Metabolites

12 pages, 9300 KB

Open AccessEditor’s ChoiceArticle

Phenolic Metabolites Protocatechuic Acid and Vanillic Acid Improve Nitric Oxide Bioavailability via the Akt-eNOS Pathway in Response to TNF-α Induced Oxidative Stress and Inflammation in Endothelial Cells

by Joseph Festa, Aamir Hussain, Zakia Al-Hareth, Stephen J. Bailey, Harprit Singh and Mariasole Da Boit

Metabolites 2024, 14(11), 613; https://doi.org/10.3390/metabo14110613 - 11 Nov 2024

Cited by 3 | Viewed by 1424

Abstract

Background/Objectives: Reduced nitric oxide (NO) bioavailability secondary to excess-superoxide-driven oxidative stress is central to endothelial dysfunction. Previous studies suggest that phenolic metabolites may improve NO bioavailability, yet limited research is available in response to an inflammatory mediator. Therefore, we assessed the effects [...] Read more.

Background/Objectives: Reduced nitric oxide (NO) bioavailability secondary to excess-superoxide-driven oxidative stress is central to endothelial dysfunction. Previous studies suggest that phenolic metabolites may improve NO bioavailability, yet limited research is available in response to an inflammatory mediator. Therefore, we assessed the effects of cyanidin-3-glucoside (C3G) and its phenolic metabolites protocatechuic acid (PCA) and vanillic acid (VA) on NO bioavailability in a TNF-α induced inflammatory environment. Methods: Primary human umbilical vein endothelial cells (HUVECs) were supplemented with either C3G, PCA, or VA at 1 μM for 24 h before being stimulated with TNF-α 20 ng/mL for an additional 24 h. Measurements included cell viability, apoptosis, reactive oxygen species (ROS), nitrite concentrations, and endothelial nitric oxide synthase (eNOS) and Akt at the mRNA and protein level. Results: Phenolic metabolites did not increase the eNOS expression or nitrite levels in the unstimulated environment; rather, the metabolites mediated NO bioavailability in response to TNF-α induced oxidative stress, with increased viability, eNOS mRNA, phosphorylation, and nitrite levels. Conclusions: Phenolic metabolites, in the presence of TNF-α, can improve NO bioavailability at physiologically relevant concentrations via the Akt-eNOS pathway. This demonstrates that the induction of inflammation is a prerequisite for phenolic metabolites to promote protective properties in endothelial cells by activating the Akt-eNOS pathway. Full article

(This article belongs to the Section Cell Metabolism)

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13 pages, 2623 KB

Open AccessEditor’s ChoiceArticle

Metabolomics of Papanicolaou Tests for the Discovery of Ovarian Cancer Biomarkers

by Samyukta Sah, Elisabeth M. Schwiebert, Samuel G. Moore, Ying Liu, David A. Gaul, Kristin L. M. Boylan, Amy P. N. Skubitz and Facundo M. Fernández

Metabolites 2024, 14(11), 600; https://doi.org/10.3390/metabo14110600 - 7 Nov 2024

Viewed by 1753

Abstract

Background: Ovarian cancer (OC) remains one of the most lethal cancers among women due to most cases going undiagnosed until later stages. The early detection and treatment of this malignancy provides the best prognosis, but the lack of an accurate and sensitive [...] Read more.

Background: Ovarian cancer (OC) remains one of the most lethal cancers among women due to most cases going undiagnosed until later stages. The early detection and treatment of this malignancy provides the best prognosis, but the lack of an accurate and sensitive screening tool combined with ambiguous symptoms hinders these diagnoses. In contrast, screening for cervical cancer via Papanicolaou (Pap) tests is a widespread practice that greatly reduces the cancer’s mortality rates. Interestingly, previous studies show evidence of OC cells in Pap tests, suggesting that proteins, and potentially lipids, shed from ovarian tumors end up in the cervix. The goal of this study is to evaluate the practicality of using Pap tests as biospecimens for OC-screening-related metabolomics. Methods: To evaluate the effectiveness of using residual Pap test samples as biospecimens for potential metabolomics work, 29 Pap test samples, collected from women over the age of 50 with normal cytology and no visible blood contamination, were first obtained from the University of Minnesota, with IRB approval. These samples were centrifuged to recover the cell pellets from the supernatants. The cell pellets underwent a biphasic extraction, followed by an RP-LC-MS analysis, while the supernatants underwent two separate extractions and analyses, including RP-LC-MS and HILIC-LC-MS. Non-targeted features were detected in the range of 220–1000 m/z to determine the sensitivity and scope of the various extraction and analytical workflows, as well as evaluating residual Pap test samples as viable metabolomics biospecimens. Results: The biphasic extraction and subsequent RP-LC-MS analysis of the isolated cell pellets from all 29 samples yielded informative, exploratory data, highlighting the potential of using residual Pap test samples as biospecimens for metabolomics, specifically lipidomics, studies. Each sample was analyzed in both the positive and negative ion mode, yielding the detection of 7318 in the positive ion mode and 3733 in the negative ion mode. Using multiple reference libraries, 22.85% and 36.19% of these features were annotated in the positive and negative ion mode, respectively. Among these detected features, 453 unique lipids, representative of 20 different lipid subclasses, were annotated in all 29 samples. Of the various lipid subclasses represented from the detected lipids, ceramides, triacylglycerols, hexosylceramides, and phosphatidylcholines contributed to over half (53.3%) of the detected lipids at 16.2%, 13.0%, 12.8%, and 11.3%, respectively. Conclusions: The detection of these 453 common lipids across all patients establishes a relative lipidome baseline for women over the age of 50 with normal cervical cytology. This exploratory study is the first investigation to utilize residual Pap test samples as biospecimens in a metabolomics/lipidomics workflow. Full article

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

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16 pages, 2250 KB

Open AccessEditor’s ChoiceArticle

MS2Lipid: A Lipid Subclass Prediction Program Using Machine Learning and Curated Tandem Mass Spectral Data

by Nami Sakamoto, Takaki Oka, Yuki Matsuzawa, Kozo Nishida, Jayashankar Jayaprakash, Aya Hori, Makoto Arita and Hiroshi Tsugawa

Metabolites 2024, 14(11), 602; https://doi.org/10.3390/metabo14110602 - 7 Nov 2024

Cited by 2 | Viewed by 1936

Abstract

Background: Untargeted lipidomics using collision-induced dissociation-based tandem mass spectrometry (CID-MS/MS) is essential for biological and clinical applications. However, annotation confidence still relies on manual curation by analytical chemists, despite the development of various software tools for automatic spectral processing based on rule-based [...] Read more.

Background: Untargeted lipidomics using collision-induced dissociation-based tandem mass spectrometry (CID-MS/MS) is essential for biological and clinical applications. However, annotation confidence still relies on manual curation by analytical chemists, despite the development of various software tools for automatic spectral processing based on rule-based fragment annotations. Methods: In this study, we present a novel machine learning model, MS2Lipid, for the prediction of known lipid subclasses from MS/MS queries, providing an orthogonal approach to existing lipidomics software programs in determining the lipid subclass of ion features. We designed a new descriptor, MCH (mode of carbon and hydrogen), to increase the specificity of lipid subclass prediction in nominal mass resolution MS data. Results: The model, trained with 6760 and 6862 manually curated MS/MS spectra for the positive and negative ion modes, respectively, classified queries into one or several of 97 lipid subclasses, achieving an accuracy of 97.4% in the test set. The program was further validated using various datasets from different instruments and curators, with the average accuracy exceeding 87.2%. Using an integrated approach with molecular spectral networking, we demonstrated the utility of MS2Lipid by annotating microbiota-derived esterified bile acids, whose abundance was significantly increased in fecal samples of obese patients in a human cohort study. This suggests that the machine learning model provides an independent criterion for lipid subclass classification, enhancing the annotation of lipid metabolites within known lipid classes. Conclusions: MS2Lipid is a highly accurate machine learning model that enhances lipid subclass annotation from MS/MS data and provides an independent criterion. Full article

(This article belongs to the Special Issue Metabolomics and Bioinformatics Approaches to Studying Human Gut Microbiota-Derived Metabolites)

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17 pages, 2954 KB

Open AccessEditor’s ChoiceArticle

Integrated Metabolomic and Transcriptomic Analysis of Nitraria Berries Indicate the Role of Flavonoids in Adaptation to High Altitude

by Qing Zhao, Jie Zhang, Yanhong Li, Zufan Yang, Qian Wang and Qiangqiang Jia

Metabolites 2024, 14(11), 591; https://doi.org/10.3390/metabo14110591 - 1 Nov 2024

Cited by 3 | Viewed by 1410

Abstract

Background: Plants of Nitraria, belonging to the Zygophyllaceae family, are not only widely distributed at an altitude of about 1000 m but also at an altitude of about 3000 m, which is a rare phenomenon. However, little is known about the effect [...] Read more.

Background: Plants of Nitraria, belonging to the Zygophyllaceae family, are not only widely distributed at an altitude of about 1000 m but also at an altitude of about 3000 m, which is a rare phenomenon. However, little is known about the effect of altitude on the accumulation of metabolites in plants of Nitraria. Furthermore, the mechanism of the high–altitude adaptation of Nitraria has yet to be fully elucidated. Methods: In this study, metabolomics and transcriptomics were used to investigate the differential accumulation of metabolites of Nitraria berries and the regulatory mechanisms in different altitudes. Results: As a result, the biosynthesis of flavonoids is the most significant metabolic pathway in the process of adaptation to high altitude, and 5 Cyanidins, 1 Pelargonidin, 3 Petunidins, 1 Peonidin, and 4 Delphinidins are highly accumulated in high–altitude Nitraria. The results of transcriptomics showed that the structural genes C4H (2), F3H, 4CL (2), DFR (2), UFGT (2), and FLS (2) were highly expressed in high–altitude Nitraria. A network metabolism map of flavonoids was constructed, and the accumulation of differential metabolites and the expression of structural genes were analyzed for correlation. Conclusions: In summary, this study preliminarily offers a new understanding of metabolic differences and regulation mechanisms in plants of Nitraria from different altitudes. Full article

(This article belongs to the Section Plant Metabolism)

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21 pages, 1539 KB

Open AccessEditor’s ChoiceReview

Exercise as a Therapeutic Strategy for Obesity: Central and Peripheral Mechanisms

by Yiyin Zhang, Ruwen Wang, Tiemin Liu and Ru Wang

Metabolites 2024, 14(11), 589; https://doi.org/10.3390/metabo14110589 - 30 Oct 2024

Cited by 4 | Viewed by 6664

Abstract

Obesity is a complex, multifactorial condition involving excessive fat accumulation due to an imbalance between energy intake and expenditure, with its global prevalence steadily rising. This condition significantly increases the risk of chronic diseases, including sarcopenia, type 2 diabetes, and cardiovascular diseases, highlighting [...] Read more.

Obesity is a complex, multifactorial condition involving excessive fat accumulation due to an imbalance between energy intake and expenditure, with its global prevalence steadily rising. This condition significantly increases the risk of chronic diseases, including sarcopenia, type 2 diabetes, and cardiovascular diseases, highlighting the need for effective interventions. Exercise has emerged as a potent non-pharmacological approach to combat obesity, targeting both central and peripheral mechanisms that regulate metabolism, energy expenditure, and neurological functions. In the central nervous system, exercise influences appetite, mood, and cognitive functions by modulating the reward system and regulating appetite-controlling hormones to manage energy intake. Concurrently, exercise promotes thermogenesis in adipose tissue and regulates endocrine path-ways and key metabolic organs, such as skeletal muscle and the liver, to enhance fat oxidation and support energy balance. Despite advances in understanding exercise’s role in obesity, the precise interaction between the neurobiological and peripheral metabolic pathways remains underexplored, particularly in public health strategies. A better understanding of these interactions could inform more comprehensive obesity management approaches by addressing both central nervous system influences on behavior and peripheral metabolic regulation. This review synthesizes recent insights into these roles, highlighting potential therapeutic strategies targeting both systems for more effective obesity interventions. Full article

(This article belongs to the Special Issue Exploring Pathological Mechanisms in Obesity, Diabetes, and Metabolic Syndrome)

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15 pages, 1886 KB

Open AccessEditor’s ChoiceArticle

Predicting the Pathway Involvement of All Pathway and Associated Compound Entries Defined in the Kyoto Encyclopedia of Genes and Genomes

by Erik D. Huckvale and Hunter N. B. Moseley

Metabolites 2024, 14(11), 582; https://doi.org/10.3390/metabo14110582 - 27 Oct 2024

Cited by 2 | Viewed by 1232

Abstract

Background/Objectives: Predicting the biochemical pathway involvement of a compound could facilitate the interpretation of biological and biomedical research. Prior prediction approaches have largely focused on metabolism, training machine learning models to solely predict based on metabolic pathways. However, there are many other [...] Read more.

Background/Objectives: Predicting the biochemical pathway involvement of a compound could facilitate the interpretation of biological and biomedical research. Prior prediction approaches have largely focused on metabolism, training machine learning models to solely predict based on metabolic pathways. However, there are many other types of pathways in cells and organisms that are of interest to biologists. Methods: While several publications have made use of the metabolites and metabolic pathways available in the Kyoto Encyclopedia of Genes and Genomes (KEGG), we downloaded all the compound entries with pathway annotations available in the KEGG. From these data, we constructed a dataset where each entry contained features representing compounds combined with features representing pathways, followed by a binary label indicating whether the given compound is associated with the given pathway. We trained multi-layer perceptron binary classifiers on variations of this dataset. Results: The models trained on 6485 KEGG compounds and 502 pathways scored an overall mean Matthews correlation coefficient (MCC) performance of 0.847, a median MCC of 0.848, and a standard deviation of 0.0098. Conclusions: This performance on all 502 KEGG pathways represents a roughly 6% improvement over the performance of models trained on only the 184 KEGG metabolic pathways, which had a mean MCC of 0.800 and a standard deviation of 0.021. These results demonstrate the capability to effectively predict biochemical pathways in general, in addition to those specifically related to metabolism. Moreover, the improvement in the performance demonstrates additional transfer learning with the inclusion of non-metabolic pathways. Full article

(This article belongs to the Special Issue Machine Learning Applications in Metabolomics Analysis)

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17 pages, 7552 KB

Open AccessEditor’s ChoiceArticle

Metabolomics Reveal Key Metabolic Pathway Responses to Anxiety State Regulated by Serotonin in Portunus trituberculatus

by Wei Zhai, Yuanyuan Fu, Lei Liu, Xinlian Huang and Sixiang Wang

Metabolites 2024, 14(10), 568; https://doi.org/10.3390/metabo14100568 - 21 Oct 2024

Cited by 1 | Viewed by 2090

Abstract

Background: Anxiety refers to the pathological persistence and intensification of emotional responses to danger, affecting health from psychological and physical aspects. Serotonin is an important neurotransmitter involved in the onset of anxiety. Methods and Results: To explore the biological changes in the formation [...] Read more.

Background: Anxiety refers to the pathological persistence and intensification of emotional responses to danger, affecting health from psychological and physical aspects. Serotonin is an important neurotransmitter involved in the onset of anxiety. Methods and Results: To explore the biological changes in the formation of anxiety in crustaceans under the regulation of serotonin, we applied the open field-like test method for assessing anxiety states of larval Portunus trituberculatus, a highly aggressive crustacean species with a more simple neural structure compared with rodents and mammals. Compared with the control group, serotonin treatment resulted in a significant decrease in the time spent by the larvae in the central zone, suggesting anxiety-like behavior. Clonazepam treatment reversed this result and provided further evidence that the behavior of larval P. trituberculatus displayed anxiety. Moreover, a non-targeted metabolomic analysis found a significant alteration in the metabolites involved in tryptophan metabolism pathways associated with anxiety, including L-kynurenine, N-acetyl serotonin, and serotonin. These metabolites are involved in the serotonin pathway, the kynurenine pathway, and other pathways that affect anxiety through tryptophan metabolism. There were no significant differences in tryptophan metabolism levels between the control and clonazepam treatment groups. Conclusions: Our results demonstrate the possible existence of anxiety-like behavior in the larvae of P. trituberculatus from two perspectives. Being a species with a simpler neural structure than that of mammals, the larvae of P. trituberculatus offer a convenient model for studying the mechanisms of anxiety in crustaceans. Full article

(This article belongs to the Special Issue Meeting the Challenge of Metabolomics Analysis by Using Multidimensional Gas Chromatography with Mass Spectrometry)

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19 pages, 658 KB

Open AccessEditor’s ChoiceReview

Research Progress on Antioxidant Peptides from Fish By-Products: Purification, Identification, and Structure–Activity Relationship

by Xinru Liu, Qiuyue Hu, Yafang Shen, Yuxin Wu, Lu Gao, Xuechao Xu and Guijie Hao

Metabolites 2024, 14(10), 561; https://doi.org/10.3390/metabo14100561 - 20 Oct 2024

Cited by 7 | Viewed by 2477

Abstract

Background/Objectives: Excessive reactive oxygen species (ROS) can lead to oxidative stress, which has become an urgent problem requiring effective solutions. Due to the drawbacks of chemically synthesized antioxidants, there is a growing interest in natural antioxidants, particularly antioxidant peptides. Methods: By reviewing [...] Read more.

Background/Objectives: Excessive reactive oxygen species (ROS) can lead to oxidative stress, which has become an urgent problem requiring effective solutions. Due to the drawbacks of chemically synthesized antioxidants, there is a growing interest in natural antioxidants, particularly antioxidant peptides. Methods: By reviewing recent literature on antioxidant peptides, particularly those extracted from various parts of fish, summarize which fish by-products are more conducive to the extraction of antioxidant peptides and elaborate on their characteristics. Results: This article summarizes recent advancements in extracting antioxidant peptides from fish processing by-products, Briefly introduced the purification and identification process of antioxidant peptides, specifically focusing on the extraction of antioxidant peptides from various fish by-products. Additionally, this article comprehensively reviews the relationship between amino acid residues that compose antioxidant peptides and their potential mechanisms of action. It explores the impact of amino acid types, molecular weight, and structure–activity relationships on antioxidant efficacy. Conclusions: Different amino acid residues can contribute to the antioxidant activity of peptides by scavenging free radicals, chelating metal ions, and modulating enzyme activities. The smaller the molecular weight of the antioxidant peptide, the stronger its antioxidant activity. Additionally, the antioxidant activity of peptides is influenced by specific amino acids located at the C-terminus and N-terminus positions. Simultaneously, this review provides a more systematic analysis and a broader perspective based on existing research, concluded that fish viscera are more favorable for the extraction of antioxidant peptides, providing new insights for the practical application of fish by-products. This could increase the utilization of fish viscera and reduce the environmental pollution caused by their waste, offering valuable references for the study and application of antioxidant peptides from fish by-products. Full article

(This article belongs to the Special Issue Insights into the Metabolic Absorption of Bioactive Peptides Derived from Food Sources)

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20 pages, 1457 KB

Open AccessEditor’s ChoiceArticle

Detailed Profiling of 17-Hydroxygeranyllinalool Diterpene Glycosides from Nicotiana Species Reveals Complex Reaction Networks of Conjugation Isomers

by Alina Ebert, Saleh Alseekh, Lucio D’Andrea, Ute Roessner, Ralph Bock and Joachim Kopka

Metabolites 2024, 14(10), 562; https://doi.org/10.3390/metabo14100562 - 20 Oct 2024

Cited by 1 | Viewed by 1417

Abstract

Background: Specialised anti-herbivory metabolites are abundant in the solanaceous genus Nicotiana. These metabolites include the large family of 17-hydroxygeranyllinalool diterpene glycosides (HGL-DTGs). Many HGL-DTGs occur exclusively within the Nicotiana genus, but information from the molecular model species N. tabacum, N. benthamiana [...] Read more.

Background: Specialised anti-herbivory metabolites are abundant in the solanaceous genus Nicotiana. These metabolites include the large family of 17-hydroxygeranyllinalool diterpene glycosides (HGL-DTGs). Many HGL-DTGs occur exclusively within the Nicotiana genus, but information from the molecular model species N. tabacum, N. benthamiana, and the tree tobacco N. glauca is limited. Objectives: We studied HGL-DTG occurrence and complexity in these species with the aim of providing in-depth reference annotations and comprehensive HGL-DTG inventories. Methods: We analysed polar metabolite extracts in comparison to the previously investigated wild reference species N. attenuata using positive ESI(+) and negative ESI(-) mode electrospray ionisation LC-MS and MS/MS. Results: We provide annotations of 66 HGL-DTGs with in-source and MS/MS fragmentation spectra for selected HGL-DTGs with exemplary fragment interpretations of ESI(+) as well as less studied ESI(-) spectra. We assemble a potential biosynthesis pathway comparing the presence of HGL-DTGs in N. tabacum, N. glauca, and N. benthamiana to N. attenuata. Approximately one-third of HGL-DTGs are chromatographically resolved isomers of hexose, deoxyhexose, or malonate conjugates. The number of isomers is especially high for conjugates with low numbers of deoxyhexose moieties. Conclusions: We extend the number of known HGL-DTGs with a focus on Nicotiana model species and demonstrate that the HGL-DTG family of N. tabacum plants can be surprisingly complex. Our study provides an improved basis with detailed references to previous studies of wild Nicotiana species and enables inference of HGL-DTG pathways with required enzymes for the biosynthesis of this important family of specialised defence metabolites. Full article

(This article belongs to the Section Plant Metabolism)

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13 pages, 5623 KB

Open AccessEditor’s ChoiceArticle

Unveiling the Metabolic Trajectory of Pig Feces Across Different Ages and Senescence

by Chuanmin Qiao, Chengzhong Liu, Ruipei Ding, Shumei Wang and Maozhang He

Metabolites 2024, 14(10), 558; https://doi.org/10.3390/metabo14100558 - 17 Oct 2024

Viewed by 1683

Abstract

Porcine models are increasingly recognized for their similarities to humans and have been utilized in disease modeling and organ grafting research. While extensive metabolomics studies have been conducted in swine, primarily focusing on conventional cohorts or specific animal models, the composition and functions [...] Read more.

Porcine models are increasingly recognized for their similarities to humans and have been utilized in disease modeling and organ grafting research. While extensive metabolomics studies have been conducted in swine, primarily focusing on conventional cohorts or specific animal models, the composition and functions of fecal metabolites in pigs across different age groups—particularly in the elderly—remain inadequately understood. In this study, an untargeted metabolomics approach was employed to analyze the fecal metabolomes of pigs at three distinct age stages: young (one year), middle-aged (four years), and elderly (eight years). The objective was to elucidate age-associated changes in metabolite composition and functionality under standardized rearing conditions. The untargeted metabolomic analysis revealed a diverse array of age-related metabolites. Notably, L-methionine sulfoxide levels were found to increase with age, whereas cytidine-5-monophosphate levels exhibited a gradual decline throughout the aging process. These metabolites demonstrated alterations across various biological pathways, including energy metabolism, pyrimidine metabolism, lipid metabolism, and amino acid metabolism. Collectively, the identified key metabolites, such as L-methionine sulfoxide and Cholecalciferol, may serve as potential biomarkers of senescence, providing valuable insights into the mechanistic understanding of aging in pigs. Full article

(This article belongs to the Special Issue Bioactive Compounds in Animal Nutrition Resources and Animal By-Products)

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17 pages, 823 KB

Open AccessEditor’s ChoiceArticle

Maternal Dietary Deficiencies in Folic Acid and Choline Change Metabolites Levels in Offspring after Ischemic Stroke

by Faizan Anwar, Mary-Tyler Mosley, Paniz Jasbi, Jinhua Chi, Haiwei Gu and Nafisa M. Jadavji

Metabolites 2024, 14(10), 552; https://doi.org/10.3390/metabo14100552 - 16 Oct 2024

Cited by 2 | Viewed by 1708

Abstract

Background/objectives: Ischemic stroke is a major health concern, and nutrition is a modifiable risk factor that can influence recovery outcomes. This study investigated the impact of maternal dietary deficiencies in folic acid (FADD) or choline (ChDD) on the metabolite profiles of offspring [...] Read more.

Background/objectives: Ischemic stroke is a major health concern, and nutrition is a modifiable risk factor that can influence recovery outcomes. This study investigated the impact of maternal dietary deficiencies in folic acid (FADD) or choline (ChDD) on the metabolite profiles of offspring after ischemic stroke. Methods: A total of 32 mice (17 males and 15 females) were used to analyze sex-specific differences in response to these deficiencies. Results: At 1-week post-stroke, female offspring from the FADD group showed the greatest number of altered metabolites, including pathways involved in cholesterol metabolism and neuroprotection. At 4 weeks post-stroke, both FADD and ChDD groups exhibited significant disruptions in metabolites linked to inflammation, oxidative stress, and neurotransmission. Conclusions: These alterations were more pronounced in females compared to males, suggesting sex-dependent responses to maternal dietary deficiencies. The practical implications of these findings suggest that ensuring adequate maternal nutrition during pregnancy may be crucial for reducing stroke susceptibility and improving post-stroke recovery in offspring. Nutritional supplementation strategies targeting folic acid and choline intake could potentially mitigate the long-term adverse effects on metabolic pathways and promote better neurological outcomes. Future research should explore these dietary interventions in clinical settings to develop comprehensive guidelines for maternal nutrition and stroke prevention. Full article

(This article belongs to the Special Issue Neuronutrition: Metabolomic Insights and Perspectives)

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12 pages, 2076 KB

Open AccessEditor’s ChoiceArticle

Liraglutide Therapy in Obese Patients Alters Macrophage Phenotype and Decreases Their Tumor Necrosis Factor Alpha Release and Oxidative Stress Markers—A Pilot Study

by Łukasz Bułdak, Aleksandra Bołdys, Estera Skudrzyk, Grzegorz Machnik and Bogusław Okopień

Metabolites 2024, 14(10), 554; https://doi.org/10.3390/metabo14100554 - 16 Oct 2024

Cited by 2 | Viewed by 1669

Abstract

Introduction: Obesity is one of the major healthcare challenges. It affects one in eight people around the world and leads to several comorbidities, including type 2 diabetes, hyperlipidemia, and arterial hypertension. GLP-1 analogs have become major players in the therapy of obesity, [...] Read more.

Introduction: Obesity is one of the major healthcare challenges. It affects one in eight people around the world and leads to several comorbidities, including type 2 diabetes, hyperlipidemia, and arterial hypertension. GLP-1 analogs have become major players in the therapy of obesity, leading to significant weight loss in patients. However, benefits resulting from their usage seem to be greater than simple appetite reduction and glucose-lowering potential. Recent data show better cardiovascular outcomes, which are connected with the improvements in the course of atherosclerosis. Macrophages are crucial cells in the forming and progression of atherosclerotic lesions. Previously, it was shown that in vitro treatment with GLP-1 analogs can affect macrophage phenotype, but there is a paucity of in vivo data. Objective: To evaluate the influence of in vivo treatment with liraglutide on basic phenotypic and functional markers of macrophages. Methods: Basic phenotypic features were assessed (including inducible nitric oxide synthase, arginase 1 and mannose receptors), proinflammatory cytokine (IL-1β, TNFα) release, and oxidative stress markers (reactive oxygen species, malondialdehyde) in macrophages obtained prior and after 3-month therapy with liraglutide in patients with obesity. Results: Three-month treatment with subcutaneous liraglutide resulted in the alteration of macrophage phenotype toward alternative activation (M2) with accompanying reduction in the TNFα release and diminished oxidative stress markers. Conclusions: Our results show that macrophages in patients treated with GLP-1 can alter their phenotype and function. Those findings may at least partly explain the pleiotropic beneficial cardiovascular effects seen in subjects treated with GLP-1 analogs. Full article

(This article belongs to the Special Issue Lipid Metabolism and Atherosclerosis: Cell Specific Functions and Molecular Mechanism of the Disease)

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12 pages, 2854 KB

Open AccessEditor’s ChoiceArticle

Multi-Modal Investigation of Metabolism in Murine Breast Cancer Cell Lines Using Fluorescence Lifetime Microscopy and Hyperpolarized 13C-Pyruvate Magnetic Resonance Spectroscopy

by Sarah Erickson-Bhatt, Benjamin L. Cox, Erin Macdonald, Jenu V. Chacko, Paul Begovatz, Patricia J. Keely, Suzanne M. Ponik, Kevin W. Eliceiri and Sean B. Fain

Metabolites 2024, 14(10), 550; https://doi.org/10.3390/metabo14100550 - 15 Oct 2024

Viewed by 1852

Abstract

Background/Objectives: Despite the role of metabolism in breast cancer metastasis, we still cannot predict which breast tumors will progress to distal metastatic lesions or remain dormant. This work uses metabolic imaging to study breast cancer cell lines (4T1, 4T07, and 67NR) with [...] Read more.

Background/Objectives: Despite the role of metabolism in breast cancer metastasis, we still cannot predict which breast tumors will progress to distal metastatic lesions or remain dormant. This work uses metabolic imaging to study breast cancer cell lines (4T1, 4T07, and 67NR) with differing metastatic potential in a 3D collagen gel bioreactor system. Methods: Within the bioreactor, hyperpolarized magnetic resonance spectroscopy (HP-MRS) is used to image lactate/pyruvate ratios, while fluorescence lifetime imaging microscopy (FLIM) of endogenous metabolites measures metabolism at the cellular scale. Results: HP-MRS results showed no lactate peak for 67NR and a comparatively large lactate/pyruvate ratio for both 4T1 and 4T07 cell lines, suggestive of greater pyruvate utilization with greater metastatic potential. Similar patterns were observed using FLIM with significant increases in FAD intensity, redox ratio, and NAD(P)H lifetime. The lactate/pyruvate ratio was strongly correlated to NAD(P)H lifetime, consistent with the role of NADH as an electron donor for the glycolytic pathway, suggestive of an overall upregulation of metabolism (both glycolytic and oxidative), for the 4T07 and 4T1 cell lines compared to the non-metastatic 67NR cell line. Conclusions: These findings support a complementary role for HP-MRS and FLIM enabled by a novel collagen gel bioreactor system to investigate metastatic potential and cancer metabolism. Full article

(This article belongs to the Section Cell Metabolism)

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31 pages, 1017 KB

Open AccessEditor’s ChoiceReview

Nutritional Modulation of the Gut–Brain Axis: A Comprehensive Review of Dietary Interventions in Depression and Anxiety Management

by Mariana Merino del Portillo, Vicente Javier Clemente-Suárez, Pablo Ruisoto, Manuel Jimenez, Domingo Jesús Ramos-Campo, Ana Isabel Beltran-Velasco, Ismael Martínez-Guardado, Alejandro Rubio-Zarapuz, Eduardo Navarro-Jiménez and José Francisco Tornero-Aguilera

Metabolites 2024, 14(10), 549; https://doi.org/10.3390/metabo14100549 - 14 Oct 2024

Cited by 14 | Viewed by 11933

Abstract

Mental health is an increasing topic of focus since more than 500 million people in the world suffer from depression and anxiety. In this multifactorial disorder, parameters such as inflammation, the state of the microbiota and, therefore, the patient’s nutrition are receiving more [...] Read more.

Mental health is an increasing topic of focus since more than 500 million people in the world suffer from depression and anxiety. In this multifactorial disorder, parameters such as inflammation, the state of the microbiota and, therefore, the patient’s nutrition are receiving more attention. In addition, food products are the source of many essential ingredients involved in the regulation of mental processes, including amino acids, neurotransmitters, vitamins, and others. For this reason, this narrative review was carried out with the aim of analyzing the role of nutrition in depression and anxiety disorders. To reach the review aim, a critical review was conducted utilizing both primary sources, such as scientific publications and secondary sources, such as bibliographic indexes, web pages, and databases. The search was conducted in PsychINFO, MedLine (Pubmed), Cochrane (Wiley), Embase, and CinAhl. The results show a direct relationship between what we eat and the state of our nervous system. The gut–brain axis is a complex system in which the intestinal microbiota communicates directly with our nervous system and provides it with neurotransmitters for its proper functioning. An imbalance in our microbiota due to poor nutrition will cause an inflammatory response that, if sustained over time and together with other factors, can lead to disorders such as anxiety and depression. Changes in the functions of the microbiota–gut–brain axis have been linked to several mental disorders. It is believed that the modulation of the microbiome composition may be an effective strategy for a new treatment of these disorders. Modifications in nutritional behaviors and the use of ergogenic components are presented as important non-pharmacological interventions in anxiety and depression prevention and treatment. It is desirable that the choice of nutritional and probiotic treatment in individual patients be based on the results of appropriate biochemical and microbiological tests. Full article

(This article belongs to the Special Issue Advances in Food Sciences: Metabolomics to Unravel the Complexity of Food Metabolites)

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24 pages, 1102 KB

Open AccessEditor’s ChoiceReview

Recent Advances in Metabolomics and Lipidomics Studies in Human and Animal Models of Multiple Sclerosis

by Petros Pousinis, Olga Begou, Marina Kleopatra Boziki, Nikolaos Grigoriadis, Georgios Theodoridis and Helen Gika

Metabolites 2024, 14(10), 545; https://doi.org/10.3390/metabo14100545 - 13 Oct 2024

Cited by 2 | Viewed by 2794

Abstract

Multiple sclerosis (MS) is a neurodegenerative and inflammatory disease of the central nervous system (CNS) that leads to a loss of myelin. There are three main types of MS: relapsing-remitting MS (RRMS) and primary and secondary progressive disease (PPMS, SPMS). The differentiation in [...] Read more.

Multiple sclerosis (MS) is a neurodegenerative and inflammatory disease of the central nervous system (CNS) that leads to a loss of myelin. There are three main types of MS: relapsing-remitting MS (RRMS) and primary and secondary progressive disease (PPMS, SPMS). The differentiation in the pathogenesis of these two latter courses is still unclear. The underlying mechanisms of MS are yet to be elucidated, and the treatment relies on immune-modifying agents. Recently, lipidomics and metabolomics studies using human biofluids, mainly plasma and cerebrospinal fluid (CSF), have suggested an important role of lipids and metabolites in the pathophysiology of MS. In this review, the results from studies on metabolomics and lipidomics analyses performed on biological samples of MS patients and MS-like animal models are presented and analyzed. Based on the collected findings, the biochemical pathways in human and animal cohorts involved were investigated and biological mechanisms and the potential role they have in MS are discussed. Limitations and challenges of metabolomics and lipidomics approaches are presented while concluding that metabolomics and lipidomics may provide a more holistic approach and provide biomarkers for early diagnosis of MS disease. Full article

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

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20 pages, 2238 KB

Open AccessEditor’s ChoiceArticle

Detection and Validation of Organic Metabolites in Urine for Clear Cell Renal Cell Carcinoma Diagnosis

by Kiana L. Holbrook, George E. Quaye, Elizabeth Noriega Landa, Xiaogang Su, Qin Gao, Heinric Williams, Ryan Young, Sabur Badmos, Ahsan Habib, Angelica A. Chacon and Wen-Yee Lee

Metabolites 2024, 14(10), 546; https://doi.org/10.3390/metabo14100546 - 13 Oct 2024

Cited by 6 | Viewed by 2226

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) comprises the majority, approximately 70–80%, of renal cancer cases and often remains asymptomatic until incidentally detected during unrelated abdominal imaging or at advanced stages. Currently, standardized screening tests for renal cancer are lacking, which presents challenges [...] Read more.

Background: Clear cell renal cell carcinoma (ccRCC) comprises the majority, approximately 70–80%, of renal cancer cases and often remains asymptomatic until incidentally detected during unrelated abdominal imaging or at advanced stages. Currently, standardized screening tests for renal cancer are lacking, which presents challenges in disease management and improving patient outcomes. This study aimed to identify ccRCC-specific volatile organic compounds (VOCs) in the urine of ccRCC-positive patients and develop a urinary VOC-based diagnostic model. Methods: This study involved 233 pretreatment ccRCC patients and 43 healthy individuals. VOC analysis utilized stir-bar sorptive extraction coupled with thermal desorption gas chromatography/mass spectrometry (SBSE-TD-GC/MS). A ccRCC diagnostic model was established via logistic regression, trained on 163 ccRCC cases versus 31 controls, and validated with 70 ccRCC cases versus 12 controls, resulting in a ccRCC diagnostic model involving 24 VOC markers. Results: The findings demonstrated promising diagnostic efficacy, with an Area Under the Curve (AUC) of 0.94, 86% sensitivity, and 92% specificity. Conclusions: This study highlights the feasibility of using urine as a reliable biospecimen for identifying VOC biomarkers in ccRCC. While further validation in larger cohorts is necessary, this study’s capability to differentiate between ccRCC and control groups, despite sample size limitations, holds significant promise. Full article

(This article belongs to the Special Issue Emerging Applications of Urinary Metabolomics in Cancer)

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24 pages, 3004 KB

Open AccessEditor’s ChoiceReview

Non/Low-Caloric Artificial Sweeteners and Gut Microbiome: From Perturbed Species to Mechanisms

by Jiahao Feng, Jingya Peng, Yun-Chung Hsiao, Chih-Wei Liu, Yifei Yang, Haoduo Zhao, Taylor Teitelbaum, Xueying Wang and Kun Lu

Metabolites 2024, 14(10), 544; https://doi.org/10.3390/metabo14100544 - 11 Oct 2024

Cited by 6 | Viewed by 10764

Abstract

Background: Non/low-caloric artificial sweeteners (NAS) are recognized as chemical additives substituting sugars to avoid caloric intake and subsequent sugar-derived diseases such as diabetes and hyperglycemia. Six NAS have been claimed safe and are authorized by the US Food and Drug Administration (FDA) for [...] Read more.

Background: Non/low-caloric artificial sweeteners (NAS) are recognized as chemical additives substituting sugars to avoid caloric intake and subsequent sugar-derived diseases such as diabetes and hyperglycemia. Six NAS have been claimed safe and are authorized by the US Food and Drug Administration (FDA) for public use, with acceptable daily intake information available: aspartame, acesulfame-K, saccharin, sucralose, neotame, and advantame. However, the impacts of NAS on the gut microbiome have raised potential concerns, since sporadic research revealed NAS-induced microbial changes in the gastrointestinal tracts and alterations in the microbiome–host interactive metabolism. Methods: Given the fact that the gut microbiome influences kaleidoscopic physiological functions in host health, this review aimed to decipher the impacts of NAS on the gut microbiome by implementing a comprehensive two-stage literature analysis based on each NAS. Results: This review documented disturbed microbiomes due to NAS exposure to a maximal resolution of species level using taxonomic clustering analysis, and recorded metabolism alterations involved in gut microbiome–host interactions. Conclusions: The results elucidated that specific NAS exhibited discrepant impacts on the gut microbiome, even though overlapping on the genera and species were identified. Some NAS caused glucose tolerance impairment in the host, but the key metabolites and their underlying mechanisms were different. Furthermore, this review embodied the challenges and future directions of current NAS–gut microbiome research to inspire advanced examination of the NAS exposure–gut microbiome–host metabolism axis. Full article

(This article belongs to the Special Issue Effects of Environmental Exposure on Host and Microbial Metabolism)

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20 pages, 662 KB

Open AccessEditor’s ChoiceReview

Hydrogen-Rich Water to Enhance Exercise Performance: A Review of Effects and Mechanisms

by Qiaorui Zhou, Huixin Li, Ye Zhang, Yirui Zhao, Can Wang and Chang Liu

Metabolites 2024, 14(10), 537; https://doi.org/10.3390/metabo14100537 - 7 Oct 2024

Cited by 4 | Viewed by 10406

Abstract

Background: Hydrogen-rich water (HRW) has garnered significant interest within the sports and exercise science community due to its selective antioxidant properties. Despite its potential benefits, comprehensive reviews specifically addressing its effects on athletic performance are limited. This review aims to assess the [...] Read more.

Background: Hydrogen-rich water (HRW) has garnered significant interest within the sports and exercise science community due to its selective antioxidant properties. Despite its potential benefits, comprehensive reviews specifically addressing its effects on athletic performance are limited. This review aims to assess the impact of HRW on sports performance and explore the underlying molecular biological mechanisms, with the goal of elucidating how HRW might enhance athletic performance. Methods: This review synthesizes research on HRW by examining articles published between 1980 and April 2024 in databases such as PubMed, the Cochrane Library, Embase, Scopus, and Web of Science. Results: It highlights HRW’s effects on various aspects of athletic performance, including endurance, strength, sprint times, lunge movements, countermovement jump height, and time to exhaustion. While the precise mechanisms by which HRW affects athletic performance remain unclear, this review investigates its general molecular biological mechanisms beyond the specific context of sports. This provides a theoretical foundation for future research aimed at understanding how HRW can enhance athletic performance. HRW targets the harmful reactive oxygen and nitrogen species produced during intense exercise, thereby reducing oxidative stress—a critical factor in muscle fatigue, inflammation, and diminished athletic performance. HRW helps to scavenge hydroxyl radicals and peroxynitrite, regulate antioxidant enzymes, mitigate lipid peroxidation, reduce inflammation, protect against mitochondrial dysfunction, and modulate cellular signaling pathways. Conclusions: In summary, while a few studies have indicated that HRW may not produce significant beneficial effects, the majority of research supports the conclusion that HRW may enhance athletic performance across various sports. The potential mechanisms underlying these benefits are thought to involve HRW’s role as a selective antioxidant, its impact on oxidative stress, and its regulation of redox homeostasis. However, the specific molecular biological mechanisms through which HRW improves athletic performance remain to be fully elucidated. Full article

(This article belongs to the Section Nutrition and Metabolism)

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13 pages, 600 KB

Open AccessEditor’s ChoiceArticle

Association between Inflammatory and Metabolic Biomarkers and Common Mental Disorders among Adults: 2015 Health Survey of São Paulo, SP, Brazil

by Letícia do Nascimento Maximiano Ferreira, Regina Mara Fisberg, Flavia Mori Sarti and Marcelo Macedo Rogero

Metabolites 2024, 14(10), 535; https://doi.org/10.3390/metabo14100535 - 5 Oct 2024

Cited by 1 | Viewed by 1262

Abstract

Recent studies suggest that plasma inflammatory biomarker concentrations may represent valuable indicators for the diagnosis and prognosis of mental disorders. At the same time, metabolic alterations may contribute to the development and progression of systemic low-grade inflammation. Background/Objectives: This study evaluated the [...] Read more.

Recent studies suggest that plasma inflammatory biomarker concentrations may represent valuable indicators for the diagnosis and prognosis of mental disorders. At the same time, metabolic alterations may contribute to the development and progression of systemic low-grade inflammation. Background/Objectives: This study evaluated the association between plasma inflammatory biomarkers and common mental disorders (CMD), exploring the relationship between metabolic biomarkers, metabolic syndrome (MetS), and inflammatory biomarkers in younger and older adults. Methods: This cross-sectional study used data from the 2015 Health Survey of São Paulo with a Focus on Nutrition Study. The occurrence of CMD was assessed through the Self-Reporting Questionnaire (SRQ-20). Blood samples were used to measure plasma concentrations of inflammatory and cardiometabolic biomarkers. MetS was defined according to the International Diabetes Federation Consensus. The Mann–Whitney test compared inflammatory biomarker concentrations across CMD groups and cardiometabolic conditions, and logistic regression models explored associations between inflammatory biomarker concentration and CMD. Results: The sample included 575 participants, 22.6% (n = 130) of whom had CMD. Concentrations of plasminogen activator inhibitor 1, C-reactive protein (CRP), and the systemic low-grade inflammation score varied significantly among CMD groups. CRP concentrations were positively associated with the presence of CMD, independent of confounding factors. Participants with insulin resistance, dyslipidemia, and MetS exhibited significantly higher CRP concentrations than individuals without these conditions. Conclusions: The findings suggest that increased plasma CRP concentrations may be a potential risk factor for CMD. Higher CRP concentrations were observed in individuals with insulin resistance, dyslipidemia, and MetS. Future interventional studies should explore these hypotheses in diverse populations. Full article

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

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16 pages, 2225 KB

Open AccessEditor’s ChoiceArticle

Resistant Potato Starch Supplementation Reduces Serum Free Fatty Acid Levels and Influences Bile Acid Metabolism

by Jason R. Bush, Izuchukwu Iwuamadi, Jun Han, David J. Schibli, David R. Goodlett and Edward C. Deehan

Metabolites 2024, 14(10), 536; https://doi.org/10.3390/metabo14100536 - 5 Oct 2024

Cited by 3 | Viewed by 3556

Abstract

Background: Resistant starches, such as high-amylose maize starch and resistant potato starch (RPS), have prebiotic effects that are linked to improved metabolism at >15 g/day, but the effects at lower doses have not been reported. Methods: We performed an exploratory post [...] Read more.

Background: Resistant starches, such as high-amylose maize starch and resistant potato starch (RPS), have prebiotic effects that are linked to improved metabolism at >15 g/day, but the effects at lower doses have not been reported. Methods: We performed an exploratory post hoc analysis of free fatty acids (FFAs), bile acids (BAs), and ketone bodies in serum previously collected from a randomized, double-blind, placebo-controlled clinical trial evaluating the effects of one- and four-week consumption of 3.5 g/day RPS versus a placebo using two-way ANOVA adjusted by pFDR. Associations between week 4 changes in FFAs, BAs, and ketone bodies were assessed by Pearson’s correlations. Results: RPS consumption reduced total FFAs relative to the placebo, including multiple unsaturated FFAs and octanedioic acid, with reductions in taurine- and glycine-conjugated secondary BAs also detected (q < 0.05). No changes in ketone bodies were observed (q > 0.05). Changes in 7-ketodeoxycholic acid (r = −0.595) and glycolithocholic acid (r = −0.471) were inversely correlated with treatment-induced reductions in FFAs for RPS but not the placebo, suggesting the effects were from the prebiotic. Shifts in β-hydroxybutyrate were further correlated with FFA changes in both treatments (q < 0.05). Conclusions: These findings demonstrate that low doses of RPS positively influence fatty acid metabolism in humans, reducing circulating levels of FFA and conjugated BAs. 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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16 pages, 1838 KB

Open AccessEditor’s ChoiceArticle

Comparative Impact of Organic Grass-Fed and Conventional Cattle-Feeding Systems on Beef and Human Postprandial Metabolomics—A Randomized Clinical Trial

by Meghan Spears, Gwendolyn Cooper, Brett Sather, Marguerite Bailey, Jane A. Boles, Brian Bothner and Mary P. Miles

Metabolites 2024, 14(10), 533; https://doi.org/10.3390/metabo14100533 - 3 Oct 2024

Cited by 5 | Viewed by 7252

Abstract

Background/Objectives: Cattle-feeding systems may have health implications for consumers of beef products. Organic grass-fed (GRA) and conventional (CON) cattle-feeding systems may result in beef products with differing metabolite profiles and therefore could impact the postprandial metabolomic response of consumers. This study aims to [...] Read more.

Background/Objectives: Cattle-feeding systems may have health implications for consumers of beef products. Organic grass-fed (GRA) and conventional (CON) cattle-feeding systems may result in beef products with differing metabolite profiles and therefore could impact the postprandial metabolomic response of consumers. This study aims to measure whole beef metabolomics and postprandial metabolomic response of consumers between GRA and CON beef to elucidate potential health implications. Methods: This study followed a randomized double-blind crossover design with healthy male and female subjects (n = 10). Plasma samples were taken at fasting (0) and postprandially for four hours after consumption of a steak from each condition. Untargeted metabolomic analysis of whole beef and human plasma samples used LC/MS. Multivariate and pathway enrichment analysis in MetaboAnalyst was used to investigate metabolite and biochemical pathways that distinguished CON and GRA. Results: Cattle-feeding systems impacted both postprandial and whole beef steak metabolomic profiles. Metabolites that contributed to this variation included carnitine species (Proionylcarnitine), fatty acids, amino acids (L-valine), and Calamendiol. These metabolites have been associated with oxidative stress, inflammation, and cardiovascular health. Functional pathway enrichment analysis revealed numerous amino acid degradation pathways, especially branched-chain amino acids, and fatty acid degradation that changed throughout the postprandial time course. Conclusions: These findings suggest that CON and GRA cattle-feeding systems differentially impact whole beef metabolomics, as well as consumer postprandial metabolic responses and the associated health implications. Full article

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

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15 pages, 8732 KB

Open AccessEditor’s ChoiceArticle

Machine Learning-Based Plasma Metabolomics in Liraglutide-Treated Type 2 Diabetes Mellitus Patients and Diet-Induced Obese Mice

by Seokjae Park and Eun-Kyoung Kim

Metabolites 2024, 14(9), 483; https://doi.org/10.3390/metabo14090483 - 2 Sep 2024

Cited by 1 | Viewed by 2066

Abstract

Liraglutide, a glucagon-like peptide-1 receptor agonist, is effective in the treatment of type 2 diabetes mellitus (T2DM) and obesity. Despite its benefits, including improved glycemic control and weight loss, the common metabolic changes induced by liraglutide and correlations between those in rodents and [...] Read more.

Liraglutide, a glucagon-like peptide-1 receptor agonist, is effective in the treatment of type 2 diabetes mellitus (T2DM) and obesity. Despite its benefits, including improved glycemic control and weight loss, the common metabolic changes induced by liraglutide and correlations between those in rodents and humans remain unknown. Here, we used advanced machine learning techniques to analyze the plasma metabolomic data in diet-induced obese (DIO) mice and patients with T2DM treated with liraglutide. Among the machine learning models, Support Vector Machine was the most suitable for DIO mice, and Gradient Boosting was the most suitable for patients with T2DM. Through the cross-evaluation of machine learning models, we found that liraglutide promotes metabolic shifts and interspecies correlations in these shifts between DIO mice and patients with T2DM. Our comparative analysis helped identify metabolic correlations influenced by liraglutide between humans and rodents and may guide future therapeutic strategies for T2DM and obesity. Full article

(This article belongs to the Special Issue Nutrition and Metabolism in Human Diseases 2nd Edition)

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16 pages, 4642 KB

Open AccessEditor’s ChoiceArticle

Sitting Interruption Modalities during Prolonged Sitting Acutely Improve Postprandial Metabolome in a Crossover Pilot Trial among Postmenopausal Women

by Jeffrey S. Patterson, Brinda K. Rana, Haiwei Gu and Dorothy D. Sears

Metabolites 2024, 14(9), 478; https://doi.org/10.3390/metabo14090478 - 30 Aug 2024

Cited by 3 | Viewed by 1913

Abstract

Older adults sit during most hours of the day; more than 30% are considered physically inactive. The accumulation of prolonged sitting time is an exercise-independent risk factor for aging-related conditions such as cardiometabolic disease and cancer. Archival plasma samples from a randomized controlled, [...] Read more.

Older adults sit during most hours of the day; more than 30% are considered physically inactive. The accumulation of prolonged sitting time is an exercise-independent risk factor for aging-related conditions such as cardiometabolic disease and cancer. Archival plasma samples from a randomized controlled, four-condition crossover study conducted in 10 postmenopausal women with overweight or obesity were analyzed. During 5-hour conditions completed on separate days, the trial tested three interruption modalities: two-minute stands each 20 min (STS), hourly ten-minute standing breaks (Stand), hourly two-minute walks (Walk), and a controlled sit. Fasting baseline and 5-hour end point (2 h postprandial) samples were used for targeted metabolomic profiling. Condition-associated metabolome changes were compared using paired t-tests. STS eliminated the postprandial elevation of amino acid metabolites that was observed in the control. A norvaline derivative shown to have anti-hypertensive and -hyperglycemic effects was significantly increased during Stand and STS. Post-hoc testing identified 19 significantly different metabolites across the interventions. Tight metabolite clustering by condition was driven by amino acid, vasoactive, and sugar metabolites, as demonstrated by partial least squares-discriminant analyses. This exploratory study suggests that brief, low-intensity modalities of interrupting prolonged sitting can acutely elucidate beneficial cardiometabolic changes in postmenopausal women with cardiometabolic risk. Full article

(This article belongs to the Special Issue The Emerging Role of Metabolomics in Epidemiological Studies of Atherosclerosis and Cardiovascular Disease)

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25 pages, 5241 KB

Open AccessEditor’s ChoiceArticle

Impact of Phenylketonuria on the Serum Metabolome and Plasma Lipidome: A Study in Early-Treated Patients

by Jorine C. van der Weerd, Annemiek M. J. van Wegberg, Theo S. Boer, Udo F. H. Engelke, Karlien L. M. Coene, Ron A. Wevers, Stephan J. L. Bakker, Pim de Blaauw, Joost Groen, Francjan J. van Spronsen and M. Rebecca Heiner-Fokkema

Metabolites 2024, 14(9), 479; https://doi.org/10.3390/metabo14090479 - 30 Aug 2024

Cited by 3 | Viewed by 2234

Abstract

Background: Data suggest that metabolites, other than blood phenylalanine (Phe), better and independently predict clinical outcomes in patients with phenylketonuria (PKU). Methods: To find new biomarkers, we compared the results of untargeted lipidomics and metabolomics in treated adult PKU patients to those of [...] Read more.

Background: Data suggest that metabolites, other than blood phenylalanine (Phe), better and independently predict clinical outcomes in patients with phenylketonuria (PKU). Methods: To find new biomarkers, we compared the results of untargeted lipidomics and metabolomics in treated adult PKU patients to those of matched controls. Samples (lipidomics in EDTA-plasma (22 PKU and 22 controls) and metabolomics in serum (35 PKU and 20 controls)) were analyzed using ultra-high-performance liquid chromatography and high-resolution mass spectrometry. Data were subjected to multivariate (PCA, OPLS-DA) and univariate (Mann–Whitney U test, p < 0.05) analyses. Results: Levels of 33 (of 20,443) lipid features and 56 (of 5885) metabolite features differed statistically between PKU patients and controls. For lipidomics, findings include higher glycerolipids, glycerophospholipids, and sphingolipids species. Significantly lower values were found for sterols and glycerophospholipids species. Seven features had unknown identities. Total triglyceride content was higher. Higher Phe and Phe catabolites, tryptophan derivatives, pantothenic acid, and dipeptides were observed for metabolomics. Ornithine levels were lower. Twenty-six metabolite features were not annotated. Conclusions: This study provides insight into the metabolic phenotype of PKU patients. Additional studies are required to establish whether the observed changes result from PKU itself, diet, and/or an unknown reason. Full article

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

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24 pages, 377 KB

Open AccessEditor’s ChoiceReview

An Overview of Pre-Analytical Factors Impacting Metabolomics Analyses of Blood Samples

by Amy Thachil, Li Wang, Rupasri Mandal, David Wishart and Tom Blydt-Hansen

Metabolites 2024, 14(9), 474; https://doi.org/10.3390/metabo14090474 - 28 Aug 2024

Cited by 9 | Viewed by 4555

Abstract

Discrepant sample processing remains a significant challenge within blood metabolomics research, introducing non-biological variation into the measured metabolome and biasing downstream results. Inconsistency during the pre-analytical phase can influence experimental processes, producing metabolome measurements that are non-representative of in vivo composition. To minimize [...] Read more.

Discrepant sample processing remains a significant challenge within blood metabolomics research, introducing non-biological variation into the measured metabolome and biasing downstream results. Inconsistency during the pre-analytical phase can influence experimental processes, producing metabolome measurements that are non-representative of in vivo composition. To minimize variation, there is a need to create and adhere to standardized pre-analytical protocols for blood samples intended for use in metabolomics analyses. This will allow for reliable and reproducible findings within blood metabolomics research. In this review article, we provide an overview of the existing literature pertaining to pre-analytical factors that influence blood metabolite measurements. Pre-analytical factors including blood tube selection, pre- and post-processing time and temperature conditions, centrifugation conditions, freeze–thaw cycles, and long-term storage conditions are specifically discussed, with recommendations provided for best practices at each stage. Full article

(This article belongs to the Special Issue Metabolomics and Machine Learning for Improved Diagnostics and as a Tool to Accelerate Drug Development)

24 pages, 1235 KB

Open AccessEditor’s ChoiceSystematic Review

Peripheral Lipid Signatures, Metabolic Dysfunction, and Pathophysiology in Schizophrenia Spectrum Disorders

by Sally Wu, Kristoffer J. Panganiban, Jiwon Lee, Dan Li, Emily C.C. Smith, Kateryna Maksyutynska, Bailey Humber, Tariq Ahmed, Sri Mahavir Agarwal, Kristen Ward and Margaret Hahn

Metabolites 2024, 14(9), 475; https://doi.org/10.3390/metabo14090475 - 28 Aug 2024

Cited by 3 | Viewed by 1843

Abstract

Metabolic dysfunction is commonly observed in schizophrenia spectrum disorders (SSDs). The causes of metabolic comorbidity in SSDs are complex and include intrinsic or biological factors linked to the disorder, which are compounded by antipsychotic (AP) medications. The exact mechanisms underlying SSD pathophysiology and [...] Read more.

Metabolic dysfunction is commonly observed in schizophrenia spectrum disorders (SSDs). The causes of metabolic comorbidity in SSDs are complex and include intrinsic or biological factors linked to the disorder, which are compounded by antipsychotic (AP) medications. The exact mechanisms underlying SSD pathophysiology and AP-induced metabolic dysfunction are unknown, but dysregulated lipid metabolism may play a role. Lipidomics, which detects lipid metabolites in a biological sample, represents an analytical tool to examine lipid metabolism. This systematic review aims to determine peripheral lipid signatures that are dysregulated among individuals with SSDs (1) with minimal exposure to APs and (2) during AP treatment. To accomplish this goal, we searched MEDLINE, Embase, and PsychINFO databases in February 2024 to identify all full-text articles written in English where the authors conducted lipidomics in SSDs. Lipid signatures reported to significantly differ in SSDs compared to controls or in relation to AP treatment and the direction of dysregulation were extracted as outcomes. We identified 46 studies that met our inclusion criteria. Most of the lipid metabolites that significantly differed in minimally AP-treated patients vs. controls comprised glycerophospholipids, which were mostly downregulated. In the AP-treated group vs. controls, the significantly different metabolites were primarily fatty acyls, which were dysregulated in conflicting directions between studies. In the pre-to-post AP-treated patients, the most impacted metabolites were glycerophospholipids and fatty acyls, which were found to be primarily upregulated and conflicting, respectively. These lipid metabolites may contribute to SSD pathophysiology and metabolic dysfunction through various mechanisms, including the modulation of inflammation, cellular membrane permeability, and metabolic signaling pathways. Full article

(This article belongs to the Special Issue Metabolomics in Disease Mechanisms and Drug Targets)

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17 pages, 1998 KB

Open AccessEditor’s ChoiceArticle

Disposition of Oral Nalbuphine and Its Metabolites in Healthy Subjects and Subjects with Hepatic Impairment: Preliminary Modeling Results Using a Continuous Intestinal Absorption Model with Enterohepatic Recirculation

by Swati Nagar, Amale Hawi, Thomas Sciascia and Ken Korzekwa

Metabolites 2024, 14(9), 471; https://doi.org/10.3390/metabo14090471 - 27 Aug 2024

Viewed by 1544

Abstract

Nalbuphine (NAL) is a mixed κ-agonist/μ-antagonist opioid with extensive first-pass metabolism. A phase 1 open-label study was conducted to characterize the pharmacokinetics (PKs) of NAL and select metabolites following single oral doses of NAL extended-release tablets in subjects with mild, moderate, and severe [...] Read more.

Nalbuphine (NAL) is a mixed κ-agonist/μ-antagonist opioid with extensive first-pass metabolism. A phase 1 open-label study was conducted to characterize the pharmacokinetics (PKs) of NAL and select metabolites following single oral doses of NAL extended-release tablets in subjects with mild, moderate, and severe hepatic impairment (Child–Pugh A, B, and C, respectively) compared to healthy matched subjects. NAL exposures were similar for subjects with mild hepatic impairment as compared to healthy subjects and nearly three-fold and eight-fold higher in subjects with moderate and severe hepatic impairment, respectively. Datasets obtained for healthy, moderate, and severe hepatic impaired groups were modeled with a mechanistic model that incorporated NAL hepatic metabolism and enterohepatic recycling of NAL and its glucuronidated metabolites. The mechanistic model includes a continuous intestinal absorption model linked to semi-physiological liver–gallbladder–compartmental PK models based on partial differential equations (termed the PDE-EHR model). In vitro studies indicated that cytochromes P450 CYP2C9 and CYP2C19 are the major CYPs involved in NAL oxidation, with glucuronidation mainly catalyzed by UGT1A8 and UGT2B7 isozymes. Complex formation and elimination kinetics of NAL and four main metabolites was well predicted by PDE-EHR. The model is expected to improve predictions of drug interactions and complex drug disposition. Full article

(This article belongs to the Special Issue The Role of Metabolites in Translational and Clinical Pharmacology)

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16 pages, 3813 KB

Open AccessEditor’s ChoiceArticle

Combining the Vaginal Microbiome and Serum Metabolome to Screen for Potential Biomarkers of Early Pregnancy in Cows

by Yan Luo, Zhen Wang, Xin Zhao, Jiankang Xing, Zhiliang Chen, Wenxue Zhao, Xiaoqing Long, Yanbing Zhang and Yongbin Shao

Metabolites 2024, 14(9), 469; https://doi.org/10.3390/metabo14090469 - 26 Aug 2024

Viewed by 1766

Abstract

Early pregnancy diagnostic techniques are of significant importance in livestock farming, particularly in dairy farming. This study aimed to screen artificially inseminated cows for potential biomarkers at day 21 of pregnancy using microbiota–metabolomics analysis. The microbiome analysis revealed significant changes (p < [...] Read more.

Early pregnancy diagnostic techniques are of significant importance in livestock farming, particularly in dairy farming. This study aimed to screen artificially inseminated cows for potential biomarkers at day 21 of pregnancy using microbiota–metabolomics analysis. The microbiome analysis revealed significant changes (p < 0.05) in the composition and abundance of the vaginal microbiota in cows after pregnancy. Notably, there was an increase in the abundance of [Eubacterium]_hallii_group (p < 0.05) associated with the production of short-chain fatty acids in the pregnant group compared with the non-pregnant group. Furthermore, significant alterations were observed in the serum metabolome, with notable changes in the concentrations of prolyl-hydroxyproline (Pro-Hyp) (p < 0.01) and bonactin (p < 0.01). The majority of differential metabolites clustered within the pathways of amino acid metabolism and lipid metabolism, with lipid metabolism exhibiting a higher proportion and playing a pivotal role in early pregnancy. An enzyme-linked immunosorbent assay was employed to quantify three key metabolites of the arachidonic acid pathway. The results demonstrated significant decreases in serum concentrations of leukotriene B4 (LTB4) (p < 0.05) and prostaglandin F2α (PGF2α) (p < 0.01) and no significant changes in arachidonic acid (AA) (NS) concentrations after 21 days of gestation in cows. Spearman’s correlation analysis was utilized to investigate the interrelationship between the vaginal microbiota and serum metabolites. In conclusion, the present study demonstrated that biomaterials such as bonactin, Pro-hyp, LTB4, PGF2α in serum metabolites and [Eubacterium]_hallii_group in the vaginal flora of cows could be utilized as potential biomarkers for 21 days of gestation in cows. Full article

(This article belongs to the Section Animal Metabolism)

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14 pages, 2082 KB

Open AccessEditor’s ChoiceArticle

Untargeted Blood Lipidomics Analysis in Critically Ill Pediatric Patients with Ventilator-Associated Pneumonia: A Pilot Study

by Christina Virgiliou, Olga Begou, Argyro Ftergioti, Maria Simitsopoulou, Maria Sdougka, Emmanuel Roilides, Georgios Theodoridis, Helen Gika and Elias Iosifidis

Metabolites 2024, 14(9), 466; https://doi.org/10.3390/metabo14090466 - 23 Aug 2024

Cited by 2 | Viewed by 1571

Abstract

This study aims to explore the diagnostic potential of blood lipid profiles in suspected ventilator-associated pneumonia (VAP). Early detection of VAP remains challenging for clinicians due to subjective clinical criteria and the limited effectiveness of current diagnostic tests. Blood samples from 20 patients, [...] Read more.

This study aims to explore the diagnostic potential of blood lipid profiles in suspected ventilator-associated pneumonia (VAP). Early detection of VAP remains challenging for clinicians due to subjective clinical criteria and the limited effectiveness of current diagnostic tests. Blood samples from 20 patients, with ages between 6 months and 15 years, were collected at days 1, 3, 6, and 12, and an untargeted lipidomics analysis was performed using a Ultra high Pressure Liquid Chromatography hyphenated with High Resolution Mass Spectrometry UPLC-HRMS (TIMS-TOF/MS) platform. Patients were stratified based on modified pediatric clinical pulmonary index score (mCPIS) into high (mCPIS ≥ 6, n = 12) and low (mCPIS < 6, n = 8) VAP suspicion groups. With the untargeted lipid profiling, we were able to identify 144 lipid species from different lipid groups such as glycerophospholipids, glycerolipids, and sphingolipids, in the blood of children with VAP. Multivariate and univariate statistical analyses revealed a distinct distribution of blood lipid profiles between the studied groups, indicating the potential utility of lipid biomarkers in discriminating VAP presence. Additionally, specific lipids were associated with pharyngeal culture results, notably the presence of Klebsiella pneumoniae and Staphylococcus aureus, underscoring the importance of lipid profiling in identifying the microbial etiology of VAP. Full article

(This article belongs to the Special Issue Metabolomics: An Emerging Potential Approach to Study Critical Illnesses, 2nd Edition)

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18 pages, 2528 KB

Open AccessEditor’s ChoiceArticle

The Effects of Maternal Nutrient Restriction during Mid to Late Gestation with Realimentation on Fetal Metabolic Profiles in the Liver, Skeletal Muscle, and Blood in Sheep

by Brandon I. Smith, Manuel A. Vásquez-Hidalgo, Xiaomeng Li, Kimberly A. Vonnahme, Anna T. Grazul-Bilska, Kendall C. Swanson, Timothy E. Moore, Sarah A. Reed and Kristen E. Govoni

Metabolites 2024, 14(9), 465; https://doi.org/10.3390/metabo14090465 - 23 Aug 2024

Cited by 1 | Viewed by 1801

Abstract

Poor maternal nutrition during gestation negatively affects offspring growth and metabolism. To evaluate the impact of maternal nutrient restriction and realimentation on metabolism in the fetal liver, skeletal muscle, and circulation, on day 50 of gestation, ewes (n = 48) pregnant with [...] Read more.

Poor maternal nutrition during gestation negatively affects offspring growth and metabolism. To evaluate the impact of maternal nutrient restriction and realimentation on metabolism in the fetal liver, skeletal muscle, and circulation, on day 50 of gestation, ewes (n = 48) pregnant with singletons were fed 100% (CON) or 60% (RES) of requirements until day 90 of gestation, when a subset of ewes (n = 7/treatment) were euthanized, and fetal samples were collected. The remaining ewes were maintained on a current diet (CON-CON, n = 6; RES-RES, n = 7) or switched to an alternative diet (CON-RES, RES-CON; n = 7/treatment). On day 130 of gestation, the remaining ewes were euthanized, and fetal samples were collected. Fetal liver, longissimus dorsi (LD), and blood metabolites were analyzed using LC-MS/MS, and pathway enrichment analysis was conducted using MetaboAnalyst. Then, 600, 518, and 524 metabolites were identified in the liver, LD, and blood, respectively, including 345 metabolites that were present in all three. Nutrient restriction was associated with changes in amino acid, carbohydrate, lipid, and transulfuration/methionine metabolic pathways, some of which were alleviated by realimentation. Fetal age also affected metabolite abundance. The differential abundance of metabolites involved in amino acid, methionine, betaine, and bile acid metabolism could impact fetal epigenetic regulation, protein synthesis, lipid metabolism, and signaling associated with glucose and lipid metabolism. Full article

(This article belongs to the Special Issue Unlocking the Mysteries of Muscle Metabolism in the Animal Sciences)

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20 pages, 590 KB

Open AccessEditor’s ChoiceArticle

Metabolite Predictors of Breast and Colorectal Cancer Risk in the Women’s Health Initiative

by Sandi L. Navarro, Brian D. Williamson, Ying Huang, G. A. Nagana Gowda, Daniel Raftery, Lesley F. Tinker, Cheng Zheng, Shirley A. A. Beresford, Hayley Purcell, Danijel Djukovic, Haiwei Gu, Howard D. Strickler, Fred K. Tabung, Ross L. Prentice, Marian L. Neuhouser and Johanna W. Lampe

Metabolites 2024, 14(8), 463; https://doi.org/10.3390/metabo14080463 - 20 Aug 2024

Cited by 4 | Viewed by 2637

Abstract

Metabolomics has been used extensively to capture the exposome. We investigated whether prospectively measured metabolites provided predictive power beyond well-established risk factors among 758 women with adjudicated cancers [n = 577 breast (BC) and n = 181 colorectal (CRC)] and n = [...] Read more.

Metabolomics has been used extensively to capture the exposome. We investigated whether prospectively measured metabolites provided predictive power beyond well-established risk factors among 758 women with adjudicated cancers [n = 577 breast (BC) and n = 181 colorectal (CRC)] and n = 758 controls with available specimens (collected mean 7.2 years prior to diagnosis) in the Women’s Health Initiative Bone Mineral Density subcohort. Fasting samples were analyzed by LC-MS/MS and lipidomics in serum, plus GC-MS and NMR in 24 h urine. For feature selection, we applied LASSO regression and Super Learner algorithms. Prediction models were subsequently derived using logistic regression and Super Learner procedures, with performance assessed using cross-validation (CV). For BC, metabolites did not increase predictive performance over established risk factors (CV-AUCs~0.57). For CRC, prediction increased with the addition of metabolites (median CV-AUC across platforms increased from ~0.54 to ~0.60). Metabolites related to energy metabolism: adenosine, 2-hydroxyglutarate, N-acetyl-glycine, taurine, threonine, LPC (FA20:3), acetate, and glycerate; protein metabolism: histidine, leucic acid, isoleucine, N-acetyl-glutamate, allantoin, N-acetyl-neuraminate, hydroxyproline, and uracil; and dietary/microbial metabolites: myo-inositol, trimethylamine-N-oxide, and 7-methylguanine, consistently contributed to CRC prediction. Energy metabolism may play a key role in the development of CRC and may be evident prior to disease development. Full article

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

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12 pages, 1894 KB

Open AccessEditor’s ChoiceArticle

Alterations in Choline Metabolism in Non-Obese Individuals with Insulin Resistance and Type 2 Diabetes Mellitus

by Haya Al-Sulaiti, Najeha Anwardeen, Sara S. Bashraheel, Khaled Naja and Mohamed A. Elrayess

Metabolites 2024, 14(8), 457; https://doi.org/10.3390/metabo14080457 - 18 Aug 2024

Cited by 5 | Viewed by 2064

Abstract

The prevalence of non-obese individuals with insulin resistance (IR) and type 2 diabetes (T2D) is increasing worldwide. This study investigates the metabolic signature of phospholipid-associated metabolites in non-obese individuals with IR and T2D, aiming to identify potential biomarkers for these metabolic disorders. The [...] Read more.

The prevalence of non-obese individuals with insulin resistance (IR) and type 2 diabetes (T2D) is increasing worldwide. This study investigates the metabolic signature of phospholipid-associated metabolites in non-obese individuals with IR and T2D, aiming to identify potential biomarkers for these metabolic disorders. The study cohort included non-obese individuals from the Qatar Biobank categorized into three groups: insulin sensitive, insulin resistant, and patients with T2D. Each group comprised 236 participants, totaling 708 individuals. Metabolomic profiling was conducted using high-resolution mass spectrometry, and statistical analyses were performed to identify metabolites associated with the progression from IS to IR and T2D. The study observed significant alterations in specific phospholipid metabolites across the IS, IR, and T2D groups. Choline phosphate, glycerophosphoethanolamine, choline, glycerophosphorylcholine (GPC), and trimethylamine N-oxide showed significant changes correlated with disease progression. A distinct metabolic signature in non-obese individuals with IR and T2D was characterized by shifts in choline metabolism, including decreased levels of choline and trimethylamine N-oxide and increased levels of phosphatidylcholines, phosphatidylethanolamines, and their degradation products. These findings suggest that alterations in choline metabolism may play a critical role in the development of glucose intolerance and insulin resistance. Targeting choline metabolism could offer potential therapeutic strategies for treating T2D. Further research is needed to validate these biomarkers and understand their functional significance in the pathogenesis of IR and T2D in non-obese populations. Full article

(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics in Health and Disease: Targeted Analysis)

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15 pages, 985 KB

Open AccessEditor’s ChoiceArticle

Local and Systemic Micro-Rheological Changes during Intestinal Anastomosis Operation: A Metabolic Dependence in an Experimental Model

by Adam Varga, Adam Attila Matrai, Barbara Bedocs-Barath, Laszlo Adam Fazekas, Felipe Salignac Brasil, Aashna Mehta, Erzsebet Vanyolos, Adam Deak, Tamas Lesznyak, Katalin Peto and Norbert Nemeth

Metabolites 2024, 14(8), 458; https://doi.org/10.3390/metabo14080458 - 18 Aug 2024

Viewed by 1538

Abstract

Hemorheological factors may show arterio-venous differences. Alterations in acid-base and metabolic parameters may also influence these factors. However, little is known about changes in micro-rheological parameters during abdominal surgery, influencing splanchnic circulation. In anesthetized pigs, the external jugular vein, femoral artery and vein [...] Read more.

Hemorheological factors may show arterio-venous differences. Alterations in acid-base and metabolic parameters may also influence these factors. However, little is known about changes in micro-rheological parameters during abdominal surgery, influencing splanchnic circulation. In anesthetized pigs, the external jugular vein, femoral artery and vein were cannulated unilaterally, and paramedian laparotomy was performed. In the anastomosis group, after resecting a bowel segment, end-to-end jejuno-jejunostomy was completed. Blood samples (from cannulas and by puncturing the portal vein) were taken before and after the intervention. Hematological, acid-base and blood gas parameters, metabolites, red blood cell (RBC) deformability and aggregation were determined. The highest hematocrit was found in portal blood, increasing further by the end of operation. A significant pH decrease was seen, and portal blood showed the highest lactate and creatinine concentration. The highest RBC aggregation values were found in arterial, the lowest in renal venous blood. The RBC aggregation increased with higher lactate concentration and lower pH. Osmotic gradient deformability declined, with the lowest values in portal and renal venous samples. In conclusion, micro-rheological parameters showed arterio-venous and porto-renal venous differences, influenced by oxygenation level, pH and lactate concentration. The intestinal anastomosis operation caused an immediate micro-rheological deterioration with portal venous dominancy in this experiment. Full article

(This article belongs to the Special Issue Metabolic Biomarkers and Nutrition in Degenerative Conditions and Gastrointestinal Cancer Surgery)

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16 pages, 3811 KB

Open AccessEditor’s ChoiceArticle

Comparison of Growth and Metabolomic Profiles of Two Afforestation Cypress Species Cupressus chengiana and Platycladus orientalis Grown at Minjiang Valley in Southwest China

by Zhengqiao Liao, Lijun Zhu, Lei Liu, Jürgen Kreuzwieser, Christiane Werner and Baoguo Du

Metabolites 2024, 14(8), 453; https://doi.org/10.3390/metabo14080453 - 17 Aug 2024

Cited by 1 | Viewed by 1177

Abstract

In recent years, afforestation has been conducted in China’s hot and dry valleys. However, there is still a paucity of knowledge regarding the performance of tree species in these semi-arid regions, particularly with regard to interspecies differences. The present study compares the growth [...] Read more.

In recent years, afforestation has been conducted in China’s hot and dry valleys. However, there is still a paucity of knowledge regarding the performance of tree species in these semi-arid regions, particularly with regard to interspecies differences. The present study compares the growth and metabolome characteristics of two widely used cypress species, namely Cupressus chengiana and Platycladus orientalis, grown at two sites with distinct climate conditions in the hot and dry Minjiang Valley in southwestern China. The findings indicate that C. chengiana trees exhibit superior growth rates compared to P. orientalis trees at both study sites. In comparison to P. orientalis trees, C. chengiana trees demonstrated a greater tendency to close their stomata in order to prevent water loss at the hotter and drier site, Llianghekou (LHK). Additionally, C. chengiana trees exhibited significantly lower hydrogen peroxide levels than P. orientalis trees, either due to lower production and/or higher scavenging of reactive oxygen species. C. chengiana trees accumulated soluble sugars as well as sugar derivatives, particularly those involved in sucrose and galactose metabolisms under stressful conditions. The species-specific differences were also reflected in metabolites involved in the tricarboxylic acid cycle, nitrogen, and secondary metabolisms. The metabolome profiles of the two species appeared to be influenced by the prevailing climatic conditions. It appeared that the trees at the drier and hotter site, LHK, were capable of efficient nitrogen uptake from the soil despite the low soil nitrogen concentration. This study is the first to compare the growth performance and metabolic profiles of two widely used tree species with high resistance to adverse conditions. In addition to the species-specific differences and adaptations to different sites, the present study also provides insights into potential management strategies to alleviate abiotic stress, particularly with regard to nitrogen nutrients, in the context of climate change. Full article

(This article belongs to the Special Issue Metabolic Responses of Plants to Abiotic Stress)

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14 pages, 2236 KB

Open AccessEditor’s ChoiceArticle

Characterizing Growth-Retarded Japanese Eels (Anguilla japonica): Insights into Metabolic and Appetite Regulation

by Xiangbiao Zeng, Jingwei Liu, Yiwen Chen, Huan Han, Yanhe Liu, Bin Xie, Tianwei Jiang, Chris Kong-Chu Wong, Kang Li and Liping Liu

Metabolites 2024, 14(8), 432; https://doi.org/10.3390/metabo14080432 - 5 Aug 2024

Cited by 1 | Viewed by 2438

Abstract

During field surveys and culture procedures, large growth disparities in Anguilla japonica have been observed. However, the potential causes are unknown. This study explored differences in digestive ability, metabolic levels, and transcriptomic profiles of appetite-related genes between growth-retarded eel (GRE) and normal-growing eel [...] Read more.

During field surveys and culture procedures, large growth disparities in Anguilla japonica have been observed. However, the potential causes are unknown. This study explored differences in digestive ability, metabolic levels, and transcriptomic profiles of appetite-related genes between growth-retarded eel (GRE) and normal-growing eel (NGE) under the same rearing conditions. The results showed that growth hormone (gh) mRNA expression in GREs was considerably lower than NGEs. The levels of total protein (TP), total cholesterol (T-CHO), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), blood ammonia (BA), blood urea nitrogen (BUN), and alkaline phosphatase (ALP) in GREs were significantly lower than in NGEs. Conversely, levels of glucose (GLU), alanine aminotransferase (ALT), and aspartate transaminase (AST) were higher in GREs. The activities of SOD, CAT, and T-AOC levels were also significantly lower in GREs, as were the activities of glucose-related enzymes including hexokinase (HK), pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6PASE). Additionally, orexigenic genes (npy and ghrelin) were dramatically downregulated, whereas anorexigenic genes (crh and pyy) were significantly upregulated in GREs. These findings suggested that variances in growth hormone, metabolic activities, and appetite level could be associated with the different growth rates of A. japonica. The present research not only revealed the characteristics of the growth, metabolism, and appetite of GREs but also offered new perspectives into the substantial growth discrepancies in A. japonica, providing novel ideas for enhancing fish growth. Full article

(This article belongs to the Special Issue Nutrition, Metabolism and Physiology in Aquatic Animals)

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25 pages, 7059 KB

Open AccessEditor’s ChoiceArticle

Propionic Acidemia, Methylmalonic Acidemia, and Cobalamin C Deficiency: Comparison of Untargeted Metabolomic Profiles

by Anna Sidorina, Giulio Catesini, Elisa Sacchetti, Cristiano Rizzo and Carlo Dionisi-Vici

Metabolites 2024, 14(8), 428; https://doi.org/10.3390/metabo14080428 - 2 Aug 2024

Cited by 3 | Viewed by 2499

Abstract

Methylmalonic acidemia (MMA), propionic acidemia (PA), and cobalamin C deficiency (cblC) share a defect in propionic acid metabolism. In addition, cblC is also involved in the process of homocysteine remethylation. These three diseases produce various phenotypes and complex downstream metabolic effects. In this [...] Read more.

Methylmalonic acidemia (MMA), propionic acidemia (PA), and cobalamin C deficiency (cblC) share a defect in propionic acid metabolism. In addition, cblC is also involved in the process of homocysteine remethylation. These three diseases produce various phenotypes and complex downstream metabolic effects. In this study, we used an untargeted metabolomics approach to investigate the biochemical differences and the possible connections among the pathophysiology of each disease. The significantly changed metabolites in the untargeted urine metabolomic profiles of 21 patients (seven MMA, seven PA, seven cblC) were identified through statistical analysis (p < 0.05; log2FC > |1|) and then used for annotation. Annotated features were associated with different metabolic pathways potentially involved in the disease’s development. Comparative statistics showed markedly different metabolomic profiles between MMA, PA, and cblC, highlighting the characteristic species for each disease. The most affected pathways were related to the metabolism of organic acids (all diseases), amino acids (all diseases), and glycine and its conjugates (in PA); the transsulfuration pathway; oxidative processes; and neurosteroid hormones (in cblC). The untargeted metabolomics study highlighted the presence of significant differences between the three diseases, pointing to the most relevant contrast in the cblC profile compared to MMA and PA. Some new biomarkers were proposed for PA, while novel data regarding the alterations of steroid hormone profiles and biomarkers of oxidative stress were obtained for cblC disease. The elevation of neurosteroids in cblC may indicate a potential connection with the development of ocular and neuronal deterioration. Full article

(This article belongs to the Special Issue New Advancements and Challenges in Clinical Metabolomics for Inborn Errors of Metabolism and Rare Diseases)

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11 pages, 4526 KB

Open AccessEditor’s ChoiceReview

Metabolic Pathways in Hydrocephalus: Profiling with Proteomics and Advanced Imaging

by Laura May Davis and Misun Hwang

Metabolites 2024, 14(8), 412; https://doi.org/10.3390/metabo14080412 - 27 Jul 2024

Cited by 1 | Viewed by 1575

Abstract

Hemorrhagic hydrocephalus is a common pathology in neonates with high mortality and morbidity. Current imaging approaches fail to capture the mechanisms behind its pathogenesis. Here, we discuss the processes underlying this pathology, the metabolic dysfunction that occurs as a result, and the ways [...] Read more.

Hemorrhagic hydrocephalus is a common pathology in neonates with high mortality and morbidity. Current imaging approaches fail to capture the mechanisms behind its pathogenesis. Here, we discuss the processes underlying this pathology, the metabolic dysfunction that occurs as a result, and the ways in which these metabolic changes inform novel methods of clinical imaging. The imaging advances described allow earlier detection of the cellular and metabolic changes, leading to better outcomes for affected neonates. Full article

(This article belongs to the Special Issue Neurometabolic Monitoring and Imaging in Pediatric Critical Care)

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12 pages, 1732 KB

Open AccessEditor’s ChoiceArticle

Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment

by Ayenachew Bezawork-Geleta, Diane Moujalled, David P. De Souza, Vinod K. Narayana, James Dimou, Rodney Luwor and Matthew J. Watt

Metabolites 2024, 14(8), 413; https://doi.org/10.3390/metabo14080413 - 27 Jul 2024

Cited by 1 | Viewed by 1743

Abstract

Glioblastoma (IDH-wildtype) represents a formidable challenge in oncology, lacking effective chemotherapeutic or biological interventions. The metabolic reprogramming of cancer cells is a hallmark of tumor progression and drug resistance, yet the role of metabolic reprogramming in glioblastoma during drug treatment remains poorly understood. [...] Read more.

Glioblastoma (IDH-wildtype) represents a formidable challenge in oncology, lacking effective chemotherapeutic or biological interventions. The metabolic reprogramming of cancer cells is a hallmark of tumor progression and drug resistance, yet the role of metabolic reprogramming in glioblastoma during drug treatment remains poorly understood. The dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 is a blood–brain barrier penetrant drug showing efficiency in in vivo models of many brain cancers. In this study, we investigated the effect of BAY2402234 in regulating the metabolic phenotype of EGFRWT and EGFRvIII patient-derived glioblastoma cell lines. Our findings reveal the selective cytotoxicity of BAY2402234 toward EGFRWT glioblastoma subtypes with minimal effect on EGFRvIII patient cells. At sublethal doses, BAY2402234 induces triglyceride synthesis at the expense of membrane lipid synthesis and fatty acid oxidation in EGFRWT glioblastoma cells, while these effects are not observed in EGFRvIII glioblastoma cells. Furthermore, BAY2402234 reduced the abundance of signaling lipid species in EGFRWT glioblastoma. This study elucidates genetic mutation-specific metabolic plasticity and efficacy in glioblastoma cells in response to drug treatment, offering insights into therapeutic avenues for precision medicine approaches. Full article

(This article belongs to the Section Lipid Metabolism)

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18 pages, 7899 KB

Open AccessEditor’s ChoiceArticle

Metabolomic Profiling of Adipose Tissue in Type 2 Diabetes: Associations with Obesity and Insulin Resistance

by Argyri Mathioudaki, Giovanni Fanni, Jan W. Eriksson and Maria J. Pereira

Metabolites 2024, 14(8), 411; https://doi.org/10.3390/metabo14080411 - 26 Jul 2024

Cited by 4 | Viewed by 2054

Abstract

The global prevalence of Type 2 Diabetes (T2D) poses significant public health challenges due to its associated severe complications. Insulin resistance is central to T2D pathophysiology, particularly affecting adipose tissue function. This cross-sectional observational study investigates metabolic alterations in subcutaneous adipose tissue (SAT) [...] Read more.

The global prevalence of Type 2 Diabetes (T2D) poses significant public health challenges due to its associated severe complications. Insulin resistance is central to T2D pathophysiology, particularly affecting adipose tissue function. This cross-sectional observational study investigates metabolic alterations in subcutaneous adipose tissue (SAT) associated with T2D to identify potential therapeutic targets. We conducted a comprehensive metabolomic analysis of SAT from 40 participants (20 T2D, 20 ND-T2D), matched for sex, age, and BMI (Body Mass Index). Metabolite quantification was performed using GC/MS and LC/MS/MS platforms. Correlation analyses were conducted to explore associations between metabolites and clinical parameters. We identified 378 metabolites, including significant elevations in TCA cycle (tricarboxylic acid cycle) intermediates, branched-chain amino acids (BCAAs), and carbohydrates, and a significant reduction in the nucleotide-related metabolites in T2D subjects compared to those without T2D. Obesity exacerbated these alterations, particularly in amino acid metabolism. Adipocyte size negatively correlated with BCAAs, while adipocyte glucose uptake positively correlated with unsaturated fatty acids and glycerophospholipids. Our findings reveal distinct metabolic dysregulation in adipose tissue in T2D, particularly in energy metabolism, suggesting potential therapeutic targets for improving insulin sensitivity and metabolic health. Future studies should validate these findings in larger cohorts and explore underlying mechanisms to develop targeted interventions. Full article

(This article belongs to the Special Issue Metabolism in Diabetes Progression and Diabetic Complications)

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19 pages, 4642 KB

Open AccessEditor’s ChoiceArticle

Photosynthetic Activities, Phytohormones, and Secondary Metabolites Induction in Plants by Prevailing Compost Residue

by Lord Abbey, Samuel Kwaku Asiedu, Sparsha Chada, Raphael Ofoe, Peter Ofori Amoako, Stella Owusu-Nketia, Nivethika Ajeethan, Anagha Pradeep Kumar and Efoo Bawa Nutsukpo

Metabolites 2024, 14(8), 400; https://doi.org/10.3390/metabo14080400 - 24 Jul 2024

Cited by 1 | Viewed by 1629

Abstract

Compost residue enriches soil health with the potential to enhance plant metabolism and hormonal balance, but has not yet been studied. A study was performed to determine how prevailing compost residue induces tomato (Solanum lycopersicum ‘Scotia’) plant morpho-physiology, phytohormones, and secondary metabolites. [...] Read more.

Compost residue enriches soil health with the potential to enhance plant metabolism and hormonal balance, but has not yet been studied. A study was performed to determine how prevailing compost residue induces tomato (Solanum lycopersicum ‘Scotia’) plant morpho-physiology, phytohormones, and secondary metabolites. Plants were grown in soils with a previous history of annual (AN) and biennial (BI) compost amendments. The controls were soil without compost (C) amendment and municipal solid waste compost (MSWC) alone. The MSWC- and AN-plants had similar and significantly (p < 0.05) highest growth and photosynthetic activities compared to the BI- or C-plants. Total phenolics and lipid peroxidase activity were significantly (p < 0.001) high in BI-plants, while hydrogen peroxide and antioxidant capacity were significantly (p < 0.001) high in AN-plants. MSWC-plants recorded the highest cis-abscisic acid, followed by AN-, and then BI- and C-plants. Cis-zeatin, trans-zeatin, and isopentenyladenine ribosides were detected in the MSWC- and AN-plants but not in the BI- or C-plants. Furthermore, gibberellins GA53, GA19, and GA8 were high in the MSWC-plants, but only GA8 was detected in the AN plants and none in the others. Besides, MSWC plants exhibited the highest content of 1-aminocyclopropane-1-carboxylic acid. Conjugated salicylic acid was highest in the BI-plants, while jasmonic acid-isoleucine was highest in MSWC-plants and C plants. In conclusion, prevailing compost chemical residues upregulate plant growth, phytohormones, and metabolic compounds that can potentially increase plant growth and abiotic stress defense. Future work should investigate the flow of these compounds in plants under abiotic stress. Full article

(This article belongs to the Special Issue Plant Biotic and Abiotic Stress Responses and Tolerance: Phytohormonal and Metabolic Insights)

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15 pages, 1353 KB

Open AccessEditor’s ChoiceArticle

Amino Acid Profile Alterations in Phenylketonuria: Implications for Clinical Practice

by Eliza Matuszewska, Joanna Matysiak, Łukasz Kałużny, Dariusz Walkowiak, Szymon Plewa, Monika Duś-Żuchowska, Natalia Rzetecka, Małgorzata Jamka, Agnieszka Klupczyńska-Gabryszak, Marcin Piorunek, Jan Matysiak and Jarosław Walkowiak

Metabolites 2024, 14(7), 397; https://doi.org/10.3390/metabo14070397 - 21 Jul 2024

Cited by 4 | Viewed by 2313

Abstract

Patients with phenylketonuria (PKU) must restrict their intake of phenylalanine, which can also affect the levels of other essential and non-essential amino acids due to inadequate supply. Therefore, our objective was to assess amino acids in serum samples from 20 PKU patients and [...] Read more.

Patients with phenylketonuria (PKU) must restrict their intake of phenylalanine, which can also affect the levels of other essential and non-essential amino acids due to inadequate supply. Therefore, our objective was to assess amino acids in serum samples from 20 PKU patients and compare them with results from 51 healthy subjects. A sample analysis was conducted using liquid chromatography–tandem mass spectrometry. We obtained levels of 28 substances, including amino acids, biogenic amines, carnitine, and acetylcarnitine. Kynurenine (p = 0.000001), tyrosine (p = 0.0002), asparagine (p = 0.001), proline (p = 0.012), and the kynurenine/tryptophan ratio (p < 0.000001) were identified as features that differed between the studied groups, being significantly lower in patients with PKU. Glycine (p = 0.000012), putrescine (p = 0.0055), asymmetric dimethylarginine (p = 0.01), creatinine (p = 0.035) levels, as well as the total level of glucogenic amino acids (p = 0.0018), and the ratios of putrescine/ornithine (p = 0.003) and citrulline/ornithine (p = 0.0043) were significantly higher in the PKU group. In conclusion, the amino acid profiles in patients with PKU differ significantly from those in healthy peers, with potential clinical implications. These findings confirm the importance of metabolic testing in clinical practice and highlight the necessity for adequate dietary monitoring and adjustment. Full article

(This article belongs to the Special Issue New Advancements and Challenges in Clinical Metabolomics for Inborn Errors of Metabolism and Rare Diseases)

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38 pages, 10637 KB

Open AccessEditor’s ChoiceArticle

A Multiomics, Molecular Atlas of Breast Cancer Survivors

by Brent A. Bauer, Caleb M. Schmidt, Kathryn J. Ruddy, Janet E. Olson, Cem Meydan, Julian C. Schmidt, Sheena Y. Smith, Fergus J. Couch, John C. Earls, Nathan D. Price, Joel T. Dudley, Christopher E. Mason, Bodi Zhang, Stephen M. Phipps and Michael A. Schmidt

Metabolites 2024, 14(7), 396; https://doi.org/10.3390/metabo14070396 - 20 Jul 2024

Viewed by 2521

Abstract

Breast cancer imposes a significant burden globally. While the survival rate is steadily improving, much remains to be elucidated. This observational, single time point, multiomic study utilizing genomics, proteomics, targeted and untargeted metabolomics, and metagenomics in a breast cancer survivor (BCS) and age-matched [...] Read more.

Breast cancer imposes a significant burden globally. While the survival rate is steadily improving, much remains to be elucidated. This observational, single time point, multiomic study utilizing genomics, proteomics, targeted and untargeted metabolomics, and metagenomics in a breast cancer survivor (BCS) and age-matched healthy control cohort (N = 100) provides deep molecular phenotyping of breast cancer survivors. In this study, the BCS cohort had significantly higher polygenic risk scores for breast cancer than the control group. Carnitine and hexanoyl carnitine were significantly different. Several bile acid and fatty acid metabolites were significantly dissimilar, most notably the Omega-3 Index (O3I) (significantly lower in BCS). Proteomic and metagenomic analyses identified group and pathway differences, which warrant further investigation. The database built from this study contributes a wealth of data on breast cancer survivorship where there has been a paucity, affording the ability to identify patterns and novel insights that can drive new hypotheses and inform future research. Expansion of this database in the treatment-naïve, newly diagnosed, controlling for treatment confounders, and through the disease progression, can be leveraged to profile and contextualize breast cancer and breast cancer survivorship, potentially leading to the development of new strategies to combat this disease and improve the quality of life for its victims. Full article

(This article belongs to the Special Issue Cancer Metabolomics 2024)

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14 pages, 3096 KB

Open AccessEditor’s ChoiceArticle

Tracking Metabolite Variations during the Degradation of Vegetables in Rice Bran Bed with Intact-State Nuclear Magnetic Resonance Spectroscopy

by Kengo Ito, Ryusei Yamamoto and Yasuyo Sekiyama

Metabolites 2024, 14(7), 391; https://doi.org/10.3390/metabo14070391 - 19 Jul 2024

Viewed by 1644

Abstract

Fermentation—a process of compound degradation by microorganisms—is a traditional food processing method utilized worldwide for the long-term preservation of fresh foods. In recent years, fermented foods have gained attention as health foods. Fermentation increases the nutritional value of ingredients, producing complex flavors and [...] Read more.

Fermentation—a process of compound degradation by microorganisms—is a traditional food processing method utilized worldwide for the long-term preservation of fresh foods. In recent years, fermented foods have gained attention as health foods. Fermentation increases the nutritional value of ingredients, producing complex flavors and aromas. To identify unknown components in fermented foods, it is necessary to analyze compounds and conditions nondestructively and comprehensively. We performed intact-state nuclear magnetic resonance (NMR) spectroscopy using intermolecular single quantum coherence (iSQC) to detect the degradation of vegetables directly and nondestructively. We used two types of vegetables and a rice bran bed (nukazuke), which is used for traditional vegetable fermentation in Japan. Major metabolites such as saccharides, organic acids, and amino acids were identified in iSQC-sliced spectra. Comparing NMR signal intensities during degradation revealed the transition of metabolites characteristic of lactic acid fermentation. A pathway-based network analysis showed pathways involved in amino acid metabolism and lactic acid fermentation. Our analytical approach with intact-state NMR spectroscopy using iSQC demonstrated that it may be effective in other experimental systems, allowing for the evaluation of phenomena that have been conventionally overlooked in their true state. Full article

(This article belongs to the Special Issue Emerging Applications of Metabolomics in Fermented Food)

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49 pages, 2291 KB

Open AccessEditor’s ChoiceReview

The Pleiotropic Effects of Lipid-Modifying Interventions: Exploring Traditional and Emerging Hypolipidemic Therapies

by Dimitris Kounatidis, Nikolaos Tentolouris, Natalia G. Vallianou, Iordanis Mourouzis, Irene Karampela, Theodora Stratigou, Eleni Rebelos, Marina Kouveletsou, Vasileios Stamatopoulos, Eleni Tsaroucha and Maria Dalamaga

Metabolites 2024, 14(7), 388; https://doi.org/10.3390/metabo14070388 - 17 Jul 2024

Cited by 8 | Viewed by 3868

Abstract

Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as a major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, with statins emerging as the cornerstone treatment. These interventions play a crucial role in both primary and [...] Read more.

Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as a major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, with statins emerging as the cornerstone treatment. These interventions play a crucial role in both primary and secondary prevention by effectively reducing cardiovascular risk through lipid profile enhancements. Beyond their primary lipid-lowering effects, extensive research indicates that these therapies exhibit pleiotropic actions, offering additional health benefits. These include anti-inflammatory properties, improvements in vascular health and glucose metabolism, and potential implications in cancer management. While statins and ezetimibe have been extensively studied, newer lipid-lowering agents also demonstrate similar pleiotropic effects, even in the absence of direct cardiovascular benefits. This narrative review explores the diverse pleiotropic properties of lipid-modifying therapies, emphasizing their non-lipid effects that contribute to reducing cardiovascular burden and exploring emerging benefits for non-cardiovascular conditions. Mechanistic insights into these actions are discussed alongside their potential therapeutic implications Full article

(This article belongs to the Special Issue Lipid Biomarkers and Cardiometabolic Diseases)

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13 pages, 1838 KB

Open AccessEditor’s ChoiceArticle

Alteration of Fecal Microbiota, Fecal Metabolites, and Serum Metabolites in Dairy Cows with Pre-Retained Placenta

by Tao Zhou, Zhenlong Du, Zhengzhong Luo, Xiaoping Li, Dan Wu, Yixin Huang, Kang Yong, Xueping Yao, Liuhong Shen, Shumin Yu, Zuoting Yan and Suizhong Cao

Metabolites 2024, 14(7), 386; https://doi.org/10.3390/metabo14070386 - 15 Jul 2024

Viewed by 1899

Abstract

Retained placenta (RP) affects lactation and fertility in dairy cows and causes economic losses to the dairy industry. Therefore, screening for early warning of this disease is important. This study used multi omics techniques to reveal the metabolic differences of dairy cows before [...] Read more.

Retained placenta (RP) affects lactation and fertility in dairy cows and causes economic losses to the dairy industry. Therefore, screening for early warning of this disease is important. This study used multi omics techniques to reveal the metabolic differences of dairy cows before RP onset and to find potential warning markers. Fecal samples and serum samples of 90 healthy Holstein cows were collected 7 days pre-calving; 10 healthy and 10 RP cows were enrolled according to normal expulsion of fetal membranes after calving. Fecal samples were subjected to 16S rRNA sequencing and untargeted metabolomics analysis, while plasma was analyzed using targeted metabolomics. Pathogenic bacteria levels increased in the intestines of cows with RP compared to those in healthy cows. Lipid metabolites constituted the largest proportion of differential metabolites between feces and plasma. Six potential warning markers for RP in cows were identified, including two fecal microbiomics markers (Oscillospiraceae UCG-005 and Escherichia-Shigella), one fecal untargeted metabolomics marker (N-acetylmuramic acid), and three plasma targeted metabolomics markers (glycylcholic acid-3 sulfate, 7-ketolithocholic acid, and 12-ketolithocholic acid). These biomarkers can predict RP occurrence in the early perinatal period. These results lay a theoretical foundation for early nutritional intervention and pathogenesis research in dairy cows. Full article

(This article belongs to the Special Issue Metabolites in Ruminant Health)

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39 pages, 1836 KB

Open AccessEditor’s ChoiceReview

Challenges of Spatially Resolved Metabolism in Cancer Research

by Andrew N. Lane, Richard M. Higashi and Teresa W-M. Fan

Metabolites 2024, 14(7), 383; https://doi.org/10.3390/metabo14070383 - 11 Jul 2024

Cited by 1 | Viewed by 2476

Abstract

Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing [...] Read more.

Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing the basis for flux analysis. As the diversity of stable isotope-enriched compounds is very high, and with newer approaches to multiplexing, the coverage of metabolism is now very extensive. However, as the complexity of the model increases, including more kinds of interacting cell types and interorgan communication, the analytical complexity also increases. Further, as studies move further into spatially resolved biology, new technical problems have to be overcome owing to the small number of analytes present in the confines of a single cell or cell compartment. Here, we review the overall goals and solutions made possible by stable isotope tracing and their applications to models of increasing complexity. Finally, we discuss progress and outstanding difficulties in high-resolution spatially resolved tracer-based metabolic studies. Full article

(This article belongs to the Special Issue Isotope-Guided Analytical Strategies for Assessing Metabolic Networks in Cancer)

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14 pages, 7624 KB

Open AccessEditor’s ChoiceArticle

Non-Alcoholic Fatty Liver Disease Induced by Feeding Medium-Chain Fatty Acids Upregulates Cholesterol and Lipid Homeostatic Genes in Skeletal Muscle of Neonatal Pigs

by Samuel D. Gerrard, Fernando H. Biase, Joseph A. Yonke, Ravi Yadav, Anthony J. Shafron, Nishanth E. Sunny, David E. Gerrard and Samer W. El-Kadi

Metabolites 2024, 14(7), 384; https://doi.org/10.3390/metabo14070384 - 11 Jul 2024

Cited by 1 | Viewed by 1957

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a range of disorders characterized by lipid accumulation in hepatocytes. Although this spectrum of disorders is associated with adult obesity, recent evidence suggests that this condition could also occur independently of obesity, even in children. Previously, we [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a range of disorders characterized by lipid accumulation in hepatocytes. Although this spectrum of disorders is associated with adult obesity, recent evidence suggests that this condition could also occur independently of obesity, even in children. Previously, we reported that pigs fed a formula containing medium-chain fatty acids (MCFAs) developed hepatic steatosis and weighed less than those fed an isocaloric formula containing long-chain fatty acids (LCFAs). Our objective was to determine the association between NAFLD and the skeletal muscle transcriptome in response to energy and lipid intake. Neonatal pigs were fed one of three formulas: a control formula (CONT, n = 6) or one of two isocaloric high-energy formulas containing either long (LCFA, n = 6) or medium (MCFA, n = 6) chain fatty acids. Pigs were fed for 22 d, and tissues were collected. Body weight at 20 and 22 d was greater for LCFA-fed pigs than their CONT or MCFA counterparts (p < 0.005). Longissimus dorsi weight was greater for LCFA compared with MCFA, while CONT was intermediate (p < 0.05). Lean gain and protein deposition were greater for LCFA than for CONT and MCFA groups (p < 0.01). Transcriptomic analysis revealed 36 differentially expressed genes (DEGs) between MCFA and LCFA, 53 DEGs between MCFA and CONT, and 52 DEGs between LCFA and CONT (FDR < 0.2). Feeding formula high in MCFAs resulted in lower body and muscle weights. Transcriptomics data suggest that the reduction in growth was associated with a disruption in cholesterol metabolism in skeletal muscles. Full article

(This article belongs to the Special Issue Unlocking the Mysteries of Muscle Metabolism in the Animal Sciences)

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22 pages, 4088 KB

Open AccessEditor’s ChoiceArticle

Metabolomics and Multi-Omics Determination of Potential Plasma Biomarkers in PRV-1-Infected Atlantic Salmon

by Lada Ivanova, Oscar D. Rangel-Huerta, Haitham Tartor, Maria K. Dahle, Silvio Uhlig and Christiane Kruse Fæste

Metabolites 2024, 14(7), 375; https://doi.org/10.3390/metabo14070375 - 2 Jul 2024

Cited by 2 | Viewed by 3063

Abstract

Metabolomic analysis has been explored to search for disease biomarkers in humans for some time. The application to animal species, including fish, however, is still at the beginning. In the present study, we have used targeted and untargeted metabolomics to identify metabolites in [...] Read more.

Metabolomic analysis has been explored to search for disease biomarkers in humans for some time. The application to animal species, including fish, however, is still at the beginning. In the present study, we have used targeted and untargeted metabolomics to identify metabolites in the plasma of Atlantic salmon (Salmo salar) challenged with Piscine orthoreovirus (PRV-1), aiming to find metabolites associated with the progression of PRV-1 infection into heart and skeletal muscle inflammation (HSMI). The metabolomes of control and PRV-1-infected salmon were compared at three time points during disease development by employing different biostatistical approaches. Targeted metabolomics resulted in the determination of affected metabolites and metabolic pathways, revealing a substantial impact of PRV-1 infection on lipid homeostasis, especially on several (lyso)phosphatidylcholines, ceramides, and triglycerides. Untargeted metabolomics showed a clear separation of the treatment groups at later study time points, mainly due to effects on lipid metabolism pathways. In a subsequent multi-omics approach, we combined both metabolomics datasets with previously reported proteomics data generated from the same salmon plasma samples. Data processing with DIABLO software resulted in the identification of significant metabolites and proteins that were representative of the HSMI development in the salmon. Full article

(This article belongs to the Special Issue Proteomic and Metabolomic Analyses of Fisheries and Aquaculture)

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19 pages, 1928 KB

Open AccessEditor’s ChoiceArticle

Automated Liquid Handling Extraction and Rapid Quantification of Underivatized Amino Acids and Tryptophan Metabolites from Human Serum and Plasma Using Dual-Column U(H)PLC-MRM-MS and Its Application to Prostate Cancer Study

by Tobias Kipura, Madlen Hotze, Alexa Hofer, Anna-Sophia Egger, Lea E. Timpen, Christiane A. Opitz, Paul A. Townsend, Lee A. Gethings, Kathrin Thedieck and Marcel Kwiatkowski

Metabolites 2024, 14(7), 370; https://doi.org/10.3390/metabo14070370 - 30 Jun 2024

Cited by 5 | Viewed by 2904

Abstract

Amino acids (AAs) and their metabolites are important building blocks, energy sources, and signaling molecules associated with various pathological phenotypes. The quantification of AA and tryptophan (TRP) metabolites in human serum and plasma is therefore of great diagnostic interest. Therefore, robust, reproducible sample [...] Read more.

Amino acids (AAs) and their metabolites are important building blocks, energy sources, and signaling molecules associated with various pathological phenotypes. The quantification of AA and tryptophan (TRP) metabolites in human serum and plasma is therefore of great diagnostic interest. Therefore, robust, reproducible sample extraction and processing workflows as well as rapid, sensitive absolute quantification are required to identify candidate biomarkers and to improve screening methods. We developed a validated semi-automated robotic liquid extraction and processing workflow and a rapid method for absolute quantification of 20 free, underivatized AAs and six TRP metabolites using dual-column U(H)PLC-MRM-MS. The extraction and sample preparation workflow in a 96-well plate was optimized for robust, reproducible high sample throughput allowing for transfer of samples to the U(H)PLC autosampler directly without additional cleanup steps. The U(H)PLC-MRM-MS method, using a mixed-mode reversed-phase anion exchange column with formic acid and a high-strength silica reversed-phase column with difluoro-acetic acid as mobile phase additive, provided absolute quantification with nanomolar lower limits of quantification within 7.9 min. The semi-automated extraction workflow and dual-column U(H)PLC-MRM-MS method was applied to a human prostate cancer study and was shown to discriminate between treatment regimens and to identify metabolites responsible for discriminating between healthy controls and patients on active surveillance. Full article

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

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14 pages, 3930 KB

Open AccessEditor’s ChoiceArticle

Investigation of Rhizopus oligosporus Metabolites in Fermented Wheat Bran and Its Bio Function in Alleviating Colitis in Mice Model

by Afifah Zahra Agista, Yu-Shan Chien, Takuya Koseki, Hazuki Nagaoka, Takuto Ohnuma, Yusuke Ohsaki, Chiu-Li Yeh, Suh-Ching Yang, Ardiansyah, Slamet Budijanto, Michio Komai and Hitoshi Shirakawa

Metabolites 2024, 14(7), 359; https://doi.org/10.3390/metabo14070359 - 26 Jun 2024

Cited by 1 | Viewed by 3383

Abstract

Wheat bran (WB) is a low-value by-product of the wheat milling industry. Solid-state fermentation with Rhizopus oligosporus is performed to improve WB’s nutritional quality (RH). Twenty-five mice (11-week-old C57BL/6N male mice) were divided into three groups. The first group was fed a control [...] Read more.

Wheat bran (WB) is a low-value by-product of the wheat milling industry. Solid-state fermentation with Rhizopus oligosporus is performed to improve WB’s nutritional quality (RH). Twenty-five mice (11-week-old C57BL/6N male mice) were divided into three groups. The first group was fed a control diet (n = 8), the second group a 10% WB-supplemented diet (n = 8), and the last group had a 10% RH-supplemented diet (n = 9). The diet treatment was administered for 4 days before dextran sodium sulfate (DSS, 3% in drinking water) was administered for 9 days. RH supplementation prevented bodyweight loss and reduced the disease activity index in mice. An increase in the level of SCFAs in mouse intestines was detected post-RH supplementation, suggesting that SCFAs might have contributed to its anti-colitis effect. Metabolome analysis was conducted to explore other bioactive compounds in RH. R. oligosporus fermentation significantly increased the amounts of ergothioneine, arginine, branched-chain amino acids, and adenosine in wheat bran. All of these compounds are known to have antioxidant and anti-inflammatory capacities. These bioactive compounds might also have contributed to the RH’s ability to ameliorate DSS-induced colitis. Full article

(This article belongs to the Special Issue Emerging Applications of Metabolomics in Fermented Food)

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