Metabolites

15 pages, 768 KiB

Open AccessArticle

Dysmagnesemia in the ICU: A Comparative Analysis of Ionized and Total Magnesium Levels and Their Clinical Associations

by Jawahar H. Al Noumani, Juhaina Salim Al-Maqbali, Mohammed Al Maktoumi, Qasim Sultan AL-Maamari, Abdul Hakeem Al-Hashim, Mujahid Al-Busaidi, Henrik Falhammar and Abdullah M. Al Alawi

Metabolites 2025, 15(8), 498; https://doi.org/10.3390/metabo15080498 - 24 Jul 2025

Abstract

Background: Magnesium (Mg) is an essential mineral that plays a vital role in various physiological processes, including enzyme regulation, neuromuscular function, and cardiovascular health. Dysmagnesemia has been associated with arrhythmias, neuromuscular dysfunction, and poor outcomes in intensive care unit (ICU) settings, representing diagnostic [...] Read more.

Background: Magnesium (Mg) is an essential mineral that plays a vital role in various physiological processes, including enzyme regulation, neuromuscular function, and cardiovascular health. Dysmagnesemia has been associated with arrhythmias, neuromuscular dysfunction, and poor outcomes in intensive care unit (ICU) settings, representing diagnostic and therapeutic challenges. However, the relationship between dysmagnesemia and health outcomes in the ICU remains inadequately defined. Aim/Objective: This study aimed to assess the prevalence of dysmagnesemia and evaluate the correlation between total (tMg) and ionized magnesium (iMg) levels in a cohort of ICU and high dependency unit (HDU) patients. It also sought to evaluate patient characteristics and relevant health outcomes by comparing both concentrations of iMg and tMg. Methods: This prospective study was conducted among adult patients admitted to the ICU and the high dependency unit (HDU). Results: Among the 134 included patients, the median age was 63.5 years (IQR: 52.0–77.0). The majority, 91.0%, required mechanical ventilation. Additionally, 50.0% were diagnosed with diabetes, 28.4% had chronic kidney disease, and proton pump inhibitors (PPIs) were administered to 67.2% of the patients. The prevalence of hypomagnesemia, as measured by iMg, was 6.7%, while hypermagnesemia was at 39.6%. When measured by tMg, hypomagnesemia and hypermagnesemia were observed at rates of 14.9% and 22.4%, respectively. The iMg measurements showed an association between the incidence of atrial fibrillation and hypomagnesemia (p = 0.015), whereas tMg measurements linked hypomagnesemia with longer hospital stays. Notably, only a few patients identified with iMg-measured hypomagnesemia received magnesium replacement during their ICU stay. Conclusions: Dysmagnesemia is prevalent among critically ill patients, with discordance between iMg and tMg measurements. iMg appears more sensitive in detecting arrhythmia risk, while tMg correlates with length of stay. These findings support the need for larger studies and suggest considering iMg in magnesium monitoring and replacement strategies. Full article

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

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17 pages, 4790 KiB

Open AccessArticle

A Comparative Study Using Reversed-Phase and Hydrophilic Interaction Liquid Chromatography to Investigate the In Vitro and In Vivo Metabolism of Five Selenium-Containing Cathinone Derivatives

by Lea Wagmann, Jana H. Schmitt, Tanja M. Gampfer, Simon D. Brandt, Kenneth Scott, Pierce V. Kavanagh and Markus R. Meyer

Metabolites 2025, 15(8), 497; https://doi.org/10.3390/metabo15080497 - 23 Jul 2025

Abstract

Background/Objectives: The emergence of cathinone-based psychostimulants necessitates ongoing research and analysis of the characteristics and properties of novel derivatives. The metabolic fate of five novel cathinone-derived substances (ASProp, MASProp, MASPent, PySProp, and PySPent) containing a selenophene moiety was investigated in vitro and [...] Read more.

Background/Objectives: The emergence of cathinone-based psychostimulants necessitates ongoing research and analysis of the characteristics and properties of novel derivatives. The metabolic fate of five novel cathinone-derived substances (ASProp, MASProp, MASPent, PySProp, and PySPent) containing a selenophene moiety was investigated in vitro and in vivo. Methods: All compounds were incubated individually with pooled human liver S9 fraction. A monooxygenase activity screening investigating the metabolic contribution of eleven recombinant phase I isoenzymes was conducted. Rat urine after oral administration was prepared by urine precipitation. Liquid chromatography–high-resolution tandem mass spectrometry was used for the analysis of all samples. Reversed-phase liquid chromatography (RPLC) and zwitterionic hydrophilic interaction liquid chromatography (HILIC) were used to evaluate and compare the metabolites’ chromatographic resolution. Results: Phase I reactions of ASProp, MASProp, MASPent, PySProp, and PySPent included N-dealkylation, hydroxylation, reduction, and combinations thereof. The monooxygenase activity screening revealed the contribution of various isozymes. Phase II reactions detected in vivo included N-acetylation and glucuronidation. Both chromatographic columns complemented each other. Conclusions: All substances revealed metabolic reactions comparable to those observed for other synthetic cathinones. Contributions from isozymes to their metabolism minimized the risk of drug–drug interactions. The identified metabolites should be considered as targets in human biosamples, especially in urine screening procedures. RPLC and HILIC can both be recommended for this purpose. Full article

(This article belongs to the Special Issue Metabolite Profiling of Novel Psychoactive Substances)

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15 pages, 2382 KiB

Open AccessArticle

Study of Metabolite Detectability in Simultaneous Profiling of Amine/Phenol and Hydroxyl Submetabolomes by Analyzing a Mixture of Two Separately Dansyl-Labeled Samples

by Sicheng Quan, Shuang Zhao and Liang Li

Metabolites 2025, 15(8), 496; https://doi.org/10.3390/metabo15080496 - 23 Jul 2025

Abstract

Background: Liquid chromatography-mass spectrometry (LC-MS), widely used in metabolomics, is often limited by low ionization efficiency and ion suppression, which reduce overall metabolite detectability and quantification accuracy. To address these challenges, chemical isotope labeling (CIL) LC-MS has emerged as a powerful approach, offering [...] Read more.

Background: Liquid chromatography-mass spectrometry (LC-MS), widely used in metabolomics, is often limited by low ionization efficiency and ion suppression, which reduce overall metabolite detectability and quantification accuracy. To address these challenges, chemical isotope labeling (CIL) LC-MS has emerged as a powerful approach, offering high sensitivity, accurate quantification, and broad metabolome coverage. This method enables comprehensive profiling by targeting multiple submetabolomes. Specifically, amine-/phenol- and hydroxyl-containing metabolites are labeled using dansyl chloride under distinct reaction conditions. While this strategy provides extensive coverage, the sequential analysis of each submetabolome reduces throughput. To overcome this limitation, we propose a two-channel mixing strategy to improve analytical efficiency. Methods: In this approach, samples labeled separately for the amine/phenol and hydroxyl submetabolomes are combined prior to LC-MS analysis, leveraging the common use of dansyl chloride as the labeling reagent. This integration effectively doubles throughput by reducing LC-MS runtime and associated costs. The method was evaluated using human urine and serum samples, focusing on peak pair detectability and metabolite identification. A proof-of-concept study was also conducted to assess the approach’s applicability in putative biomarker discovery. Results: Results demonstrate that the two-channel mixing strategy enhances throughput while maintaining analytical robustness. Conclusions: This method is particularly suitable for large-scale studies that require rapid sample processing, where high efficiency is essential. Full article

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

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13 pages, 656 KiB

Open AccessArticle

Comparison of Anthropometric and Metabolic Indexes in the Diagnosis of Metabolic Syndrome: A Large-Scale Analysis of Spanish Workers

by Juan José Guarro Miquel, Pedro Juan Tárraga López, María Dolores Marzoa Jansana, Ángel Arturo López-González, Pere Riutord Sbert, Carla Busquets-Cortés and José Ignacio Ramirez-Manent

Metabolites 2025, 15(8), 495; https://doi.org/10.3390/metabo15080495 - 23 Jul 2025

Abstract

Background: Metabolic syndrome (MS) is a major public health concern linked to an elevated risk of type 2 diabetes and cardiovascular disease. Simple, reliable screening tools are needed for early identification, especially in working populations. Objective: To compare the diagnostic accuracy of body [...] Read more.

Background: Metabolic syndrome (MS) is a major public health concern linked to an elevated risk of type 2 diabetes and cardiovascular disease. Simple, reliable screening tools are needed for early identification, especially in working populations. Objective: To compare the diagnostic accuracy of body mass index (BMI), waist-to-height ratio (WtHR), triglyceride–glucose index (TyG), and waist–triglyceride index (WTI) for detecting MS based on NCEP ATP III and IDF criteria in a large cohort of Spanish workers. Methods: This cross-sectional study analyzed data from 386,924 Spanish workers. MS was diagnosed using NCEP ATP III and IDF definitions. The four indexes were evaluated by sex using a receiver operating characteristic (ROC) curve analysis. Area under the curve (AUC), optimal cut-off points, and Youden’s index were calculated. Results: TyG and WTI had the highest AUC values in men (0.911 and 0.901, respectively) for NCEP ATP III-defined MS, while WtHR and WTI achieved the best performance in women (0.955 and 0.953, respectively). WtHR outperformed BMI in all subgroups. Optimal cut-off values were identified according to sex and the definition of MS: TyG (8.95 men, 8.51 women), WtHR (0.54 men, 0.51 women), and WTI (170.6 men, 96.5 women), supporting their practical implementation in occupational health programs. All indexes showed significant discriminatory capacity (p < 0.001). Conclusions: TyG, WtHR, and WTI are more effective than BMI in detecting MS among Spanish workers, with sex-specific patterns. Their ease of use and diagnostic strength support their adoption in occupational health programs for early cardiometabolic risk detection. Full article

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

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20 pages, 1795 KiB

Open AccessReview

Sex Hormone-Binding Globulin and Metabolic Syndrome in Children and Adolescents: A Focus on Puberty

by Banu Aydin and Stephen J. Winters

Metabolites 2025, 15(8), 494; https://doi.org/10.3390/metabo15080494 - 22 Jul 2025

Abstract

Metabolic syndrome (MetS) is a cluster of conditions, including obesity, insulin resistance (IR), dyslipidemia, and hypertension, that increase the risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). While studied often in adults, the increasing prevalence of MetS in children and [...] Read more.

Metabolic syndrome (MetS) is a cluster of conditions, including obesity, insulin resistance (IR), dyslipidemia, and hypertension, that increase the risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). While studied often in adults, the increasing prevalence of MetS in children and adolescents underscores the need for its early detection and intervention. Among various biomarkers, sex hormone-binding globulin (SHBG) has gained substantial attention due to its associations with metabolic health and disease. This review provides a comprehensive overview of SHBG and its association with MetS, with a focus on the pediatric and adolescent population. The interplay between SHBG, puberty, and metabolic risk factors is explored, including racial and ethnic variations. SHBG plays a crucial role in transporting sex hormones and regulating their bioavailability and has been found to correlate inversely with obesity and IR, two key components of MetS. Puberty represents a critical period during which hormonal changes and metabolic shifts may further influence SHBG levels and metabolic health. Understanding SHBG’s role in early metabolic risk detection could provide novel insights into the prevention and management of MetS. Full article

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

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20 pages, 8392 KiB

Open AccessArticle

Annual Dynamic Changes in Lignin Synthesis Metabolites in Catalpa bungei ‘Jinsi’

by Chenxia Song, Yan Wang, Tao Sun, Yi Han, Yanjuan Mu, Xinyue Ji, Shuxin Zhang, Yanguo Sun, Fusheng Wu, Tao Liu, Ningning Li, Qingjun Han, Boqiang Tong, Xinghui Lu and Yizeng Lu

Metabolites 2025, 15(8), 493; https://doi.org/10.3390/metabo15080493 - 22 Jul 2025

Abstract

Background: Catalpa bungei ‘Jinsi’ has excellent wood properties and golden texture, which is widely used in producing furniture and crafts. The lignin content and structural composition often determine the use and value of wood. Hence, investigating the characteristics of the annual dynamics [...] Read more.

Background: Catalpa bungei ‘Jinsi’ has excellent wood properties and golden texture, which is widely used in producing furniture and crafts. The lignin content and structural composition often determine the use and value of wood. Hence, investigating the characteristics of the annual dynamics of lignin anabolic metabolites in C. bungei ‘Jinsi’ and analyzing their synthesis pathways are particularly important. Methods: We carried out targeted metabolomics analysis of lignin synthesis metabolites using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) on the xylem samples of C. bungei ‘Jinsi’ in February, April, July, October 2022, and January 2023. Results: A total of 10 lignin synthesis–related metabolites were detected: L-phenylalanine, cinnamic acid, p-coumaraldehyde, sinapic acid, p-coumaric acid, coniferaldehyde, ferulic acid, sinapaldehyde, caffeic acid, and sinapyl alcohol (annual total content from high to low). These metabolites were mainly annotated to the synthesis of secondary metabolites and phenylpropane biosynthesis. The annual total content of the 10 metabolites showed the tendency of “decreasing, then increasing, and then decreasing”. Conclusions: C. bungei ‘Jinsi’ is a typical G/S-lignin tree species, and the synthesis of G-lignin occurs earlier than that of S-lignin. The total metabolite content decreased rapidly, and the lignin anabolism process was active from April to July; the metabolites were accumulated, and the lignin anabolism process slowed down from July to October; the total metabolite content remained basically unchanged, and lignin synthesis slowed down or stagnated from October to January of the following year. This reveals the annual dynamic pattern of lignin biosynthesis, which contributes to improving the wood quality and yield of C. bungei ‘Jinsi’ and provides a theoretical basis for its targeted breeding. Full article

(This article belongs to the Special Issue Phenological Regulation of Secondary Metabolism)

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16 pages, 1988 KiB

Open AccessArticle

The Impact of Uranium-Induced Pulmonary Fibrosis on Gut Microbiota and Related Metabolites in Rats

by Ruifeng Dong, Xiaona Gu, Lixia Su, Qingdong Wu, Yufu Tang, Hongying Liang, Xiangming Xue, Teng Zhang and Jingming Zhan

Metabolites 2025, 15(8), 492; https://doi.org/10.3390/metabo15080492 - 22 Jul 2025

Abstract

Background/Objectives: This study aimed to evaluate the effects of lung injury induced by insoluble uranium oxide particles on gut microbiota and related metabolites in rats. Methods: The rats were randomly divided into six UO₂ dose groups. A rat lung injury [...] Read more.

Background/Objectives: This study aimed to evaluate the effects of lung injury induced by insoluble uranium oxide particles on gut microbiota and related metabolites in rats. Methods: The rats were randomly divided into six UO₂ dose groups. A rat lung injury model was established through UO₂ aerosol. The levels of uranium in lung tissues were detected by ICP-MS. The expression levels of the inflammatory factors and fibrosis indexes were measured by enzyme-linked immunosorbent assay. Paraffin embedding-based hematoxylin & eosin staining for the lung tissue was performed to observe the histopathological imaging features. Metagenomic sequencing technology and HM700-targeted metabolomics were conducted in lung tissues. Results: Uranium levels in the lung tissues increased with dose increase. The expression levels of Tumor Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β), Collagen I, and Hydroxyproline (Hyp) in rat lung homogenate increased with dose increase. Inflammatory cell infiltration and the deposition of extracellular matrix were observed in rat lung tissue post-exposure. Compared to the control group, the ratio of Firmicutes and Bacteroides in the gut microbiota decreased, the relative abundance of Akkermansia_mucinphila decreased, and the relative abundance of Bacteroides increased. The important differential metabolites mainly include αlpha-linolenic acid, gamma-linolenic acid, 2-Hydroxybutyric acid, Beta-Alanine, Maleic acid, Hyocholic acid, L-Lysine, L-Methionine, L-Leucine, which were mainly concentrated in unsaturated fatty acid biosynthesis, propionic acid metabolism, aminoacyl-tRNA biosynthesis, phenylalanine metabolism, and other pathways in the UO₂ group compared to the control group. Conclusions: These findings suggest that uranium-induced lung injury can cause the disturbance of gut microbiota and its metabolites in rats, and these changes are mainly caused by Akkermansia_mucinphila and Bacteroides, focusing on unsaturated fatty acid biosynthesis and the propionic acid metabolism pathway. Full article

(This article belongs to the Section Animal Metabolism)

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12 pages, 246 KiB

Open AccessArticle

Riboflavin Transporter Deficiency Type 2: Expanding the Phenotype of the Lebanese Founder Mutation p.Gly306Arg in the SLC52A2 Gene

by Jean-Marc T. Jreissati, Leonard Lawandos, Julien T. Jreissati and Pascale E. Karam

Metabolites 2025, 15(7), 491; https://doi.org/10.3390/metabo15070491 - 21 Jul 2025

Abstract

Background: Riboflavin transporter deficiency type 2 is an ultra-rare, yet treatable, inborn error of metabolism. This autosomal recessive disorder is caused by pathogenic mutations in the SLC52A2 gene leading to progressive ataxia, polyneuropathy, and hearing and visual impairment. The early initiation of [...] Read more.

Background: Riboflavin transporter deficiency type 2 is an ultra-rare, yet treatable, inborn error of metabolism. This autosomal recessive disorder is caused by pathogenic mutations in the SLC52A2 gene leading to progressive ataxia, polyneuropathy, and hearing and visual impairment. The early initiation of riboflavin therapy can prevent or mitigate the complications. To date, only 200 cases have been reported, mostly in consanguineous populations. The p.Gly306Arg founder mutation, identified in patients of Lebanese descent, is the most frequently reported worldwide. It was described in a homozygous state in a total of 21 patients. Therefore, studies characterizing the phenotypic spectrum of this mutation remain scarce. Methods: A retrospective review of charts of patients diagnosed with riboflavin transporter deficiency type 2 at a tertiary-care reference center in Lebanon was performed. Clinical, biochemical, and molecular profiles were analyzed and compared to reported cases in the literature. Results: A total of six patients from three unrelated families were diagnosed between 2018 and 2023. All patients exhibited the homozygous founder mutation, p.Gly306Arg, with variable phenotypes, even among family members. The median age of onset was 3 years. Diagnosis was achieved by exome sequencing at a median age of 5 years, as clinical and biochemical profiles were inconsistently suggestive. The response to riboflavin was variable. One patient treated with high-dose riboflavin recovered his motor function, while the others were stabilized. Conclusions: This study expands the current knowledge of the phenotypic spectrum associated with the p.Gly306Arg mutation in the SLC52A2 gene. Increased awareness among physicians of the common manifestations of this rare disorder is crucial for early diagnosis and treatment. In the absence of a consistent clinical or biochemical phenotype, the use of next-generation sequencing as a first-tier diagnostic test may be considered. Full article

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

18 pages, 2513 KiB

Open AccessArticle

Decoding Fish Origins: How Metals and Metabolites Differentiate Wild, Cultured, and Escaped Specimens

by Warda Badaoui, Kilian Toledo-Guedes, Juan Manuel Valero-Rodriguez, Adrian Villar-Montalt and Frutos C. Marhuenda-Egea

Metabolites 2025, 15(7), 490; https://doi.org/10.3390/metabo15070490 - 21 Jul 2025

Abstract

Background: Fish escape events from aquaculture facilities are increasing and pose significant ecological, economic, and traceability concerns. Accurate methods to differentiate between wild, cultured, and escaped fish are essential for fishery management and seafood authentication. Methods: This study analyzed muscle tissue from Sparus [...] Read more.

Background: Fish escape events from aquaculture facilities are increasing and pose significant ecological, economic, and traceability concerns. Accurate methods to differentiate between wild, cultured, and escaped fish are essential for fishery management and seafood authentication. Methods: This study analyzed muscle tissue from Sparus aurata, Dicentrarchus labrax, and Argyrosomus regius using a multiomics approach. Heavy metals were quantified by ICP-MS, fatty acid profiles were assessed via GC-MS, and metabolomic and lipidomic signatures were identified using 1H NMR spectroscopy. Multivariate statistical models (MDS and PLS-LDA) were applied to classify fish origins. Results: Wild seabream showed significantly higher levels of arsenic (9.5-fold), selenium (3.5-fold), and DHA and ARA fatty acids (3.2-fold), while cultured fish exhibited increased linoleic and linolenic acids (6.5-fold). TMAO concentrations were up to 5.3-fold higher in wild fish, serving as a robust metabolic biomarker. Escaped fish displayed intermediate biochemical profiles. Multivariate models achieved a 100% classification accuracy across species and analytical techniques. Conclusions: The integration of heavy metal analysis, fatty acid profiling, and NMR-based metabolomics enables the accurate differentiation of fish origin. While muscle tissue provides reliable biomarkers relevant to human exposure, future studies should explore additional tissues such as liver and gills to improve the resolution of traceability. These methods support seafood authentication, enhance aquaculture traceability, and aid in managing the ecological impacts of escape events. Full article

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

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28 pages, 8123 KiB

Open AccessArticle

Human Metabolism of Sirolimus Revisited

by Baharak Davari, Touraj Shokati, Alexandra M. Ward, Vu Nguyen, Jost Klawitter, Jelena Klawitter and Uwe Christians

Metabolites 2025, 15(7), 489; https://doi.org/10.3390/metabo15070489 - 20 Jul 2025

Abstract

Background: Sirolimus (SRL, rapamycin) is a clinically important mTOR inhibitor used in immunosuppression, oncology, and cardiovascular drug-eluting devices. Despite its long-standing FDA approval, the human metabolic profile of SRL remains incompletely characterized. SRL is primarily metabolized by CYP3A enzymes in the liver and [...] Read more.

Background: Sirolimus (SRL, rapamycin) is a clinically important mTOR inhibitor used in immunosuppression, oncology, and cardiovascular drug-eluting devices. Despite its long-standing FDA approval, the human metabolic profile of SRL remains incompletely characterized. SRL is primarily metabolized by CYP3A enzymes in the liver and intestine, but the diversity, pharmacokinetics, and biological activity of its metabolites have been poorly explored due to the lack of structurally identified standards. Methods: To investigate SRL metabolism, we incubated SRL with pooled human liver microsomes (HLM) and isolated the resulting metabolites. Structural characterization was performed using high-resolution mass spectrometry (HRMS) and ion trap MSⁿ. We also applied Density Functional Theory (DFT) calculations to assess the energetic favorability of metabolic transformations and conducted molecular dynamics (MD) simulations to model metabolite interactions within the CYP3A4 active site. Results: We identified 21 unique SRL metabolites, classified into five major structural groups: O-demethylated, hydroxylated, didemethylated, di-hydroxylated, and mixed hydroxylated/demethylated derivatives. DFT analyses indicated that certain demethylation and hydroxylation reactions were energetically preferred, correlating with metabolite abundance. MD simulations further validated these findings by demonstrating the favorable orientation and accessibility of key sites within the CYP3A4 binding pocket. Conclusions: This study provides a comprehensive structural map of SRL metabolism, offering mechanistic insights into the formation of its metabolites. Our integrated approach of experimental and computational analyses lays the groundwork for future investigations into the pharmacodynamic and toxicodynamic effects of SRL metabolites on the mTOR pathway. Full article

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

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20 pages, 1836 KiB

Open AccessArticle

Advancing Semiochemical Tools for Mountain Pine Beetle Management: Dendroctonus ponderosae Responses to Saprophytic Fungal Volatiles

by Leah Crandall, Rashaduz Zaman, Guncha Ishangulyyeva and Nadir Erbilgin

Metabolites 2025, 15(7), 488; https://doi.org/10.3390/metabo15070488 - 20 Jul 2025

Abstract

Background/Objectives: Within their host trees, mountain pine beetles (MPBs, Dendroctonus ponderosae) interact with many fungal species, each releasing a unique profile of volatile organic compounds (VOCs). The FVOCs released by the two primary symbionts of MPBs, Grosmannia clavigera and Ophiostoma montium, [...] Read more.

Background/Objectives: Within their host trees, mountain pine beetles (MPBs, Dendroctonus ponderosae) interact with many fungal species, each releasing a unique profile of volatile organic compounds (VOCs). The FVOCs released by the two primary symbionts of MPBs, Grosmannia clavigera and Ophiostoma montium, have been found to enhance MPB attraction in the field and laboratory studies. Opportunistic, saprophytic fungal species, such as Aspergillus sp. and Trichoderma atroviride, are also common in MPB galleries and can negatively impact MPB fitness. However, little is known about the FVOCs produced by these fungal species and how they may impact MPB feeding and attraction. Methods: To address this knowledge gap, we characterized the FVOC profile of T. atroviride, and performed bioassays to test the effects of its FVOCs on MPB attraction and feeding activity. Results: Our chemical analysis revealed several FVOCs from T. atroviride known to inhibit the growth of competing fungal species and impact subcortical-beetle attraction. Conclusions: From those FVOCs, we recommended four compounds—2-pentanone, 2-heptanone, 2-pentanol, and phenylethyl alcohol—for use in future field tests as anti-attraction lures for MPBs. In bioassays, we also observed strong MPB repellency from FVOCs released by T. atroviride, as well as the mild effects of FVOCs on MPB feeding activity. Our findings highlight the potential for these FVOCs to be utilized in the development of more effective MPB anti-attractant lures, which are crucial for the monitoring and management of low-density MPB populations. Full article

(This article belongs to the Special Issue Dysbiosis and Metabolic Disorders of the Microbiota)

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26 pages, 2170 KiB

Open AccessArticle

Exploratory Metabolomic and Lipidomic Profiling in a Manganese-Exposed Parkinsonism-Affected Population in Northern Italy

by Freeman Lewis, Daniel Shoieb, Somaiyeh Azmoun, Elena Colicino, Yan Jin, Jinhua Chi, Hari Krishnamurthy, Donatella Placidi, Alessandro Padovani, Andrea Pilotto, Fulvio Pepe, Marinella Tula, Patrizia Crippa, Xuexia Wang, Haiwei Gu and Roberto Lucchini

Metabolites 2025, 15(7), 487; https://doi.org/10.3390/metabo15070487 - 20 Jul 2025

Abstract

Background/Objectives: Chronic manganese (Mn) exposure is a recognized environmental contributor to Parkinsonian syndromes, including Mn-induced Parkinsonism (MnIP). This study aimed to evaluate whole-blood Mn levels and investigate disease/exposure-status-related alterations in metabolomic and lipidomic profiles. Methods: A case–control study (N = 97) was conducted [...] Read more.

Background/Objectives: Chronic manganese (Mn) exposure is a recognized environmental contributor to Parkinsonian syndromes, including Mn-induced Parkinsonism (MnIP). This study aimed to evaluate whole-blood Mn levels and investigate disease/exposure-status-related alterations in metabolomic and lipidomic profiles. Methods: A case–control study (N = 97) was conducted in Brescia, Italy, stratifying participants by Parkinsonism diagnosis and residential Mn exposure. Whole-blood Mn was quantified using ICP-MS. Untargeted metabolomic and lipidomic profiling was conducted using LC-MS. Statistical analyses included Mann–Whitney U tests, conditional logistic regression, ANCOVA, and pathway analysis. Results: Whole-blood Mn levels were significantly elevated in Parkinsonism cases vs. controls (median: 1.55 µg/dL [IQR: 0.75] vs. 1.02 µg/dL [IQR: 0.37]; p = 0.001), with Mn associated with increased odds of Parkinsonism (OR = 2.42, 95% CI: 1.13–5.17; p = 0.022). The disease effect metabolites included 3-sulfoxy-L-tyrosine (β = 1.12), formiminoglutamic acid (β = 0.99), and glyoxylic acid (β = 0.83); all FDR p < 0.001. The exposure effect was associated with elevated glycocholic acid (β = 0.51; FDR p = 0.006) and disrupted butanoate (Impact = 0.03; p = 0.004) and glutamate metabolism (p = 0.03). Additionally, SLC-mediated transmembrane transport was enriched (p = 0.003). The interaction effect identified palmitelaidic acid (β = 0.30; FDR p < 0.001), vitamin B6 metabolism (Impact = 0.08; p = 0.03), and glucose homeostasis pathways. In lipidomics, triacylglycerols and phosphatidylethanolamines were associated with the disease effect (e.g., TG(16:0_10:0_18:1), β = 0.79; FDR p < 0.01). Ferroptosis and endocannabinoid signaling were enriched in both disease and interaction effects, while sphingolipid metabolism was specific to the interaction effect. Conclusions: Mn exposure and Parkinsonism are associated with distinct metabolic and lipidomic perturbations. These findings support the utility of omics in identifying environmentally linked Parkinsonism biomarkers and mechanisms. Full article

(This article belongs to the Special Issue Metabolomics in Human Diseases and Health)

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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-Feng Tsai, Yen-Ju Chiu, Yu-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

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

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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