, 1025 KiB

Open AccessReview

Amino Acid Metabolism in Liver Mitochondria: From Homeostasis to Disease

by Ranya Erdal, Kıvanç Birsoy and Gokhan Unlu

Metabolites 2025, 15(7), 446; https://doi.org/10.3390/metabo15070446 - 2 Jul 2025

Abstract

Hepatic mitochondria play critical roles in sustaining systemic nutrient balance, nitrogen detoxification, and cellular bioenergetics. These functions depend on tightly regulated mitochondrial processes, including amino acid catabolism, ammonia clearance via the urea cycle, and transport through specialized solute carriers. Genetic disruptions in these [...] Read more.

Hepatic mitochondria play critical roles in sustaining systemic nutrient balance, nitrogen detoxification, and cellular bioenergetics. These functions depend on tightly regulated mitochondrial processes, including amino acid catabolism, ammonia clearance via the urea cycle, and transport through specialized solute carriers. Genetic disruptions in these pathways underlie a range of inborn errors of metabolism, often resulting in systemic toxicity and neurological dysfunction. Here, we review the physiological functions of hepatic mitochondrial amino acid metabolism, with a focus on subcellular compartmentalization, disease mechanisms, and therapeutic strategies. We discuss how emerging genetic and metabolic interventions—including dietary modulation, cofactor replacement, and gene therapy—are reshaping treatment of liver-based metabolic disorders. Understanding these pathways offers mechanistic insights into metabolic homeostasis and reveals actionable vulnerabilities in metabolic disease and cancer. Full article

(This article belongs to the Special Issue The Multifaceted Roles of Biomarkers in Metabolic Disorders: From Diagnosis and Monitoring to Prediction, Management, and Treatment)

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15 pages, 281 KiB

Open AccessArticle

Impacts of Protease Sources on Growth and Carcass Response, Gut Health, Nutrient Digestibility, and Cecal Microbiota Profiles in Broilers Fed Poultry-by-Product-Meal-Based Diets

by Muhammad Shahbaz Zafar, Shafqat Nawaz Qaisrani, Saima, Zafar Hayat and Kashif Nauman

Metabolites 2025, 15(7), 445; https://doi.org/10.3390/metabo15070445 - 2 Jul 2025

Abstract

Background: The current study aimed to evaluate the effects of the supplementation of protease sources on growth and carcass response, gut health, nutrient digestibility, and cecal microbiota profiles in broilers fed poultry-by-product-meal (PBM)-containing diets. Methods: In total, 800 one-day-old mixed-sex broilers (Arbor Acres) [...] Read more.

Background: The current study aimed to evaluate the effects of the supplementation of protease sources on growth and carcass response, gut health, nutrient digestibility, and cecal microbiota profiles in broilers fed poultry-by-product-meal (PBM)-containing diets. Methods: In total, 800 one-day-old mixed-sex broilers (Arbor Acres) were weighed and allocated to one of the four dietary treatments in a completely randomized design, with eight replicates and 25 birds each per replicate. The treatments were as follows: (1) T₀, control diet (without protease supplementation and 3% PBM); (2) T₁, control diet supplemented with acidic protease at 100 g/ton (50,000 U/g); (3) T₂, control diet supplemented with alkaline protease at 200 g/ton (25,000 U/g); (4) T₃, control diet supplemented with neutral protease at 200 g/ton (25,000 U/g). Results: Protease supplementation enhanced (p < 0.05) body weight gain and the feed conversion ratio, predominantly in broilers fed PBM-based diets containing alkaline protease. Alkaline protease supplementation increased (p < 0.05) the apparent ileal digestibility of proteins (AIDP) by 4.3% and the apparent ileal digestibility of amino acids (AIDAA) by up to 5.8%, except for ornithine. Increments (p < 0.05) in carcass, breast, and leg quarter yields due to protease supplementation were evident, particularly in broilers fed diets containing alkaline protease. Alkaline protease improved (p < 0.05) the duodenal villus height (VH), reduced the crypt depth (CD), and increased the villus height to crypt depth ratio (VCR). Alkaline protease supplementation reduced (p < 0.05) cecal counts of Salmonella, Escherichia coli, and Clostridium in the broilers, whereas it increased (p < 0.05) the Lactobacillus counts. Conclusions: the supplemented alkaline protease resulted in improved growth performance and carcass traits, better gut health, as well as improved ileal digestibility of nutrients, including crude protein (CP) and acid insoluble ash (AIA), with a more balanced cecal microbial composition in broilers. Full article

(This article belongs to the Section Animal Metabolism)

17 pages, 2581 KiB

Open AccessReview

Uric Acid in Primary Hyperparathyroidism: Marker, Consequence, or Bystander?

by Matteo Malagrinò and Guido Zavatta

Metabolites 2025, 15(7), 444; https://doi.org/10.3390/metabo15070444 - 2 Jul 2025

Abstract

Background: Several recent studies have documented an increased cardiovascular risk in patients with primary hyperparathyroidism (PHPT), thereby stimulating interest in the association with uric acid (UA), a metabolite linked to cardiovascular disease and chronic kidney disease (CKD) progression, whose role in these conditions [...] Read more.

Background: Several recent studies have documented an increased cardiovascular risk in patients with primary hyperparathyroidism (PHPT), thereby stimulating interest in the association with uric acid (UA), a metabolite linked to cardiovascular disease and chronic kidney disease (CKD) progression, whose role in these conditions is still the subject of study. The aim of this review is to summarize the underlying pathophysiological mechanisms of the PHPT-UA relation and discuss their potential clinical implications. Methods: We conducted a comprehensive literature review, with a focus on the physiological and clinical aspects of the relationship between PHPT and UA. Results: The evidence in the literature supports the association between PHPT and elevated UA levels, although the underlying mechanisms still need to be elucidated. Key mechanisms seem to involve tubular and intestinal transporters, particularly the ABCG2 transporter, as well as indirect effects mediated by hypercalcemia and inflammatory processes. Conclusions: The association between PHPT and UA, though recognized for years, highlights the existence of linked pathophysiological mechanisms between mineral and purine metabolism. However, the current knowledge does not clarify whether uric acid plays an active role in the development of complications related to hyperparathyroidism or if it just represents an indirect marker of metabolic dysfunction. In the absence of specific guidelines, measuring UA levels to screen for hyperuricemia, especially in patients with additional risk factors, should be considered to prevent related complications. Future studies could clarify the role of UA in PHPT, improving our understanding of the disease and potentially leading to new therapeutic strategies to prevent cardiovascular, renal and joint manifestations. Full article

(This article belongs to the Special Issue Primary Hyperparathyroidism: Mechanisms and Treatment)

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16 pages, 1611 KiB

Open AccessArticle

Angiotensin-Converting Enzyme Inhibitory Activity of Selected Phenolic Acids, Flavonoids, Their O-Glucosides, and Low-Molecular-Weight Phenolic Metabolites in Relation to Their Oxidation Potentials

by Danuta Zielińska, Małgorzata Starowicz, Małgorzata Wronkowska and Henryk Zieliński

Metabolites 2025, 15(7), 443; https://doi.org/10.3390/metabo15070443 - 1 Jul 2025

Abstract

Background/Objectives: In this study, the angiotensin-converting enzyme (ACE) inhibitory activity of selected phenolic acids, flavonoids, their O-glucosides, and low-molecular-weight phenolic metabolites was addressed to show their importance against blood hypertension. Methods: A fluorescence assay was used for the determination of [...] Read more.

Background/Objectives: In this study, the angiotensin-converting enzyme (ACE) inhibitory activity of selected phenolic acids, flavonoids, their O-glucosides, and low-molecular-weight phenolic metabolites was addressed to show their importance against blood hypertension. Methods: A fluorescence assay was used for the determination of the ACE inhibitory activity, whereas the first anodic peak oxidation potential (

E_{p a}

) was provided by the differential pulse voltammetry (DPV) method. The relationship between the ACE inhibitory activity and

E_{p a}

was evaluated. Results: Phenolic acids showed a very low ACE inhibitory activity, and their rank was chlorogenic acid > p-coumaric acid > sinapic acid > gentisic acid > ferulic acid > syringic acid > vanillic acid > protocatechuic acid > caffeic acid. The low-molecular-weight phenolic metabolites of flavonoids showed a moderate ACE inhibitory activity. In contrast, flavonoid aglicones had the highest ACE inhibitory activity, and the order was luteolin > quercetin > kaempferol > cyanidin > delphinidin > pelargonin > naringenin. A lower inhibition activity was noted for quercetin-3-O-glucoside, luteolin-4′-O-glucosides, cyanidin-3-O-glucoside, and pelargonidin-3-O-glucosides, whereas a higher ACE inhibition activity was observed for 7-O-glucosides of luteolin, apigenin, and kaempferol. A lack of correlation was found between the IC₅₀ of phenolic acids, low-molecular-weight phenolic metabolites, and their

E_{p a}

values. In contrast, weak positive correlations were found between the IC₅₀ of aglicons, 3-O-glucosides, 7-O-glucosides, and their

E_{p a}

values provided by the DPV (r = 0.61, r = 0.66 and r = 0.88, respectively). Conclusions: This study expands our knowledge of the ACE inhibitory activity of phenolic compounds. Full article

(This article belongs to the Special Issue Flavonoids: Novel Therapeutic Potential for Chronic Diseases)

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28 pages, 1108 KiB

Open AccessReview

Inflammatory Mechanisms in the Management and Treatment of Retinal Detachment

by Pablo Redruello-Guerrero, María Gómez-Tomás, Tomás Rechi-Sierra, Laura Molinero-Sicilia, Nadia Galindo-Cabello, Ricardo Usategui-Martín and Salvador Pastor-Idoate

Metabolites 2025, 15(7), 442; https://doi.org/10.3390/metabo15070442 - 1 Jul 2025

Abstract

Retinal detachment (RD) is a serious clinical condition that significantly impacts patients’ quality of life. Its management involves considering several clinical factors that may affect the therapeutic approach. Inflammatory complications can affect visual recovery, long-term outcomes, and prognosis. Understanding the underlying inflammatory mechanisms [...] Read more.

Retinal detachment (RD) is a serious clinical condition that significantly impacts patients’ quality of life. Its management involves considering several clinical factors that may affect the therapeutic approach. Inflammatory complications can affect visual recovery, long-term outcomes, and prognosis. Understanding the underlying inflammatory mechanisms is key to improving personalized medicine and optimizing therapeutic approaches to management. This review comprehensively searched scientific databases (Medline, Web of Science, and Scopus), considering clinical and experimental studies published between 1999 and 2025. Specific MeSH terms and predefined inclusion and exclusion criteria were used to select the most relevant papers. A total of 140 studies were analyzed. The findings were analyzed qualitatively and illustrated with images from clinical practice. Several studies have demonstrated the critical role of cytokines in retinal inflammation, highlighting their importance in regulating the immune response following RD. In addition, oxidative stress, apoptotic mechanisms, and glia activation, particularly Müller cells and microglia, have been identified as crucial elements in the progression of retinal damage. In this sense, inflammation poses significant clinical challenges that require more effective therapeutic strategies. In conclusion, this review differs from previous literature by emphasizing the translational implications of inflammatory mechanisms in RD and by comparing experimental and clinical data. The management of RD should consider not only surgical aspects, but also modulation of the inflammatory response to improve visual outcomes and prevent long-term complications. Full article

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

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20 pages, 397 KiB

Open AccessArticle

Association Between Habitual Dietary Intake and Urinary Metabolites in Adults—Results of a Population-Based Study

by Annika Blümlhuber, Dennis Freuer, Nina Wawro, Florian Rohm, Christine Meisinger and Jakob Linseisen

Metabolites 2025, 15(7), 441; https://doi.org/10.3390/metabo15070441 - 1 Jul 2025

Abstract

Background: Chronic non-communicable diseases (NCDs) are a major global health challenge, with unhealthy diets contributing significantly to their burden. Metabolomics data offer new possibilities for identifying nutritional biomarkers, as demonstrated in short-term intervention studies. This study investigated associations between habitual dietary intake and [...] Read more.

Background: Chronic non-communicable diseases (NCDs) are a major global health challenge, with unhealthy diets contributing significantly to their burden. Metabolomics data offer new possibilities for identifying nutritional biomarkers, as demonstrated in short-term intervention studies. This study investigated associations between habitual dietary intake and urinary metabolites, a not well-studied area. Methods: Data were available from 496 participants of the population-based MEIA study. Linear and median regression models examined associations between habitual dietary intake and metabolites, adjusted for possible confounders. K-means clustering identified urinary metabolite clusters, and multinomial regression models were applied to analyze associations between food intake and metabolite clusters. Results: Using linear regression models, previously reported associations could be replicated, including citrus intake with proline betaine, protein intake with urea, and fiber intake with hippurate. Novel findings include positive associations of poultry intake with taurine, indoxyl sulfate, 1-methylnicotinamide, and trimethylamine-N-oxide. Milk substitutes were positively associated with urinary uracil, pseudouridine, 4-hydroxyhippurate, and 3-hydroxyhippurate, and inversely associated with quinic acid. Dietary fiber intake showed a positive association with 3-(3-hydroxyphenyl)-3-hydroxypropionic acid and a negative association with indoxyl sulfate. We identified sucrose and taurine as key metabolites differentiating metabolite clusters. Multinomial regression analysis confirmed significantly different dietary associations across clusters, particularly for fruits, processed meat, poultry, and alcoholic beverages. Conclusions: This study highlights established and novel food–metabolite associations, demonstrating the potential of urinary metabolomics for use as nutritional biomarkers in individuals from the general population. Full article

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

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14 pages, 1211 KiB

Open AccessArticle

Impact of Heavy Metals on the Antioxidant Activity of Vitamin D: A Metabolic Perspective

by Ji Seo Park, Mi-Ri Gwon, Jae Hwa Lee, Jin Ju Park, Hae Won Lee, Duk-Hee Lee, Sook Jin Seong and Young-Ran Yoon

Metabolites 2025, 15(7), 440; https://doi.org/10.3390/metabo15070440 - 1 Jul 2025

Abstract

Background/Objectives: Vitamin D (VD) is metabolized in the body and plays a crucial role in regulating the antioxidant system. While exposure to heavy metals (HMs) inhibits VD activity, HMs can also be absorbed following VD stimulation. Despite differing views on the interaction [...] Read more.

Background/Objectives: Vitamin D (VD) is metabolized in the body and plays a crucial role in regulating the antioxidant system. While exposure to heavy metals (HMs) inhibits VD activity, HMs can also be absorbed following VD stimulation. Despite differing views on the interaction between HM and VD activity, the effects of HM exposure on VD-related pathways have not been examined using metabolomics. This study aimed to investigate the impact of HM exposure on VD-related antioxidant activity under VD deficiency conditions using untargeted metabolic profiling. Methods: In this retrospective cohort study, 46 plasma samples were analyzed using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Metabolic profiling was performed on two groups: individuals with severe VD deficiency and low HM exposure (SVDD–LHM) and those with VD deficiency and high HM exposure (VDD–HHM). Results: As a compensatory response to oxidative stress induced by HMs, VD-related antioxidant pathways may be associated with elevated levels of antioxidants, including bilirubin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). In-creases in EPA and DHA were also linked to alterations in lipid metabolism, including diacylglycerol and phosphatidylcholine levels. DHA showed an area under the curve (AUC) of 0.850 (95% CI: 0.651–0.990), suggesting that DHA could serve as a potential biomarker for VD activity in response to HM exposure. Conclusions: The identified metabolites and metabolic pathways suggest that HM exposure may stimulate VD-related antioxidant activity, even under VD-deficient conditions. Full article

(This article belongs to the Section Environmental Metabolomics)

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18 pages, 3098 KiB

Open AccessArticle

(-)-Epigallocatechin-3-Gallate Suppresses Hyperexcitability in Rat Primary Nociceptive Neurons Innervating Inflamed Tissues: A Comparison with Lidocaine

by Syogo Utugi, Yukito Sashide and Mamoru Takeda

Metabolites 2025, 15(7), 439; https://doi.org/10.3390/metabo15070439 - 1 Jul 2025

Abstract

Objective: Given the side effects and reduced efficacy of conventional local anesthetics in inflammatory conditions, there is a compelling need for complementary alternative medicine (CAM), particularly those based on phytochemicals. While a previous study showed that in vivo local injection of (-)-epigallocatechin-3-gallate (EGCG) [...] Read more.

Objective: Given the side effects and reduced efficacy of conventional local anesthetics in inflammatory conditions, there is a compelling need for complementary alternative medicine (CAM), particularly those based on phytochemicals. While a previous study showed that in vivo local injection of (-)-epigallocatechin-3-gallate (EGCG) into the peripheral receptive field suppresses the excitability of rat trigeminal ganglion (TG) neurons in the absence of inflammation, the acute effects of EGCG in vivo, especially on TG neurons under inflammatory conditions, are still unknown. We aimed to determine if acute local EGCG administration into inflamed tissue effectively attenuates the excitability of nociceptive TG neurons evoked by mechanical stimulation. Methods: The escape reflex threshold was measured to assess hyperalgesia caused by complete Freund’s adjuvant (CFA)-induced inflammation. To assess neuronal activity, extracellular single-unit recordings were performed on TG neurons in anesthetized CFA-inflamed rats in response to orofacial mechanical stimulation. Results: The mechanical escape threshold was significantly lower in CFA-inflamed rats compared to before CFA injection. EGCG (1–10 mM) reversibly and dose-dependently inhibited the mean firing frequency of TG neurons evoked by both non-noxious and noxious mechanical stimuli (p < 0.05). For comparison, 1% lidocaine (37 mM), a local anesthetic, also caused reversible inhibition of the mean firing frequency in inflamed TG neurons responding to mechanical stimuli. Importantly, 10 mM EGCG produced a significantly greater magnitude of inhibition on TG neuronal discharge frequency than 1% lidocaine (noxious, lidocaine vs. EGCG, 19.7 ± 3.3% vs. 42.3 ± 3.4%, p < 0.05). Conclusions: Local injection of EGCG into inflamed tissue effectively suppresses the excitability of nociceptive primary sensory TG neurons, as indicated by these findings. Significantly, locally administered EGCG exerted a more potent local analgesic action compared to conventional voltage-gated sodium channel blockers. This heightened efficacy originates from EGCG’s ability to inhibit both generator potentials and action potentials directly at nociceptive primary nerve terminals. As a result, EGCG stands out as a compelling candidate for novel analgesic development, holding particular relevance for CAM strategies. Full article

(This article belongs to the Special Issue Flavonoids: Novel Therapeutic Potential for Chronic Diseases)

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27 pages, 1713 KiB

Open AccessArticle

Vitamin B12 and Folate in Adherent and Non-Adherent Individuals with Phenylketonuria: A Cross-Sectional Study, Systematic Review, and Meta-Analysis

by Kamila Bokayeva, Małgorzata Jamka, Dariusz Walkowiak, Monika Duś-Żuchowska, Łukasz Kałużny, Natalia Wichłacz-Trojanowska, Agnieszka Chrobot, Renata Mozrzymas, Gulnara Sultanova, Karl-Heinz Herzig and Jarosław Walkowiak

Metabolites 2025, 15(7), 438; https://doi.org/10.3390/metabo15070438 - 1 Jul 2025

Abstract

Background/Objectives: The impact of dietary adherence and regular formula intake on the vitamin levels in individuals with phenylketonuria (PKU) remains unclear. This study aimed to assess the influence of both adherence to dietary management and regular formula intake on the vitamin B12 and [...] Read more.

Background/Objectives: The impact of dietary adherence and regular formula intake on the vitamin levels in individuals with phenylketonuria (PKU) remains unclear. This study aimed to assess the influence of both adherence to dietary management and regular formula intake on the vitamin B12 and folate levels in individuals with PKU. Methods: This cross-sectional multicentre study included 63 patients with PKU aged 12–41 years. The participants were classified as adherent or non-adherent based on their mean plasma phenylalanine levels or as regular or irregular formula consumers. The participants’ vitamin B12 and folate levels were compared across these groups. In addition, a systematic search of PubMed, Web of Science, Scopus, and Cochrane Library identified 11,631 studies comparing vitamin B12 and folate levels between adherent vs. non-adherent patients and regular vs. irregular formula intake groups, of which eight met the inclusion criteria. Analyses were conducted using random-effects and fixed-effects models and effect sizes were expressed as standardised mean differences (SMDs). Results: This cross-sectional study showed significantly higher vitamin B12 and folate levels in adherent vs. non-adherent individuals (767.6 ± 264.5 vs. 524.7 ± 216.4 pg/mL; 13.44 ± 1.96 vs. 10.62 ± 3.36 ng/mL, both p < 0.001) and in regular vs. irregular formula consumers (746.7 ± 228.4 vs. 527.4 ± 281.9 pg/mL; 13.32 ± 2.25 vs. 10.48 ± 3.23 ng/mL, p < 0.0001 and p < 0.001 respectively). The meta-analysis found no significant differences between the adherent and non-adherent groups, which were defined based on their phenylalanine levels, but showed higher vitamin B12 levels (fixed-effects model, SMD: 1.080, 95% CI: 0.754, 1.405, p < 0.0001) and a near-significant trend toward higher folate levels (random-effects model, SMD: 0.729, 95% CI: −0.032, 1.490, p = 0.061) in regular formula consumers. Conclusions: Regular formula intake is a key determinant of vitamin B12 in patients with PKU. These findings highlight the importance of consistent formula use in dietary management and warrant further research. Full article

(This article belongs to the Special Issue Effects of Micronutrients on Human Metabolism)

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11 pages, 3387 KiB

Open AccessArticle

Imprint Desorption Electrospray Ionization Mass Spectrometry Imaging (IDESI-MSI) Reveals Absorption of Triclopyr-Based Herbicide in Plants and Mouse Organs

by Hanzhi Liu, Yunshuo Tian, Ruolun Wei, Yifan Meng and Richard N. Zare

Metabolites 2025, 15(7), 437; https://doi.org/10.3390/metabo15070437 - 30 Jun 2025

Abstract

Background: Understanding the absorption and distribution of herbicides in plants and animal tissues is essential for assessing their potential risks to human health. Method: In this study, we employed imprint desorption electrospray ionization mass spectrometry imaging (IDESI-MSI) to visualize in both vegetable and [...] Read more.

Background: Understanding the absorption and distribution of herbicides in plants and animal tissues is essential for assessing their potential risks to human health. Method: In this study, we employed imprint desorption electrospray ionization mass spectrometry imaging (IDESI-MSI) to visualize in both vegetable and animal tissues the absorption of Roundup which is a widely used herbicide. Results: Using IDESI-MSI with a pixel size of 150 µm, we detected the herbicide alongside several endogenous metabolites on oil-absorbing films applied to carrot sections. Time-course experiments revealed progressive herbicide penetration into carrot tissue, with penetration depth increasing linearly over time at a rate of approximately 0.25 mm/h. In contrast, green pepper samples showed minimal herbicide infiltration, likely owing to their hydrophobic cuticle barrier. Additionally, mice fed with herbicide-treated carrots exhibited detectable levels of herbicide in liver and kidney tissues. Conclusions: These findings highlight the utility of IDESI-MSI as a powerful analytical platform for the rapid evaluation of chemical migration and absorption in food and biological systems, with important implications for food safety and toxicological research. Full article

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

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20 pages, 1272 KiB

Open AccessReview

Nutri-Epigenetic Regulation of Vitamin D—Impact on Metabolism and Biological Functions: Narrative Review

by Magdalena Kowalówka, Ilona Górna, Marta Karaźniewicz-Łada, Dominika Kusyk, Juliusz Przysławski and Sławomira Drzymała-Czyż

Metabolites 2025, 15(7), 436; https://doi.org/10.3390/metabo15070436 - 30 Jun 2025

Abstract

Vitamin D deficiency is widespread. It increases the risk of several diseases. Therefore, researchers have long studied the factors that influence vitamin D levels in the body. These include its metabolism, catabolism, transport and binding of vitamin D to the receptor VDR. Currently, [...] Read more.

Vitamin D deficiency is widespread. It increases the risk of several diseases. Therefore, researchers have long studied the factors that influence vitamin D levels in the body. These include its metabolism, catabolism, transport and binding of vitamin D to the receptor VDR. Currently, an increasing number of studies are focusing on genetic factors. Variations in vitamin D levels, including vitamin D deficiency, are under substantial genetic control. There is a reciprocity between the vitamin D system and epigenetic mechanisms. Vitamin D metabolism, on the one hand, is regulated by epigenetic mechanisms and, on the other hand, is involved in regulating epigenetic events. To appraise recent advances in nutrigenomics with its application in public health, several databases, including PubMed, Scopus and Web of Science, were investigated in detail. Nutri-epigenetics deals with the interplay between dietary components and the possible resulting changes in the epigenome. There is, therefore, great potential for the development of nutri-epigenetics. The purpose of the narrative review is to highlight the genetic aspects of vitamin D, its receptor VDR and vitamin D-related gene polymorphisms with a particular focus on vitamin D gene regulation. Particular attention is paid to the vitamin D response index. Full article

(This article belongs to the Special Issue Vitamin D Metabolism and Human Health)

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13 pages, 4302 KiB

Open AccessArticle

Analysis of Processing Impact on Raspberries Based on Broad-Spectrum Metabolomics

by Xiaoge Wang, Qiyuan Liao, Fan Wang, Xuelin Rui, Yushan Liu and Rui Wang

Metabolites 2025, 15(7), 435; https://doi.org/10.3390/metabo15070435 - 26 Jun 2025

Abstract

Objective: Our objective was to explore the regulatory mechanism of salt processing on the metabolome of the raspberry and its potential efficacy against diabetic nephropathy (DN), providing metabolomic and network pharmacological evidence for the scientific connotation of traditional Chinese medicine processing. Methods: Ultra-high-performance [...] Read more.

Objective: Our objective was to explore the regulatory mechanism of salt processing on the metabolome of the raspberry and its potential efficacy against diabetic nephropathy (DN), providing metabolomic and network pharmacological evidence for the scientific connotation of traditional Chinese medicine processing. Methods: Ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS)-based metabolomics was used to compare the metabolic profiles between raw and salt-processed raspberries. Network pharmacology was applied to screen the common targets of the active components in the salt-processed raspberry and DN-related pathways, followed by in vitro cell experiments to validate the regulation of the MAPK signaling pathway. Results: The metabolomic analysis identified 80 differentially expressed metabolites, among which 13 key components (VIP ≥ 1, FC ≥ 2) were significantly altered, including enriched flavonoids (e.g., luteolin-7-O-glucoside), triterpenoid saponins (Raspberryides H/F), and phenolic acids (ellagic acid). The network pharmacology revealed that the salt-processed raspberries regulated the DN-related pathways through 122 common targets, with the core nodes focusing on the signaling molecules (e.g., AKT1, EGFR) involved in the MAPK signaling pathway and apoptosis regulation. The in vitro experiments confirmed that the salt-processed raspberry extract (160–640 μg/mL) significantly inhibited the phosphorylation levels of p38/ERK/JNK in high-glucose-induced renal cells. Conclusions: This study firstly combines metabolomics and network pharmacology to reveal the regulatory mechanism of salt processing on the active components of raspberries. The salt-processing technology enhanced the inhibitory effect of raspberries on the MAPK signaling pathway, thereby ameliorating the progression of DN. These findings provide scientific support for establishing a metabolomics-based quality control system for traditional Chinese medicine processing. The current findings are primarily based on in vitro models, and in vivo validation using DN animal models is essential to confirm the therapeutic efficacy and safety of salt-processed raspberries. Full article

(This article belongs to the Special Issue Advances in Secondary Metabolites: Phytochemical Analysis and Bioactivity Assays)

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