Metabolites

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

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, 774 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

21 pages, 2655 KiB

Open AccessArticle

Integrative Modeling of Urinary Metabolomics and Metal Exposure Reveals Systemic Impacts of Electronic Waste in Exposed Populations

by Fiona Hui, Zhiqiang Pang, Charles Viau, Gerd U. Balcke, Julius N. Fobil, Niladri Basu and Jianguo Xia

Metabolites 2025, 15(7), 456; https://doi.org/10.3390/metabo15070456 - 5 Jul 2025

Abstract

Background: Informal electronic waste (e-waste) recycling practices release a complex mixture of pollutants, particularly heavy metals, into the environment. Chronic exposure to these contaminants has been linked to a range of health risks, but the molecular underpinnings remain poorly understood. In this [...] Read more.

Background: Informal electronic waste (e-waste) recycling practices release a complex mixture of pollutants, particularly heavy metals, into the environment. Chronic exposure to these contaminants has been linked to a range of health risks, but the molecular underpinnings remain poorly understood. In this study, we investigated the alterations in metabolic profiles due to e-waste exposure and linked these metabolites to systemic biological effects. Methods: We applied untargeted high-resolution metabolomics using dual-column LC-MS/MS and a multi-step analysis workflow combining MS1 feature detection, MS2 annotation, and chemical ontology classification, to characterize urinary metabolic alterations in 91 e-waste workers and 51 community controls associated with the Agbogbloshie site (Accra, Ghana). The impacts of heavy metal exposure in e-waste workers were assessed by establishing linear regression and four-parameter logistic (4PL) models between heavy metal levels and metabolite concentrations. Results: Significant metal-associated metabolomic changes were identified. Both linear and nonlinear models revealed distinct sets of exposure-responsive compounds, highlighting diverse biological responses. Ontology-informed annotation revealed systemic effects on lipid metabolism, oxidative stress pathways, and xenobiotic biotransformation. This study demonstrates how integrating chemical ontology and nonlinear modeling facilitates exposome interpretation in complex environments and provides a scalable template for environmental biomarker discovery. Conclusions: Integrating dose–response modeling and chemical ontology analysis enables robust interpretation of exposomics datasets when direct compound identification is limited. Our findings indicate that e-waste exposure induces systemic metabolic alterations that can underlie health risks and diseases. Full article

(This article belongs to the Special Issue Method Development in Metabolomics and Exposomics)

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Graphical abstract

12 pages, 243 KiB

Open AccessArticle

Effects of Eight Weeks of Aerobic Training Combined with Carbohydrate Mouth Rinse on Body Composition and Exercise Performance in Adult Men with Obesity: Evidence from Korea

by Jae-Myun Ko, Wi-Young So and Sung-Eun Park

Metabolites 2025, 15(7), 455; https://doi.org/10.3390/metabo15070455 - 5 Jul 2025

Abstract

Background: Considering that the prevalence of obesity has risen rapidly in recent decades, the aim of this study was to investigate the effects of a carbohydrate mouth rinse (CMR) on the outcomes of aerobic training among adult men with obesity, focusing particularly on [...] Read more.

Background: Considering that the prevalence of obesity has risen rapidly in recent decades, the aim of this study was to investigate the effects of a carbohydrate mouth rinse (CMR) on the outcomes of aerobic training among adult men with obesity, focusing particularly on the effects of repeated use on body composition and exercise performance. Methods: The intervention targeted 20 men with obesity in their 20s and 30s randomly assigned to either a CMR group (n = 10) or a placebo mouth rinse (PMR) group (n = 10). Both groups completed treadmill-based aerobic training three times per week for eight weeks. Prior to each session, participants used a mouth rinse at 60, 40, and 20 s before the start of each exercise, holding either a 6% maltodextrin solution (CMR) or purified water (PMR) in their mouths for 5 to 10 s before expectorating. Pre- and post-intervention assessments included body composition (body weight and body fat percentage), resting metabolic rate (RMR), maximal oxygen uptake (VO₂max), and exercise performance (rate of perceived exertion [RPE], exercise distance, speed, and time). Data were analyzed using 2 × 2 repeated measures analysis of variance. Results: Following the intervention, the CMR group showed significantly greater improvements than the PMR group did in body fat percentage, RMR, VO₂max, exercise distance, speed, and time (p < 0.01). However, the interaction effect for RPE was not statistically significant between the groups (p = 0.175). Overall, the repeated use of the CMR during aerobic training contributed to enhanced exercise performance and favorable physiological changes without additional caloric intake. Conclusions: A CMR may be a practical and non-caloric ergogenic aid to support exercise performance and metabolic function in individuals with obesity. Its repeated use during aerobic training appears to be effective and safe, especially when fasting while exercising, when improving endurance without compromising fat loss is essential. Full article

(This article belongs to the Special Issue Effects of Various Exercise Methods on Metabolic Health)

22 pages, 4243 KiB

Open AccessReview

Extracellular Vesicle Metabolomics Holds Promise for Adult Axon Regeneration

by Maria D. Cabrera Gonzalez, Jackson Watson, Laura Leal, Isabella Moceri, Camille Plummer, Biraj Mahato, Abdelrahman Y. Fouda and Sanjoy K. Bhattacharya

Metabolites 2025, 15(7), 454; https://doi.org/10.3390/metabo15070454 - 4 Jul 2025

Abstract

Extracellular vesicles (EVs) are bilayer lipid membrane particles that are released by every cell type. These secretions are further classified as exosomes, ectosomes, and microvesicles. They contain biomolecules (RNAs, proteins, metabolites, and lipids) with the ability to modulate various biological processes and have [...] Read more.

Extracellular vesicles (EVs) are bilayer lipid membrane particles that are released by every cell type. These secretions are further classified as exosomes, ectosomes, and microvesicles. They contain biomolecules (RNAs, proteins, metabolites, and lipids) with the ability to modulate various biological processes and have been shown to play a role in intercellular communication and cellular rejuvenation. Various studies suggest exosomes and/or microvesicles as a potential platform for drug delivery. EVs may deliver lipids and nucleotides directly to an injury site in an axon, promoting growth cone stabilization and membrane expansion as well as repair, thus positively modulating adult axon regeneration. In this review, we will provide a perspective on the metabolite composition of EVs in adult axonal regeneration relevant to the central nervous system (CNS), specifically that pertaining to the optic nerve. We will present an overview of the methods for isolation, enrichment, omics data analysis and quantification of extracellular vesicles with the goal of providing direction for future studies relevant to axon regeneration. We will also include current resources for multi-omics data integration relevant to extracellular vesicles from diverse cell types. Full article

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

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