Metabolites

1 pages, 335 KiB

Open AccessCorrection

Correction: Sadler et al. Lipid Metabolism Is Dysregulated in the Motor Cortex White Matter in Amyotrophic Lateral Sclerosis. Metabolites 2022, 12, 554

by Gemma L. Sadler, Katherine N. Lewis, Vinod K. Narayana, David P. De Souza, Joel Mason, Catriona McLean, David G. Gonsalvez, Bradley J. Turner and Samantha K. Barton

Metabolites 2025, 15(7), 486; https://doi.org/10.3390/metabo15070486 - 18 Jul 2025

Abstract

In the original publication [...] Full article

17 pages, 10755 KiB

Open AccessArticle

Reduction of Dietary Fat Rescues High-Fat Diet-Induced Depressive Phenotypes and the Associated Hippocampal Astrocytic Deficits in Mice

by Kai-Pi Cheng, Hsin-Hao Chao, Chin-Ju Hsu, Sheng-Fang Tsai, Yen-Ju Chiu, Yun-Min Kuo and Yun-Wen Chen

Metabolites 2025, 15(7), 485; https://doi.org/10.3390/metabo15070485 - 18 Jul 2025

Abstract

Background/Objectives: Depression is frequently comorbid with obesity. We previously showed that astrocyte-mediated hyperactive ventral hippocampal glutamatergic afferents to the nucleus accumbens determined the exhibition of depression-like behaviors in obese murine models. However, it remains unclear if the metabolic disorder-induced depressive phenotypes and astrocytic [...] Read more.

Background/Objectives: Depression is frequently comorbid with obesity. We previously showed that astrocyte-mediated hyperactive ventral hippocampal glutamatergic afferents to the nucleus accumbens determined the exhibition of depression-like behaviors in obese murine models. However, it remains unclear if the metabolic disorder-induced depressive phenotypes and astrocytic maladaptation in the ventral hippocampus (vHPC) could be reversed following the amelioration of key metabolic impairments such as insulin resistance and dyslipidemia. Method: Male mice were fed a high-fat diet (HFD) for 12 weeks, followed by either continued HFD feeding (HFD/HFD group) or a switch to a standard diet for 4 weeks (HFD/SD group). Results: Results showed that HFD/HFD mice displayed not only glucose/lipid metabolic dysfunction, but also depression-like behaviors. In contrast, HFD/SD mice showed improvements in metabolic disorders and depressive phenotypes. Mechanistically, dietary fat reduction restored astrocyte morphology and glutamate transporter expression (GLT-1, GLAST) in the vHPC and suppressed neuroinflammatory signaling, as evidenced by reduced levels of phospho-IKK, TNF-α, IL-1β, and IL-6 in the vHPC. Conclusions: These findings suggest that dietary fat reduction reverses obesity-induced depressive phenotypes, astrocytic deficits, at least in part via suppression of neuroinflammation through the NF-κB signaling pathway. Full article

(This article belongs to the Special Issue Lipid Signaling, Therapeutics and Controlled-Release)

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14 pages, 1649 KiB

Open AccessArticle

LC-MS-Based Untargeted Metabolic Profiling in Plasma Following Dapagliflozin Administration in Healthy Volunteers

by Hyeon Ji Kim, Jae Hwa Lee, Ji Seo Park, Jin Ju Park, Hae Won Lee, Heeyoun Bunch, Sook Jin Seong, Mi-Ri Gwon and Young-Ran Yoon

Metabolites 2025, 15(7), 484; https://doi.org/10.3390/metabo15070484 - 17 Jul 2025

Abstract

Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, treats type 2 diabetes by blocking renal glucose reabsorption and promoting urinary glucose excretion. This mechanism lowers blood glucose concentrations independently of insulin. The resulting caloric loss also contributes to weight reduction. Although these effects are well [...] Read more.

Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, treats type 2 diabetes by blocking renal glucose reabsorption and promoting urinary glucose excretion. This mechanism lowers blood glucose concentrations independently of insulin. The resulting caloric loss also contributes to weight reduction. Although these effects are well documented in patients with diabetes, their magnitude and underlying mechanisms in healthy individuals remain poorly understood. Background/Objectives: We investigated metabolic alterations after a single 10 mg dose of dapagliflozin in healthy adults with normal body-mass indices (BMIs) using untargeted metabolomics. Methods: Thirteen healthy volunteers completed this study. Plasma was collected before and 24 h after dosing. Untargeted metabolic profiling was performed with ultra-high-performance liquid chromatography–quadrupole time-of-flight/mass spectrometry. Results: Twenty-five endogenous metabolites were annotated; ten were putatively identified. Eight metabolites increased significantly, whereas two decreased. Up-regulated metabolites included phosphatidylcholine (PC) species (PC O-36:5, PC 36:3), phosphatidylserine (PS) species (PS 40:2, PS 40:3, PS 36:1, PS 40:4), lysophosphatidylserine 22:1, and uridine. Dehydroepiandrosterone sulfate and bilirubin were down-regulated. According to the Human Metabolome Database, these metabolites participate in glycerophospholipid, branched-chain amino acid, pyrimidine, and steroid-hormone metabolism. Conclusions: Dapagliflozin may affect pathways related to energy metabolism and homeostasis beyond glucose regulation. These data provide a reference for future investigations into energy balance and metabolic flexibility in metabolic disorders. Full article

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

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9 pages, 1359 KiB

Open AccessArticle

Clay Attenuates Diarrhea Induced by Fat in a Mouse Model

by Shalom Emmanuel, Nyma Siddiqui, Ting Du, Eric Asare, Yuan Chen, Huan Xie, Dong Liang and Song Gao

Metabolites 2025, 15(7), 483; https://doi.org/10.3390/metabo15070483 - 17 Jul 2025

Abstract

Background: Diarrhea induced by an excessive amount of fat is a prevalent gastrointestinal disorder. Currently, there are limited animal models and treatment options for diarrhea associated with fat. This study aims to develop a mouse model of high-fat-associated diarrhea using glyceryl-trioleate (GTO) and [...] Read more.

Background: Diarrhea induced by an excessive amount of fat is a prevalent gastrointestinal disorder. Currently, there are limited animal models and treatment options for diarrhea associated with fat. This study aims to develop a mouse model of high-fat-associated diarrhea using glyceryl-trioleate (GTO) and evaluate the potential of montmorillonite clay (MMT) in mitigating this condition. Methods: GTO was administered to mice at different doses through oral gavage to induce diarrhea. Clay was treated through oral gavage to evaluate its anti-diarrhea effect. Fecal conditions were monitored. Intestinal tissues were subjected to histological examination to assess structural integrity. The total fecal bile acids were evaluated using a bile acid assay kit to determine the mechanism of action. Results: The results showed that a diarrhea model was established by administering GTO at 2000 mg/kg. When the animals were treated with clay, diarrhea incidence and severity were decreased significantly in a dose-dependent manner. Compared to the untreated group receiving GTO alone, clay co-administration at 2000 mg/kg reduced diarrhea scores by approximately 48%, while the higher dose of 4000 mg/kg achieved an 83% reduction. Fecal bile acid analysis showed that diarrhea is associated with total bile acid levels in the feces. Histological exams showed that diarrhea is associated with tissue inflammation in the colon. Conclusions: This study showed that GTO administration induced diarrhea in mice, and clay effectively alleviates fat-induced diarrhea through modulation of fecal bile acid composition. These findings suggest that this model can be used to evaluate diarrhea associated with excessive amounts of fat and clay that can be further tested for diarrhea attenuation. Full article

(This article belongs to the Special Issue Advances in Murine Models for Metabolic Diseases: Insights into Diabetes, Obesity, and Cardiovascular Conditions)

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13 pages, 3191 KiB

Open AccessArticle

Assessment of Fatty Acid Concentrations Among Blood Matrices

by Ysphaneendra Mallimoggala, Monalisa Biswas, Leslie Edward S. Lewis, Vijetha Shenoy Belle, Arjun Asok and Varashree Bolar Suryakanth

Metabolites 2025, 15(7), 482; https://doi.org/10.3390/metabo15070482 - 17 Jul 2025

Abstract

Background/Objectives: Fatty acids, the building blocks of lipids, contribute to numerous crucial life processes and are implicated in numerous disease pathologies. Circulating fatty acids can be extracted/trans-esterified to their respective methyl ester forms and quantified from a variety of biological samples. This [...] Read more.

Background/Objectives: Fatty acids, the building blocks of lipids, contribute to numerous crucial life processes and are implicated in numerous disease pathologies. Circulating fatty acids can be extracted/trans-esterified to their respective methyl ester forms and quantified from a variety of biological samples. This study aims to identify quantifiable fatty acids (through alkali trans-esterification) in human circulation, assess the correlation of the detectable fatty acid methyl esters (FAMEs) compounds between whole blood, serum and plasma matrices and propose the most ideal matrix for quantification of FAMEs. Methods: This anonymised study was carried out in a tertiary hospital after obtaining ethical approval and involved analysis of residual fasting whole blood, serum and plasma samples obtained from 20 apparently healthy subjects attending the routine health check services at the study centre. Fatty acids were converted to its methyl ester form by methanolic KOH trans-esterification and subjected to GCMS analysis. Paired t test, Pearsons’s correlation, linear regression and Bland Altman test were employed to assess the agreeability between matrices. Results: 9 out of 37 FAME compounds were detected in all three matrices. Strong correlations and statistically significant regression equations were obtained for the 9 compounds between plasma and serum matrices. Undecanoate, pentadecanoate, linolenate, and palmitate levels were lowest in plasma, while stearate, heptadecanoate levels were highest in whole blood. Myristate was highest in serum, dodecanoate was highest in plasma while docosahexanoate was found to be comparable in all three matrices. Methyl ester forms of dodeconate, myristate, pentadecanoate, palmitate, heptadecanoate, stearate, and linolenate were observed in higher concentrations in plasma when compared to serum. Conclusions: The current study shows similar & correlating FAME concentrations between serum and plasma matrix; however, whole blood FAME concentrations appear significantly different. Plasma serves as the most ideal matrix for detection and quantification of circulating fatty acids. Full article

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

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17 pages, 1902 KiB

Open AccessArticle

Enhanced Mitochondrial Dynamics and Reactive Oxygen Species Levels with Reduced Antioxidant Defenses in Human Epicardial Adipose Tissue

by Ana Burgeiro, Diana Santos, Ana Catarina R. G. Fonseca, Inês Baldeiras, Ermelindo C. Leal, João Moura, João Costa-Nunes, Patrícia Monteiro Seraphim, Aryane Oliveira, António Canotilho, Gonçalo Coutinho, David Prieto, Pedro Antunes, Manuel Antunes and Eugenia Carvalho

Metabolites 2025, 15(7), 481; https://doi.org/10.3390/metabo15070481 - 16 Jul 2025

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Abstract

Background/Objectives: Epicardial adipose tissue (EAT) is metabolically active and is in dynamic crosstalk with the surrounding cardiomyocytes, modulating their function and metabolism. Oxidative stress is a key contributor to cell death and cardiac remodeling, is a hallmark of diabetes (DM) and cardiovascular [...] Read more.

Background/Objectives: Epicardial adipose tissue (EAT) is metabolically active and is in dynamic crosstalk with the surrounding cardiomyocytes, modulating their function and metabolism. Oxidative stress is a key contributor to cell death and cardiac remodeling, is a hallmark of diabetes (DM) and cardiovascular disease, such as coronary artery disease (CAD). However, little is known about these processes in EAT from patients undergoing cardiac surgery. This study investigates changes in mitochondrial dynamics, reactive oxygen species (ROS) production, and antioxidant defense levels in EAT compared to subcutaneous adipose tissue (SAT) in patients undergoing cardiac surgery, with a focus on the impact of DM and CAD. Methods: Adipose tissue biopsies were collected from 128 patients undergoing surgical cardiac intervention. Mitochondrial dynamics and oxidative stress markers were analyzed. Results: EAT exhibited increased expression of mitochondrial fusion markers [mitofusin 1 (p ≤ 0.001), mitofusin 2 (p = 0.038), and optic atrophy 1 (p ≤ 0.001)], as well as fission markers [fission 1 (p ≤ 0.001) and dynamin-related protein 1 (p ≤ 0.001)] relative to SAT. Additionally, ROS levels (dihydroethidium, p = 0.004) were elevated, while lipid peroxidation (malondialdehyde, p ≤ 0.001) was reduced in EAT compared to SAT. Reduced glutathione (GSH) levels (p ≤ 0.001) and the redox buffer ratio between reduced and oxidized glutathione (GSH/GSSG, p ≤ 0.001) were significantly increased in EAT. Interestingly, glutathione peroxidase activity (p ≤ 0.001) and the antioxidant defense markers catalase (p ≤ 0.001) and superoxide dismutase 2 (p = 0.001) were significantly reduced in EAT compared to SAT. Conclusions: The findings provide a unique molecular insight into the mitochondrial dynamics and oxidative stress profiles of EAT, highlighting potential avenues for a novel diagnostic method and therapeutic strategies for cardiac disease. Full article

(This article belongs to the Special Issue Interplay Between Metabolism, Oxidative Stress, and Cellular Signaling in Health and Disease)

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12 pages, 894 KiB

Open AccessReview

Review: Piglets’ (Re)Feeding Patterns, Mineral Metabolism, and Their Twisty Tail

by Theo van Kempen and Eugeni Roura

Metabolites 2025, 15(7), 480; https://doi.org/10.3390/metabo15070480 - 16 Jul 2025

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Abstract

The appearance rate of nutrients into systemic circulation affects hormones like insulin and through that efficiency of growth. This also affects mineral requirements critical for metabolism, notably phosphate (P), magnesium (Mg), and potassium (K). Fasting animals have a downregulated metabolism, upon which P, [...] Read more.

The appearance rate of nutrients into systemic circulation affects hormones like insulin and through that efficiency of growth. This also affects mineral requirements critical for metabolism, notably phosphate (P), magnesium (Mg), and potassium (K). Fasting animals have a downregulated metabolism, upon which P, Mg, and K are exported from their cells into the blood and are subsequently excreted in their urine. Abrupt resumption of feed intake, especially of highly glycemic feeds, creates an acute need for these minerals, which can result in deficiency symptoms, particularly with P deficiency. In human medicine, this is called refeeding syndrome: a large meal after a period of fasting can prove fatal. Young animals seem to be especially sensitive, likely driven by their ability to grow rapidly and thus to drastically upregulate their metabolism in response to insulin. Symptoms of P deficiency are fairly a-specific and, consequently, not often recognized. They include edema, which makes it appear as if piglets are growing well, explaining the high gain/feed rate typically seen immediately after weaning, even when piglets are eating at or below the maintenance requirements. Phosphate deficiency can also result in hypoxia and hypercarbia, which may trigger ear necrosis, Streptococcus suis infections, or even death. Hypophosphatemia can also trigger rhabdomyolysis, which may contribute to tail-biting, but this requires further study. Arguably, when fasting cannot be avoided, diets for newly weaned piglets should be formulated to avoid these problems by lowering their glycemic load and by formulating diets according to the piglets’ actual requirements inspired by their genuine intake and health and not simply by extrapolating from older animals. Full article

(This article belongs to the Special Issue Nutritional and Metabolic Influences on Animal Growth and Reproduction)

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19 pages, 1309 KiB

Open AccessReview

The Complexity of Oxidative Stress in Human Age-Related Diseases—A Review

by Alicja Płóciniczak, Ewelina Bukowska-Olech and Ewa Wysocka

Metabolites 2025, 15(7), 479; https://doi.org/10.3390/metabo15070479 - 15 Jul 2025

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Abstract

The aging process is a complex and dynamic phenomenon influenced by genetic, environmental, and biochemical factors. One of the key contributors to aging and age-related diseases is oxidative stress, resulting from an imbalance between the generation of reactive oxygen species (ROS) and the [...] Read more.

The aging process is a complex and dynamic phenomenon influenced by genetic, environmental, and biochemical factors. One of the key contributors to aging and age-related diseases is oxidative stress, resulting from an imbalance between the generation of reactive oxygen species (ROS) and the efficiency of antioxidant defense systems. In this review, we introduce the concept of the oxidative stress complexity—a network encompassing ROS-generating systems, enzymatic and non-enzymatic antioxidants, and genetic determinants that collectively shape redox homeostasis. Emerging research highlights the significant influence of genetic variability on the activity and expression of selected and most examined antioxidant enzymes, including superoxide dismutase (SOD), paraoxonase 1 (PON1), catalase (CAT), and glutathione peroxidase (GPx), thereby modulating individual susceptibility to oxidative damage, disease onset, and the pace of aging. Particular attention is paid to the interplay among oxidative stress, chronic inflammation, and metabolic dysfunction in the pathogenesis of various age-related disorders. By integrating findings from molecular studies, clinical research, and population genetics, we discuss the diagnostic and prognostic potential of antioxidant enzymes as biomarkers of aging and explore strategies for redox-modulating interventions. Understanding these interrelations is essential for identifying biomarkers of biological aging and developing personalized strategies aimed at promoting healthy aging and reducing the risk of chronic disease. Full article

(This article belongs to the Special Issue Inflammation and Oxidative Stress in Age-Related Metabolic Changes and Disorders)

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31 pages, 2163 KiB

Open AccessReview

The Role of Probiotics, Prebiotics, Synbiotics, and Postbiotics in Livestock and Poultry Gut Health: A Review

by Taojing Yue, Yanan Lu, Wenli Ding, Bowen Xu, Cai Zhang, Lei Li, Fuchun Jian and Shucheng Huang

Metabolites 2025, 15(7), 478; https://doi.org/10.3390/metabo15070478 - 15 Jul 2025

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Abstract

Background: The gut health of livestock and poultry is of utmost importance as it significantly impacts their growth performance, disease resistance, and product quality. With the increasing restrictions on antibiotic use in animal husbandry, probiotics, prebiotics, synbiotics, and postbiotics (PPSP) have emerged as [...] Read more.

Background: The gut health of livestock and poultry is of utmost importance as it significantly impacts their growth performance, disease resistance, and product quality. With the increasing restrictions on antibiotic use in animal husbandry, probiotics, prebiotics, synbiotics, and postbiotics (PPSP) have emerged as promising alternatives. This review comprehensively summarizes the roles of PPSP in promoting gut health in livestock and poultry. Results: Probiotics, such as Lactobacillus, Bifidobacterium, and Saccharomyces, modulate the gut microbiota, enhance the gut barrier, and regulate the immune system. Prebiotics, including fructooligosaccharides, isomalto-oligosaccharides, galactooligosaccharides, and inulin, selectively stimulate the growth of beneficial bacteria and produce short-chain fatty acids, thereby improving gut health. Synbiotics, combinations of probiotics and prebiotics, have shown enhanced effects in improving gut microbiota and animal performance. Postbiotics, consisting of inanimate microorganisms and their constituents, restore the gut microbiota balance and have anti-inflammatory and antibacterial properties. Additionally, the review looks ahead to the future development of PPSP, emphasizing the importance of encapsulation technology and personalized strategies to maximize their efficacy. Conclusions: Our aim is to provide scientific insights for PPSP to improve the gut health of livestock and poultry. Full article

(This article belongs to the Special Issue Metabolomics Approaches to Nutrition, Intestine and Farm Animal)

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15 pages, 1363 KiB

Open AccessArticle

The Effects of Dietary Supplementation of Chestnut Tannic Acid on the Growth Performance, Gut Morphology and Microbiota of Weaned Piglets

by Jinzhou Zhang, Yuting Zhang, Yuya Wang, Yanwei Li, Dongyang Liu, Hongbing Xie, Yongqiang Wang, Meinan Chang, Liping Guo and Zhiguo Miao

Metabolites 2025, 15(7), 477; https://doi.org/10.3390/metabo15070477 - 15 Jul 2025

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Abstract

Background/Objectives: This study investigated the effects of chestnut tannic acid (TA) on the growth performance, the expression of tight junction proteins and the composition of the gut microbiota of weaned piglets, which could provide novel insights into the application of TA in [...] Read more.

Background/Objectives: This study investigated the effects of chestnut tannic acid (TA) on the growth performance, the expression of tight junction proteins and the composition of the gut microbiota of weaned piglets, which could provide novel insights into the application of TA in swine production. Methods: In a 42-day trial, 180 healthy, 21-day-old Duroc × Landrace × Yorkshire piglets were randomly assigned to a Control group and four treatment groups (TA1–4), fed commercial diets supplemented with 0, 0.06%, 0.12%, 0.18% or 0.24% TA. Each group had six replicates of six pigs each. Results: The average daily gain in all TA groups, the jejunal and ileal villus height and the villus height-to-crypt depth ratio in the TA3 and TA4 groups were markedly increased (p < 0.05). The mRNA levels of MUC2 and ZO-1 were upregulated in the TA3 group, as were those of MUC4 in the jejunum and ileum and claudin in the duodenum and ileum; glutathione peroxidase and total antioxidant capacity were upregulated in the duodenum and jejunum in the TA3 group, and total superoxide dismutase was increased in all the TA2 groups (p < 0.05). Conversely, the malondialdehyde significantly decreased in all the TA groups (p < 0.05). TA supplementation improved the alpha diversity of the intestinal microflora and augmented probiotic abundance while reducing that of pathogenic bacteria. The contents of acetic, isobutyric, valeric, isovaleric, hexanoic and propionic acids, as well as total short-chain fatty acids (SCFA), were higher in the TA2 and TA3 groups (p < 0.05). Conclusions: TA inclusion in piglet diets improved the intestinal environment by upregulating the antioxidant enzymes, improving intestinal morphology and promoting probiotic growth and SCFA production while reducing pathogenic bacterial abundance, consequently enhancing the gut barrier and the growth of weaned piglets. Full article

(This article belongs to the Section Animal Metabolism)

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21 pages, 5607 KiB

Open AccessArticle

EM Dipeptide Enhances Milk Protein Secretion: Evidence from Integrated Metabolomic and Transcriptomic Analysis

by Yuqing Liu, Yuhao Yan, Runjun Yang, Xiaohui Li, Chuang Zhai, Xuan Wu, Xibi Fang and Boqun Liu

Metabolites 2025, 15(7), 476; https://doi.org/10.3390/metabo15070476 - 14 Jul 2025

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Abstract

Background/Objectives: Breast milk provides essential nutrition and immune protection to support infant growth and development. However, insufficient breast milk remains a serious issue, and bioactive peptides represent a potential strategy to promote lactation. In this study, we investigated the impact of a methionine-containing [...] Read more.

Background/Objectives: Breast milk provides essential nutrition and immune protection to support infant growth and development. However, insufficient breast milk remains a serious issue, and bioactive peptides represent a potential strategy to promote lactation. In this study, we investigated the impact of a methionine-containing dipeptide, EM, on MCF-10A mammary epithelial cells. Methods: MCF-10A cells were treated with EM, and cell proliferation and the expression of key milk protein genes were assessed. Integrated transcriptomic and untargeted metabolomic analyses were performed to identify EM-induced changes in metabolic and gene expression pathways. Results: EM treatment significantly enhanced cell proliferation and upregulated the expression of key milk protein genes (CSN1S1 (casein alpha-S1, encoding alpha-S1 casein), CSN2 (casein beta, encoding beta-casein), and CSN3 (casein kappa, encoding kappa-casein)) at both transcriptional and protein levels compared to controls. Integrated transcriptomic and metabolomic analyses revealed that EM reprogrammed amino acid metabolism, lipid biosynthesis, and nutrient transport pathways. Core genes such as SLC7A11, APOE, and ABCA1 were identified as critical nodes linking metabolic and transcriptional networks. Conclusions: These findings indicate that EM may promote lactogenic activity by modulating metabolic and transcriptional networks in vitro, highlighting the potential of dipeptide-based nutritional interventions, which warrants further in vivo validation. Full article

(This article belongs to the Section Nutrition and Metabolism)

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14 pages, 1915 KiB

Open AccessArticle

Preliminary Study to Understand the Role of Gut Microbiota in Coronary Slow Flow Phenomenon (CSFP)

by Tayfun Gurol, Tayyip Karaman, Yesim Gurol, Osman Ugur Sezerman and Sinem Oktem Okullu

Metabolites 2025, 15(7), 475; https://doi.org/10.3390/metabo15070475 - 14 Jul 2025

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Abstract

Background/Objectives: Coronary slow flow phenomenon (CSFP) is a cardiovascular condition characterized by delayed passage of contrast medium through the coronary arteries, predominantly affecting young male smokers admitted with acute coronary syndrome. Although over 80% of patients experience recurrent chest pain and more than [...] Read more.

Background/Objectives: Coronary slow flow phenomenon (CSFP) is a cardiovascular condition characterized by delayed passage of contrast medium through the coronary arteries, predominantly affecting young male smokers admitted with acute coronary syndrome. Although over 80% of patients experience recurrent chest pain and more than 20% require readmission, the etiology of CSFP remains poorly understood. Given the emerging role of gut microbiome in cardiovascular diseases, this study investigates the microbial composition associated with CSFP. Methods: Stool samples were collected from patients diagnosed with CSFP and healthy control individuals. Microbiota profiling was performed using 16S rRNA sequencing. Taxonomic differences were evaluated to identify microbial markers potentially associated with CSFP. Results: The analysis revealed a notable enrichment of the genus Gemmiger and the species Anaerobutyricum in CSFP patients, specifically within the selenium metabolism pathway. This is of particular interest given the established link between selenium deficiency and heightened cardiovascular risk, suggesting a possible microbiome-mediated modulation of selenium bioavailability in CSFP pathophysiology. Moreover, a marked increase in taxa associated with the biosynthesis of trimethylamine (TMA), a proatherogenic metabolite implicated in the onset and progression of various cardiovascular disorders, was observed in the CSFP cohort, further supporting a potential mechanistic role of gut microbiota in the disease’s underlying etiology. Conclusions: Although statistical significance could not be established due to the limited sample size, the observed trends support the hypothesis that specific gut microbes and metabolic pathways, particularly those linked to selenium metabolism and TMA production, may serve as potential microbial indicators for CSFP. These preliminary findings warrant further investigation in larger cohorts. Full article

(This article belongs to the Special Issue Environmental Exposure and Its Effects on Cardio-Respiratory and Metabolic Health)

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15 pages, 444 KiB

Open AccessArticle

Cross-Sectional and Longitudinal Assessment of Sociodemographic and Lifestyle Determinants of Metabolic Syndrome and Hypertriglyceridemic Waist Phenotypes in 139,634 Spanish Workers

by Joan Obrador de Hevia, Ángel Arturo López-González, José Ignacio Ramírez-Manent, Carla Busquets-Cortés, Pedro Juan Tárraga López and Pere Riutord-Sbert

Metabolites 2025, 15(7), 474; https://doi.org/10.3390/metabo15070474 - 14 Jul 2025

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Abstract

Objective: The objective of this study was to analyze the prevalence and key sociodemographic and lifestyle determinants of metabolic syndrome (MetS) and the hypertriglyceridemic waist (HTGW) phenotype in a large occupational cohort. Background: Metabolic syndrome (MetS) and the hypertriglyceridemic waist (HTGW) phenotype, defined [...] Read more.

Objective: The objective of this study was to analyze the prevalence and key sociodemographic and lifestyle determinants of metabolic syndrome (MetS) and the hypertriglyceridemic waist (HTGW) phenotype in a large occupational cohort. Background: Metabolic syndrome (MetS) and the hypertriglyceridemic waist (HTGW) phenotype, defined as the simultaneous presence of elevated waist circumference and high triglyceride levels, are major predictors of cardiometabolic morbidity and mortality. Despite their clinical relevance, data on their distribution and determinants in large occupational populations remain limited. Methods: A cross-sectional analysis was conducted on 139,634 employed adults (56,352 women and 83,282 men) across Spain, based on standardized clinical evaluations and validated questionnaires assessing physical activity, diet, smoking, alcohol consumption, education, and occupational class. Logistic regression models were used to estimate associations with MetS and HTGW. A longitudinal subsample of 40,431 individuals was followed over a 10-year period (2009–2019) to assess trends in metabolic risk phenotypes. Results: Male sex, older age, lower educational attainment, and unhealthy lifestyle behaviors were associated with a higher prevalence of both MetS and the HTGW phenotype. Physical inactivity, low adherence to the Mediterranean diet, and alcohol consumption were significantly associated with increased risk. The HTGW phenotype proved useful in identifying high-risk individuals, with a steadily increasing prevalence over time. Conclusions: Sociodemographic disparities and modifiable lifestyle factors significantly influence the prevalence and progression of MetS and HTGW in the Spanish workforce. Preventive strategies should emphasize early workplace screening, promotion of healthy behaviors, and reduction in educational and socioeconomic inequalities to mitigate cardiometabolic risk. Full article

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

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15 pages, 972 KiB

Open AccessArticle

Pharmacometabolomics Study of Sulfamethoxazole and Trimethoprim in Kidney Transplant Recipients: Real-World Metabolism and Urinary Excretion

by Marieke A. J. Hof, Hessel de Haan, Stepan Stepanovic, Stephan J. L. Bakker, Eelko Hak, Gérard Hopfgartner, Frank Klont and TransplantLines Investigators

Metabolites 2025, 15(7), 473; https://doi.org/10.3390/metabo15070473 - 11 Jul 2025

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Abstract

Background/Objectives: The increased use of antibiotics is raising concerns about environmental contamination and antibiotic resistance, exemplified by the case of cotrimoxazole, a widely prescribed combination of sulfamethoxazole and trimethoprim. After oral administration and absorption, both drugs are excreted in their parent and [...] Read more.

Background/Objectives: The increased use of antibiotics is raising concerns about environmental contamination and antibiotic resistance, exemplified by the case of cotrimoxazole, a widely prescribed combination of sulfamethoxazole and trimethoprim. After oral administration and absorption, both drugs are excreted in their parent and metabolized forms, which is a factor that is commonly considered in environmental studies. Many studies, however, rely on pharmacokinetic data from drug developers, who mostly investigate drug metabolism in healthy male volunteers rather than in actual patient populations. Methods: We investigated the real-world metabolism and urinary excretion of cotrimoxazole in an LC-SWATH/MS-based pharmacometabolomics study of 149 kidney transplant recipients who took part in the TransplantLines Biobank and Cohort Study (NCT0327284). Results: Our study confirmed (as “putatively characterized compound classes”) the presence of all the expected metabolites, and we (putatively) identified several previously unreported metabolites, including glucuronide conjugates of both drugs and two isoxazole ring-opened variants of sulfamethoxazole. The relative metabolite profiles furthermore indicated that the active drug trimethoprim accounted for 75% of the total signal intensity. For sulfamethoxazole, its acetylated metabolite was the main metabolite (59%), followed by the active parent drug (17%) and its glucuronide (7%). Alongside trimethoprim, these substances could serve as analytical targets for environmental cotrimoxazole monitoring, given their abundance (all three substances), activity (parent drug), and/or back-transformation potential (both conjugated metabolites). The isoxazole ring-opened variants (2–3%) may also warrant attention, considering their (presumed) absolute excreted quantities and potential pharmacological activity. Conclusions: This study underscores the value of pharmacometabolomics in elucidating real-world metabolite profiles, and it provides novel insights into cotrimoxazole metabolism and excretion, with implications for environmental and clinical monitoring. Full article

(This article belongs to the Special Issue Drug Metabolism: Latest Advances and Prospects)

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17 pages, 3763 KiB

Open AccessArticle

Aerobic Exercise Delays Age-Related Sarcopenia in Mice via Alleviating Imbalance in Mitochondrial Quality Control

by Danlin Zhu, Lian Wang, Haoyang Gao, Ze Wang, Ke Li, Xiaotong Ma, Linlin Zhao and Weihua Xiao

Metabolites 2025, 15(7), 472; https://doi.org/10.3390/metabo15070472 - 11 Jul 2025

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Abstract

Background: Sarcopenia is a syndrome associated with aging, characterized by a progressive decline in skeletal muscle mass and function. Its onset compromises the health and longevity of older adults by increasing susceptibility to falls, fractures, and various comorbid conditions, thereby diminishing quality of [...] Read more.

Background: Sarcopenia is a syndrome associated with aging, characterized by a progressive decline in skeletal muscle mass and function. Its onset compromises the health and longevity of older adults by increasing susceptibility to falls, fractures, and various comorbid conditions, thereby diminishing quality of life and capacity for independent living. Accumulating evidence indicates that moderate-intensity aerobic exercise is an effective strategy for promoting overall health in older adults and exerts a beneficial effect that mitigates age-related sarcopenia. However, the underlying molecular mechanisms through which exercise confers these protective effects remain incompletely understood. Methods: In this study, we established a naturally aging mouse model to investigate the effects of a 16-week treadmill-based aerobic exercise regimen on skeletal muscle physiology. Results: Results showed that aerobic exercise mitigated age-related declines in muscle mass and function, enhanced markers associated with protein synthesis, reduced oxidative stress, and modulated the expression of genes and proteins implicated in mitochondrial quality control. Notably, a single session of aerobic exercise acutely elevated circulating levels of β-hydroxybutyrate (β-HB) and upregulated the expression of BDH1, HCAR2, and PPARG in the skeletal muscle, suggesting a possible role of β-HB–related signaling in exercise-induced muscle adaptations. However, although these findings support the beneficial effects of aerobic exercise on skeletal muscle aging, further investigation is warranted to elucidate the causal relationships and to characterize the chronic signaling mechanisms involved. Conclusions: This study offers preliminary insights into how aerobic exercise may modulate mitochondrial quality control and β-HB–associated signaling pathways during aging. Full article

(This article belongs to the Special Issue Nutrition and Metabolic Changes in Aging and Age-Related Diseases)

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14 pages, 1006 KiB

Open AccessArticle

Investigating Systemic Metabolic Effects of Betula alba Leaf Extract in Rats via Urinary Metabolomics

by Gregorio Peron, Alina Yerkassymova, Gokhan Zengin and Stefano Dall’Acqua

Metabolites 2025, 15(7), 471; https://doi.org/10.3390/metabo15070471 - 10 Jul 2025

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Abstract

Background/Objectives: Herbal extracts from Betula alba (birch) are traditionally used for their purported diuretic effects, but scientific evidence supporting these claims remains limited. In this pilot study, we evaluated the short-term effects of a standardized B. alba leaf extract in healthy adult rats [...] Read more.

Background/Objectives: Herbal extracts from Betula alba (birch) are traditionally used for their purported diuretic effects, but scientific evidence supporting these claims remains limited. In this pilot study, we evaluated the short-term effects of a standardized B. alba leaf extract in healthy adult rats using an untargeted urinary metabolomics approach based on UPLC-QTOF. Methods: Two doses, 25 or 50 mg/kg, of a standardized B. alba extract were orally administered to rats. The extract contains hyperoside (0.53%), quercetin glucuronide (0.36%), myricetin glucoside (0.32%), and chlorogenic acid (0.28%) as its main constituents. After 3 days of treatment, the 24 h urine output was measured. Results: While no statistically significant changes were observed in the 24 h urine volume or the urinary Na⁺ and K⁺ excretion, multivariate metabolomic analysis revealed treatment-induced alterations in the urinary metabolic profile. Notably, the levels of two glucocorticoids, i.e., corticosterone and 11-dehydrocorticosterone, were increased in treated animals, suggesting that the extract may influence corticosteroid metabolism or excretion, potentially impacting antidiuretic hormone signaling. Elevated bile-related compounds, including bile acids and bilin, and glucuronidated metabolites were also observed, indicating changes in bile acid metabolism, hepatic detoxification, and possibly gut microbiota activity. Conclusions: Although this study did not confirm a diuretic effect of B. alba extract, the observed metabolic shifts suggest broader systemic bioactivities that warrant further investigation. Overall, the results indicate that the approach based on urinary metabolomics may be valuable in uncovering the mechanisms of action and evaluating the bioactivity of herbal extracts with purported diuretic properties. Full article

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

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17 pages, 1736 KiB

Open AccessArticle

The Adjuvant Effect of Hyperbaric Oxygenation for Loxosceles rufescens Bite: A Case Series

by Simona Mrakic-Sposta, Alessandra Vezzoli, Carmela Graci, Maristella Gussoni, Attilio Cimmino, Cinzia Dellanoce, Enrico Maria Camporesi, Giovanni Sesana and Gerardo Bosco

Metabolites 2025, 15(7), 470; https://doi.org/10.3390/metabo15070470 - 10 Jul 2025

Viewed by 909

Abstract

Background. The venom of Loxoscelesrufescens (L.r.), also known as the violin and/or brown spider, contains a wide variety of proteins and can induce a complex, intense, and uncontrolled inflammatory response, hemolysis, thrombocytopenia, dermo-necrosis, and renal failure. Studies have postulated the efficacy of [...] Read more.

Background. The venom of Loxoscelesrufescens (L.r.), also known as the violin and/or brown spider, contains a wide variety of proteins and can induce a complex, intense, and uncontrolled inflammatory response, hemolysis, thrombocytopenia, dermo-necrosis, and renal failure. Studies have postulated the efficacy of hyperbaric oxygen therapy (HBOT) for Loxosceles bites. However, data describing the use and beneficial effects of HBO are, to date, relatively scarce. Only a few cases of Loxosceles bites in Northern Italy have been documented, and there is no laboratory test available for the diagnosis. Objectives. We present seven cases (aged 54.5 ± 4.2 years) of patients who presented to the emergency room (E.R.) of Niguarda Hospital in Milan from March to October 2022. Methods. Blood and urine samples were collected and biomarkers of oxidative stress (OxS) (reactive oxygen species (ROS), total antioxidant capacity (TAC), lipid peroxidation (8iso-PFG2α), DNA damage (8-OH-dG)), inflammation (IL-6, IL-1β, TNF-α, sICAM1), and renal function (creatinine, neopterin, uric acid) before (T0), during (T1, T2), and after (1–2 wk T3–T4; 1 month T5) the HBOT treatment (US Navy Treatment Table 15 protocol) were studied. Results. At T0, patients showed a significant unbalance of OxS; high levels of ROS, 8-isoPGF2α, and inflammatory status (IL-6, TNF-α; sICAM); and a low level of antioxidant capacity. At the end of HBOT (T2), a significant reduction in Oxy-inflammation levels over time—8-iso −26%, 8-OH-dG −9%, IL-6 −71%, IL-1bβ −12%, TNF-α −13%, and sICAM1 −17%—associated with clinical improvement was shown. Conclusions. These reductions, along with those in renal function markers, mirrored the observed improvement in the evolution of the skin lesion and the patients’ self-reported general wellness and pain. In conclusion, HBOT should be considered a valuable therapeutic tool after L.r. bites. Full article

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

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15 pages, 3716 KiB

Open AccessArticle

Prediagnostic Plasma Metabolomic Profiles Using NMR for Exfoliation Glaucoma Among US Health Professionals

by Akiko Hanyuda, Oana A. Zeleznik, Yoshihiko Raita, Danielle E. Haslam, Qi Sun, Kazuno Negishi, Louis R. Pasquale, Jessica Lasky-Su, Janey L. Wiggs and Jae H. Kang

Metabolites 2025, 15(7), 469; https://doi.org/10.3390/metabo15070469 - 9 Jul 2025

Viewed by 253

Abstract

Background: Exfoliation glaucoma (XFG) represents a form of deleterious ocular aging of unclear etiology. We evaluated prediagnostic nuclear magnetic resonance (NMR)-based metabolites in relation to XFG risk, expanding on our prior findings of XFG-related metabotypes using liquid chromatography-mass spectrometry (LC-MS). Methods: We identified [...] Read more.

Background: Exfoliation glaucoma (XFG) represents a form of deleterious ocular aging of unclear etiology. We evaluated prediagnostic nuclear magnetic resonance (NMR)-based metabolites in relation to XFG risk, expanding on our prior findings of XFG-related metabotypes using liquid chromatography-mass spectrometry (LC-MS). Methods: We identified 217 XFG cases and 217 matched controls nested within three prospective health professional cohorts with plasma collected a mean 11.8 years before case identification. Plasma metabolites were analyzed using the targeted NMR Nightingale platform. Conditional logistic models and Metabolite Set Enrichment Analysis were performed. Multiple comparison issues were addressed using the number of effective tests (NEF) and false discovery rate (FDR). Results: Among 235 profiled metabolites, higher glucose was significantly associated with a lower risk of XFG (odds ratio (95%CI) = 0.42 (0.26, 0.7); NEF = 0.03). Among metabolite classes, lipoprotein subclasses and branched-chain amino acids were inversely associated, while relative lipoprotein lipid concentrations were adversely associated (FDR < 0.05). Conclusion: NMR profiling revealed that glucose, branched-chain amino acids, lipoprotein subclasses, and relative lipoprotein lipid concentrations may play important roles in XFG etiology. Full article

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

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10 pages, 1166 KiB

Open AccessArticle

Avian Influenza Virus Strain Specificity in the Volatile Metabolome

by Young Eun Lee, Richard A. Bowen and Bruce A. Kimball

Metabolites 2025, 15(7), 468; https://doi.org/10.3390/metabo15070468 - 9 Jul 2025

Viewed by 225

Abstract

Background/Objectives: Outbreaks of highly pathogenic avian influenza virus (AIV) result in significant financial losses and the death or depopulation of millions of domestic birds. Early and rapid detection and surveillance are needed to slow the spread of AIV and prevent its spillover to [...] Read more.

Background/Objectives: Outbreaks of highly pathogenic avian influenza virus (AIV) result in significant financial losses and the death or depopulation of millions of domestic birds. Early and rapid detection and surveillance are needed to slow the spread of AIV and prevent its spillover to humans. The volatile metabolome (i.e., the pattern of volatile metabolites emitted by a living subject) represents one such source of health information that can be monitored for disease diagnosis. Indeed, dogs have been successfully trained to recognize patterns of “body odors” associated with many diseases. Because little is known regarding the mechanisms involved in the alteration of the volatile metabolome in response to health perturbation, questions still arise regarding the specificity, or lack thereof, of these alterations. Methods: To address this concern, we experimentally infected twenty mallard ducks with one of two different strains of low-pathogenic AIV (ten ducks per strain) and collected cloacal swabs at various time points before and after infection. Results: Headspace analyses revealed that four volatiles were significantly altered following infection, with distinct profiles associated with each viral strain. The volatiles that differed between strains among post-infection sampling periods included ethylbenzyl ether (p = 0.00006), 2-phenoxyethanol (p = 0.00017), 2-hydroxybenzaldehyde (p = 0.00022), and 6-methyl-5-hepten-2-one (p = 0.00034). Conclusions: These findings underscore that AIV-induced changes to the volatile metabolome are strain-specific, emphasizing the need for disease-specific profiling in diagnostic development. 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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30 pages, 2043 KiB

Open AccessReview

Berberine as a Bioactive Alkaloid: Multi-Omics Perspectives on Its Role in Obesity Management

by Bartłomiej Zieniuk and Magdalena Pawełkowicz

Metabolites 2025, 15(7), 467; https://doi.org/10.3390/metabo15070467 - 9 Jul 2025

Viewed by 357

Abstract

Berberine, a bioactive isoquinoline alkaloid derived from medicinal plants such as Berberis and Coptis species, shows significant promise for managing obesity and associated metabolic disorders. This review synthesizes evidence on its modulation of AMP-activated protein kinase (AMPK) signaling, gut microbiota composition, lipid metabolism, [...] Read more.

Berberine, a bioactive isoquinoline alkaloid derived from medicinal plants such as Berberis and Coptis species, shows significant promise for managing obesity and associated metabolic disorders. This review synthesizes evidence on its modulation of AMP-activated protein kinase (AMPK) signaling, gut microbiota composition, lipid metabolism, and adipokine networks, elucidating how these actions converge to suppress adipogenesis and improve insulin sensitivity. Metabolomic profiling reveals critical shifts in bile acid metabolism, short-chain fatty acid production, and mitochondrial function. Recent studies also highlight berberine’s anti-inflammatory effects and regulatory influence on glucose homeostasis. Despite its promise, challenges in oral bioavailability and drug interactions necessitate the development of advanced delivery strategies. We further discuss nanoformulations and multi-omics approaches, which integrate data from genomics, transcriptomics, proteomics, and metabolomics, provide new insights into berberine’s mechanisms, and may guide personalized therapeutic applications. While promising, further studies are needed to validate these findings in humans and translate them into effective clinical strategies. 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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27 pages, 3492 KiB

Open AccessArticle

Amelioration of Metabolic Syndrome by Co-Administration of Lactobacillus johnsonii CRL1231 and Wheat Bran in Mice via Gut Microbiota and Metabolites Modulation

by Matias Russo, Antonela Marquez, Estefanía Andrada, Sebastián Torres, Arlette Santacruz, Roxana Medina and Paola Gauffin-Cano

Metabolites 2025, 15(7), 466; https://doi.org/10.3390/metabo15070466 - 9 Jul 2025

Viewed by 202

Abstract

Background/Objectives: Lactobacillus johnsonii CRL1231 (Lj CRL1231) is a strain with feruloyl esterase (FE) activity that enhances ferulic acid (FA) release from wheat bran (WB) and has potential as a probiotic for metabolic syndrome (MS). Given the potential health benefits of FA and [...] Read more.

Background/Objectives: Lactobacillus johnsonii CRL1231 (Lj CRL1231) is a strain with feruloyl esterase (FE) activity that enhances ferulic acid (FA) release from wheat bran (WB) and has potential as a probiotic for metabolic syndrome (MS). Given the potential health benefits of FA and its microbial metabolites, this study aimed to evaluate the therapeutic effect of Lj CRL1231 co-administered with WB in a mouse model of metabolic syndrome (MS) induced by a high-fat diet (HFD). Methods: Mice were divided into three groups and fed for 14 weeks as follows: the Control group (standard diet), the MS group (HFD+WB), and the MS+Lj group (HFD+WB and Lj CRL1231-dose 10⁸ cells/day). Specifically, we analyzed the changes in the intestinal microbiota (IM), colonic FE activity, generation of FA-derived and fermentation metabolites, and metabolic and inflammatory parameters. Results: Improvements in the MS+Lj group compared to the MS group included the following: a—a 38% increase in colonic FE activity, leading to elevated levels of FA-derived metabolites (e.g., dihydroferulic, dihydroxyphenylpropionic, and hydroxyphenylpropionic acids); b—a significant shift in the IM composition, with a 3.4-fold decrease in Firmicutes and a 2.9-fold increase in Bacteroidetes; c—a decrease in harmful bacteria (Desulfovibrio) by 93%, and beneficial bacteria like Bifidobacterium increased significantly (6.58 log cells/g); d—a 33% increase in total SCFAs; e—a 26% reduction in the adiposity index; f—a 12% increase in HDL cholesterol and a 19% reduction in triglycerides; g—normalized glucose and insulin resulting in a 2-fold lower HOMA-IR index; h—an improved inflammatory profile by decreasing TNF-α, IFN-γ, and IL-6 (3-, 5-, and 2-fold, respectively) and increasing IL-10 by 2-fold; i—alleviation of liver damage by normalizing of transaminases AST (19.70 ± 2.97 U/L) and ALT (13.12 ± 0.88 U/L); j—evidence of reduced oxidative damage. Conclusions: The co-administration of L. johnsonii CRL1231 and WB exerts a synergistic effect in mitigating the features of MS in HFD-fed mice. This effect is mediated by modulation of the gut microbiota, increased release of bioactive FA-derived compounds, and restoration of metabolic and inflammatory homeostasis. This strategy represents a promising dietary approach for MS management through targeted microbiota–metabolite interactions. Full article

(This article belongs to the Special Issue Functional Foods and Natural Bioactive Compounds: Strategies to Face Metabolic Syndrome and Related Non-Communicable Diseases)

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12 pages, 1407 KiB

Open AccessArticle

Amide Proton Transfer-Weighted MR Imaging and Signal Variations in a Rat Model of Lipopolysaccharide-Induced Sepsis-Associated Encephalopathy

by Donghoon Lee, HyunJu Ryu, Yeon Ji Chae, Hind Binjaffar, Chul-Woong Woo, Dong-Cheol Woo and Do-Wan Lee

Metabolites 2025, 15(7), 465; https://doi.org/10.3390/metabo15070465 - 9 Jul 2025

Viewed by 288

Abstract

Introduction: Sepsis-associated encephalopathy (SAE) is an acute brain dysfunction secondary to systemic infection, occurring without direct central nervous system involvement. Despite its clinical relevance, reliable biomarkers for diagnosing SAE and assessing its severity remain limited. This study aimed to evaluate the feasibility of [...] Read more.

Introduction: Sepsis-associated encephalopathy (SAE) is an acute brain dysfunction secondary to systemic infection, occurring without direct central nervous system involvement. Despite its clinical relevance, reliable biomarkers for diagnosing SAE and assessing its severity remain limited. This study aimed to evaluate the feasibility of amide proton transfer-weighted (APTw) chemical exchange saturation transfer (CEST) MRI as a non-invasive molecular imaging technique for detecting metabolic alterations related to neuroinflammation in SAE. Using a lipopolysaccharide (LPS)-induced rat model, we focused on hippocampal changes associated with neuronal inflammation. Materials and Methods: Twenty-one Sprague–Dawley rats (8 weeks old, male) were divided into three groups: control (CTRL, n = 7), LPS-induced sepsis at 5 mg/kg (LPS05, n = 7), and 10 mg/kg (LPS10, n = 7). Sepsis was induced via a single intraperitoneal injection of LPS. APTw imaging was performed using a 7 T preclinical MRI system, and signal quantification in the hippocampus was conducted using the magnetization transfer ratio asymmetry analysis. Results and Discussion: APTw imaging at 7 T demonstrated significantly elevated hippocampal APTw signals in SAE model rats (LPS05 and LPS10) compared to the control (CTRL) group: CTRL (−1.940 ± 0.207%) vs. LPS05 (−0.472 ± 0.485%) (p < 0.001) and CTRL vs. LPS10 (−0.491 ± 0.279%) (p < 0.001). However, no statistically significant difference was observed between the LPS05 and LPS10 groups (p = 0.994). These results suggest that APTw imaging can effectively detect neuroinflammation-related metabolic alterations in the hippocampus. Conclusion: Our findings support the feasibility of APTw CEST imaging as a non-invasive molecular MRI technique for SAE, with potential applications in diagnosis, disease monitoring, and therapeutic evaluation. Full article

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

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16 pages, 2086 KiB

Open AccessArticle

High-Coverage Profiling of Hydroxyl and Amino Compounds in Sauce-Flavor Baijiu Using Bromine Isotope Labeling and Ultra-High Performance Liquid Chromatography–High-Resolution Mass Spectrometry

by Zixuan Wang, Youlan Sun, Tiantian Chen, Lili Jiang, Yuhao Shang, Xiaolong You, Feng Hu, Di Yu, Xinyu Liu, Bo Wan, Chunxiu Hu and Guowang Xu

Metabolites 2025, 15(7), 464; https://doi.org/10.3390/metabo15070464 - 9 Jul 2025

Viewed by 262

Abstract

Background: Hydroxyl and amino compounds play a significant role in defining the flavor and quality of sauce-flavor Baijiu, yet their comprehensive analysis remains challenging due to limitations in detection sensitivity. In this study, we developed a novel bromine isotope labeling approach combined [...] Read more.

Background: Hydroxyl and amino compounds play a significant role in defining the flavor and quality of sauce-flavor Baijiu, yet their comprehensive analysis remains challenging due to limitations in detection sensitivity. In this study, we developed a novel bromine isotope labeling approach combined with ultra-high performance liquid chromatography–high-resolution mass spectrometry (UHPLC-HRMS) to achieve high-coverage profiling of these compounds in sauce-flavor Baijiu. Methods: The method employs 5-bromonicotinoyl chloride (BrNC) for rapid (30 s) and mild (room temperature) labeling of hydroxyl and amino functional groups, utilizing bromine’s natural isotopic pattern (Δm/z = 1.998 Da) for efficient screening. Annotation was performed hierarchically at five confidence levels by integrating retention time, accurate mass, and MS/MS spectra. Results: A total of 309 hydroxyl and amino compounds, including flavor substances (e.g., tyrosol and phenethyl alcohol) and bioactive compounds (e.g., 3-phenyllactic acid), were identified in sauce-flavor Baijiu. The method exhibited excellent analytical performance, with wide linearity (1–4 orders of magnitude), precision (RSD < 18.3%), and stability (RSD < 15% over 48 h). When applied to sauce-flavor Baijiu samples of different grades, distinct compositional patterns were observed: premium-grade products showed greater metabolite diversity and higher contents of bioactive compounds, whereas lower-grade samples exhibited elevated concentrations of acidic flavor compounds. Conclusions: These results demonstrate that the established method is efficient for the comprehensive analysis of hydroxyl and amino compounds in complex food matrices. The findings provide valuable insights for quality control and flavor modulation in sauce-flavor Baijiu production. Full article

(This article belongs to the Special Issue New Analytical Techniques and Applications of Metabolomics and Lipidomics)

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22 pages, 307 KiB

Open AccessArticle

The Long-Term Impact of Preterm Birth on Metabolic Bone Profile and Bone Mineral Density in Childhood

by Panagiota Markopoulou, Artemis Doulgeraki, Arsinoi Koutroumpa, Georgios Polyzois, Helen Athanasopoulou, Christina Kanaka-Gantenbein and Tania Siahanidou

Metabolites 2025, 15(7), 463; https://doi.org/10.3390/metabo15070463 - 8 Jul 2025

Viewed by 192

Abstract

Background/Objectives: Recent data on long-term consequences of prematurity on bone health are conflicting. The aim of this study was to assess the metabolic bone profile and bone mineral density (BMD) in prepubertal children born prematurely and to examine possible associations between bone [...] Read more.

Background/Objectives: Recent data on long-term consequences of prematurity on bone health are conflicting. The aim of this study was to assess the metabolic bone profile and bone mineral density (BMD) in prepubertal children born prematurely and to examine possible associations between bone health parameters and perinatal morbidity factors. Methods: This cross-sectional observational study included 144 children of mean (SD) age 10.9 (1.6) years: 49 children born very preterm (≤32 gestational weeks), 37 moderate-to-late preterm (32⁺¹ to 36⁺⁶ gestational weeks), and 58 born at term (controls). Serum levels of calcium/Ca, phosphorus/P, alkaline phosphatase/ALP, 25-hydroxyvitamin D/25(OH)D, bone formation markers (osteocalcin/OC, procollagen type I C-terminal propeptide/PICP, and insulin growth factor-1/IGF-1), and bone resorption markers (serum tartrate-resistant acid phosphatase 5b/bone TRAP5band urinary calcium-to-creatinine ratio) were measured. Total-body and lumbar-spine BMD and BMD Z-scores were calculated using dual-energy X-ray absorptiometry/DXA. Results: Children born very preterm showed significantly higher ALP, OC, PICP, and bone TRAP5b levels compared to controls, as well as compared to children born moderate-to-late preterm. Total-body and lumbar-spine BMD Z-scores were significantly lower in the very preterm-born group compared to controls. Gestational diabetes, preeclampsia, and bronchopulmonary dysplasia were associated with lower total-body BMD in the very preterm-born population. Conclusions: Preterm birth is associated with impaired metabolic bone profile and lower total-body and lumbar-spine BMD in childhood. Moderate-to-late preterm-born children exhibit altered metabolic bone parameters compared to very preterm-born children. Further research in children might allow better insight into the long-term impact of preterm birth on bone health. Full article

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

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23 pages, 2960 KiB

Open AccessArticle

Understanding the Metabolic Effects of Surgically Induced Renal Ischemia in Humans: A Temporal Approach

by Bhargav Arimilli, Tyler A. On, Vaishnavi S. Srirama, Ye Yang, Gitanjali Asampille, Jeffrey R. Brender, Murali C. Krishna, Jessica Y. Hseuh, Viraj P. Chegu, Zachary Kozel, Sandeep Gurram, Mark W. Ball, William Marston Linehan and Daniel R. Crooks

Metabolites 2025, 15(7), 462; https://doi.org/10.3390/metabo15070462 - 8 Jul 2025

Viewed by 248

Abstract

Background/Objectives: Thousands of nephrectomies are performed annually in the United States, but the short-term metabolic effects of surgically induced renal ischemia remain unclear. The conventional metabolic markers used to characterize post-surgical renal function, such as creatinine and GFR, are measured in the [...] Read more.

Background/Objectives: Thousands of nephrectomies are performed annually in the United States, but the short-term metabolic effects of surgically induced renal ischemia remain unclear. The conventional metabolic markers used to characterize post-surgical renal function, such as creatinine and GFR, are measured in the serum but do not provide metabolic information about the renal parenchyma itself. We aimed to characterize the immediate metabolic effects of surgical ischemia on renal parenchyma within a temporal framework. Methods: Timed renal parenchyma biopsies were collected from eight patients undergoing nephrectomy for renal cell carcinoma both prior to and after ligation of the renal hilum. These samples were ground, extracted, and analyzed using nuclear magnetic resonance (NMR) spectroscopy to measure changes in lactate, succinate, glucose, alanine, and glycine levels. Results: Due to experimental limitations, we were only able to draw limited conclusions from three patients. Of the five remaining patients, all had significant increases in lactate and succinate levels as a function of time, though the degree to which these increases occurred varied between each patient. Glucose levels generally decreased in the renal parenchyma but did not necessarily correlate with lactate production, assuming all glucose underwent fermentation to lactate in a hypoxic environment. Alanine and glycine levels did not change in a predictable pattern across patients. Conclusions: There are significant changes in lactate, glucose and succinate levels within minutes of the onset of renal ischemia in human patients. The degree of change in the metabolites analyzed varied significantly between patients. The length of surgical ischemia must be considered during surgical procurement of tumor specimens for metabolomic analysis. Full article

(This article belongs to the Special Issue Nuclear Magnetic Resonance-Powered Metabolomics: Progress and Future Prospects)

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18 pages, 2012 KiB

Open AccessArticle

ATP Supply from Cytosol to Mitochondria Is an Additional Role of Aerobic Glycolysis to Prevent Programmed Cell Death by Maintenance of Mitochondrial Membrane Potential

by Akane Sawai, Takeo Taniguchi, Kohsuke Noguchi, Taisuke Seike, Nobuyuki Okahashi, Masak Takaine and Fumio Matsuda

Metabolites 2025, 15(7), 461; https://doi.org/10.3390/metabo15070461 - 7 Jul 2025

Viewed by 414

Abstract

Eukaryotic cells generate ATP primarily via oxidative and substrate-level phosphorylation. Despite the superior efficiency of oxidative phosphorylation, eukaryotic cells often use both pathways as aerobic glycolysis, even in the presence of oxygen. However, its role in cell survival remains poorly understood. Objectives: In [...] Read more.

Eukaryotic cells generate ATP primarily via oxidative and substrate-level phosphorylation. Despite the superior efficiency of oxidative phosphorylation, eukaryotic cells often use both pathways as aerobic glycolysis, even in the presence of oxygen. However, its role in cell survival remains poorly understood. Objectives: In this study, aerobic glycolysis was compared between the Warburg effect in breast cancer cells (MCF7) and the Crabtree effect in a laboratory strain of Saccharomyces cerevisiae (S288C). Methods: The metabolic adaptations of MCF7 and S288C cells were compared following treatment with electron transport chain inhibitors, including FCCP, antimycin A, and oligomycin. Results: MCF7 and S288C cells exhibited strikingly similar metabolic rewiring toward substrate-level phosphorylation upon inhibitor treatment, suggesting that mitochondrial oxidative phosphorylation and cytosolic substrate-level phosphorylation communicate through a common mechanism. Measurement of mitochondrial membrane potential (MMP) and ATP concentrations further indicated that cytosolic ATP was transported into the mitochondria under conditions of reduced electron transport chain activity. This ATP was likely utilized in the reverse mode of H⁺/ATPase to maintain MMP, which contributed to the avoidance of programmed cell death. Conclusions: These results suggest that the ATP supply to mitochondria plays a conserved role in aerobic glycolysis in yeast and mammalian cancer cells. This mechanism likely contributes to cell survival under conditions of fluctuating oxygen availability. Full article

(This article belongs to the Section Cell Metabolism)

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27 pages, 686 KiB

Open AccessReview

Fracture Risk in Chronic Kidney Disease: Addressing an Overlooked Complication

by Guido Gembillo, Concetto Sessa, Walter Morale, Luca Zanoli, Antonino Catalano, Salvatore Silipigni, Luca Soraci, Andrea Corsonello, Maria Princiotto, Carlo Lomonte and Domenico Santoro

Metabolites 2025, 15(7), 460; https://doi.org/10.3390/metabo15070460 - 7 Jul 2025

Viewed by 428

Abstract

Fracture risk is a serious yet underrecognized complication among patients with chronic kidney disease (CKD), especially in those with stages G3-G5D. The overlap between CKD-Mineral and Bone Disorder (CKD-MBD) and osteoporosis leads to complex bone changes that increase the likelihood of fragility fractures. [...] Read more.

Fracture risk is a serious yet underrecognized complication among patients with chronic kidney disease (CKD), especially in those with stages G3-G5D. The overlap between CKD-Mineral and Bone Disorder (CKD-MBD) and osteoporosis leads to complex bone changes that increase the likelihood of fragility fractures. Studies show that 18% to 32% of CKD patients also have osteoporosis, and these individuals are more than 2.5 times as likely to suffer from fractures compared to those without CKD. In the advanced stages of the disease, fracture risk is up to four times higher than in the general population, with the femur, forearm, and humerus being the most commonly affected sites. Hip fractures are of particular concern as they are linked to longer hospital stays and higher rates of morbidity and mortality. Furthermore, dialysis patients who experience hip fractures have a mortality rate 2.4 times higher than those in the general population with similar fractures. This increased risk underscores the need for proactive bone health maintenance in CKD patients to prevent fractures and related complications. This review explores the underlying pathophysiological mechanisms, diagnostic challenges, and treatment options related to bone fragility in CKD. Diagnostic tools, such as bone mineral density (BMD) assessments, the trabecular bone score (TBS), and biochemical markers, remain underused, especially in advanced CKD stages. Recent treatment strategies emphasize a multidisciplinary, stage-specific approach, incorporating calcium and vitamin D supplements, anti-resorptive agents like denosumab, and anabolic therapies such as teriparatide and romosozumab. Effective management needs to be tailored to the patient’s bone turnover status and stage of CKD. Despite progress in understanding bone fragility in CKD, significant gaps remain in both diagnosis and treatment. Personalized care, guided by updated KDIGO recommendations and based on an interdisciplinary approach, is essential to reduce fracture risk and improve outcomes in this vulnerable population. Further research is needed to validate risk assessment tools and refine therapeutic protocols. 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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19 pages, 1172 KiB

Open AccessFeature PaperArticle

Serum Osteopontin and Procollagen Type 1 N-Terminal Propeptide Concentrations: Links to Liver Function, Muscle Mass, and Bone Mineral Density in MASLD and Hypertension

by Anna F. Sheptulina, Anastasia Yu. Elkina, Elvira M. Mamutova, Yuriy S. Timofeev, Victoria A. Metelskaya and Oxana M. Drapkina

Metabolites 2025, 15(7), 459; https://doi.org/10.3390/metabo15070459 - 6 Jul 2025

Viewed by 310

Abstract

Background/Objectives: Increasing evidence suggests that metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertension (HTN), a well-established cardiometabolic risk factor, both negatively impact bone metabolism. This study aimed to investigate the associations between bone turnover markers (BTMs)—namely, osteopontin (OPN) and procollagen type 1 N-terminal [...] Read more.

Background/Objectives: Increasing evidence suggests that metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertension (HTN), a well-established cardiometabolic risk factor, both negatively impact bone metabolism. This study aimed to investigate the associations between bone turnover markers (BTMs)—namely, osteopontin (OPN) and procollagen type 1 N-terminal propeptide (P1NP)—and metabolic health indicators, non-invasive measures of liver disease severity, as well as skeletal muscle mass (SMM), muscle strength, and bone mineral density (BMD) in patients with MASLD and HTN. Methods: We enrolled 117 patients diagnosed with MASLD and HTN and conducted anthropometric measurements, laboratory analyses, abdominal ultrasound, and point shear-wave elastography. Muscle strength was evaluated using grip strength measurements and the Five Times Sit-to-Stand Test (FTSST). SMM and BMD were quantified using dual-energy X-ray absorptiometry (DEXA). Serum OPN and P1NP concentrations were quantified using enzyme-linked immunosorbent assays (ELISAs). Results: Serum OPN concentrations below 2.89 ng/mL were associated with significantly elevated levels of AST (p = 0.001), ALT (p = 0.006), and GGT (p = 0.025), while serum P1NP concentrations above 47.5 pg/mL were associated only with significantly elevated GGT levels (p = 0.024). In addition, patients with MASLD and HTN with lower serum OPN levels had higher liver stiffness values (p = 0.003). Serum OPN concentrations were inversely associated with the following metabolic health indicators: waist circumference (WC, p < 0.001) and epicardial fat thickness (EFT, p = 0.001). In addition, they were significantly elevated in patients with MASLD and HTN who had decreased spinal BMD (p = 0.017). In turn, serum P1NP levels were reduced in patients with decreased SMM (p = 0.023). Conclusions: These findings in patients with MASLD and HTN suggest an association between serum P1NP levels and SMM, and between OPN levels and spinal BMD, indicating a potential interplay among liver function, muscle mass, and bone health. Furthermore, OPN appeared to be strongly associated with overall metabolic health indicators, such as WC and EFT, whereas P1NP exhibited a stronger association with muscle mass. Full article

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

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20 pages, 6441 KiB

Open AccessArticle

Tissue-Based Metabolomic Profiling of Endometrial Cancer and Hyperplasia

by Khalid Akkour, Afshan Masood, Maha Al Mogren, Reem H. AlMalki, Assim A. Alfadda, Salini Scaria Joy, Ali Bassi, Hani Alhalal, Maria Arafah, Othman Mahmoud Othman, Hadeel Mohammad Awwad, Anas M. Abdel Rahman and Hicham Benabdelkamel

Metabolites 2025, 15(7), 458; https://doi.org/10.3390/metabo15070458 - 5 Jul 2025

Viewed by 525

Abstract

Background: Endometrial cancer (EC) is the sixth most common cancer among women globally, with an estimated 420,000 new cases diagnosed annually. Methods: This study comprised patients with endometrial cancer (EC) (n = 17), hyperplasia (HY) (n = 17), and controls (CO) [...] Read more.

Background: Endometrial cancer (EC) is the sixth most common cancer among women globally, with an estimated 420,000 new cases diagnosed annually. Methods: This study comprised patients with endometrial cancer (EC) (n = 17), hyperplasia (HY) (n = 17), and controls (CO) (n = 20). Tissue was collected from the endometrium of all 54 patients, including patients with HY, EC, and CO, who underwent total hysterectomy. EC and HY diagnoses were confirmed based on histological examination. Untargeted metabolomics profiling was conducted using LC-HRMS. The partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA) models were used for univariate and multivariate statistical analysis. The fitness of the model (R2Y) and predictive ability (Q2) were used to create OPLS-DA models. ROC analysis was carried out, followed by network analysis using Ingenuity Pathway Analysis. Results: The top metabolites that can discriminate EC and HY from CO were identified. This revealed a decrease in the levels of the lipid species, specifically phosphatidic acid (PA) (PA (14:1/14:0), PA(10:0/17:0), PA(18:1-O(12,13)/12:0)), PG(a-13:0/a-13:0), ganglioside GA1 (d18:1/18:1), PS(14:1/14:0), TG(20:0/18:4/14:1), and CDP-DG(PGF2alpha/18:2), while the levels of 3-Dehydro-L-gulonate, Uridine diphosphate-N-acetylglucosamine, ganglioside GT2 (d18:1/14:0), gamma-glutamyl glutamic acid and oxidized glutathione were increased in cases of EC and HY as compared to CO. Bioinformatics analysis, specifically using Ingenuity Pathway Analysis (IPA), revealed distinct pathway enrichments for EC and HY. For EC, the most highly scored pathways were associated with cell-to-cell signaling and interaction, skeletal and muscular system development and function, and small-molecule biochemistry. In contrast, HY cases showed the highest scoring pathways related to inflammatory disease, inflammatory response, and organismal injury and abnormalities. Conclusions: Developing sensitive biomarkers could improve diagnosis and guide treatment decisions, particularly in identifying which patients with HY may safely avoid hysterectomy and be managed with hormonal therapy. Full article

(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics for Advancing Personalized Medicine)

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19 pages, 322 KiB

Open AccessArticle

Nutraceutical Potential of Havardia pallens and Vachellia rigidula in the Diet Formulation for Male Goat

by Jesús Humberto Reyna-Fuentes, Cecilia Carmela Zapata-Campos, Jorge Ariel Torres-Castillo, Daniel López-Aguirre, Juan Antonio Núñez-Colima, Luis Eliezer Cruz-Bacab, Fabián Eliseo Olazarán-Santibáñez, Fernando Sánchez-Dávila, Aida Isabel Leal-Robles and Juan Antonio Granados-Montelongo

Metabolites 2025, 15(7), 457; https://doi.org/10.3390/metabo15070457 - 5 Jul 2025

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Abstract

Background: Xerophilous scrubland is a semi-desert ecosystem characterized by a wide diversity of shrubs, which have secondary compounds with nutraceutical potential that could be used as feed for livestock, specifically by goats, since this species has developed behavioral and physiological adaptations that [...] Read more.

Background: Xerophilous scrubland is a semi-desert ecosystem characterized by a wide diversity of shrubs, which have secondary compounds with nutraceutical potential that could be used as feed for livestock, specifically by goats, since this species has developed behavioral and physiological adaptations that allow it to take advantage of the plant resources of said scrubland. Objective: To evaluate the nutraceutical potential of Havardia pallens and Vachellia rigidula, native species of the xerophilous scrubland, when incorporated as ingredients in goat diets. Methods: Integral diets for male goats were prepared, formulated with 35% inclusion of Havardia pallens, Vachellia rigidula, and Medicago sativa, the latter used as a plant control species. The content of flavonoids and total phenols was compared using colorimetric methods, and the antioxidant capacity was measured using the FRAP method. RP-HPLC-ESI-MS characterized the bioactive compounds in the different extracts. Statistical analysis was performed by ANOVA. Results: The aqueous extraction of Vachellia rigidula showed the highest concentration of total phenols (

\bar{x}

= 18.22 mg GAE/g⁻¹), followed by the ethanolic extract in the same species (

\bar{x}

= 17.045 mg GAE/g⁻¹). Similarly, Vachellia rigidula presented the highest antioxidant capacity (

\bar{x}

= 144,711.53 µmol TE/g⁻¹), while Medicago sativa presented the lowest (

\bar{x}

= 11,701.92 µmol TE/g). The RP-HPLC-ESI-MS analysis revealed that Vachellia rigidula presented a higher abundance of flavones, catechins, flavonols, methoxyflavones, and tyrosols. However, Harvardia pallens presented higher levels of methoxycinnamic and hydroxycinnamic acids. One-way ANOVA results showed that diets containing 35% Vachellia rigidula and Havardia pallens significantly contrasted (p < 0.05), increased the content of secondary compounds and antioxidant capacity compared to the control species. Furthermore, including Vachellia rigidula led to a significantly higher antioxidant capacity (p < 0.05) than diets with Havardia pallens or Medicago sativa. Conclusions: Incorporating the leguminous shrubs Vachellia rigidula and Havardia pallens into the formulation of comprehensive diets for buck goats improves the content and availability of phenols, flavonoids, and antioxidants. However, in vivo evaluation of these diets is important to determine their physiological and productive effects on the animals. Full article

(This article belongs to the Section Food Metabolomics)

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Metabolites, Volume 15, Issue 7 (July 2025) – 68 articles

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