Metabolites

53 pages, 1912 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Endoplasmic Reticulum Stress and Its Role in Metabolic Reprogramming of Cancer

by Salvatore Zarrella, Maria Rosaria Miranda, Verdiana Covelli, Ignazio Restivo, Sara Novi, Giacomo Pepe, Luisa Tesoriere, Manuela Rodriquez, Alessia Bertamino, Pietro Campiglia, Mario Felice Tecce and Vincenzo Vestuto

Metabolites 2025, 15(4), 221; https://doi.org/10.3390/metabo15040221 - 24 Mar 2025

Viewed by 1150

Abstract

Background/Objectives: Endoplasmic reticulum (ER) stress occurs when ER homeostasis is disrupted, leading to the accumulation of misfolded or unfolded proteins. This condition activates the unfolded protein response (UPR), which aims to restore balance or trigger cell death if homeostasis cannot be achieved. In [...] Read more.

Background/Objectives: Endoplasmic reticulum (ER) stress occurs when ER homeostasis is disrupted, leading to the accumulation of misfolded or unfolded proteins. This condition activates the unfolded protein response (UPR), which aims to restore balance or trigger cell death if homeostasis cannot be achieved. In cancer, ER stress plays a key role due to the heightened metabolic demands of tumor cells. This review explores how metabolomics can provide insights into ER stress-related metabolic alterations and their implications for cancer therapy. Methods: A comprehensive literature review was conducted to analyze recent findings on ER stress, metabolomics, and cancer metabolism. Studies examining metabolic profiling of cancer cells under ER stress conditions were selected, with a focus on identifying potential biomarkers and therapeutic targets. Results: Metabolomic studies highlight significant shifts in lipid metabolism, protein synthesis, and oxidative stress management in response to ER stress. These metabolic alterations are crucial for tumor adaptation and survival. Additionally, targeting ER stress-related metabolic pathways has shown potential in preclinical models, suggesting new therapeutic strategies. Conclusions: Understanding the metabolic impact of ER stress in cancer provides valuable opportunities for drug development. Metabolomics-based approaches may help identify novel biomarkers and therapeutic targets, enhancing the effectiveness of antitumor therapies. Full article

(This article belongs to the Special Issue NMR-Metabolomics in Peptide and Antibody Drug Discovery)

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20 pages, 15032 KiB

Open AccessEditor’s ChoiceArticle

Multi-Omics Profiling Reveals Glycerolipid Metabolism-Associated Molecular Subtypes and Identifies ALDH2 as a Prognostic Biomarker in Pancreatic Cancer

by Jifeng Liu, Shurong Ma, Dawei Deng, Yao Yang, Junchen Li, Yunshu Zhang, Peiyuan Yin and Dong Shang

Metabolites 2025, 15(3), 207; https://doi.org/10.3390/metabo15030207 - 18 Mar 2025

Cited by 1 | Viewed by 679

Abstract

Background: The reprogramming of lipid metabolism, especially glycerolipid metabolism (GLM), plays a key role in cancer progression and response to therapy. However, the role and molecular characterization of GLM in pancreatic cancer (PC) remain unclear. Methods: A pan-cancer analysis of glycerolipid [...] Read more.

Background: The reprogramming of lipid metabolism, especially glycerolipid metabolism (GLM), plays a key role in cancer progression and response to therapy. However, the role and molecular characterization of GLM in pancreatic cancer (PC) remain unclear. Methods: A pan-cancer analysis of glycerolipid metabolism-related genes (GMRGs) was first conducted to assess copy-number variants, single-nucleotide variations, methylation, and mRNA expression. Subsequently, GLM in PC was characterized using lipidomics, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomic analysis. A cluster analysis based on bulk RNA sequencing data from 930 PC samples identified GLM-associated subtypes, which were then analyzed for differences in prognosis, biological function, immune microenvironment, and drug sensitivity. To prioritize prognostically relevant GMRGs in PC, we employed a random forest (RF) algorithm to rank their importance across 930 PC samples. Finally, the key biomarker of PC was validated using PCR and immunohistochemistry. Results: Pan-cancer analysis identified molecular features of GMRGs in cancers, while scRNA-seq, spatial transcriptomics, and lipidomics highlighted GLM heterogeneity in PC. Two GLM-associated subtypes with significant prognostic, biofunctional, immune microenvironmental, and drug sensitivity differences were identified in 930 PC samples. Finally, ALDH2 was identified as a novel prognostic biomarker in PC and validated in a large number of datasets and clinical samples. Conclusions: This study highlights the crucial role of GLM in PC and defines a new PC subtype and prognostic biomarker. These findings establish a novel avenue for studying prognostic prediction and precision medicine in PC patients. Full article

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

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29 pages, 3266 KiB

Open AccessEditor’s ChoiceReview

Ceramide as a Promising Tool for Diagnosis and Treatment of Clinical Diseases: A Review of Recent Advances

by Xueping Shen, Rui Feng, Rui Zhou, Zhaoyang Zhang, Kaiyong Liu and Sheng Wang

Metabolites 2025, 15(3), 195; https://doi.org/10.3390/metabo15030195 - 11 Mar 2025

Viewed by 1404

Abstract

Background/Objectives: Ceramide, a sphingolipid metabolite, has emerged as a key player in various physiological and pathological processes. Changes in ceramide levels are associated with the occurrence and development of various diseases, highlighting its potential as a biomarker of various clinical diseases. Methods: The [...] Read more.

Background/Objectives: Ceramide, a sphingolipid metabolite, has emerged as a key player in various physiological and pathological processes. Changes in ceramide levels are associated with the occurrence and development of various diseases, highlighting its potential as a biomarker of various clinical diseases. Methods: The biosynthesis and metabolism of ceramide are discussed, along with its functions in cell signaling, apoptosis, and inflammation. This study further examines the potential of ceramide as a biomarker for disease diagnosis and treatment. Results: This article highlights the involvement of ceramide in several diseases, including cardiovascular diseases, dermatosis, cancer, neurodegenerative disorders and metabolic syndromes. For each disease, the potential of ceramide as a biomarker for disease diagnosis and prognosis is explored, and the feasibility of therapeutic strategies targeting ceramide metabolism are reviewed. Additionally, the challenges and future directions in the field of ceramide research are addressed. Conclusions: This review article provides an overview of the recent advances in understanding the role of ceramide in clinical diseases and its potential as a diagnostic and therapeutic tool. Full article

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

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19 pages, 1710 KiB

Open AccessEditor’s ChoiceReview

Metatranscriptomics for Understanding the Microbiome in Food and Nutrition Science

by Christina F. Butowski, Yash Dixit, Marlon M. Reis and Chunlong Mu

Metabolites 2025, 15(3), 185; https://doi.org/10.3390/metabo15030185 - 10 Mar 2025

Viewed by 1220

Abstract

Microbiome science has greatly expanded our understanding of the diverse composition and function of gut microorganisms over the past decades. With its rich microbial composition, the microbiome hosts numerous functionalities essential for metabolizing food ingredients and nutrients, resulting in the production of active [...] Read more.

Microbiome science has greatly expanded our understanding of the diverse composition and function of gut microorganisms over the past decades. With its rich microbial composition, the microbiome hosts numerous functionalities essential for metabolizing food ingredients and nutrients, resulting in the production of active metabolites that affect food fermentation or gut health. Most of these processes are mediated by microbial enzymes such as carbohydrate-active enzymes and amino acid metabolism enzymes. Metatranscriptomics enables the capture of active transcripts within the microbiome, providing invaluable functional insights into metabolic activities. Given the inter-kingdom complexity of the microbiome, metatranscriptomics could further elucidate the activities of fungi, archaea, and bacteriophages in the microbial ecosystem. Despite its potential, the application of metatranscriptomics in food and nutrition sciences remains limited but is growing. This review highlights the latest advances in food science (e.g., flavour formation and food enzymology) and nutrition science (e.g., dietary fibres, proteins, minerals, and probiotics), emphasizing the integration of metatranscriptomics with other technologies to address key research questions. Ultimately, metatranscriptomics represents a powerful tool for uncovering the microbiome activity, particularly in relation to active metabolic processes. Full article

(This article belongs to the Special Issue Gut Microbiome and Host Metabolism)

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15 pages, 1023 KiB

Open AccessEditor’s ChoiceReview

The Functions of Major Gut Microbiota in Obesity and Type 2 Diabetes

by Siman Liu, Zhipeng Tao, Mingyu Qiao and Limin Shi

Metabolites 2025, 15(3), 167; https://doi.org/10.3390/metabo15030167 - 1 Mar 2025

Cited by 1 | Viewed by 948

Abstract

Background: Gut microbiomes play a vital role in maintaining whole-body metabolic homeostasis. It has gained significant attention in recent years due to advancements in genome sequencing technologies and a deeper understanding of its relationship with obesity. However, the specific ways in which different [...] Read more.

Background: Gut microbiomes play a vital role in maintaining whole-body metabolic homeostasis. It has gained significant attention in recent years due to advancements in genome sequencing technologies and a deeper understanding of its relationship with obesity. However, the specific ways in which different microorganisms directly or indirectly influence host obesity, as well as the underlying mechanisms, remain uncertain because of the complexity of gut microbiota composition. Methods: In this review, we summarize the roles of the major gut microbiota phyla such as Bacteroidetes, Firmicutes, Proteobacteria, and Verrucomicrobia in obesity and type 2 diabetes based on studies published in the past five years on PubMed and Google Scholar. The current therapeutic strategies associated with gut microbiota are also explored from clinical trials, and challenges and future directions are discussed. Results and Conclusions: This review will provide a deeper understanding of the functions of major gut microbiota in obesity and type 2 diabetes, which could lead to more individualized and effective treatments for metabolic diseases. Full article

(This article belongs to the Special Issue Targeting Microbiota and Metabolites for Prevention and Treatment of Human Diseases)

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21 pages, 5553 KiB

Open AccessEditor’s ChoiceArticle

Identification of Bioactive Metabolites of Capirona macrophylla by Metabolomic Analysis, Molecular Docking, and In Vitro Antiparasitic Assays

by Joseph Evaristo, Elise de Laia, Bruna Tavares, Esdras Mendonça, Larissa Grisostenes, Caroline Rodrigues, Welington do Nascimento, Carolina Garcia, Sheila Guterres, Fábio Nogueira, Fernando Zanchi and Geisa Evaristo

Metabolites 2025, 15(3), 157; https://doi.org/10.3390/metabo15030157 - 26 Feb 2025

Cited by 1 | Viewed by 814

Abstract

Capirona macrophylla is a Rubiaceae known as “mulateiro”. Ethnobotanical extracts have been used for skin treatment and in the management of leishmaniasis and malaria. Objectives: The metabolites in aqueous extracts from wood bark, leaves, and stems were identified, and their in silico docking [...] Read more.

Capirona macrophylla is a Rubiaceae known as “mulateiro”. Ethnobotanical extracts have been used for skin treatment and in the management of leishmaniasis and malaria. Objectives: The metabolites in aqueous extracts from wood bark, leaves, and stems were identified, and their in silico docking and in vitro cellular efficacy against Leishmania amazonensis and Plasmodium falciparum were evaluated. Methods: The extracts were analyzed by UHPLC/HRMSⁿ using untargeted metabolomics approach with MSDial, MSFinder, and GNPS software for metabolite identification and spectra clustering. The most abundant metabolites underwent molecular docking using AutoDock via PyRx, targeting the dihydroorotate dehydrogenase from Leishmania and P. falciparum, and evaluated through molecular dynamics simulations using Gromacs. In vitro biological assays were conducted on 60 HPLC-fractions against these parasites. Results: Metabolomics analysis identified 5100 metabolites in ESI+ and 2839 in ESI− spectra among the “mulateiro” samples. GNPS clustering highlighted large clusters of quercetin and chlorogenic acid groups. The most abundant metabolites were isofraxidin, scopoletin, 5(S)-5-carboxystrictosidine, loliolide, quercetin, quinic acid, caffeoylquinic acid (and isomers), chlorogenic acid, neochlorogenic acid, tryptophan, N-acetyltryptophan, epicatechin, procyanidin, and kaempferol-3-O-robinoside-7-O-rhamnoside. Molecular docking pointed to 3,4-dicaffeoylquinic acid and kaempferol as promising inhibitors. The in vitro assays yielded four active HPLC-fractions against L. amazonensis with IC50 values ranging from 175.2 μg/mL to 194.8 μg/mL, and fraction G29 showed an IC50 of 119.8 μg/mL against P. falciparum. Conclusions: The ethnobotanical use of “mulateiro” wood bark tea as an antimalarial and antileishmanial agent was confirmed through in vitro assays. We speculate that these activities are attributed to linoleic acids and quinic acids. Full article

(This article belongs to the Special Issue Advanced Metabolic Profiling via Gas Chromatography–Mass Spectrometry and Liquid Chromatography–Mass Spectrometry)

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22 pages, 5013 KiB

Open AccessEditor’s ChoiceArticle

Polar Metabolite Profiles Distinguish Between Early and Severe Sub-Maintenance Nutritional States of Wild Bighorn Sheep

by Galen O’Shea-Stone, Brian Tripet, Jennifer Thomson, Robert Garrott and Valérie Copié

Metabolites 2025, 15(3), 154; https://doi.org/10.3390/metabo15030154 - 24 Feb 2025

Viewed by 831

Abstract

Background: Understanding the metabolic adaptations of wild bighorn sheep (Ovis c. canadensis) to nutritional stress is crucial for their conservation. Methods: This study employed ¹H nuclear magnetic resonance (NMR) metabolomics to investigate the biochemical responses of these animals to varying [...] Read more.

Background: Understanding the metabolic adaptations of wild bighorn sheep (Ovis c. canadensis) to nutritional stress is crucial for their conservation. Methods: This study employed ¹H nuclear magnetic resonance (NMR) metabolomics to investigate the biochemical responses of these animals to varying sub-maintenance nutritional states. Serum samples from 388 wild bighorn sheep collected between 2014 and 2017 from December (early sub-maintenance) through March (severe sub-maintenance) across Wyoming and Montana were analyzed. Multivariate statistics and machine learning analyses were employed to identify characteristic metabolic patterns and metabolic interactions between early and severe sub-maintenance nutritional states. Results: Significant differences were observed in the levels of 15 of the 49 quantified metabolites, including formate, thymine, glucose, choline, and others, pointing to disruptions in one-carbon, amino acid, and central carbon metabolic pathways. These metabolites may serve as indicators of critical physiological processes such as nutritional intake, immune function, energy metabolism, and protein catabolism, which are essential for understanding how wild bighorn sheep adapt to nutritional stress. Conclusions: This study has generated valuable insights into molecular networks underlying the metabolic resilience of wild bighorn sheep, highlighting the potential for using specific biochemical markers to evaluate nutritional and energetic states in free-ranging ungulates. These insights may help wildlife managers and ecologists compare populations across different times in seasonal cycles, providing information to assess the adequacy of seasonal ranges and support conservation efforts. This research strengthens our understanding of metabolic adaptations to environmental stressors in wild ruminants, offering a foundation for improving management practices to maintain healthy bighorn sheep populations. Full article

(This article belongs to the Section Animal Metabolism)

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29 pages, 1618 KiB

Open AccessEditor’s ChoiceReview

From Microbes to Metabolites: Advances in Gut Microbiome Research in Type 1 Diabetes

by Lente Blok, Nordin Hanssen, Max Nieuwdorp and Elena Rampanelli

Metabolites 2025, 15(2), 138; https://doi.org/10.3390/metabo15020138 - 19 Feb 2025

Cited by 1 | Viewed by 1629

Abstract

Background: Type 1 diabetes (T1D) is a severe chronic T-cell mediated autoimmune disease that attacks the insulin-producing beta cells of the pancreas. The multifactorial nature of T1D involves both genetic and environmental components, with recent research focusing on the gut microbiome as a [...] Read more.

Background: Type 1 diabetes (T1D) is a severe chronic T-cell mediated autoimmune disease that attacks the insulin-producing beta cells of the pancreas. The multifactorial nature of T1D involves both genetic and environmental components, with recent research focusing on the gut microbiome as a crucial environmental factor in T1D pathogenesis. The gut microbiome and its metabolites play an important role in modulating immunity and autoimmunity. In recent years, studies have revealed significant alterations in the taxonomic and functional composition of the gut microbiome associated with the development of islet autoimmunity and T1D. These changes include reduced production of short-chain fatty acids, altered bile acid and tryptophan metabolism, and increased intestinal permeability with consequent perturbations of host (auto)immune responses. Methods/Results: In this review, we summarize and discuss recent observational, mechanistic and etiological studies investigating the gut microbiome in T1D and elucidating the intricate role of gut microbes in T1D pathogenesis. Moreover, we highlight the recent advances in intervention studies targeting the microbiota for the prevention or treatment of human T1D. Conclusions: A deeper understanding of the evolution of the gut microbiome before and after T1D onset and of the microbial signals conditioning host immunity may provide us with essential insights for exploiting the microbiome as a prognostic and therapeutic tool. Full article

(This article belongs to the Special Issue The Role of Gut Microbes in Metabolism Regulation: 2nd Edition)

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34 pages, 3911 KiB

Open AccessEditor’s ChoiceReview

Polyphenols, Alkaloids, and Terpenoids Against Neurodegeneration: Evaluating the Neuroprotective Effects of Phytocompounds Through a Comprehensive Review of the Current Evidence

by Enzo Pereira de Lima, Lucas Fornari Laurindo, Vitor Cavallari Strozze Catharin, Rosa Direito, Masaru Tanaka, Iris Jasmin Santos German, Caroline Barbalho Lamas, Elen Landgraf Guiguer, Adriano Cressoni Araújo, Adriana Maria Ragassi Fiorini and Sandra Maria Barbalho

Metabolites 2025, 15(2), 124; https://doi.org/10.3390/metabo15020124 - 13 Feb 2025

Cited by 8 | Viewed by 3099

Abstract

Neurodegenerative diseases comprise a group of chronic, usually age-related, disorders characterized by progressive neuronal loss, deformation of neuronal structure, or loss of neuronal function, leading to a substantially reduced quality of life. They remain a significant focus of scientific and clinical interest due [...] Read more.

Neurodegenerative diseases comprise a group of chronic, usually age-related, disorders characterized by progressive neuronal loss, deformation of neuronal structure, or loss of neuronal function, leading to a substantially reduced quality of life. They remain a significant focus of scientific and clinical interest due to their increasing medical and social importance. Most neurodegenerative diseases present intracellular protein aggregation or their extracellular deposition (plaques), such as α-synuclein in Parkinson’s disease and amyloid beta (Aβ)/tau aggregates in Alzheimer’s. Conventional treatments for neurodegenerative conditions incur high costs and are related to the development of several adverse effects. In addition, many patients are irresponsive to them. For these reasons, there is a growing tendency to find new therapeutic approaches to help patients. This review intends to investigate some phytocompounds’ effects on neurodegenerative diseases. These conditions are generally related to increased oxidative stress and inflammation, so phytocompounds can help prevent or treat neurodegenerative diseases. To achieve our aim to provide a critical assessment of the current literature about phytochemicals targeting neurodegeneration, we reviewed reputable databases, including PubMed, EMBASE, and COCHRANE, seeking clinical trials that utilized phytochemicals against neurodegenerative conditions. A few clinical trials investigated the effects of phytocompounds in humans, and after screening, 13 clinical trials were ultimately included following PRISMA guidelines. These compounds include polyphenols (flavonoids such as luteolin and quercetin, phenolic acids such as rosmarinic acid, ferulic acid, and caffeic acid, and other polyphenols like resveratrol), alkaloids (such as berberine, huperzine A, and caffeine), and terpenoids (such as ginkgolides and limonene). The gathered evidence underscores that quercetin, caffeine, ginkgolides, and other phytochemicals are primarily anti-inflammatory, antioxidant, and neuroprotective, counteracting neuroinflammation, neuronal oxidation, and synaptic dysfunctions, which are crucial aspects of neurodegenerative disease intervention in various included conditions, such as Alzheimer’s and other dementias, depression, and neuropsychiatric disorders. In summary, they show that the use of these compounds is related to significant improvements in cognition, memory, disinhibition, irritability/lability, aberrant behavior, hallucinations, and mood disorders. Full article

(This article belongs to the Special Issue Plants and Plant-Based Foods for Metabolic Disease Prevention)

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17 pages, 7353 KiB

Open AccessEditor’s ChoiceArticle

Multifluid Metabolomics Identifies Novel Biomarkers for Irritable Bowel Syndrome

by Daniel Kirk, Panayiotis Louca, Ilias Attaye, Xinyuan Zhang, Kari E. Wong, Gregory A. Michelotti, Mario Falchi, Ana M. Valdes, Frances M. K. Williams and Cristina Menni

Metabolites 2025, 15(2), 121; https://doi.org/10.3390/metabo15020121 - 12 Feb 2025

Cited by 1 | Viewed by 1385

Abstract

Background/Objectives: Irritable bowel syndrome (IBS) is a complex disorder affecting 10% of the global population, but the underlying mechanisms remain poorly understood. By integrating multifluid metabolomics, we aimed to identify metabolite markers of IBS in a large population-based cohort. Methods: We [...] Read more.

Background/Objectives: Irritable bowel syndrome (IBS) is a complex disorder affecting 10% of the global population, but the underlying mechanisms remain poorly understood. By integrating multifluid metabolomics, we aimed to identify metabolite markers of IBS in a large population-based cohort. Methods: We included individuals from TwinsUK with and without IBS, ascertained using the Rome III criteria, and analysed serum (232 cases, 1707 controls), urine (185 cases, 1341 controls), and stool (186 cases, 1284 controls) metabolites (Metabolon Inc.). Results: After adjusting for covariates, and multiple testing, 44 unique metabolites (25 novel) were associated with IBS, including lipids, amino acids, and xenobiotics. Androsterone sulphate, a sulfated steroid hormone precursor, was associated with lower odds of IBS in both urine (0.69 [95% confidence interval = 0.56–0.85], p = 2.34 × 10⁻⁴) and serum (0.75 [0.63–0.90], p = 1.54 × 10⁻³. Moreover, suberate (C8-DC) was associated with higher odds of IBS in serum (1.36 [1.15–1.61]; p = 1.84 × 10⁻⁴) and lower odds of IBS in stool (0.76 [0.63–0.91]; p = 2.30 × 10⁻³). On the contrary, 32 metabolites appeared to be fluid-specific, including indole, 13-HODE + 9-HODE, pterin, bilirubin (E,Z or Z,Z), and urolithin. The remaining 10 metabolites were associated with IBS in one fluid with suggestive evidence (p < 0.05) in another fluid. Finally, we identified androgenic signalling, dicarboxylates, haemoglobin, and porphyrin metabolism to be significantly over-represented in individuals with IBS compared to controls. Conclusions: Our results highlight the utility of a multi-fluid approach in IBS research, revealing distinct metabolic signatures across biofluids. Full article

(This article belongs to the Special Issue Advances in Metabolomics and Multi-Omics Integration)

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22 pages, 1356 KiB

Open AccessEditor’s ChoiceArticle

A New, Validated GC-PICI-MS Method for the Quantification of 32 Lipid Fatty Acids via Base-Catalyzed Transmethylation and the Isotope-Coded Derivatization of Internal Standards

by Petr Vodrážka, Lucie Řimnáčová, Petra Berková, Jan Vojtíšek, Miroslav Verner, Martin Moos and Petr Šimek

Metabolites 2025, 15(2), 104; https://doi.org/10.3390/metabo15020104 - 7 Feb 2025

Viewed by 862

Abstract

Background: Fatty acids (FAs) represent a ubiquitous class of nonpolar alkyl carboxylate metabolites with diverse biological functions. Nutrition, metabolism, and endogenous and exogenous stress influence the overall FA metabolic status and transport via the bloodstream. FAs esterified in lipids are of particular interest, [...] Read more.

Background: Fatty acids (FAs) represent a ubiquitous class of nonpolar alkyl carboxylate metabolites with diverse biological functions. Nutrition, metabolism, and endogenous and exogenous stress influence the overall FA metabolic status and transport via the bloodstream. FAs esterified in lipids are of particular interest, as they represent promising biomarkers of pathological diseases and nutritional status. Methods: Here, we report a validated gas chromatographic-mass spectrometric (GC-MS) method for the quantitative analysis of 32 FAs exclusively bound in esterified lipids. The developed sample preparation protocol comprises three steps using only 5 µL of human serum for Folch extraction, sodium methoxide-catalyzed transesterification in tert-butyl methyl ether, and re-extraction in isooctane prior to a quantitative GC-MS analysis with positive ion chemical ionization (PICI) and selected ion monitoring (SIM). Results: The base-catalyzed transmethylation step was studied for 14 lipid classes and was found to be efficient under mild conditions for all major esterified lipids but not for free FAs, lipid amides, or sphingolipids. To minimize matrix effects and instrument bias, internal fatty acid trideuteromethyl esters (D3-FAME) standards were prepared through isotope-coded derivatization with D3-labeled methylchloroformate/methanol medium mixed with each transmethylated serum extract for the assay. The method was validated according to FDA guidelines and evaluated by analyzing NIST SRM 2378 Serum 1 and sera from three healthy donors. Conclusions: The measured quantitative FA values are consistent with the reference data of SRM 2378, and they demonstrate the application potential of the described method for general FA analysis in esterified lipids as a novel complementary tool for lipidomics, as well as for the analysis of membrane FAs in dry blood spots and red blood cells. Full article

(This article belongs to the Section Lipid Metabolism)

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31 pages, 5603 KiB

Open AccessEditor’s ChoiceArticle

Oregano Young Plants Cultured at Low Temperature Reveal an Enhanced Healing Effect of Their Extracts: Anatomical, Physiological and Cytotoxicity Approach

by Aikaterina L. Stefi, Maria Chalkiadaki, Katerina Dimitriou, Konstantina Mitsigiorgi, Dimitrios Gkikas, Danae Papageorgiou, Georgia C. Ntroumpogianni, Dido Vassilacopoulou, Maria Halabalaki and Nikolaos S. Christodoulakis

Metabolites 2025, 15(2), 103; https://doi.org/10.3390/metabo15020103 - 7 Feb 2025

Viewed by 1256

Abstract

Background: The germination and early development of Origanum vulgare L. subsp. hirtum (Link) Ietswaart (Greek oregano) were studied to assess the plant’s response to different temperatures. Methods: After germination, seedlings were cultivated in control (25 °C) and cold (15 °C) chambers with standard [...] Read more.

Background: The germination and early development of Origanum vulgare L. subsp. hirtum (Link) Ietswaart (Greek oregano) were studied to assess the plant’s response to different temperatures. Methods: After germination, seedlings were cultivated in control (25 °C) and cold (15 °C) chambers with standard growth parameters. Comparative analyses of plant morphology and leaf anatomy were conducted to identify structural modifications induced by different temperatures. Physiological evaluations, including photosynthetic pigment measurements, phenolic content, and antioxidant activity, were performed to assess differences between the plants grown under the two temperature conditions. Methanolic extracts from the leaves were tested for cytotoxicity on MCF-7 breast adenocarcinoma cells and SH-SY5Y neuroblastoma cells, as well as on nine microbial strains. Additionally, biomarkers from the leaves affected by temperature changes were determined using LC-HRMS/MS analysis. Results: Comparative analyses revealed distinct structural and physiological modifications under cold conditions. The methanolic extracts from plants grown at 15 °C exhibited notably higher cytotoxic activity in both cell lines but demonstrated no activity against microbial strains. The results highlight the influence of low temperature on enhancing the bioactive properties of Greek oregano. Conclusions: The findings provide valuable insights into the environmental adaptability of oregano, demonstrating the impact of low temperature on its bioactive properties. The therapeutic potential of methanolic extracts cultured at 15 °C is imprinted in cytotoxicity in SH-SY5Y and MCF-7 cells and the absence of any activity against microbial strains. Full article

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

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25 pages, 2912 KiB

Open AccessEditor’s ChoiceReview

Metabolic Objectives and Trade-Offs: Inference and Applications

by Da-Wei Lin, Saanjh Khattar and Sriram Chandrasekaran

Metabolites 2025, 15(2), 101; https://doi.org/10.3390/metabo15020101 - 6 Feb 2025

Viewed by 1206

Abstract

Background/Objectives: Determining appropriate cellular objectives is crucial for the system-scale modeling of biological networks for metabolic engineering, cellular reprogramming, and drug discovery applications. The mathematical representation of metabolic objectives can describe how cells manage limited resources to achieve biological goals within mechanistic and [...] Read more.

Background/Objectives: Determining appropriate cellular objectives is crucial for the system-scale modeling of biological networks for metabolic engineering, cellular reprogramming, and drug discovery applications. The mathematical representation of metabolic objectives can describe how cells manage limited resources to achieve biological goals within mechanistic and environmental constraints. While rapidly proliferating cells like tumors are often assumed to prioritize biomass production, mammalian cell types can exhibit objectives beyond growth, such as supporting tissue functions, developmental processes, and redox homeostasis. Methods: This review addresses the challenge of determining metabolic objectives and trade-offs from multiomics data. Results: Recent advances in single-cell omics, metabolic modeling, and machine/deep learning methods have enabled the inference of cellular objectives at both the transcriptomic and metabolic levels, bridging gene expression patterns with metabolic phenotypes. Conclusions: These in silico models provide insights into how cells adapt to changing environments, drug treatments, and genetic manipulations. We further explore the potential application of incorporating cellular objectives into personalized medicine, drug discovery, tissue engineering, and systems biology. Full article

(This article belongs to the Special Issue Comprehensive Insights into Metabolic Pathways: Genome-Scale Modeling Techniques)

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29 pages, 821 KiB

Open AccessEditor’s ChoiceReview

Practical Recommendations in the Treatment of Acute and Chronic Life-Threatening Infectious Diseases in Patients with Acute Hepatic Porphyria

by Bruno de Mattos Lombardi Badia, Paulo de Lima Serrano, João Paulo Barile, Daniel Delgado Seneor, Patrícia Marques Mendes, Renan Brandão Rambaldi Cavalheiro, Kaliny Oliveira Peixoto, Igor Braga Farias, Roberta Ismael Lacerda Machado, Wladimir Bocca Vieira de Rezende Pinto, Acary Souza Bulle Oliveira and Paulo Sgobbi

Metabolites 2025, 15(2), 99; https://doi.org/10.3390/metabo15020099 - 5 Feb 2025

Viewed by 879

Abstract

Background: Acute hepatic porphyrias (AHPs) represent inherited metabolic disorders of the heme biosynthesis pathway, leading to neurological and systemic impairment. Despite the presence of well-recognized chronic symptoms and signs, acute neurological, both neuromuscular and central neurological complications pose a significant challenge in clinical [...] Read more.

Background: Acute hepatic porphyrias (AHPs) represent inherited metabolic disorders of the heme biosynthesis pathway, leading to neurological and systemic impairment. Despite the presence of well-recognized chronic symptoms and signs, acute neurological, both neuromuscular and central neurological complications pose a significant challenge in clinical practice, with a potential risk of greater severity and mortality during acute decompensation episodes of AHPs. Care related to the prescription of medications, considering the risk of porphyrinogenicity, is a major and recurring concern in the acute and chronic management of AHP patients. Infectious clinical complications are significant issues in both outpatient and hospital settings for patients with AHPs. It is crucial to identify therapeutic regimens with the best safety and efficacy profiles for treating such infectious complications in AHP patients. The scarcity of structured knowledge available in guidelines and recommendations often leads to the use of therapeutic options with higher potential risks in treating patients with AHPs. Objectives: This review article aims to provide practical recommendations for managing the most significant infectious complications in clinical practice, with a focus on their impact on the clinical care of patients with AHPs. Full article

(This article belongs to the Special Issue The Comorbidity of Neurodegenerative and Metabolic Diseases)

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16 pages, 6875 KiB

Open AccessEditor’s ChoiceArticle

Metabolomic-Based Assessment of Earthworm (Eisenia fetida) Exposure to Different Petroleum Fractions in Soils

by Meiyu Liu, Mutian Wang, Xiaowen Fu, Fanyong Song, Fangyuan Zhou, Tianyuan Li and Jianing Wang

Metabolites 2025, 15(2), 97; https://doi.org/10.3390/metabo15020097 - 5 Feb 2025

Viewed by 1088

Abstract

Background/Objectives: Petroleum contamination in soil exerts toxic effects on earthworms (Eisenia fetida) through non-polar narcotic mechanisms. However, the specific toxicities of individual petroleum components remain insufficiently understood. Methods: This study investigates the effects of four petroleum components—saturated hydrocarbons, aromatic hydrocarbons, resins, [...] Read more.

Background/Objectives: Petroleum contamination in soil exerts toxic effects on earthworms (Eisenia fetida) through non-polar narcotic mechanisms. However, the specific toxicities of individual petroleum components remain insufficiently understood. Methods: This study investigates the effects of four petroleum components—saturated hydrocarbons, aromatic hydrocarbons, resins, and asphaltenes—on earthworms in artificially contaminated soil, utilizing a combination of biochemical biomarker analysis and metabolomics to uncover the underlying molecular mechanisms. Results: The results revealed that aromatic hydrocarbons are the most toxic fraction, with EC50 concentrations significantly lower than those of other petroleum fractions. All tested fractions triggered notable metabolic disturbances and immune responses in earthworms after 7 days of exposure, as evidenced by significant changes in metabolite abundance within critical pathways such as arginine synthesis, a-linolenic acid metabolism, and the pentose phosphate pathway. According to the KEGG pathway analysis, saturated hydrocarbon fractions induced marked changes in glycerophospholipid metabolism, and arginine and proline metabolism pathways, contributing to the stabilization of the protein structure and membrane integrity. Aromatic hydrocarbon fractions disrupted the arachidonic acid metabolic pathway, leading to increased myotube production and enhanced immune defense mechanisms. The TCA cycle and riboflavin metabolic pathway were significantly altered during exposure to the colloidal fraction, affecting energy production and cellular respiration. The asphaltene fraction significantly impacted glycolysis, accelerating energy cycling to meet stress-induced increases in energy demands. Conclusions: Aromatic hydrocarbons accounted for the highest level of toxicity among the four components in petroleum-contaminated soils. However, the contributions of other fractions to overall toxicity should not be ignored, as each fraction uniquely affects key metabolic pathways and biological functions. These findings emphasize the importance of monitoring metabolic perturbations caused by petroleum components in non-target organisms such as earthworms. They also reveal the specificity of the toxic metabolic effects of different petroleum components on earthworms. Full article

(This article belongs to the Section Environmental Metabolomics)

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18 pages, 2363 KiB

Open AccessEditor’s ChoiceArticle

Metabolites and Free Fatty Acids in Japanese Black Beef During Wet Aging

by Shuji Ueda, Yuka Yoshida, Yuka Tateoka, Biniam Kebede, Masakazu Shinohara, Hiroki Nakanishi, Itsuko Fukuda and Yasuhito Shirai

Metabolites 2025, 15(2), 94; https://doi.org/10.3390/metabo15020094 - 3 Feb 2025

Cited by 2 | Viewed by 1717

Abstract

Background: Japanese Black beef is known for its high intramuscular fat content, an important factor in its distinctive Wagyu aroma. Wet aging, which involves vacuum-packing meat and storing it at low temperatures, enhances flavor, texture, and tenderness and is essential for maintaining and [...] Read more.

Background: Japanese Black beef is known for its high intramuscular fat content, an important factor in its distinctive Wagyu aroma. Wet aging, which involves vacuum-packing meat and storing it at low temperatures, enhances flavor, texture, and tenderness and is essential for maintaining and improving meat quality. In this study, changes in metabolites and lipid profiles were investigated during the wet aging of Japanese Black and Holstein beef. Methods/Results: Gas chromatography–mass spectrometry identified 113 metabolites in Japanese Black beef and 94 in Holstein beef, with significant increases in metabolites like aspartic acid and maleic acid over the aging period. Regarding lipid composition, total free fatty acids significantly increased with wet aging, with Japanese Black beef showing significantly higher concentrations of oleic and linoleic acids than Holstein beef. Additionally, lipid analysis by liquid chromatography–mass spectrometry revealed a reduction in specific phospholipids, particularly lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), with notable decreases in LPC (18:1), LPC (18:2), LPE (18:1), and LPE (18:2). Conclusions: These results suggest that wet aging influences the stability of membrane lipids, facilitating the degradation of phospholipids into free fatty acids, and improving the flavor of Japanese Black beef. Full article

(This article belongs to the Special Issue The Digital Revolution in Livestock Production and Metabolism: Foodomics for a Viable Future and Beyond)

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Graphical abstract

24 pages, 602 KiB

Open AccessEditor’s ChoiceReview

Optimised Skeletal Muscle Mass as a Key Strategy for Obesity Management

by Thomas M. Barber, Stefan Kabisch, Andreas F. H. Pfeiffer and Martin O. Weickert

Metabolites 2025, 15(2), 85; https://doi.org/10.3390/metabo15020085 - 1 Feb 2025

Cited by 2 | Viewed by 1698

Abstract

The ‘Body Mass Index’ (BMI) is an anachronistic and outdated ratio that is used as an internationally accepted diagnostic criterion for obesity, and to prioritise, stratify, and outcome-assess its management options. On an individual level, the BMI has the potential to mislead, including [...] Read more.

The ‘Body Mass Index’ (BMI) is an anachronistic and outdated ratio that is used as an internationally accepted diagnostic criterion for obesity, and to prioritise, stratify, and outcome-assess its management options. On an individual level, the BMI has the potential to mislead, including inaccuracies in cardiovascular risk assessment. Furthermore, the BMI places excessive emphasis on a reduction in overall body weight (rather than optimised body composition) and contributes towards a misunderstanding of the quiddity of obesity and a dispassionate societal perspective and response to the global obesity problem. The overall objective of this review is to provide an overview of obesity that transitions away from the BMI and towards a novel vista: viewing obesity from the perspective of the skeletal muscle (SM). We resurrect the SM as a tissue hidden in plain sight and provide an overview of the key role that the SM plays in influencing metabolic health and efficiency. We discuss the complex interlinks between the SM and the adipose tissue (AT) through key myokines and adipokines, and argue that rather than two separate tissues, the SM and AT should be considered as a single entity: the ‘Adipo–Muscle Axis’. We discuss the vicious circle of sarcopenic obesity, in which aging- and obesity-related decline in SM mass contributes to a worsened metabolic status and insulin resistance, which in turn further compounds SM mass and function. We provide an overview of the approaches that can mitigate against the decline in SM mass in the context of negative energy balance, including the optimisation of dietary protein intake and resistance physical exercises, and of novel molecules in development that target the SM, which will play an important role in the future management of obesity. Finally, we argue that the Adipo–Muscle Ratio (AMR) would provide a more clinically meaningful descriptor and definition of obesity than the BMI and would help to shift our focus regarding its effective management away from merely inducing weight loss and towards optimising the AMR with proper attention to the maintenance and augmentation of SM mass and function. Full article

(This article belongs to the Special Issue Obesity and Metabolic Health)

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15 pages, 1801 KiB

Open AccessEditor’s ChoiceArticle

Is N1-Methylnicotinamide a Good Organic Cation Transporter 2 (OCT2) Biomarker?

by Anoud Sameer Ailabouni, Gautam Vijaywargi, Sandhya Subash, Dilip Kumar Singh, Zsuzsanna Gaborik and Bhagwat Prasad

Metabolites 2025, 15(2), 80; https://doi.org/10.3390/metabo15020080 - 29 Jan 2025

Cited by 1 | Viewed by 1136

Abstract

Background/Objectives: The impact of potential precipitant drugs on plasma or urinary exposure of endogenous biomarkers is emerging as an alternative approach to evaluating drug–drug interaction (DDI) liability. N1-Methylnicotinamide (NMN) has been proposed as a potential biomarker for renal organic cation transporter 2 [...] Read more.

Background/Objectives: The impact of potential precipitant drugs on plasma or urinary exposure of endogenous biomarkers is emerging as an alternative approach to evaluating drug–drug interaction (DDI) liability. N1-Methylnicotinamide (NMN) has been proposed as a potential biomarker for renal organic cation transporter 2 (OCT2). NMN is synthesized in the liver from nicotinamide by nicotinamide N-methyltransferase (NNMT) and is subsequently metabolized by aldehyde oxidase (AO). Multiple clinical studies have shown a reduction in NMN plasma concentration following the administration of OCT inhibitors such as cimetidine, trimethoprim, and pyrimethamine, which contrasts with their inhibition of NMN renal clearance by OCT2. We hypothesized that OCT1-mediated NMN release from hepatocytes is inhibited by the administration of OCT inhibitors. Methods: Re-analysis of the reported NMN pharmacokinetics with and without OCT inhibitor exposure was performed. We assessed the effect of cimetidine on NMN uptake in OCT1-HEK293 cells and evaluated the potential confounding effects of cimetidine on enzymes involved in NMN formation and metabolism. Results: A re-analysis of previous NMN pharmacokinetic DDI data suggests that NMN plasma systemic exposure decreased by 17–41% during the first 4 h following different OCT inhibitor administration except dolutegravir. Our findings indicate that NMN uptake was significantly higher (by 2.5-fold) in OCT1-HEK293 cells compared to mock cells, suggesting that NMN is a substrate of OCT1. Additionally, our results revealed that cimetidine does not inhibit NNMT and AO activity. Conclusions: Our findings emphasize the limitations of using NMN as an OCT2 biomarker and reveal potential mechanisms behind the reduction in NMN plasma levels associated with OCT inhibitors. Instead, our data suggest that NMN could be tested further as a potential biomarker for OCT1 activity. Full article

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

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15 pages, 1672 KiB

Open AccessEditor’s ChoiceArticle

Colostrum-Derived Melatonin Plus PEG Microspheres Modulate the Oxidative Metabolism of Human Colostrum Phagocytes

by Caroline G. Silva, Viviane F. Luz, Victor L. Nunes, Ana B. M. Verzoto, Aron C. de M. Cotrim, Wagner B. dos Santos, Eduardo L. França and Adenilda C. Honorio-França

Metabolites 2025, 15(1), 57; https://doi.org/10.3390/metabo15010057 - 16 Jan 2025

Cited by 2 | Viewed by 814

Abstract

Background/Objectives: Exogenous melatonin adsorbed onto PEG microspheres can modulate the functional activity of phagocytes in colostrum, but no data are available on the activity of melatonin found in colostrum. Therefore, the objective of this study was to extract melatonin from human colostrum, develop [...] Read more.

Background/Objectives: Exogenous melatonin adsorbed onto PEG microspheres can modulate the functional activity of phagocytes in colostrum, but no data are available on the activity of melatonin found in colostrum. Therefore, the objective of this study was to extract melatonin from human colostrum, develop and characterize PEG microspheres with the extracted melatonin adsorbed onto them, and evaluate the effects of this system on the oxidative metabolism of colostrum phagocytes. Methods: Thirty colostrum samples were collected; ten were used for melatonin extraction, while twenty were used to obtain phagocytes. Melatonin was extracted from the colostrum supernatant through affinity chromatography and quantified by ELISA. The polyethylene glycol microspheres produced were analyzed using fluorescence microscopy and flow cytometry. Oxidative metabolism was assessed by measuring the release of the superoxide anion and superoxide enzymes. A control was conducted using commercial melatonin. Results: The fluorescence microscopy and flow cytometry analyses demonstrated that PEG microspheres can adsorb melatonin. There was an increase in superoxide release in phagocytes incubated with colostrum-derived or synthetic melatonin. When exposed to bacteria, colostrum phagocytes treated with colostrum melatonin adsorbed to PEG microspheres exhibited increased superoxide, accompanied by a decrease in the release of superoxide dismutase (SOD) and a lower SOD-to-superoxide ratio. In contrast, synthetic melatonin reduced the release of superoxide and increased the release of the enzyme and the SOD-to-superoxide ratio. Conclusions: These data highlight the importance of melatonin on cellular metabolism and suggest that colostrum-derived melatonin may be a more effective option for controlling oxidative metabolism, particularly during infectious processes. Full article

(This article belongs to the Section Cell Metabolism)

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28 pages, 10002 KiB

Open AccessEditor’s ChoiceArticle

Silymarin as a Therapeutic Agent for Hepatocellular Carcinoma: A Multi-Approach Computational Study

by Ouided Benslama, Sabrina Lekmine, Hamza Moussa, Hichem Tahraoui, Mohammad Shamsul Ola, Jie Zhang and Abdeltif Amrane

Metabolites 2025, 15(1), 53; https://doi.org/10.3390/metabo15010053 - 15 Jan 2025

Cited by 2 | Viewed by 1322

Abstract

Background: Hepatocellular carcinoma (HCC) is a prevalent and lethal form of liver cancer with limited treatment options. Silymarin, a flavonoid complex derived from milk thistle, has shown promise in liver disease treatment due to its antioxidant, anti-inflammatory, and anticancer properties. This study aims [...] Read more.

Background: Hepatocellular carcinoma (HCC) is a prevalent and lethal form of liver cancer with limited treatment options. Silymarin, a flavonoid complex derived from milk thistle, has shown promise in liver disease treatment due to its antioxidant, anti-inflammatory, and anticancer properties. This study aims to explore the therapeutic potential of silymarin in HCC through a comprehensive in silico approach. Methods: This study employed a network pharmacology approach to identify key molecular targets of silymarin in HCC. The Genecards and Metascape databases were used for target identification and functional annotation. Molecular docking analysis was conducted on the primary silymarin components against VEGFA and SRC proteins, which are critical in HCC progression. MD simulations followed to assess the stability and interactions of the docked complexes. Results: Network pharmacology analysis identified several key molecular targets and pathways implicated in HCC. The molecular docking results revealed strong binding affinities of silymarin components to VEGFA and SRC, with Silybin A and Isosilybin B showing the highest affinities. MD simulations confirmed the stability of these interactions, indicating potential inhibitory effects on HCC progression. Conclusions: This study provides a comprehensive in silico evaluation of silymarin’s therapeutic potential in HCC. The findings suggest that silymarin, particularly its components Silybin A and Isosilybin B, may effectively target VEGFA and SRC proteins, offering a promising avenue for HCC treatment. Further experimental validation is warranted to confirm these findings and facilitate the development of silymarin-based therapeutics for HCC. Full article

(This article belongs to the Special Issue Metabolism of Bioactives and Natural Products)

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16 pages, 5126 KiB

Open AccessEditor’s ChoiceArticle

Chemical Diversity of UK-Grown Tea Explored Using Metabolomics and Machine Learning

by Amanda J. Lloyd, Alina Warren-Walker, Jasen Finch, Jo Harper, Kathryn Bennet, Alison Watson, Laura Lyons, Pilar Martinez Martin, Thomas Wilson and Manfred Beckmann

Metabolites 2025, 15(1), 52; https://doi.org/10.3390/metabo15010052 - 15 Jan 2025

Cited by 2 | Viewed by 995

Abstract

Background/Objectives: Dartmoor Estate Tea plantation in Devon, UK, is renowned for its unique microclimate and varied soil conditions, which contribute to the distinctive flavours and chemical profiles of tea. The chemical diversity of fresh leaf samples from various garden locations was explored within [...] Read more.

Background/Objectives: Dartmoor Estate Tea plantation in Devon, UK, is renowned for its unique microclimate and varied soil conditions, which contribute to the distinctive flavours and chemical profiles of tea. The chemical diversity of fresh leaf samples from various garden locations was explored within the plantation. Methods: Fresh leaf, which differed by location, cultivar, time of day, and variety, was analysed using Flow Infusion Electrospray Ionisation Mass Spectrometry (FIE-MS). Results: Random forest classification revealed no significant differences between Georgian N2 cultivar garden locations. However, a significant degree of variability was observed within four tri-clonal variants (Tocklai Variety) with TV9 exhibiting greater similarity to the Georgian N2 cultivar compared to TV8 and TV11, while TV11 was found to be most like TV1. The intraclass variability in leaf composition was similar between the varieties. We explored the metabolic changes over the day in one variant (Camellia assamica Masters), yielding a model with a significant R² value of 0.617 (p < 0.01, 3000 permutations). Starch and sucrose metabolism was found to be significant where the abundance of these chemical features increased throughout the day and then began to decrease at night. Conclusions: This research highlights the complex interplay of cultivars, geographical location, and temporal factors on the chemical composition of tea. It provides insightful data on the metabolic pathways influencing tea cultivation and production and underscores the importance of these variables in determining the final chemical profile and organoleptic characteristics of tea products. Full article

(This article belongs to the Section Plant Metabolism)

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38 pages, 1117 KiB

Open AccessEditor’s ChoiceSystematic Review

The Current Applications of Metabolomics in Understanding Endometriosis: A Systematic Review

by Blake Collie, Jacopo Troisi, Martina Lombardi, Steven Symes and Sean Richards

Metabolites 2025, 15(1), 50; https://doi.org/10.3390/metabo15010050 - 14 Jan 2025

Cited by 3 | Viewed by 1239

Abstract

Endometriosis is a common gynecological disease that affects approximately 10–15% of reproductive-aged women worldwide. This debilitating disease has a negative impact on the quality of life of those affected. Despite this condition being very common, the pathogenesis is not well understood. Metabolomics is [...] Read more.

Endometriosis is a common gynecological disease that affects approximately 10–15% of reproductive-aged women worldwide. This debilitating disease has a negative impact on the quality of life of those affected. Despite this condition being very common, the pathogenesis is not well understood. Metabolomics is the study of the array of low-weight metabolites in a given sample. This emerging field of omics-based science has proved to be effective at furthering the understanding of endometriosis. In this systematic review, we seek to provide an overview of the application of metabolomics in endometriosis. We highlight the use of metabolomics in locating biomarkers for identification, understanding treatment mechanisms and symptoms, and relating external factors to endometriosis. The literature search took place in the Web of Science, Pubmed, and Google Scholar based on the keywords “metabolomics” AND “endometriosis” or “metabolome” AND “endometriosis”. We found 58 articles from 2012 to 2024 that met our search criteria. Significant alterations of lipids, amino acids, as well as other compounds were present in human and animal models. Discrepancies among studies of significantly altered metabolites make it difficult to make general conclusions on the metabolic signature of endometriosis. However, several individual metabolites were elevated in multiple studies of women with endometriosis; these include 3-hydroxybutyrate, lactate, phosphatidic acids, succinate, pyruvate, tetradecenoylcarnitine, hypoxanthine, and xanthine. Accordingly, L-isoleucine and citrate were reduced in multiple studies of women with endometriosis. Including larger cohorts, standardizing testing methods, and studying the individual phenotypes of endometriosis may lead to more separable results. Full article

(This article belongs to the Special Issue Towards Clinical Interpretation of Metabolomic Data)

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13 pages, 1625 KiB

Open AccessEditor’s ChoiceArticle

MetaboLabPy—An Open-Source Software Package for Metabolomics NMR Data Processing and Metabolic Tracer Data Analysis

by Christian Ludwig

Metabolites 2025, 15(1), 48; https://doi.org/10.3390/metabo15010048 - 14 Jan 2025

Viewed by 1224

Abstract

Introduction: NMR spectroscopy is a powerful technique for studying metabolism, either in metabolomics settings or through tracing with stable isotope-enriched metabolic precursors. MetaboLabPy (version 0.9.66) is a free and open-source software package used to process 1D- and 2D-NMR spectra. The software implements a [...] Read more.

Introduction: NMR spectroscopy is a powerful technique for studying metabolism, either in metabolomics settings or through tracing with stable isotope-enriched metabolic precursors. MetaboLabPy (version 0.9.66) is a free and open-source software package used to process 1D- and 2D-NMR spectra. The software implements a complete workflow for NMR data pre-processing to prepare a series of 1D-NMR spectra for multi-variate statistical data analysis. This includes a choice of algorithms for automated phase correction, segmental alignment, spectral scaling, variance stabilisation, export to various software platforms, and analysis of metabolic tracing data. The software has an integrated help system with tutorials that demonstrate standard workflows and explain the capabilities of MetaboLabPy. Materials and Methods: The software is implemented in Python and uses numerous Python toolboxes, such as numpy, scipy, pandas, etc. The software is implemented in three different packages: metabolabpy, qtmetabolabpy, and metabolabpytools. The metabolabpy package contains classes to handle NMR data and all the numerical routines necessary to process and pre-process 1D NMR data and perform multiplet analysis on 2D-¹H, ¹³C HSQC NMR data. The qtmetabolabpy package contains routines related to the graphical user interface. Results: PySide6 is used to produce a modern and user-friendly graphical user interface. The metabolabpytools package contains routines which are not specific to just handling NMR data, for example, routines to derive isotopomer distributions from the combination of NMR multiplet and GC-MS data. A deep-learning approach for the latter is currently under development. MetaboLabPy is available via the Python Package Index or via GitHub. Full article

(This article belongs to the Special Issue Open-Source Software in Metabolomics)

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19 pages, 4057 KiB

Open AccessEditor’s ChoiceArticle

A Comprehensive Machine Learning Approach for COVID-19 Target Discovery in the Small-Molecule Metabolome

by Md. Shaheenur Islam Sumon, Md Sakib Abrar Hossain, Haya Al-Sulaiti, Hadi M. Yassine and Muhammad E. H. Chowdhury

Metabolites 2025, 15(1), 44; https://doi.org/10.3390/metabo15010044 - 11 Jan 2025

Cited by 1 | Viewed by 1146

Abstract

Background/Objectives: Respiratory viruses, including Influenza, RSV, and COVID-19, cause various respiratory infections. Distinguishing these viruses relies on diagnostic methods such as PCR testing. Challenges stem from overlapping symptoms and the emergence of new strains. Advanced diagnostics are crucial for accurate detection and effective [...] Read more.

Background/Objectives: Respiratory viruses, including Influenza, RSV, and COVID-19, cause various respiratory infections. Distinguishing these viruses relies on diagnostic methods such as PCR testing. Challenges stem from overlapping symptoms and the emergence of new strains. Advanced diagnostics are crucial for accurate detection and effective management. This study leveraged nasopharyngeal metabolome data to predict respiratory virus scenarios including control vs. RSV, control vs. Influenza A, control vs. COVID-19, control vs. all respiratory viruses, and COVID-19 vs. Influenza A/RSV. Method: We proposed a stacking-based ensemble technique, integrating the top three best-performing ML models from the initial results to enhance prediction accuracy by leveraging the strengths of multiple base learners. Key techniques such as feature ranking, standard scaling, and SMOTE were used to address class imbalances, thus enhancing model robustness. SHAP analysis identified crucial metabolites influencing positive predictions, thereby providing valuable insights into diagnostic markers. Results: Our approach not only outperformed existing methods but also revealed top dominant features for predicting COVID-19, including Lysophosphatidylcholine acyl C18:2, Kynurenine, Phenylalanine, Valine, Tyrosine, and Aspartic Acid (Asp). Conclusions: This study demonstrates the effectiveness of leveraging nasopharyngeal metabolome data and stacking-based ensemble techniques for predicting respiratory virus scenarios. The proposed approach enhances prediction accuracy, provides insights into key diagnostic markers, and offers a robust framework for managing respiratory infections. Full article

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

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15 pages, 697 KiB

Open AccessEditor’s ChoiceArticle

Pharmacometabolomics Enables Real-World Drug Metabolism Sciences

by Fleur B. Nijdam, Marieke A. J. Hof, Hans Blokzijl, Stephan J. L. Bakker, Eelko Hak, Gérard Hopfgartner, Frank Klont and on behalf of the TransplantLines Investigators

Metabolites 2025, 15(1), 39; https://doi.org/10.3390/metabo15010039 - 10 Jan 2025

Viewed by 1213

Abstract

Background/Objectives: Pharmacogenomics (PGx) has revolutionized personalized medicine, notably by predicting drug responses through the study of the metabolic genotype of drug-metabolizing enzymes. However, these genotypes rely heavily on the availability and completeness of drug metabolism information and do not account for (all) [...] Read more.

Background/Objectives: Pharmacogenomics (PGx) has revolutionized personalized medicine, notably by predicting drug responses through the study of the metabolic genotype of drug-metabolizing enzymes. However, these genotypes rely heavily on the availability and completeness of drug metabolism information and do not account for (all) “phenoconversion” factors, like drug–drug interactions and comorbidities. To address these limitations, a more phenotypic approach would be desirable, for which pharmacometabolomics (PMx) could be useful by studying and elucidating drug metabolism in patient samples, such as blood and urine. Methods: This study explored the potential of PMx to analyze real-world drug metabolite profiles of the extensively studied drug cyclosporine (CsA) using 24-h urine samples from 732 kidney and 350 liver transplant recipients included in the TransplantLines Biobank and Cohort Study (NCT identifier NCT03272841). Detected metabolites were matched with existing information on CsA metabolism gathered through a comprehensive literature review, aiming to confirm previously reported metabolites and identify potentially unreported ones. Results: Our analyses confirmed the urinary presence of CsA and six known metabolites. Additionally, we detected three known metabolites not previously reported in urine and identified one unreported metabolite, potentially suggesting the involvement of glutathione conjugation. Lastly, the observed metabolic patterns showed no notable differences between kidney and liver transplant recipients. Conclusions: Our findings demonstrate the potential of PMx to enhance the understanding of drug metabolism, even for well-studied compounds such as CsA. Moreover, this study highlights the value of PMx in real-world drug metabolism research and its potential to complement PGx in advancing personalized medicine. Full article

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

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13 pages, 2980 KiB

Open AccessEditor’s ChoiceArticle

Untargeted Metabolomics Reveals the Metabolic Characteristics and Biomarkers of Antioxidant Properties of Gardeniae Fructus from Different Geographical Origins in China

by Wu Jiang, Lingling Jiang, Xiaoli Yin, Shuhui Zhang, Xiaojing Duan, Jiadong Chen, Yingying Liu, Hong Zheng and Zhengming Tao

Metabolites 2025, 15(1), 38; https://doi.org/10.3390/metabo15010038 - 10 Jan 2025

Cited by 1 | Viewed by 889

Abstract

Background/Objectives: Gardeniae Fructus (GF) has been widely used as both food and medicinal purposes for thousands of years, but their antioxidant properties and potential metabolite biomarkers remain unclear. Methods: The purposes of this study were to examine antioxidant activities of 21 GF [...] Read more.

Background/Objectives: Gardeniae Fructus (GF) has been widely used as both food and medicinal purposes for thousands of years, but their antioxidant properties and potential metabolite biomarkers remain unclear. Methods: The purposes of this study were to examine antioxidant activities of 21 GF varieties from different geographical origins in China and identify potential biomarkers of antioxidant properties using an untargeted LC–MS-based metabolomics approach. Results: The results demonstrate that metabolomics had the ability to trace the geographical origins of GF. We found that antioxidant activities varied with different varieties of GF, which was dependent on their chemical compositions. The key chemical categories were obtained as the primary contributors of the antioxidant activity, including prenol lipids, flavonoids, coumarins and derivatives, as well as steroids and steroid derivatives. In addition, adouetine Y, coagulin R 3-glucoside and epicatechin 3-glucoside were identified as potential biomarkers for the antioxidant activity of GF. Conclusions: Therefore, our study sheds light on the metabolic characteristics and biomarkers of the antioxidant properties of GF, contributing to the selection and cultivation of a high antioxidant variety. Full article

(This article belongs to the Special Issue Analysis of Specialized Metabolites in Natural Products)

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11 pages, 3050 KiB

Open AccessEditor’s ChoiceArticle

Docosahexaenoic and Eicosapentaenoic Acid Supplementation Could Attenuate Negative Effects of Maternal Metabolic Syndrome on Liver Lipid Metabolism and Liver Betacellulin Expression in Male and Female Rat Offspring

by Tomislav Mašek, Petra Roškarić, Sunčica Sertić and Kristina Starčević

Metabolites 2025, 15(1), 32; https://doi.org/10.3390/metabo15010032 - 9 Jan 2025

Viewed by 943

Abstract

Background/Objectives: This study investigated the effects of maternal metabolic syndrome during pregnancy on hepatic fatty acid metabolism and betacellulin expression in rat offspring. A rat model of maternal metabolic syndrome was created with a high-fructose diet (15% fructose in drinking water for [...] Read more.

Background/Objectives: This study investigated the effects of maternal metabolic syndrome during pregnancy on hepatic fatty acid metabolism and betacellulin expression in rat offspring. A rat model of maternal metabolic syndrome was created with a high-fructose diet (15% fructose in drinking water for six months). Methods: The females with metabolic syndrome were divided into the CON group, the HF group, which received fructose in drinking water, and the HF-DHA group, which received fructose in water and increased amounts of DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) in the diet (2.5% fish oil in the diet). The male and female offspring were killed at birth and their liver tissue was analyzed for the fatty acid profile and expression of Δ-9-desaturase and betacellulin. Results: When the rat offspring were exposed in utero to maternal fatty acids altered by the high-fructose diet, this resulted in a similarly altered fatty acid profile in the liver, with the most significant changes being Δ-9 desaturation and a dramatic increase in monounsaturated fatty acids. The offspring also showed an overexpression of hepatic betacellulin. Supplementation with DHA and EPA increased the DHA content and normalized the fatty acid composition of oleic acid, saturated fatty acids, linoleic acid and n3-docosapentaenoic acid in the offspring of mothers on a high-fructose diet. In addition, the DHA/EPA supplementation of fructose-fed mothers normalized hepatic Δ-9-desaturase and betacellulin overexpression in the offspring, suggesting that DHA/EPA supplementation affects not only the fatty acid content but also the liver function. Conclusions: The changes observed in this study suggest that DHA/EPA supplementation may modulate the effects of maternal programming on disorders of the lipid metabolism in the offspring. Full article

(This article belongs to the Special Issue Fat and Glucose Metabolism)

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17 pages, 867 KiB

Open AccessEditor’s ChoiceArticle

DisCo P-ad: Distance-Correlation-Based p-Value Adjustment Enhances Multiple Testing Corrections for Metabolomics

by Debmalya Nandy, Debashis Ghosh and Katerina Kechris

Metabolites 2025, 15(1), 28; https://doi.org/10.3390/metabo15010028 - 8 Jan 2025

Viewed by 1086

Abstract

Background: Due to scientific advancements in high-throughput data production technologies, omics studies, such as genomics and metabolomics, often give rise to numerous measurements per sample/subject containing several noisy variables that potentially cloud the true signals relevant to the desired study outcome(s). Therefore, correcting [...] Read more.

Background: Due to scientific advancements in high-throughput data production technologies, omics studies, such as genomics and metabolomics, often give rise to numerous measurements per sample/subject containing several noisy variables that potentially cloud the true signals relevant to the desired study outcome(s). Therefore, correcting for multiple testing is critical while performing any statistical test of significance to minimize the chances of false or missed discoveries. Such correction practice is commonplace in genome-wide association studies (GWAS) but is also becoming increasingly relevant to metabolome-wide association studies (MWAS). However, many existing procedures may be too conservative or too lenient, only assume a linear association between the features, or have not been evaluated on metabolomics data. Methods: One such multiple testing correction strategy is to estimate the number of statistically independent tests, called the effective number of tests, based on the eigen-analysis of the correlation matrix between the features. This effective number is then used for a subsequent single-step adjustment to obtain the pointwise significance level. We propose a modification to the p-value adjustment based on a more general measure of association between two predictors, the distance correlation, with a specific focus on MWAS. Results: We assessed common GWAS p-value adjustment procedures and one tailored for MWAS, which rely on eigen-analysis of the Pearson’s correlation matrix. Our study, including varying sample size-to-feature ratios, response types, and metabolite groupings, highlights the superior performance of the distance correlation. Conclusion: We propose the distance-correlation-based p-value adjustment (DisCo P-ad) as a novel modification that can enhance existing eigen-analysis-based multiple testing correction procedures by increasing power or reducing false positives. While our focus is on metabolomics, DisCo P-ad can also readily be applied to other high-dimensional omics studies. Full article

(This article belongs to the Section Bioinformatics and Data Analysis)

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40 pages, 3770 KiB

Open AccessEditor’s ChoiceArticle

Impact of Ketogenic and Mediterranean Diets on Gut Microbiota Profile and Clinical Outcomes in Drug-Naïve Patients with Diabesity: A 12-Month Pilot Study

by Vanessa Palmas, Andrea Deledda, Vitor Heidrich, Giuseppina Sanna, Giulia Cambarau, Michele Fosci, Lorenzo Puglia, Enrico Antonio Cappai, Alessio Lai, Andrea Loviselli, Aldo Manzin and Fernanda Velluzzi

Metabolites 2025, 15(1), 22; https://doi.org/10.3390/metabo15010022 - 6 Jan 2025

Cited by 1 | Viewed by 9282

Abstract

Background/Objectives: Managing type 2 diabetes mellitus (T2DM) and obesity requires a multidimensional, patient-centered approach including nutritional interventions (NIs) and physical activity. Changes in the gut microbiota (GM) have been linked to obesity and the metabolic alterations typical of T2DM and obesity, and [...] Read more.

Background/Objectives: Managing type 2 diabetes mellitus (T2DM) and obesity requires a multidimensional, patient-centered approach including nutritional interventions (NIs) and physical activity. Changes in the gut microbiota (GM) have been linked to obesity and the metabolic alterations typical of T2DM and obesity, and they are strongly influenced by diet. However, few studies have evaluated the effects on the GM of a very-low-calorie ketogenic diet (VLCKD) in patients with T2DM, especially in the mid-term and long-term. This longitudinal study is aimed at evaluating the mid-term and long-term impact of the VLCKD and Mediterranean diet (MD) on the GM and on the anthropometric, metabolic, and lifestyle parameters of 11 patients with T2DM and obesity (diabesity). This study extends previously published results evaluating the short-term (three months) impact of these NIs on the same patients. Methods: At baseline, patients were randomly assigned to either a VLCKD (KETO group) or a Mediterranean diet (MEDI group). After two months, the KETO group gradually shifted to a Mediterranean diet (VLCKD-MD), according to current VLCKD guidelines. From the fourth month until the end of the study both groups followed a similar MD. Previous published results showed that VLCKD had a more beneficial impact than MD on several variables for 3 months of NI. In this study, the analyses were extended until six (T6) and twelve months (T12) of NI by comparing data prospectively and against baseline (T0). The GM analysis was performed through next-generation sequencing. Results: Improvements in anthropometric and metabolic parameters were more pronounced in the KETO group at T6, particularly for body mass index (−5.8 vs. −1.7 kg/m²; p = 0.006) and waist circumference (−15.9 vs. −5.2 cm; p = 0.011). At T6, a significant improvement in HbA1c (6.7% vs. 5.5% p = 0.02) and triglyceride (158 vs. 95 mg/dL p = 0.04) values compared to T0 was observed only in the KETO group, which maintained the results achieved at T3. The VLCKD-MD had a more beneficial impact than the MD on the GM phenotype. A substantial positive modulatory effect was observed especially up to the sixth month of the NI in KETO due to the progressive increase in bacterial markers of human health. After the sixth month, most markers of human health decreased, though they were still increased compared with baseline. Among them, the Verrucomicrobiota phylum was identified as the main biomarker in the KETO group, together with its members Verrucomicrobiae, Akkermansiaceae, Verrucomicrobiales, and Akkermansia at T6 compared with baseline. Conclusions: Both dietary approaches ameliorated health status, but VLCKD, in support of the MD, has shown greater improvements on anthropometric and metabolic parameters, as well as on GM profile, especially up to T6 of NI. Full article

(This article belongs to the Special Issue Impact of Macronutrients on Metabolism)

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13 pages, 1086 KiB

Open AccessEditor’s ChoiceArticle

The Validation of a Novel, Sex-Specific LDL-Cholesterol Equation and the Friedewald, Sampson-NIH, and Extended-Martin–Hopkins Equations Against Direct Measurement in Korean Adults

by Hyun Suk Yang, Soo-Nyung Kim, Seungho Lee and Mina Hur

Metabolites 2025, 15(1), 18; https://doi.org/10.3390/metabo15010018 - 5 Jan 2025

Viewed by 1035

Abstract

Background/Objectives: The currently established equations for calculating low-density lipoprotein cholesterol (LDLc) do not reflect the sex-specific differences in lipid metabolism. We aimed to develop a sex-specific LDLc equation (SSLE) and validate it with three established equations (Friedewald, Sampson-NIH, and ext-Martin–Hopkins) against direct [...] Read more.

Background/Objectives: The currently established equations for calculating low-density lipoprotein cholesterol (LDLc) do not reflect the sex-specific differences in lipid metabolism. We aimed to develop a sex-specific LDLc equation (SSLE) and validate it with three established equations (Friedewald, Sampson-NIH, and ext-Martin–Hopkins) against direct LDLc measurement in Korean adults. Methods: This study included 23,757 subjects (51% male; median age, 51 years) from the 2009–2022 Korean National Health and Nutrition Examination Survey. We developed the SSLE through multiple linear regression incorporating total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), triglycerides (TG), and sex. The validation metrics included Bland–Altman analysis for mean absolute percentage error (MAPE) and agreement of the categorization based on the NCEP ATP-III guidelines, assessed by sex and lipid subgroups. Results: The derived SSLE equation was as follows: for TG < 200 mg/dL, LDLc = 0.963 × TC − 0.881 × HDLc − 0.111 × TG + 0.982 × Sex − 6.958; for TG ≥ 200 mg/dL, LDLc = 0.884 × TC − 0.646 × HDLc − 0.126 × TG + 3.742 × Sex − 3.214 (male = 1, female = 0). The MAPE was similar between males and females for the SSLE (4.6% for both) and ext-Martin–Hopkins (5.0% vs. 4.9%) but higher in males for the Sampson-NIH (5.4% vs. 4.9%) and Friedewald (7.6% vs. 5.7%). In the TG ≥ 400 mg/dL group, the MAPE increased progressively: SSLE (10.2%), ext-Martin–Hopkins (12.0%), Sampson-NIH (12.7%), and Friedewald (27.4%). In the LDLc < 70 mg/dL group, the MAPE was as follows: SSLE (8.0%), Sampson-NIH (8.6%), ext-Martin–Hopkins (9.7%), and Friedewald (12.8%). At TG 200–400 mg/dL, the SSLE revealed very good agreement (κ = 0.801) versus good agreement for other equations (ext-Martin–Hopkins κ = 0.794, Sampson-NIH κ = 0.782, Friedewald κ = 0.696). Conclusions: The novel SSLE demonstrated superior accuracy and agreement in Korean adults. Further validation studies across different ethnic populations are warranted. Full article

(This article belongs to the Special Issue Lipid Biomarkers and Cardiometabolic Diseases—2nd Edition)

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20 pages, 3377 KiB

Open AccessEditor’s ChoiceArticle

Metabolomic Insights into the Allelopathic Effects of Ailanthus altissima (Mill.) Swingle Volatile Organic Compounds on the Germination Process of Bidens pilosa (L.)

by Leonardo Bruno, Diana M. Mircea and Fabrizio Araniti

Metabolites 2025, 15(1), 12; https://doi.org/10.3390/metabo15010012 - 3 Jan 2025

Cited by 2 | Viewed by 999

Abstract

Background/Objectives: This study explores the allelopathic effects of volatile organic compounds (VOCs) emitted by the invasive species Ailanthus altissima (Mill.) Swingle on the seed germination of Bidens pilosa. A. altissima is known for releasing allelopathic VOCs that suppress the growth of neighbouring [...] Read more.

Background/Objectives: This study explores the allelopathic effects of volatile organic compounds (VOCs) emitted by the invasive species Ailanthus altissima (Mill.) Swingle on the seed germination of Bidens pilosa. A. altissima is known for releasing allelopathic VOCs that suppress the growth of neighbouring plants, contributing to its invasive potential. Methods: To examine these effects, we exposed B. pilosa seeds to varying concentrations of A. altissima VOCs, assessing germination rates and metabolic changes through untargeted metabolomics. Results: Our findings revealed that VOCs from A. altissima significantly inhibited the germination speed and overall germination rates of B. pilosa in a dose-dependent manner. Metabolomic profiling showed disruptions in energy and amino acid metabolism pathways, specifically involving delayed breakdown of starch and key metabolites, indicating inhibition of critical metabolic processes during early germination stages. This metabolic delay likely impairs B. pilosa’s establishment and competitiveness, enhancing A. altissima’s ecological dominance. Conclusions: The results underscore the potential of VOC-based allelopathy as a mechanism of plant invasion, offering insights into the role of VOCs in interspecies plant competition and ecosystem dynamics. 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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17 pages, 2872 KiB

Open AccessEditor’s ChoiceArticle

Serum Uric Acid and Bone Health in Middle-Aged and Elderly Hypertensive Patients: A Potential U-Shaped Association and Implications for Future Fracture Risk

by Shuaiwei Song, Xintian Cai, Junli Hu, Qing Zhu, Di Shen, Huimin Ma, Yingying Zhang, Rui Ma, Pan Zhou, Wenbo Yang, Jing Hong and Nanfang Li

Metabolites 2025, 15(1), 15; https://doi.org/10.3390/metabo15010015 - 3 Jan 2025

Cited by 5 | Viewed by 1146

Abstract

Background: The influence of serum uric acid (SUA) on bone metabolism, as suggested by previous studies, remains a contentious issue. SUA plays a complex role in bone health and hypertension, making it challenging to discern its impact on the skeletal status of middle-aged [...] Read more.

Background: The influence of serum uric acid (SUA) on bone metabolism, as suggested by previous studies, remains a contentious issue. SUA plays a complex role in bone health and hypertension, making it challenging to discern its impact on the skeletal status of middle-aged and elderly hypertensive patients. This study aims to elucidate the effects of SUA on bone health, with a particular focus on its association with osteoporosis and the risk of fractures. Methods: Multiple linear regression analyzed SUA levels against bone mineral density (BMD) and future fracture risk. Additionally, multivariate logistic regression was used to examine the association between SUA and osteoporosis. Dose–response relationship analysis was conducted using generalized smooth curve fitting (GSCF) and restricted cubic spline (RCS) methods. Results: With the exception of the total femur region, SUA and BMD showed a positive connection. GSCF analysis revealed an inverted U-shaped relationship between SUA and BMD, alongside a U-shaped trend with FRAX scores. Moreover, RCS analysis indicated a U-shaped relationship between osteoporosis risk and SUA levels, with higher risks identified in the first and third tertiles compared to the second tertile. Conclusions: In individuals with middle-aged and older hypertension, SUA is substantially linked to bone health. The identification of an inverted U-shaped relationship with BMD and U-shaped relationships with FRAX scores and osteoporosis risk highlights the nuanced influence of SUA. These findings suggest that both low and high SUA levels may adversely affect bone health, emphasizing the need for further research. Full article

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

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15 pages, 1699 KiB

Open AccessEditor’s ChoiceArticle

Evaluating Metabolic Profiling of Human Milk Using Biocrates MxP^® QUANT 500 Assay

by Daniela Hampel, Setareh Shahab-Ferdows, Gilberto Kac and Lindsay H. Allen

Metabolites 2025, 15(1), 14; https://doi.org/10.3390/metabo15010014 - 3 Jan 2025

Viewed by 1203

Abstract

Background/Objectives: Metabolic profiling of human milk (HM) is indispensable for elucidating mother-milk-infant relationships. Methods: We evaluated the Biocrates MxP^® Quant 500 assay for HM-targeted metabolomics (106 small molecules, 524 lipids) and analyzed in a feasibility test HM from apparently healthy Brazilian mothers [...] Read more.

Background/Objectives: Metabolic profiling of human milk (HM) is indispensable for elucidating mother-milk-infant relationships. Methods: We evaluated the Biocrates MxP^® Quant 500 assay for HM-targeted metabolomics (106 small molecules, 524 lipids) and analyzed in a feasibility test HM from apparently healthy Brazilian mothers (A: 2–8, B: 28–50, C: 88–119 days postpartum, n_total = 25). Results: Of the 630 possible signatures detectable with this assay, 506 were above the limits of detection in an HM-pool (10 µL) used for assay evaluation, 12 of them above the upper limit of quantitation. Analyzing five different HM-pool volumes (2–20 µL) revealed acceptable linearity for 458 metabolites. Intraday accuracy of 80–120% was attained by 469 metabolites after spiking and for 342 after a 1:2 dilution. Analyzing HM from Brazilian mothers revealed significantly lower concentrations in colostrum vs. mature milk for many flow-injection analyses (FIA) and only a few LC-MS metabolites, including triglycerides, sphingomyelins, and phosphatidylcholines. Higher concentrations at the later lactation stages were found predominantly for amino acids and related compounds. Conclusions: The MxP Quant^® 500 assay is a useful tool for HM metabolic profiling, minimizing analytical bias between matrices, and enhancing our ability to study milk as a biological system. Full article

(This article belongs to the Special Issue Advanced Metabolic Profiling via Gas Chromatography–Mass Spectrometry and Liquid Chromatography–Mass Spectrometry)

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32 pages, 1927 KiB

Open AccessEditor’s ChoiceReview

Lipidomics of Huntington’s Disease: A Comprehensive Review of Current Status and Future Directions

by Ali Yilmaz, Sumeyya Akyol, Nadia Ashrafi, Nazia Saiyed, Onur Turkoglu and Stewart F. Graham

Metabolites 2025, 15(1), 10; https://doi.org/10.3390/metabo15010010 - 2 Jan 2025

Cited by 1 | Viewed by 1629

Abstract

Background: Huntington’s disease (HD) is a multifaceted neurological disorder characterized by the progressive deterioration of motor, cognitive, and psychiatric functions. Despite a limited understanding of its pathogenesis, research has implicated abnormal trinucleotide cytosine-adenine-guanine CAG repeat expansion in the huntingtin gene (HTT) as a [...] Read more.

Background: Huntington’s disease (HD) is a multifaceted neurological disorder characterized by the progressive deterioration of motor, cognitive, and psychiatric functions. Despite a limited understanding of its pathogenesis, research has implicated abnormal trinucleotide cytosine-adenine-guanine CAG repeat expansion in the huntingtin gene (HTT) as a critical factor. The development of innovative strategies is imperative for the early detection of predictive biomarkers, enabling timely intervention and mitigating irreversible cellular damage. Lipidomics, a comprehensive analytical approach, has emerged as an indispensable tool for systematically characterizing lipid profiles and elucidating their role in disease pathology. Method: A MedLine search was performed to identify studies that use lipidomics for the characterization of HD. Search terms included “Huntington disease”; “lipidomics”; “biomarker discovery”; “NMR”; and “Mass spectrometry”. Results: This review highlights the significance of lipidomics in HD diagnosis and treatment, exploring changes in brain lipids and their functions. Recent breakthroughs in analytical techniques, particularly mass spectrometry and NMR spectroscopy, have revolutionized brain lipidomics research, enabling researchers to gain deeper insights into the complex lipidome of the brain. Conclusions: A comprehensive understanding of the broad spectrum of lipidomics alterations in HD is vital for precise diagnostic evaluation and effective disease management. The integration of lipidomics with artificial intelligence and interdisciplinary collaboration holds promise for addressing the clinical variability of HD. Full article

(This article belongs to the Special Issue Lipidomics in Health and Disease)

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21 pages, 2010 KiB

Open AccessEditor’s ChoiceArticle

Longitudinal Metabolomics Data Analysis Informed by Mechanistic Models

by Lu Li, Huub Hoefsloot, Barbara M. Bakker, David Horner, Morten A. Rasmussen, Age K. Smilde and Evrim Acar

Metabolites 2025, 15(1), 2; https://doi.org/10.3390/metabo15010002 - 24 Dec 2024

Cited by 2 | Viewed by 991

Abstract

Background: Metabolomics measurements are noisy, often characterized by a small sample size and missing entries. While data-driven methods have shown promise in terms of analyzing metabolomics data, e.g., revealing biomarkers of various phenotypes, metabolomics data analysis can significantly benefit from incorporating prior [...] Read more.

Background: Metabolomics measurements are noisy, often characterized by a small sample size and missing entries. While data-driven methods have shown promise in terms of analyzing metabolomics data, e.g., revealing biomarkers of various phenotypes, metabolomics data analysis can significantly benefit from incorporating prior information about metabolic mechanisms. This paper introduces a novel data analysis approach to incorporate mechanistic models in metabolomics data analysis. Methods: We arranged time-resolved metabolomics measurements of plasma samples collected during a meal challenge test from the COPSAC₂₀₀₀ cohort as a third-order tensor: subjects by metabolites by time samples. Simulated challenge test data generated using a human whole-body metabolic model were also arranged as a third-order tensor: virtual subjects by metabolites by time samples. Real and simulated data sets were coupled in the metabolites mode and jointly analyzed using coupled tensor factorizations to reveal the underlying patterns. Results: Our experiments demonstrated that the joint analysis of simulated and real data had better performance in terms of pattern discovery, achieving higher correlations with a BMI (body mass index)-related phenotype compared to the analysis of only real data in males, while in females, the performance was comparable. We also demonstrated the advantages of such a joint analysis approach in the presence of incomplete measurements and its limitations in the presence of wrong prior information. Conclusions: The joint analysis of real measurements and simulated data (generated using a mechanistic model) through coupled tensor factorizations guides real data analysis with prior information encapsulated in mechanistic models and reveals interpretable patterns. Full article

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

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25 pages, 11702 KiB

Open AccessEditor’s ChoiceArticle

Gallic Acid: A Potent Metabolite Targeting Shikimate Kinase in Acinetobacter baumannii

by Mansour S. Alturki, Abdulaziz H. Al Khzem, Mohamed S. Gomaa, Nada Tawfeeq, Marwah H. Alhamadah, Futun M. Alshehri, Raghad Alzahrani, Hanin Alghamdi, Thankhoe A. Rants’o, Khaled A. G. Ayil, Abdulaziz K. Al Mouslem and Mohammed Almaghrabi

Metabolites 2024, 14(12), 727; https://doi.org/10.3390/metabo14120727 - 23 Dec 2024

Viewed by 1672

Abstract

Background/Objectives: Acinetobacter baumannii is a highly multidrug-resistant pathogen resistant to almost all classes of antibiotics; new therapeutic strategies against this infectious agent are urgently needed. Shikimate kinase is an enzyme belonging to the shikimate pathway and has become a potential target for [...] Read more.

Background/Objectives: Acinetobacter baumannii is a highly multidrug-resistant pathogen resistant to almost all classes of antibiotics; new therapeutic strategies against this infectious agent are urgently needed. Shikimate kinase is an enzyme belonging to the shikimate pathway and has become a potential target for drug development. This work describes the search for Food and Drug Administration (FDA)-approved drugs and natural compounds, including gallic acid, that could be repurposed as selective shikimate kinase inhibitors by integrated computational and experimental approaches. Methods: Approaches to drug design using structure-based and ligand-based methodology, in-silico screening, molecular docking, and molecular dynamics for the study of both binding affinity and stability. Experimental Validation Determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) on Acinetobacter baumannii and Enterococcus faecalis. Results/Conclusions: Among them, gallic acid, obtained from plants, proved to be the most promising compound that showed sufficient binding with shikimate kinase through computational studies. Gallic acid showed very good activity against Acinetobacter baumannii and Enterococcus faecalis in the MIC and MBC assay, respectively. Gallic acid exhibited better activity against Acinetobacter baumannii due to the overexpression of shikimate kinase. Gallic acid has emerged as a potential therapeutic candidate drug against A. baumannii infection and, therefore, as a strategy against the appearance of multidrug-resistant microorganisms. This study not only identifies a novel repurposing opportunity for gallic acid but also provides a comprehensive computational and experimental framework for accelerating antimicrobial drug discovery against multidrug-resistant pathogens. Full article

(This article belongs to the Special Issue Novel Approaches for Metabolomics in Drugs and Biomarkers Discovery: 2nd Edition)

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23 pages, 960 KiB

Open AccessEditor’s ChoiceReview

Diagnosis, Severity, and Prognosis from Potential Biomarkers of COVID-19 in Urine: A Review of Clinical and Omics Results

by Jennifer Narro-Serrano and Frutos Carlos Marhuenda-Egea

Metabolites 2024, 14(12), 724; https://doi.org/10.3390/metabo14120724 - 22 Dec 2024

Viewed by 1598

Abstract

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has spurred an extraordinary scientific effort to better understand the disease’s pathophysiology and develop diagnostic and prognostic tools to guide more precise and effective clinical management. Among the biological samples analyzed for biomarker identification, urine [...] Read more.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has spurred an extraordinary scientific effort to better understand the disease’s pathophysiology and develop diagnostic and prognostic tools to guide more precise and effective clinical management. Among the biological samples analyzed for biomarker identification, urine stands out due to its low risk of infection, non-invasive collection, and suitability for frequent, large-volume sampling. Integrating data from omics studies with standard biochemical analyses offers a deeper and more comprehensive understanding of COVID-19. This review aims to provide a detailed summary of studies published to date that have applied omics and clinical analyses on urine samples to identify potential biomarkers for COVID-19. In July 2024, an advanced search was conducted in Web of Science using the query: “covid* (Topic) AND urine (Topic) AND metabol* (Topic)”. The search included results published up to 14 October 2024. The studies retrieved from this digital search were evaluated through a two-step screening process: first by reviewing titles and abstracts for eligibility, and then by retrieving and assessing the full texts of articles that met the specific criteria. The initial search retrieved 913 studies, of which 45 articles were ultimately included in this review. The most robust biomarkers identified include kynurenine, neopterin, total proteins, red blood cells, ACE2, citric acid, ketone bodies, hypoxanthine, amino acids, and glucose. The biological causes underlying these alterations reflect the multisystemic impact of COVID-19, highlighting key processes such as systemic inflammation, renal dysfunction, critical hypoxia, and metabolic stress. Full article

(This article belongs to the Special Issue Advanced Metabolomics and Lipidomics Approaches in Studying Human Diseases)

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32 pages, 2169 KiB

Open AccessEditor’s ChoiceReview

Circadian Influences on Brain Lipid Metabolism and Neurodegenerative Diseases

by Yusuf Hussain, Mohammad Irfan Dar and Xiaoyue Pan

Metabolites 2024, 14(12), 723; https://doi.org/10.3390/metabo14120723 - 22 Dec 2024

Viewed by 1941

Abstract

Circadian rhythms are intrinsic, 24 h cycles that regulate key physiological, mental, and behavioral processes, including sleep–wake cycles, hormone secretion, and metabolism. These rhythms are controlled by the brain’s suprachiasmatic nucleus, which synchronizes with environmental signals, such as light and temperature, and consequently [...] Read more.

Circadian rhythms are intrinsic, 24 h cycles that regulate key physiological, mental, and behavioral processes, including sleep–wake cycles, hormone secretion, and metabolism. These rhythms are controlled by the brain’s suprachiasmatic nucleus, which synchronizes with environmental signals, such as light and temperature, and consequently maintains alignment with the day–night cycle. Molecular feedback loops, driven by core circadian “clock genes”, such as Clock, Bmal1, Per, and Cry, are essential for rhythmic gene expression; disruptions in these feedback loops are associated with various health issues. Dysregulated lipid metabolism in the brain has been implicated in the pathogenesis of neurological disorders by contributing to oxidative stress, neuroinflammation, and synaptic dysfunction, as observed in conditions such as Alzheimer’s and Parkinson’s diseases. Disruptions in circadian gene expression have been shown to perturb lipid regulatory mechanisms in the brain, thereby triggering neuroinflammatory responses and oxidative damage. This review synthesizes current insights into the interconnections between circadian rhythms and lipid metabolism, with a focus on their roles in neurological health and disease. It further examines how the desynchronization of circadian genes affects lipid metabolism and explores the potential mechanisms through which disrupted circadian signaling might contribute to the pathophysiology of neurodegenerative disorders. Full article

(This article belongs to the Special Issue Cellular Metabolism in Neurological Disorders)

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15 pages, 3111 KiB

Open AccessEditor’s ChoiceArticle

Analysis of Immunosuppression and Antioxidant Damage in Diploid and Triploid Crucian Carp (Carassius auratus) Induced by Saline-Alkaline Environmental Stress: From Metabolomic Insight

by Fangying Yuan, Xiaofeng Wei, Dongping Li, Xiaofeng Jin, Jing Wang and Yanchun Sun

Metabolites 2024, 14(12), 721; https://doi.org/10.3390/metabo14120721 - 21 Dec 2024

Cited by 1 | Viewed by 952

Abstract

Objectives: The salinization of the water environment worldwide is increasing, which has brought great challenges to the sustainability of fish farming of aquatic animals. Methods: Three NaHCO₃ concentration groups (0 mmol/L, 20 mmol/L, and 60 mmol/L) were set up in this study [...] Read more.

Objectives: The salinization of the water environment worldwide is increasing, which has brought great challenges to the sustainability of fish farming of aquatic animals. Methods: Three NaHCO₃ concentration groups (0 mmol/L, 20 mmol/L, and 60 mmol/L) were set up in this study to investigate growth and metabolic differences between diploid and triploid crucian carp under saline-alkaline stresses. Purpose: This study utilized UPLC-QTOF/MS metabolomics to analyze significant metabolites and metabolic pathways in the serum of diploid and triploid crucian carp, exposing them to different NaHCO₃ concentrations in saline-alkaline habitats, elucidating the mechanism of their metabolic differences. Results: Results revealed that in the CA20 group, diploid and triploid crucian carp shared 69 differential metabolites, primarily enriched in pathways such as sphingolipid metabolism, glycerophospholipid metabolism, and linoleic acid metabolism. In the CA60 group, 46 differentially metabolites (DMs) were identified, mainly enriched in pathways such as linoleic acid metabolism, unsaturated fatty acid biosynthesis and sphingolipid metabolism. Conclusions: The analysis indicated that under different carbonate-saline-alkaline concentrations, diploid and triploid crucian carp primarily enriched in metabolic pathways such as glycerophospholipid metabolism, sphingolipid metabolism, and unsaturated fatty acid biosynthesis. With increasing carbonate-alkaline concentrations, hemolytic phospholipids associated with cell apoptosis were significantly upregulated and sphingolipid metabolism related to inflammation was more significantly enriched in triploid crucian carp, indicating that triploid crucian carp exhibited significant sensitivity to high carbonate-saline-alkaline stress and poorer carbonate-saline-alkaline tolerance. The results of this study provided a scientific theoretical basis for the later cultivation and aquaculture research of saline-alkaline-tolerant fish species. Full article

(This article belongs to the Special Issue Metabolic Physiology Under Environmental Coercion)

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13 pages, 2660 KiB

Open AccessEditor’s ChoiceArticle

Cyperus rotundus Extract and Its Active Metabolite α-Cyperone Alleviates Paclitaxel-Induced Neuropathic Pain via the Modulation of the Norepinephrine Pathway

by Keun-Tae Park, Insuk Sim, Jae-Chul Lee, Young-Ho Jin and Woojin Kim

Metabolites 2024, 14(12), 719; https://doi.org/10.3390/metabo14120719 - 20 Dec 2024

Cited by 1 | Viewed by 1319

Abstract

Background: Paclitaxel is a widely used anticancer drug for ovarian, lung, breast, and stomach cancers; however, its clinical use is often limited by the side effects of peripheral neuropathy. This study evaluated the effects of Cyperus rotundus (C. rotundus) extract and [...] Read more.

Background: Paclitaxel is a widely used anticancer drug for ovarian, lung, breast, and stomach cancers; however, its clinical use is often limited by the side effects of peripheral neuropathy. This study evaluated the effects of Cyperus rotundus (C. rotundus) extract and its active metabolite, α-cyperone, on paclitaxel-induced neuropathic pain. Methods: The oral administration of C. rotundus extract at doses of 500 mg/kg and intraperitoneal administration of α-cyperone at doses of 480 and 800 μg/kg prevented both the development of cold and mechanical pain. Results: The gene and protein expressions of tyrosine hydroxylase and noradrenergic receptors (α1- and α2-adrenergic), which were upregulated by paclitaxel, were significantly downregulated in the C. rotundus extract-treated group. In the locus coeruleus region of the mouse brain, C. rotundus extract administration also reduced the elevated expression of tyrosine hydroxylase induced by paclitaxel. The concentration of α-cyperone in C. rotundus extract was quantified using high-performance liquid chromatography (HPLC). In the group treated with α-cyperone, at levels corresponding to its content in C. rotundus, both cold and mechanical allodynia were effectively prevented. Conclusions: This study suggests that α-cyperone shows potential as a preventive agent for paclitaxel-induced neuropathic pain. Full article

(This article belongs to the Section Plant Metabolism)

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16 pages, 2393 KiB

Open AccessEditor’s ChoiceArticle

Chemical Diversity of Mediterranean Seagrasses Volatilome

by Salomé Coquin, Elena Ormeno, Vanina Pasqualini, Briac Monnier, Gérald Culioli, Caroline Lecareux, Catherine Fernandez and Amélie Saunier

Metabolites 2024, 14(12), 705; https://doi.org/10.3390/metabo14120705 - 14 Dec 2024

Cited by 3 | Viewed by 943

Abstract

Background/Objectives: Biogenic volatile organic compounds (BVOCs), extensively studied in terrestrial plants with global emissions around 1 PgC yr⁻¹, are also produced by marine organisms. However, benthic species, especially seagrasses, are understudied despite their global distribution (177,000–600,000 km²). This study [...] Read more.

Background/Objectives: Biogenic volatile organic compounds (BVOCs), extensively studied in terrestrial plants with global emissions around 1 PgC yr⁻¹, are also produced by marine organisms. However, benthic species, especially seagrasses, are understudied despite their global distribution (177,000–600,000 km²). This study aims to examine BVOC emissions from key Mediterranean seagrass species (Cymodocea nodosa, Posidonia oceanica, Zostera noltei, and Zostera marina) in marine and coastal lagoon environments. Methods: BVOCs were collected using headspace solid-phase microextraction (HS-SPME) using divinylbenzene/carboxen/polydimethylsiloxane (DVB/CAR/PDMS) fibers and analyzed by gas chromatography–mass spectrometry (GC-MS). Results: An important chemical diversity was found with a total of 92 volatile compounds (61 for Z. noltei, 59 for C. nodosa, 55 for P. oceanica, and 51 for Z. marina), from different biosynthetic pathways (e.g., terpenoids, benzenoids, and fatty acid derivatives) and with several types of chemical functions (e.g., alkanes, esters, aldehydes, and ketones) or heteroatoms (e.g., sulfur). No differences in chemical richness or diversity of compounds were observed between species. The four species shared 29 compounds enabling us to establish a specific chemical footprint for Mediterranean marine plants, including compounds like benzaldehyde, benzeneacetaldehyde, 8-heptadecene, heneicosane, heptadecane, nonadecane, octadecane, pentadecane, tetradecane, and tridecanal. PLS-DA and Heatmap show that the four species presented significantly different chemical profiles. The major compounds per species in relative abundance were isopropyl myristate for C. nodosa (25.6%), DMS for P. oceanica (39.3%), pentadecane for Z. marina (42.9%), and heptadecane for Z. noltei (46%). Conclusions: These results highlight the potential of BVOCs’ emission from seagrass ecosystems and reveal species-specific chemical markers. Full article

(This article belongs to the Special Issue Unlocking Nature's Toolbox: Advances in Plant Metabolites Identification)

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17 pages, 1794 KiB

Open AccessEditor’s ChoiceReview

The Role of Diet, Additives, and Antibiotics in Metabolic Endotoxemia and Chronic Diseases

by Ji-Eun Park, Ho-Young Park, Young-Soo Kim and Miri Park

Metabolites 2024, 14(12), 704; https://doi.org/10.3390/metabo14120704 - 13 Dec 2024

Cited by 4 | Viewed by 1868

Abstract

Background/Objectives: Dietary patterns, including high-fat and high-carbohydrate diets (HFDs and HCDs), as well as non-dietary factors such as food additives and antibiotics, are strongly linked to metabolic endotoxemia, a critical driver of low-grade chronic inflammation. This review explores the mechanisms through which [...] Read more.

Background/Objectives: Dietary patterns, including high-fat and high-carbohydrate diets (HFDs and HCDs), as well as non-dietary factors such as food additives and antibiotics, are strongly linked to metabolic endotoxemia, a critical driver of low-grade chronic inflammation. This review explores the mechanisms through which these factors impair intestinal permeability, disrupt gut microbial balance, and facilitate lipopolysaccharide (LPS) translocation into the bloodstream, contributing to metabolic disorders such as obesity, type 2 diabetes mellitus, and inflammatory bowel disease. Methods: The analysis integrates findings from recent studies on the effects of dietary components and gut microbiota interactions on intestinal barrier function and systemic inflammation. Focus is given to experimental designs assessing gut permeability using biochemical and histological methods, alongside microbiota profiling in both human and animal models. Results: HFDs and HCDs were shown to increase intestinal permeability and systemic LPS levels, inducing gut dysbiosis and compromising barrier integrity. The resulting endotoxemia promoted a state of chronic inflammation, disrupting metabolic regulation and contributing to the pathogenesis of various metabolic diseases. Food additives and antibiotics further exacerbated these effects by altering microbial composition and increasing gut permeability. Conclusions: Diet-induced alterations in gut microbiota and barrier dysfunction emerge as key mediators of metabolic endotoxemia and related disorders. Addressing dietary patterns and their impact on gut health is crucial for developing targeted interventions. Further research is warranted to standardize methodologies and elucidate mechanisms for translating these findings into clinical applications. Full article

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

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15 pages, 1109 KiB

Open AccessEditor’s ChoiceArticle

Using Serum Metabolomic Signatures to Investigate Effects of Acupuncture on Pain-Fatigue-Sleep Disturbance in Breast Cancer Survivors

by Hongjin Li, Ardith Z. Doorenbos, Yinglin Xia, Jun Sun, Hannah Choi, Richard E. Harris, Shuang Gao, Katy Sullivan and Judith M. Schlaeger

Metabolites 2024, 14(12), 698; https://doi.org/10.3390/metabo14120698 - 10 Dec 2024

Cited by 2 | Viewed by 1239

Abstract

Background/Objectives: Acupuncture is an efficacious integrative therapy for treating pain, fatigue, and sleep disturbance (the psychoneurological symptom cluster) in breast cancer survivors. However, the mechanisms underlying its effects remain unclear, and related metabolomics studies are limited. This study aimed to examine serum metabolite [...] Read more.

Background/Objectives: Acupuncture is an efficacious integrative therapy for treating pain, fatigue, and sleep disturbance (the psychoneurological symptom cluster) in breast cancer survivors. However, the mechanisms underlying its effects remain unclear, and related metabolomics studies are limited. This study aimed to examine serum metabolite changes after acupuncture and their relationships to symptom improvement. Methods: Forty-two breast cancer survivors experiencing pain, fatigue, and sleep disturbance participated in a single-arm acupuncture trial. They received a 10-session acupuncture intervention over 5 weeks. Fasting blood samples and symptom surveys were collected before and after the acupuncture intervention, and untargeted metabolomics profiling was conducted on serum samples. Mixed-effects models adjusting for covariates (age, race, body mass index, and antidepressant use) were applied for analysis. Results: After acupuncture, there was a significant reduction in the psychoneurological symptom cluster (mean reduction = −6.2, p < 0.001).Bonferroni correction was applied to 40 independent metabolite clusters (α = 0.00125); cysteine-glutathione disulfide (p = 0.0006) significantly increased, and retinal (p = 0.0002) and cis-urocanate (p = 0.0005) were significantly decreased. Dimethyl sulfone (p = 0.00139) showed a trend towards reduction after acupuncture and its change (p = 0.04, β =1.97) was positively associated with reduction in the psychoneurological symptom cluster. Also, increased lauroylcarnitine (p = 0.0009) and decreased cytosine (p = 0.0008) can modulate the therapeutic effects of acupuncture. Conclusions: Acupuncture demonstrates beneficial effects on the psychoneurological symptom cluster in breast cancer survivors. Dimethyl sulfone may be a promising mediator in the relationship between acupuncture and psychoneurological symptoms, while acylcarnitine metabolism may modulate the therapeutic effect of acupuncture. Full article

(This article belongs to the Special Issue Investigation of the Metabolic Mechanisms Underlying Breast Cancer: Navigating from Diagnosis to Survivorship)

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14 pages, 7233 KiB

Open AccessEditor’s ChoiceArticle

Non-Targeted Metabolomics Analysis Reveals Metabolite Profiles Change During Whey Fermentation with Kluyveromyces marxianus

by Yansong Gao, Lei Gao, You Kang, Ge Yang, Zijian Zhao, Yujuan Zhao and Shengyu Li

Metabolites 2024, 14(12), 694; https://doi.org/10.3390/metabo14120694 - 9 Dec 2024

Cited by 1 | Viewed by 1341

Abstract

Background: Whey fermentation could produce bioactive substances with immunomodulatory effects, metabolic syndrome modulation, and antioxidant properties, thereby imparting functional characteristics to products and facilitating the development of novel foods with health-promoting potential. Methods: A non-targeted metabolomics approach using liquid chromatography–mass spectrometry (LC-MS) was [...] Read more.

Background: Whey fermentation could produce bioactive substances with immunomodulatory effects, metabolic syndrome modulation, and antioxidant properties, thereby imparting functional characteristics to products and facilitating the development of novel foods with health-promoting potential. Methods: A non-targeted metabolomics approach using liquid chromatography–mass spectrometry (LC-MS) was employed to investigate changes in the metabolite profiles of whey fermented by Kluyveromyces marxianus strain KM812 over varying fermentation durations. Results: The findings demonstrated a progressive enrichment of metabolites over time. A total of 151 differential metabolites were identified and categorized primarily into amino acids, peptides, and analogues, fatty acids and conjugates, and carbohydrates and conjugates, as well as benzoic acids and derivatives. The highest relative content of whey metabolites was observed at 48 h of fermentation, with a cumulative increase of 1.45-fold, 1.49-fold, 3.39-fold, and 1.24-fold for peptides and amino acids, peptides, and analogues, fatty acids and conjugates, and carbohydrates and conjugates, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed associations with 23 specific metabolites and delineated 9 metabolic pathways, predominantly involved in amino acid and lipid metabolism. Conclusions: Based on the above, KM812 could effectively degrade macromolecular substances in whey into small molecules such as L-isoleucine, ornithine, betaine, α-linolenic acid, and palmitoleic acid, thereby influencing the nutritional and functional properties of whey. In-depth analysis of the metabolic products in KM812-fermented whey could provide a theoretical basis for the development of functional foods derived from small molecules in the future. Full article

(This article belongs to the Section Food Metabolomics)

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14 pages, 8565 KiB

Open AccessEditor’s ChoiceArticle

Role of Milk Intake in Modulating Serum Lipid Profiles and Gut Metabolites

by Ting Xu, Chang Zhang, Yufeng Yang, Liang Huang, Qingyou Liu, Ling Li, Qingkun Zeng and Zhipeng Li

Metabolites 2024, 14(12), 688; https://doi.org/10.3390/metabo14120688 - 7 Dec 2024

Viewed by 1083

Abstract

Background/Objectives: Milk is one of the main sources of nutrition in people’s daily diet, but the fat in milk raises health concerns in consumers. Here, we aimed to elucidate the impact of Buffalo milk and Holstein cow milk consumption on blood lipid health [...] Read more.

Background/Objectives: Milk is one of the main sources of nutrition in people’s daily diet, but the fat in milk raises health concerns in consumers. Here, we aimed to elucidate the impact of Buffalo milk and Holstein cow milk consumption on blood lipid health through metabolomics analysis. Methods: Golden hamsters were administered Murrah Buffalo milk (BM) or Holstein cow milk (HM), and the body weight and serum lipid indicators were tested and recorded. The hamsters receiving equal amounts of physiological saline were used as the negative control (NC). Serum and fecal samples were collected, and LC-MS was used to identify the metabolites in the samples. Results: The results showed that both the BM and HM groups exhibited a significant reduction in body weight compared to that of the NC group from day 9, and the serum TG, TC, and LDL-C levels were significantly lower than those of the NC group. Further analysis identified 564 and 567 metabolites in the serum and fecal samples shared in the BM and HM groups and significantly different from those in the NC group, which were mainly enriched in the pathways related to lipid metabolism, such as fatty acid biosynthesis, arachidonic acid metabolism, and primary bile acid biosynthesis. Correlation analysis further suggested that milk intake can increase the levels of Muramic Acid, Oleoyl Ethanolamide, Seratrodast, Chenodeoxycholic Acid, Docosahexaenoic Acid Ethyl Ester, and Deoxycholic Acid in the serum and gut microbiota, which may affect TG, TC, HDL-C, and LDL-C in the serum, and thereby benefit the body’s lipid health. Conclusions: The results further confirmed that milk intake has a beneficial effect on blood lipid health by altering multiple metabolites in the serum and the gut. This study provides novel evidence that milk consumption is beneficial to health and is a reference for guiding people to a healthy diet. Full article

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

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9 pages, 1324 KiB

Open AccessEditor’s ChoiceArticle

The Role of Beta-Hydroxybutyrate in Mitigating the Inflammatory and Metabolic Consequences of Uric Acid

by Nicole P. Remund, John G. Larsen, Marley J. Shin, Cali E. Warren, Isabelle L. Palmer, Iris J. Kim, Elijah T. Cooper-Leavitt, Derek M. Clarke, Colson G. Beus, Richard J. Johnson, Juan A. Arroyo, Paul R. Reynolds and Benjamin T. Bikman

Metabolites 2024, 14(12), 679; https://doi.org/10.3390/metabo14120679 - 4 Dec 2024

Cited by 3 | Viewed by 5216

Abstract

Background: Uric acid (UA), a metabolite of purine and fructose metabolism, is linked to inflammation and metabolic disorders, including gout and cardiovascular disease. Its pro-inflammatory effects are largely driven by the activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) [...] Read more.

Background: Uric acid (UA), a metabolite of purine and fructose metabolism, is linked to inflammation and metabolic disorders, including gout and cardiovascular disease. Its pro-inflammatory effects are largely driven by the activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, leading to increased cytokine production. Beta-hydroxybutyrate (BHB), a ketone produced during fasting or carbohydrate restriction, has been shown to reduce inflammation. This study explores the role of BHB in mitigating the inflammatory and metabolic effects of elevated uric acid levels. Methods: We utilized a murine muscle cell culture treated with UA and BHB. Results: Muscle cells treated with UA had increased production of pro-inflammatory cytokines and reduced cell viability. Co-treatment with BHB reversed these effects, improving cell survival and reducing cytokine levels. Additionally, uric acid impaired mitochondrial function and increased oxidative stress, which were mitigated by BHB. Furthermore, uric acid disrupted insulin signaling, but BHB co-treatment restored insulin sensitivity. Conclusions: These findings suggest that BHB holds therapeutic potential by counteracting the inflammatory and metabolic disruptions caused by elevated uric acid, making it a promising target for conditions such as hyperuricemia and metabolic syndrome. Full article

(This article belongs to the Special Issue Exploring Uric Acid and Beyond)

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13 pages, 2027 KiB

Open AccessEditor’s ChoiceArticle

Antihypertensive Effect of Perla and Esmeralda Barley (Hordeum vulgare L.) Sprouts in an Induction Model with L-NAME In Vivo

by Abigail García-Castro, Alma D. Román-Gutiérrez, Fabiola A. Guzmán-Ortiz and Raquel Cariño-Cortés

Metabolites 2024, 14(12), 678; https://doi.org/10.3390/metabo14120678 - 3 Dec 2024

Viewed by 3759

Abstract

Background: Hypertension is one of the leading causes of premature death worldwide. Despite advances in conventional treatments, there remains a significant need for more effective and natural alternatives to control hypertension. In this context, sprouted barley extracts have emerged as a potential therapeutic [...] Read more.

Background: Hypertension is one of the leading causes of premature death worldwide. Despite advances in conventional treatments, there remains a significant need for more effective and natural alternatives to control hypertension. In this context, sprouted barley extracts have emerged as a potential therapeutic option. This study presents the evaluation of the bioactive properties of extracts from two varieties of barley germinated for different periods (3, 5, and 7 days), focusing on their potential to regulate blood pressure mechanisms. Objectives/Methods: The main objective was to assess the effects of these extracts on blood pressure regulation in N(ω)-Nitro-L-Arginine Methyl Ester (L-NAME)-induced hypertensive rats. Renal (creatinine, urea, uric acid, and total protein) and endothelial (NOx levels) function, angiotensin-converting enzyme (ACE) I and II activity, and histopathological effects on heart and kidney tissues were evaluated. Results: In particular, Esmeralda barley extract demonstrated 83% inhibition of ACE activity in vitro. Furthermore, the combined administration of sprouted barley extract (SBE) and captopril significantly reduced blood pressure and ACE I and II activity by 22%, 81%, and 76%, respectively, after 3, 5, and 7 days of germination. The treatment also led to reductions in protein, creatinine, uric acid, and urea levels by 3%, 38%, 42%, and 48%, respectively, along with a 66% increase in plasma NO concentrations. Conclusions: This study highlights the bioactive properties of barley extracts with different germination times, emphasizing their potential health benefits as a more effective alternative to conventional antihypertensive therapies. Full article

(This article belongs to the Special Issue Plants and Plant-Based Foods for Metabolic Disease Prevention)

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18 pages, 7658 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Blood Metabolome and Exposome Analysis, Annotation, and Interpretation in E-Waste Workers

by Zhiqiang Pang, Charles Viau, Julius N. Fobil, Niladri Basu and Jianguo Xia

Metabolites 2024, 14(12), 671; https://doi.org/10.3390/metabo14120671 - 2 Dec 2024

Viewed by 1193

Abstract

Background: Electronic and electrical waste (e-waste) production has emerged to be of global environmental public health concern. E-waste workers, who are frequently exposed to hazardous chemicals through occupational activities, face considerable health risks. Methods: To investigate the metabolic and exposomic changes in these [...] Read more.

Background: Electronic and electrical waste (e-waste) production has emerged to be of global environmental public health concern. E-waste workers, who are frequently exposed to hazardous chemicals through occupational activities, face considerable health risks. Methods: To investigate the metabolic and exposomic changes in these workers, we analyzed whole blood samples from 100 male e-waste workers and 49 controls from the GEOHealth II project (2017–2018 in Accra, Ghana) using LC-MS/MS. A specialized computational workflow was established for exposomics data analysis, incorporating two curated reference libraries for metabolome and exposome profiling. Two feature detection algorithms, asari and centWave, were applied. Results: In comparison to centWave, asari showed better sensitivity in detecting MS features, particularly at trace levels. Principal component analysis demonstrated distinct metabolic profiles between e-waste workers and controls, revealing significant disruptions in key metabolic pathways, including steroid hormone biosynthesis, drug metabolism, bile acid biosynthesis, vitamin metabolism, and prostaglandin biosynthesis. Correlation analyses linked metal exposures to alterations in hundreds to thousands of metabolic features. Functional enrichment analysis highlighted significant perturbations in pathways related to liver function, vitamin metabolism, linoleate metabolism, and dynorphin signaling, with the latter being observed for the first time in e-waste workers. Conclusions: This study provides new insights into the biological impact of prolonged metal exposure in e-waste workers. Full article

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

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16 pages, 3208 KiB

Open AccessEditor’s ChoiceArticle

Essential Oils from Papaver rhoeas and Their Metabolomic Profiling

by Valeria Cavalloro, Francesco Saverio Robustelli della Cuna, Alberto Malovini, Carla Villa, Cristina Sottani, Matteo Balestra, Francesco Bracco, Emanuela Martino and Simona Collina

Metabolites 2024, 14(12), 664; https://doi.org/10.3390/metabo14120664 - 1 Dec 2024

Viewed by 792

Abstract

Background/Objectives: Essential oils (EOs) have been exploited by humans for centuries, but many sources remain poorly investigated, mainly due to the low yields associated with conventional extraction. Recently, new techniques have been developed, like solvent-free microwave extraction (SFME), able to enhance efficiency [...] Read more.

Background/Objectives: Essential oils (EOs) have been exploited by humans for centuries, but many sources remain poorly investigated, mainly due to the low yields associated with conventional extraction. Recently, new techniques have been developed, like solvent-free microwave extraction (SFME), able to enhance efficiency and sustainability. The use of Papaver rhoeas L. in traditional medicine has led researchers to investigate non-volatile fractions, but there are little data available on EOs. Methods: In the present work, we prepared EOs from the petals and leaves of P. rhoeas by SFME. GC/MS analysis of EOs revealed the presence of 106 compounds belonging to 13 different classes. Isomers of the different alkenes were identified thanks to an alkylthiolation reaction. Results: The results highlighted a predominance of saturated and unsaturated hydrocarbons, alcohols, and esters that might suggest a specific relationship with pollinators. Each population has been compared using PCA, heatmap, and barplot tools, highlighting differences in terms of composition by both comparing leaves and flowers and hill and lowland samples. Furthermore, cantharidin, a metabolite usually produced by insects, was detected in the flowers, possible present for attractiveness purposes. Conclusions: These results could contribute to ensuring a better understanding of the pollination process and of the biological activities of EOs from P. rhoeas. Full article

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

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13 pages, 2396 KiB

Open AccessEditor’s ChoiceArticle

Exploration of Freshness Identification Method for Refrigerated Vegetables Based on Metabolomics

by Zixuan Meng, Haichao Zhang, Jing Wang, Lianfeng Ai and Weijun Kang

Metabolites 2024, 14(12), 665; https://doi.org/10.3390/metabo14120665 - 1 Dec 2024

Cited by 1 | Viewed by 1089

Abstract

Background: The rapid development of refrigerated transportation technology for fresh vegetables has extended their shelf life. Some vegetables may appear undamaged on the surface, but their freshness may have decreased, often resulting in the phenomenon of passing off inferior vegetables as good. [...] Read more.

Background: The rapid development of refrigerated transportation technology for fresh vegetables has extended their shelf life. Some vegetables may appear undamaged on the surface, but their freshness may have decreased, often resulting in the phenomenon of passing off inferior vegetables as good. It is very important to establish a detection method for identifying and assessing the freshness of vegetables. Methods: Therefore, based on metabolomics methods, this study innovatively employed UHPLC-Q-Exactive Orbitrap MS and GC–MS techniques to investigate the metabolites in the refrigerated storage of four vegetables, namely chard (Beta vulgaris var. cicla L), lettuce (Lactuca sativa var. ramose Hort.), crown daisy (Glebionis coronaria (L.) Cass. ex Spach), and tomato (Solanum lycopersicum L.), exploring key biomarkers for assessing their freshness. UPLC-TQ MS was used for the quantitative analysis of key metabolites. Results: The results showed that arginine biosynthesis and the metabolism of alanine, aspartate, and glutamate are key pathways in vegetable metabolism. Four key metabolites were selected from chard, five from lettuce, three from crown daisy, and five from tomato. Conclusions: Comparing the content of substances such as alanine and arginine can help infer the freshness and nutritional value of the vegetables, providing important references for detecting spoilage, determining storage time, and improving transportation conditions. This research holds significant relevance for the vegetable transportation industry. Full article

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

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