Metabolites

11 pages, 1234 KiB

Open AccessArticle

Metabolic Changes in Synaptosomes in an Animal Model of Schizophrenia Revealed by ¹H and ¹H,¹³C NMR Spectroscopy

by Brian R. Barnett, Fariba Fathi, Paulo Falco Cobra, Sue Y. Yi, Jacqueline M. Anderson, Hamid R. Eghbalnia, John L. Markley and John-Paul J. Yu

Metabolites 2020, 10(2), 79; https://doi.org/10.3390/metabo10020079 - 23 Feb 2020

Cited by 1 | Viewed by 3831

Abstract

Synaptosomes are isolated nerve terminals that contain synaptic components, including neurotransmitters, metabolites, adhesion/fusion proteins, and nerve terminal receptors. The essential role of synaptosomes in neurotransmission has stimulated keen interest in understanding both their proteomic and metabolic composition. Mass spectrometric (MS) quantification of synaptosomes [...] Read more.

Synaptosomes are isolated nerve terminals that contain synaptic components, including neurotransmitters, metabolites, adhesion/fusion proteins, and nerve terminal receptors. The essential role of synaptosomes in neurotransmission has stimulated keen interest in understanding both their proteomic and metabolic composition. Mass spectrometric (MS) quantification of synaptosomes has illuminated their proteomic composition, but the determination of the metabolic composition by MS has been met with limited success. In this study, we report a proof-of-concept application of one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy for analyzing the metabolic composition of synaptosomes. We utilize this approach to compare the metabolic composition synaptosomes from a wild-type rat with that from a newly generated genetic rat model (Disc1 svΔ2), which qualitatively recapitulates clinically observed early DISC1 truncations associated with schizophrenia. This study demonstrates the feasibility of using NMR spectroscopy to identify and quantify metabolites within synaptosomal fractions. Full article

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11 pages, 888 KiB

Open AccessArticle

Chronic Influence of Inspiratory Muscle Training at Different Intensities on the Serum Metabolome

by Camila A. Sakaguchi, David C. Nieman, Etore F. Signini, Raphael M. de Abreu, Claudio D. Silva, Patrícia Rehder-Santos, Maria G. A. Carosio, Roberta M. Maria, Carla C. Dato, Heloisa S. S. de Araújo, Tiago Venâncio, Antônio G. Ferreira and Aparecida M. Catai

Metabolites 2020, 10(2), 78; https://doi.org/10.3390/metabo10020078 - 21 Feb 2020

Cited by 2 | Viewed by 2585

Abstract

This study investigated the chronic effect of inspiratory muscle training (IMT) on the human serum metabolome in healthy male recreational cyclists. Using a randomized, parallel group design, twenty-eight participants were randomized to three IMT groups: low intensity (LI, n = 7); moderate intensity [...] Read more.

This study investigated the chronic effect of inspiratory muscle training (IMT) on the human serum metabolome in healthy male recreational cyclists. Using a randomized, parallel group design, twenty-eight participants were randomized to three IMT groups: low intensity (LI, n = 7); moderate intensity (MI, n = 10); and high intensity (HI, n = 11). The IMT was performed for 11 weeks. Another group of participants under the same conditions, who did not perform the IMT but participated in all procedures, was included as controls (CG, n = 6). Blood samples were collected one week before and after 11 weeks of IMT and analyzed for metabolite shifts using 1H NMR. Statistical analysis included a 4 (group) × 2 (time) repeated measures ANOVA using the general linear model (GLM), and multivariate principal component analysis (PCA). Untargeted metabolomics analysis of serum samples identified 22 metabolites, including amino acids, lipids, and tricarboxylic acid cycle intermediates. Metabolites shifts did not differ between groups, indicating that IMT at three intensity levels did not alter the serum metabolome relative to the control group. These results reveal novel insights into the metabolic effects of the IMT and are consistent with the results from other studies showing negligible chronic alterations in the serum metabolome in response to physical training. Full article

(This article belongs to the Special Issue Exercise Metabonomics)

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16 pages, 686 KiB

Open AccessReview

The Determinants of the Human Milk Metabolome and Its Role in Infant Health

by Anna Ojo-Okunola, Stefano Cacciatore, Mark P. Nicol and Elloise du Toit

Metabolites 2020, 10(2), 77; https://doi.org/10.3390/metabo10020077 - 20 Feb 2020

Cited by 30 | Viewed by 5939

Abstract

Human milk is needed for optimal growth as it satisfies both the nutritional and biological needs of an infant. The established relationship between breastfeeding and an infant’s health is attributable to the nutritional and non-nutritional, functional components of human milk including metabolites such [...] Read more.

Human milk is needed for optimal growth as it satisfies both the nutritional and biological needs of an infant. The established relationship between breastfeeding and an infant’s health is attributable to the nutritional and non-nutritional, functional components of human milk including metabolites such as the lipids, amino acids, biogenic amines and carbohydrates. These components have diverse roles, including protecting the infant against infections and guiding the development of the infant’s immature immune system. In this review, we provide an in-depth and updated insight into the immune modulatory and anti-infective role of human milk metabolites and their effects on infant health and development. We also review the literature on potential determinants of the human milk metabolome, including maternal infectious diseases such as human immunodeficiency virus and mastitis. Full article

(This article belongs to the Special Issue Applications of Metabolomics in Maternal and Child Health)

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10 pages, 793 KiB

Open AccessArticle

Independent and Opposite Associations Between Branched-Chain Amino Acids and Lysophosphatidylcholines With Incident Diabetes in Thais

by La-or Chailurkit, Nitchawat Paiyabhroma, Piyamit Sritara, Prin Vathesatogkit, Sukit Yamwong, Nisakron Thonmung and Boonsong Ongphiphadhanakul

Metabolites 2020, 10(2), 76; https://doi.org/10.3390/metabo10020076 - 20 Feb 2020

Cited by 4 | Viewed by 3029

Abstract

Branched-chain amino acids (BCAAs) and lysophosphatidylcholines (LPCs) have been reported to be associated with diabetes. The purpose of the present study was to investigate the relative contributions of BCAAs and LPCs to the progression of prediabetes to diabetes using a targeted metabolomic approach. [...] Read more.

Branched-chain amino acids (BCAAs) and lysophosphatidylcholines (LPCs) have been reported to be associated with diabetes. The purpose of the present study was to investigate the relative contributions of BCAAs and LPCs to the progression of prediabetes to diabetes using a targeted metabolomic approach. This study was part of a health survey of employees of the Electricity Generating Authority of Thailand (n = 79; nine females and 70 males). A targeted metabolomics analysis was performed using an AbsoluteIDQ^® p180 kit, flow injection analysis, and liquid chromatography-tandem mass spectrometry. The highest variable importance in projection (VIP) scores for the progression to diabetes of the amino acids and phospholipids were associated with isoleucine and LPC acyl C28:1, respectively. Using logistic regression analysis, we found that high baseline isoleucine concentration was associated with a higher incidence of diabetes, while high LPC acyl 28:1 was associated with a lower incidence. Isoleucine and LPC acyl 28:1 were independently associated with incident diabetes in a model that also included conventional risk factors for diabetes (baseline fasting plasma glucose (FPG), age, sex, and body mass index (BMI)). In addition, isoleucine and LPC acyl 28:1 were independently associated with serum HbA1c 5 years later in a robust regression model that also included baseline FPG, age, sex, and BMI. Isoleucine, LPC acyl 28:1, age, and FPG were significantly associated with HbA1c at this time. In conclusion, these results provide evidence that isoleucine and LPC acyl C28:1 have respective positive and negative independent associations with incident diabetes. Full article

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9 pages, 759 KiB

Open AccessArticle

LAMA-1: A Cerebroside Isolated from the Deep-Sea-Derived Fungus Penicillium chrysogenum

by Samah O. Alshehri, Rania T. Malatani, Hanin A. Bogari, Ahmad O. Noor, Amany K. Ibrahim, Sameh S. Elhady and Reda F. A. Abdelhameed

Metabolites 2020, 10(2), 75; https://doi.org/10.3390/metabo10020075 - 20 Feb 2020

Cited by 8 | Viewed by 3355

Abstract

Chemical investigation of the ethyl acetate extract of Penicillium chrysogenum strain S003, a fungus isolated from Red Sea deep sediment, led to the isolation of a cerebroside molecular species LAMA (1) along with three other known compounds, ergosterol (2), [...] Read more.

Chemical investigation of the ethyl acetate extract of Penicillium chrysogenum strain S003, a fungus isolated from Red Sea deep sediment, led to the isolation of a cerebroside molecular species LAMA (1) along with three other known compounds, ergosterol (2), epidioxyergosterol (3), and kojic acid (4). The structures of the isolated compounds were elucidated by interpretation of spectral data, including detailed 1D and 2D NMR (One and two dimensional Nuclear Magnetic Resonance) and mass spectrometry. The cytotoxic activities of isolated compounds 1–4 against five human carcinoma cells were evaluated using sulforhodamine B (SRB) assay. Compounds 2 and 3 displayed promising cytotoxic profiles against lung cancer (A-549), prostate (DU-145), breast adenocarcinoma (MCF-7), and hepatocellular (HepG2) cell lines, with IC₅₀ values of 21.26, 19.3; 1.50, 6.10; 16.95, 13.6; and 2.89, 3.07 µM, respectively, while they were inactive against HeLa cells. Compounds 1 and 4 showed weak cytotoxic profiles against all cell lines under investigation. Full article

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20 pages, 4000 KiB

Open AccessArticle

Absolute Quantification of the Central Carbon Metabolome in Eight Commonly Applied Prokaryotic and Eukaryotic Model Systems

by Lisa M. Røst, Lilja Brekke Thorfinnsdottir, Kanhaiya Kumar, Katsuya Fuchino, Ida Eide Langørgen, Zdenka Bartosova, Kåre Andre Kristiansen and Per Bruheim

Metabolites 2020, 10(2), 74; https://doi.org/10.3390/metabo10020074 - 19 Feb 2020

Cited by 36 | Viewed by 7488

Abstract

Absolute quantification of intracellular metabolite pools is a prerequisite for modeling and in-depth biological interpretation of metabolomics data. It is the final step of an elaborate metabolomics workflow, with challenges associated with all steps—from sampling to quantifying the physicochemically diverse metabolite pool. Chromatographic [...] Read more.

Absolute quantification of intracellular metabolite pools is a prerequisite for modeling and in-depth biological interpretation of metabolomics data. It is the final step of an elaborate metabolomics workflow, with challenges associated with all steps—from sampling to quantifying the physicochemically diverse metabolite pool. Chromatographic separation combined with mass spectrometric (MS) detection is the superior platform for high coverage, selective, and sensitive detection of metabolites. Herein, we apply our quantitative MS-metabolomics workflow to measure and present the central carbon metabolome of a panel of commonly applied biological model systems. The workflow includes three chromatographic methods combined with isotope dilution tandem mass spectrometry to allow for absolute quantification of 68 metabolites of glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle, and the amino acid and (deoxy) nucleoside pools. The biological model systems; Bacillus subtilis, Saccharomyces cerevisiae, two microalgal species, and four human cell lines were all cultured in commonly applied culture media and sampled in exponential growth phase. Both literature and databases are scarce with comprehensive metabolite datasets, and existing entries range over several orders of magnitude. The workflow and metabolite panel presented herein can be employed to expand the list of reference metabolomes, as encouraged by the metabolomics community, in a continued effort to develop and refine high-quality quantitative metabolomics workflows. Full article

(This article belongs to the Special Issue 10th Anniversary of Metabolites: The Changing Landscape of Metabolomics)

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28 pages, 2734 KiB

Open AccessReview

Nidulantes of Aspergillus (Formerly Emericella): A Treasure Trove of Chemical Diversity and Biological Activities

by Najla Ali Alburae, Afrah E. Mohammed, Hajer Saeed Alorfi, Adnan Jaman Turki, Hani Zakaria Asfour, Walied Mohamed Alarif and Ahmed Abdel-Lateff

Metabolites 2020, 10(2), 73; https://doi.org/10.3390/metabo10020073 - 17 Feb 2020

Cited by 10 | Viewed by 4261

Abstract

The genus Emericella (Ascomycota) includes more than thirty species with worldwide distribution across many ecosystems. It is considered a rich source of diverse metabolites. The published classes of natural compounds that are discussed here are organized according to the following biosynthetic pathways: polyketides [...] Read more.

The genus Emericella (Ascomycota) includes more than thirty species with worldwide distribution across many ecosystems. It is considered a rich source of diverse metabolites. The published classes of natural compounds that are discussed here are organized according to the following biosynthetic pathways: polyketides (azaphilones, cyclopentenone pigments, dicyanides, furan derivatives, phenolic ethers, and xanthones and anthraquinones); shikimate derivatives (bicoumarins); mevalonate derivatives (meroterpenes, sesquiterpenes, sesterterpenes and steroids) and amino acids derivatives (alkaloids (indole-derivatives, isoindolones, and piperazine) and peptides (depsipeptides)). These metabolites produce the wide array of biological effects associated with Emericella, including antioxidant, antiproliferative, antimalarial, antiviral, antibacterial, antioxidant, antihypertensive, anti-inflammatory, antifungal and kinase inhibitors. Careful and extensive study of the diversity and distribution of metabolites produced by the genus Emericella (either marine or terrestrial) revealed that, no matter the source of the fungus, the composition of the culture medium effectively controls the metabolites produced. The topic of this review is the diversity of metabolites that have been identified from Emericella, along with the contextual information on either their biological or geographic sources. This review presents 236 natural compounds, which were reported from marine and terrestrial Emericella. Amongst the reported compounds, only 70.2% were biologically assayed for their effects, including antimicrobial or cytotoxicity. This implies the need for substantial investigation of alternative activities. This review includes a full discussion of compound structures and disease management, based on materials published from 1982 through December 2019. Full article

(This article belongs to the Special Issue Fungal and Mycotoxin Metabolism)

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20 pages, 347 KiB

Open AccessReview

Metabolomics in Psychiatric Disorders: What We Learn from Animal Models

by Elke Humer, Thomas Probst and Christoph Pieh

Metabolites 2020, 10(2), 72; https://doi.org/10.3390/metabo10020072 - 17 Feb 2020

Cited by 30 | Viewed by 5852

Abstract

Biomarkers are a recent research target within biological factors of psychiatric disorders. There is growing evidence for deriving biomarkers within psychiatric disorders in serum or urine samples in humans, however, few studies have investigated this differentiation in brain or cerebral fluid samples in [...] Read more.

Biomarkers are a recent research target within biological factors of psychiatric disorders. There is growing evidence for deriving biomarkers within psychiatric disorders in serum or urine samples in humans, however, few studies have investigated this differentiation in brain or cerebral fluid samples in psychiatric disorders. As brain samples from humans are only available at autopsy, animal models are commonly applied to determine the pathogenesis of psychiatric diseases and to test treatment strategies. The aim of this review is to summarize studies on biomarkers in animal models for psychiatric disorders. For depression, anxiety and addiction disorders studies, biomarkers in animal brains are available. Furthermore, several studies have investigated psychiatric medication, e.g., antipsychotics, antidepressants, or mood stabilizers, in animals. The most notable changes in biomarkers in depressed animal models were related to the glutamate-γ-aminobutyric acid-glutamine-cycle. In anxiety models, alterations in amino acid and energy metabolism (i.e., mitochondrial regulation) were observed. Addicted animals showed several biomarkers according to the induced drugs. In summary, animal models provide some direct insights into the cellular metabolites that are produced during psychiatric processes. In addition, the influence on biomarkers due to short- or long-term medication is a noticeable finding. Further studies should combine representative animal models and human studies on cerebral fluid to improve insight into mental disorders and advance the development of novel treatment strategies. Full article

(This article belongs to the Special Issue Metabolomics Analysis for Biomarker Discovery and Human Health)

12 pages, 1803 KiB

Open AccessArticle

Addressing Glutathione Redox Status in Clinical Samples by Two-Step Alkylation with N-ethylmaleimide Isotopologues

by Tamara Tomin, Matthias Schittmayer and Ruth Birner-Gruenberger

Metabolites 2020, 10(2), 71; https://doi.org/10.3390/metabo10020071 - 16 Feb 2020

Cited by 22 | Viewed by 4908

Abstract

Determination of the ratio of reduced to oxidized glutathione is of profound clinical interest in assessing the oxidative status of tissues and body fluids. However, this ratio is not yet a routine clinical parameter due to the analytically challenging interconversion of reduced (free) [...] Read more.

Determination of the ratio of reduced to oxidized glutathione is of profound clinical interest in assessing the oxidative status of tissues and body fluids. However, this ratio is not yet a routine clinical parameter due to the analytically challenging interconversion of reduced (free) glutathione to oxidized (bound) glutathione. We aimed to facilitate this ratio determination in order to aid its incorporation as a routine clinical parameter. To this end, we developed a simple derivatization route that yields different isotopologues of N-ethylmaleimide alkylated glutathione from reduced and oxidized glutathione (after its chemical reduction) for mass spectrometric analysis. A third isotopologue can be used as isotopic standard for simultaneous absolute quantification. As all isotopologues have similar chromatographic properties, matrix effects arising from different sample origins can only impact method sensitivity but not quantification accuracy. Robustness, simplified data analysis, cost effectiveness by one common standard, and highly improved mass spectrometric sensitivity by conversion of oxidized glutathione to an alkylated glutathione isotopologue are the main advantages of our approach. We present a method fully optimized for blood, plasma, serum, cell, and tissue samples. In addition, we propose production of N-ethylmaleimide customized blood collection tubes to even further facilitate the analysis in a clinical setting. Full article

(This article belongs to the Special Issue Stable Isotope Guided Metabolomics)

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13 pages, 281 KiB

Open AccessArticle

¹H NMR Based Metabolomics in Human Sepsis and Healthy Serum

by Henna Jaurila, Vesa Koivukangas, Marjo Koskela, Fiia Gäddnäs, Sami Myllymaa, Arja Kullaa, Tuula Salo and Tero I. Ala-Kokko

Metabolites 2020, 10(2), 70; https://doi.org/10.3390/metabo10020070 - 15 Feb 2020

Cited by 33 | Viewed by 3682

Abstract

Early diagnosis is essential but challenging in severe sepsis. Quantifying and comparing metabolite concentrations in serum has been suggested as a new diagnostic tool. Here we used proton nuclear magnetic resonance spectroscopy (¹H NMR) based metabolomics to analyze the possible differences [...] Read more.

Early diagnosis is essential but challenging in severe sepsis. Quantifying and comparing metabolite concentrations in serum has been suggested as a new diagnostic tool. Here we used proton nuclear magnetic resonance spectroscopy (¹H NMR) based metabolomics to analyze the possible differences in metabolite concentrations between sera taken from septic patients and healthy controls, as well as between sera of surviving and non-surviving sepsis patients. We took serum samples from 44 sepsis patients when the first sepsis induced organ dysfunction was found. Serum samples were also collected from 14 age and gender matched healthy controls. The samples were analyzed by quantitative ¹H NMR spectroscopy for non-lipid metabolites. We found that the serum levels of glucose, glycine, 3-hydroxybutyrate, creatinine and glycoprotein acetyls (mostly alpha-1-acid glycoprotein, AGP) were significantly (p < 0.05) higher in sepsis compared to healthy sera, whereas citrate and histidine were significantly (p < 0.05) lower in sepsis patients compared to healthy controls. We found statistically significantly higher serum lactate and citrate concentrations in non-survivors compared to 30-day survivors. According to our study, 3-hydroxybutyrate, citrate, glycine, histidine, and AGP are candidates for further studies to enable identification of phenotype association in the early stages of sepsis. Full article

(This article belongs to the Special Issue Metabolomics in Clinical Research)

16 pages, 3770 KiB

Open AccessArticle

Altered Brain Metabolome Is Associated with Memory Impairment in the rTg4510 Mouse Model of Tauopathy

by Mireia Tondo, Brandi Wasek, Joan Carles Escola-Gil, David de Gonzalo-Calvo, Clinton Harmon, Erland Arning and Teodoro Bottiglieri

Metabolites 2020, 10(2), 69; https://doi.org/10.3390/metabo10020069 - 14 Feb 2020

Cited by 11 | Viewed by 3124

Abstract

Alzheimer’s disease (AD) is characterized, amongst other features, by the pathologic accumulation of abnormally phosphorylated tau filaments in neurons that lead to neurofibrillary tangles. However, the molecular mechanisms by which the abnormal processing of tau leads to neurodegeneration and cognitive impairment remain unknown. [...] Read more.

Alzheimer’s disease (AD) is characterized, amongst other features, by the pathologic accumulation of abnormally phosphorylated tau filaments in neurons that lead to neurofibrillary tangles. However, the molecular mechanisms by which the abnormal processing of tau leads to neurodegeneration and cognitive impairment remain unknown. Metabolomic techniques can comprehensively assess disturbances in metabolic pathways that reflect changes downstream from genomic, transcriptomic and proteomic systems. In the present study, we undertook a targeted metabolomic approach to determine a total of 187 prenominated metabolites in brain cortex tissue from wild type and rTg4510 animals (a mice model of tauopathy), in order to establish the association of metabolic pathways with cognitive impairment. This targeted metabolomic approach revealed significant differences in metabolite concentrations of transgenic mice. Brain glutamine, serotonin and sphingomyelin C18:0 were found to be predictors of memory impairment. These findings provide informative data for future research on AD, since some of them agree with pathological alterations observed in diseased humans. Full article

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20 pages, 3775 KiB

Open AccessArticle

Metabolite and Phytohormone Profiling Illustrates Metabolic Reprogramming as an Escape Strategy of Deepwater Rice during Partially Submerged Stress

by Atsushi Fukushima, Takeshi Kuroha, Keisuke Nagai, Yoko Hattori, Makoto Kobayashi, Tomoko Nishizawa, Mikiko Kojima, Yoshinori Utsumi, Akira Oikawa, Motoaki Seki, Hitoshi Sakakibara, Kazuki Saito, Motoyuki Ashikari and Miyako Kusano

Metabolites 2020, 10(2), 68; https://doi.org/10.3390/metabo10020068 - 14 Feb 2020

Cited by 18 | Viewed by 4716

Abstract

Rice varieties that can survive under submergence conditions respond to flooding either by enhancing internode elongation or by quiescence of shoot elongation. Despite extensive efforts to identify key metabolites triggered by complete submergence of rice possessing SUBMERGENCE 1 (SUB1) locus, metabolic [...] Read more.

Rice varieties that can survive under submergence conditions respond to flooding either by enhancing internode elongation or by quiescence of shoot elongation. Despite extensive efforts to identify key metabolites triggered by complete submergence of rice possessing SUBMERGENCE 1 (SUB1) locus, metabolic responses of internode elongation of deepwater rice governed by the SNORKEL 1 and 2 genes remain elusive. This study investigated specific metabolomic responses under partial submergence (PS) to deepwater- (C9285) and non-deepwater rice cultivars (Taichung 65 (T65)). In addition, we examined the response in a near-isogenic line (NIL-12) that has a C9285 genomic fragment on chromosome 12 introgressed into the genetic background of T65. Under short-term submergence (0–24 h), metabolite profiles of C9285, NIL-12, and T65 were compared to extract significantly changed metabolites in deepwater rice under PS conditions. Comprehensive metabolite and phytohormone profiling revealed increases in metabolite levels in the glycolysis pathway in NIL-12 plants. Under long-term submergence (0–288 h), we found decreased amino acid levels. These metabolomic changes were opposite when compared to those in flood-tolerant rice with SUB1 locus. Auxin conjugate levels related to stress response decreased in NIL-12 lines relative to T65. Our analysis helped clarify the complex metabolic reprogramming in deepwater rice as an escape strategy. Full article

(This article belongs to the Special Issue Plant Metabolomics)

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17 pages, 2156 KiB

Open AccessArticle

Lipidomic Analysis of Cells and Extracellular Vesicles from High- and Low-Metastatic Triple-Negative Breast Cancer

by Nao Nishida-Aoki, Yoshihiro Izumi, Hiroaki Takeda, Masatomo Takahashi, Takahiro Ochiya and Takeshi Bamba

Metabolites 2020, 10(2), 67; https://doi.org/10.3390/metabo10020067 - 13 Feb 2020

Cited by 58 | Viewed by 6188

Abstract

Extracellular vesicles (EVs) are lipid bilayer nanovesicles secreted from almost all cells including cancer. Cancer-derived EVs contribute to cancer progression and malignancy via educating the surrounding normal cells. In breast cancer, epidemiological and experimental observations indicated that lipids are associated with cancer malignancy. [...] Read more.

Extracellular vesicles (EVs) are lipid bilayer nanovesicles secreted from almost all cells including cancer. Cancer-derived EVs contribute to cancer progression and malignancy via educating the surrounding normal cells. In breast cancer, epidemiological and experimental observations indicated that lipids are associated with cancer malignancy. However, lipid compositions of breast cancer EVs and their contributions to cancer progression are unexplored. In this study, we performed a widely targeted quantitative lipidomic analysis in cells and EVs derived from high- and low-metastatic triple-negative breast cancer cell lines, using supercritical fluid chromatography fast-scanning triple-quadrupole mass spectrometry. We demonstrated the differential lipid compositions between EVs and cells of their origin, and between high- and low-metastatic cell lines. Further, we demonstrated EVs from highly metastatic breast cancer accumulated unsaturated diacylglycerols (DGs) compared with EVs from lower-metastatic cells, without increasing the amount in cells. The EVs enriched with DGs could activate the protein kinase D signaling pathway in endothelial cells, which can lead to stimulated angiogenesis. Our results indicate that lipids are selectively loaded into breast cancer EVs to support tumor progression. Full article

(This article belongs to the Special Issue Intercellular Metabolome)

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14 pages, 740 KiB

Open AccessProtocol

EFMviz: A COBRA Toolbox Extension to Visualize Elementary Flux Modes in Genome-Scale Metabolic Models

by Chaitra Sarathy, Martina Kutmon, Michael Lenz, Michiel E. Adriaens, Chris T. Evelo and Ilja C.W. Arts

Metabolites 2020, 10(2), 66; https://doi.org/10.3390/metabo10020066 - 12 Feb 2020

Cited by 7 | Viewed by 5983

Abstract

Elementary Flux Modes (EFMs) are a tool for constraint-based modeling and metabolic network analysis. However, systematic and automated visualization of EFMs, capable of integrating various data types is still a challenge. In this study, we developed an extension for the widely adopted COBRA [...] Read more.

Elementary Flux Modes (EFMs) are a tool for constraint-based modeling and metabolic network analysis. However, systematic and automated visualization of EFMs, capable of integrating various data types is still a challenge. In this study, we developed an extension for the widely adopted COBRA Toolbox, EFMviz, for analysis and graphical visualization of EFMs as networks of reactions, metabolites and genes. The analysis workflow offers a platform for EFM visualization to improve EFM interpretability by connecting COBRA toolbox with the network analysis and visualization software Cytoscape. The biological applicability of EFMviz is demonstrated in two use cases on medium (Escherichia coli, iAF1260) and large (human, Recon 2.2) genome-scale metabolic models. EFMviz is open-source and integrated into COBRA Toolbox. The analysis workflows used for the two use cases are detailed in the two tutorials provided with EFMviz along with the data used in this study. Full article

(This article belongs to the Special Issue Metabolic Networks)

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15 pages, 2525 KiB

Open AccessArticle

In Vivo Rate of Formaldehyde Condensation with Tetrahydrofolate

by Hai He, Elad Noor, Perla A. Ramos-Parra, Liliana E. García-Valencia, Jenelle A. Patterson, Rocío I. Díaz de la Garza, Andrew D. Hanson and Arren Bar-Even

Metabolites 2020, 10(2), 65; https://doi.org/10.3390/metabo10020065 - 12 Feb 2020

Cited by 15 | Viewed by 4854

Abstract

Formaldehyde is a highly reactive compound that participates in multiple spontaneous reactions, but these are mostly deleterious and damage cellular components. In contrast, the spontaneous condensation of formaldehyde with tetrahydrofolate (THF) has been proposed to contribute to the assimilation of this intermediate during [...] Read more.

Formaldehyde is a highly reactive compound that participates in multiple spontaneous reactions, but these are mostly deleterious and damage cellular components. In contrast, the spontaneous condensation of formaldehyde with tetrahydrofolate (THF) has been proposed to contribute to the assimilation of this intermediate during growth on C₁ carbon sources such as methanol. However, the in vivo rate of this condensation reaction is unknown and its possible contribution to growth remains elusive. Here, we used microbial platforms to assess the rate of this condensation in the cellular environment. We constructed Escherichia coli strains lacking the enzymes that naturally produce 5,10-methylene-THF. These strains were able to grow on minimal medium only when equipped with a sarcosine (N-methyl-glycine) oxidation pathway that sustained a high cellular concentration of formaldehyde, which spontaneously reacts with THF to produce 5,10-methylene-THF. We used flux balance analysis to derive the rate of the spontaneous condensation from the observed growth rate. According to this, we calculated that a microorganism obtaining its entire biomass via the spontaneous condensation of formaldehyde with THF would have a doubling time of more than three weeks. Hence, this spontaneous reaction is unlikely to serve as an effective route for formaldehyde assimilation. Full article

(This article belongs to the Special Issue Metabolic Engineering and Synthetic Biology Volume 2)

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13 pages, 2231 KiB

Open AccessArticle

Seminal Fluid Metabolomic Markers of Oligozoospermic Infertility in Humans

by Federica Murgia, Valentina Corda, Marianna Serrenti, Valeria Usai, Maria Laura Santoru, K. Joseph Hurt, Mauro Passaretti, Maria Carla Monni, Luigi Atzori and Giovanni Monni

Metabolites 2020, 10(2), 64; https://doi.org/10.3390/metabo10020064 - 11 Feb 2020

Cited by 38 | Viewed by 4064

Abstract

Infertility affects 12–15% of couples worldwide, and male factors are the cause of nearly half of all cases. Studying seminal fluid composition could lead to additional diagnostic accuracy and a better understanding of the pathophysiology of male factor infertility. Metabolomics offers a new [...] Read more.

Infertility affects 12–15% of couples worldwide, and male factors are the cause of nearly half of all cases. Studying seminal fluid composition could lead to additional diagnostic accuracy and a better understanding of the pathophysiology of male factor infertility. Metabolomics offers a new opportunity to evaluate biomarkers and better understand pathological mechanisms. The aim of the study was to identify new markers or therapeutic targets to improve outcomes in male factor or idiopathic infertility patients. Semen samples were obtained from 29 men with a normal spermogram test, and from 18 oligozoospermic men. Samples were processed and analyzed by Nuclear Magnetic Resonance spectroscopy and, subsequently, multivariate and univariate statistical analyses. Receiving Operator Curves (ROC) and Spearman correlations were also performed. An Orthogonal Partial Least Square Discriminant Analysis supervised multivariate model was devised to compare the groups. The levels of fructose, myo-inositol, aspartate and choline were altered. Moreover, Spearman Correlation associated fructose, aspartate and myo-inositol with the total amount of spermatozoa, total motile spermatozoa, % of immotility and % of “in situ” spermatozoic motility respectively. NMR-based metabolomics allowed the identification of a specific metabolic fingerprint of the seminal fluids of patients affected by oligozoospermia. Full article

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12 pages, 1425 KiB

Open AccessArticle

Gut Microbiota Is the Key to the Antidepressant Effect of Chaihu-Shu-Gan-San

by Meng Yu, Hong-Mei Jia, Tao Zhang, Hai Shang, Hong-Wu Zhang, Li-Yan Ma and Zhong-Mei Zou

Metabolites 2020, 10(2), 63; https://doi.org/10.3390/metabo10020063 - 10 Feb 2020

Cited by 11 | Viewed by 3449

Abstract

Accumulating evidence highlights the link between gut microbiota and depression. As an antidepressant herbal drug in clinic, Chaihu-Shu-Gan-San (CSGS) has also been used in China for the treatment of various gastrointestinal disorders. Therefore, we hypothesize that the gut microbiota might be involved in [...] Read more.

Accumulating evidence highlights the link between gut microbiota and depression. As an antidepressant herbal drug in clinic, Chaihu-Shu-Gan-San (CSGS) has also been used in China for the treatment of various gastrointestinal disorders. Therefore, we hypothesize that the gut microbiota might be involved in the effect of CSGS. Here, we investigated the antidepressant effects of CSGS against chronic variable stress (CVS)-induced depression rats with and without antibiotic treatment using 16S rRNA gene sequencing and ultra-performance liquid chromatography coupled with time of flight mass spectrometry (UPLC-Q-TOF/MS) based metabolomics approaches. As a result, the prominent effects of CSGS against the depression-like behavioral disorder of CVS-induced rats were significantly weakened when the gut microbiota was changed after oral administration of the broad-spectrum antibiotic. The mediation of CSGS on hippocampal levels of serotonin (5-HT) and glutamic acid (Glu) was also receded with the antibiotic treatment. Further investigation on the diversity of microbiome indicated that the improvement effect of CSGS on gut microbiota dysbiosis—especially the phylum level of Firmicutes—was attenuated after the CSGS combined antibiotic treatment. Moreover, 3-hydroxypicolinic acid (H4) and inosine (H8) in the hippocampus were considered as important biomarkers for depression and are also associated with gut microbiota mediated CSGS efficacy. Taken together, our current study indicated that gut microbiota is a critical factor in the antidepressant effect of CSGS, which improve depression-related metabolic disturbance partly through gut microbiota. Full article

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

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11 pages, 1442 KiB

Open AccessArticle

Use of Chemometrics for Correlating Carobs Nutritional Compositional Values with Geographic Origin

by Rebecca Kokkinofta, Stelios Yiannopoulos, Marinos A. Stylianou and Agapios Agapiou

Metabolites 2020, 10(2), 62; https://doi.org/10.3390/metabo10020062 - 10 Feb 2020

Cited by 11 | Viewed by 2942

Abstract

Carobs unique compositional and biological synthesis enables their characterization as functional foods. In the present study, 76 samples derived from fruit and seeds of carobs, with origin from the countries of the Mediterranean region (Cyprus, Greece, Italy, Spain, Turkey, Jordan and Palestine) were [...] Read more.

Carobs unique compositional and biological synthesis enables their characterization as functional foods. In the present study, 76 samples derived from fruit and seeds of carobs, with origin from the countries of the Mediterranean region (Cyprus, Greece, Italy, Spain, Turkey, Jordan and Palestine) were analyzed for their nutritional composition, in order to identify potential markers for their provenance and address the carobs’ authenticity issue. Moisture, ash, fat, proteins, sugars (fructose, glucose, sucrose), dietary fibers and minerals (Ca, K, Mg, Na, P, Cu, Fe, Mn, Zn) were estimated following official methods. Due to the large number of data (76 samples × 17 parameters × 7 countries), chemometric techniques were employed to process them and extract conclusions. The samples of different geographical origin were discriminated with 79% success in total. The carobs from Cyprus, Italy and Spain were correctly classified without error. The main discriminators were found to be the dietary fibers, the carbohydrates and Cu, Zn and Mn, which emphasize their specific nutritional added value to the product and the country of origin impact. The results suggest that the proposed analytical approach is a powerful tool that enables the discrimination of carobs based on their country of origin. This research contributes to authenticity of carobs, adding value to local products. Full article

(This article belongs to the Special Issue Metabolomics Methodologies and Applications)

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11 pages, 282 KiB

Open AccessArticle

Association of Circulating COMP and YKL-40 as Markers of Metabolic Changes of Cartilage with Adipocytokines in Juvenile Idiopathic Arthritis

by Katarzyna Winsz-Szczotka, Kornelia Kuźnik-Trocha, Anna Gruenpeter, Magdalena Wojdas, Klaudia Dąbkowska and Krystyna Olczyk

Metabolites 2020, 10(2), 61; https://doi.org/10.3390/metabo10020061 - 10 Feb 2020

Cited by 5 | Viewed by 2341

Abstract

The aim of this study was to evaluate the association of circulating cartilage oligomeric matrix protein (COMP) and human cartilage glycoprotein-39 (YKL-40) as markers of metabolic changes of cartilage, with leptin, adiponectin, and resistin in juvenile idiopathic arthritis (JIA) patients before and after [...] Read more.

The aim of this study was to evaluate the association of circulating cartilage oligomeric matrix protein (COMP) and human cartilage glycoprotein-39 (YKL-40) as markers of metabolic changes of cartilage, with leptin, adiponectin, and resistin in juvenile idiopathic arthritis (JIA) patients before and after treatment. A significant decrease of COMP and an increase of YKL-4 were found in blood of untreated patients. JIA treatment leading to clinical improvement resulted in normalization of COMP levels only. Concentrations of both markers in treated patients, while showing no clinical improvement, differed from those in controls and patients with remission. The leptin level decreased (p < 0.05) in untreated patients; however, concentrations of adiponectin and resistin increased (p < 0.05) as compared to controls. JIA treatment resulted in normalization of adipocytokine levels in remissive patients but not those with active JIA. Untreated patients showed a correlation between COMP and leptin, adiponectin, and body mass index (BMI) and between YKL-40 and leptin, adiponectin, BMI, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). In inactive JIA, a correlation between YKL-40 and leptin was shown. Treated patients with an active JIA demonstrated a correlation between COMP and adiponectin and between YKL-40 and leptin, adiponectin, BMI, CRP, and ESR. The results of this work indicate that leptin and adiponectin but not resistin may be involved in the development and progression of joint dysfunction in JIA. Additionally, we suggest that YKL-40 may be a useful biomarker of disease activity and may be used to assess treatment towards remission, as compared to COMP. Full article

(This article belongs to the Special Issue Metabolomics Analysis for Biomarker Discovery and Human Health)

15 pages, 16697 KiB

Open AccessArticle

Systemic Effects of Radiotherapy and Concurrent Chemo-Radiotherapy in Head and Neck Cancer Patients—Comparison of Serum Metabolome Profiles

by Karol Jelonek, Aleksandra Krzywon, Patrycja Jablonska, Ewa M. Slominska, Ryszard T. Smolenski, Joanna Polanska, Tomasz Rutkowski, Jolanta Mrochem-Kwarciak, Krzysztof Skladowski and Piotr Widlak

Metabolites 2020, 10(2), 60; https://doi.org/10.3390/metabo10020060 - 7 Feb 2020

Cited by 19 | Viewed by 3442

Abstract

Anticancer treatment induces systemic molecular changes that could be detected at the level of biofluids. Understanding how human metabolism is influenced by these treatments is crucial to predict the individual response and adjust personalized therapies. Here, we aimed to compare profiles of metabolites [...] Read more.

Anticancer treatment induces systemic molecular changes that could be detected at the level of biofluids. Understanding how human metabolism is influenced by these treatments is crucial to predict the individual response and adjust personalized therapies. Here, we aimed to compare profiles of metabolites in serum of head and neck cancer patients treated with concurrent chemo-radiotherapy, radiotherapy alone, or induction chemotherapy. Serum samples were analyzed by a targeted quantitative approach using combined direct flow injection and liquid chromatography coupled to tandem mass spectrometry, which allowed simultaneous quantification of 149 metabolites. There were 45 metabolites whose levels were significantly changed between pretreatment and within- or post-treatment serum samples, including 38 phospholipids. Concurrent chemo-radiotherapy induced faster and stronger effects than radiotherapy alone. On the other hand, chemotherapy alone did not result in significant changes. The decreased level of total phospholipids was the most apparent effect observed during the first step of the treatment. This corresponded to the loss of patients’ body mass, yet no correlation between both parameters was observed for individual patients. We concluded that different molecular changes were measured at the level of serum metabolome in response to different treatment modalities. Full article

(This article belongs to the Special Issue Metabolomics/Lipidomics in Radiation Research)

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19 pages, 15696 KiB

Open AccessArticle

TGF-ß1 Induces Changes in the Energy Metabolism of White Adipose Tissue-Derived Human Adult Mesenchymal Stem/Stromal Cells In Vitro

by Olga Hahn, Lena-Christin Ingwersen, Abdelrahman Soliman, Mohamed Hamed, Georg Fuellen, Markus Wolfien, Julia Scheel, Olaf Wolkenhauer, Dirk Koczan, Günter Kamp and Kirsten Peters

Metabolites 2020, 10(2), 59; https://doi.org/10.3390/metabo10020059 - 7 Feb 2020

Cited by 6 | Viewed by 3680

Abstract

Adipose tissue plays an active role in the regulation of the body’s energy balance. Mesenchymal stem/stromal cells from adipose tissue (adMSC) are the precursor cells for repair and adipogenesis. Since the balance of the differentiation state of adipose tissue-resident cells is associated with [...] Read more.

Adipose tissue plays an active role in the regulation of the body’s energy balance. Mesenchymal stem/stromal cells from adipose tissue (adMSC) are the precursor cells for repair and adipogenesis. Since the balance of the differentiation state of adipose tissue-resident cells is associated with the development of various diseases, the examination of the regulation of proliferation and differentiation of adMSC might provide new therapeutic targets. Transforming growth factor-β1 (TGF-ß1) is synthetized by many cell types and is involved in various biological processes. Here, we investigated the effects of different concentrations of TGF-ß1 (1–10 ng/mL) on adMSC proliferation, metabolic activity, and analyzed the gene expression data obtained from DNA microarrays by bioinformatics. TGF-ß1 induced the concentration- and time-dependent increase in the cell number of adMSC with simultaneously unchanged cell cycle distributions. The basal oxygen consumption rates did not change significantly after TGF-ß1 exposure. However, glycolytic activity was significantly increased. The gene expression analysis identified 3275 differentially expressed genes upon exposure to TGF-ß1. According to the pathway enrichment analyses, they also included genes associated with energy metabolism. Thus, it was shown that TGF-ß1 induces changes in the energy metabolism of adMSC. Whether these effects are of relevance in vivo and whether they contribute to pathogenesis should be addressed in further examinations. Full article

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

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10 pages, 1060 KiB

Open AccessArticle

Selection for Growth and Precocity Alters Muscle Metabolism in Nellore Cattle

by Nara Regina Brandão Cônsolo, Juliana da Silva, Vicente Luiz Macedo Buarque, Angel Higuera-Padilla, Luis Carlos Garibaldi Simon Barbosa, Andressa Zawadzki, Luis Alberto Colnago, Arlindo Saran Netto, David Edwin Gerrard and Saulo Luz Silva

Metabolites 2020, 10(2), 58; https://doi.org/10.3390/metabo10020058 - 6 Feb 2020

Cited by 23 | Viewed by 3242

Abstract

To clarify the relationship between beef genetic selection for growth and precocity with muscle metabolism and metabolites, we performed metabolomic analysis using Longissimus lumborum (LL) muscle from Nellore cattle with divergent selection for these traits (high growth, HG; low growth, LG; high precocity, [...] Read more.

To clarify the relationship between beef genetic selection for growth and precocity with muscle metabolism and metabolites, we performed metabolomic analysis using Longissimus lumborum (LL) muscle from Nellore cattle with divergent selection for these traits (high growth, HG; low growth, LG; high precocity, HP; low precocity, LP). Genetic potential for growth affected muscle protein and energetic metabolism. HG animals had a high concentration of arginine, carnosine, and leucine compared to LG animals. HP animals presented a high concentration of glutamine, betaine, creatinine, isoleucine, carnitine, acetyl carnitine, and lower levels of glucose compared to LP animals, affecting protein and fatty acid metabolism. Intensity of selection (high or low) was correlated with changes in protein metabolism, and the type of selection (growth or precocity) affected fat metabolism. In conclusion, both HG and HP appear to be correlated with a high concentration of protein metabolites and changes in protein metabolic pathways, while selection for precocity is more correlated with changes in fat metabolism compared to animals selected for growth. Full article

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17 pages, 1747 KiB

Open AccessArticle

Background Diet Influences TMAO Concentrations Associated with Red Meat Intake without Influencing Apparent Hepatic TMAO-Related Activity in a Porcine Model

by Rebekka Thøgersen, Martin Krøyer Rasmussen, Ulrik K. Sundekilde, Sophie A. Goethals, Thomas Van Hecke, Els Vossen, Stefaan De Smet and Hanne Christine Bertram

Metabolites 2020, 10(2), 57; https://doi.org/10.3390/metabo10020057 - 6 Feb 2020

Cited by 21 | Viewed by 4556

Abstract

Red meat has been associated with an increased cardiovascular disease (CVD) risk, possibly through gut microbial-derived trimethylamine-N-oxide (TMAO). However, previous reports are conflicting, and influences from the background diet may modulate the impact of meat consumption. This study investigated the effect of red [...] Read more.

Red meat has been associated with an increased cardiovascular disease (CVD) risk, possibly through gut microbial-derived trimethylamine-N-oxide (TMAO). However, previous reports are conflicting, and influences from the background diet may modulate the impact of meat consumption. This study investigated the effect of red and white meat intake combined with two different background diets on urinary TMAO concentration and its association with the colon microbiome in addition to apparent hepatic TMAO-related activity. For 4 weeks, 32 pigs were fed chicken or red and processed meat combined with a prudent or western background diet. ¹H NMR-based metabolomics analysis was conducted on urine samples and hepatic Mrna expression of TMAO-related genes determined. Lower urinary TMAO concentrations were observed after intake of red and processed meat when consumed with a prudent compared to a western background diet. In addition, correlation analyses between urinary TMAO concentrations and relative abundance of colon bacterial groups suggested an association between TMAO and specific bacterial taxa. Diet did not affect the hepatic Mrna expression of genes related to TMAO formation. The results suggest that meat-induced TMAO formation is regulated by mechanisms other than alterations at the hepatic gene expression level, possibly involving modulations of the gut microbiota. Full article

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21 pages, 5346 KiB

Open AccessArticle

Self-Redirection of Metabolic Flux toward Squalene and Ethanol Pathways by Engineered Yeast

by Robina Manzoor, Maqbool Ahmed, Naveeda Riaz, Bushra Hafeez Kiani, Ullah Kaleem, Yasmeen Rashid, Ali Nawaz, Muhammad Umer Farooq Awan, Hooria Khan, Umera Imtiaz, Yasir Rasheed, Imdad Kaleem and Aamir Rasool

Metabolites 2020, 10(2), 56; https://doi.org/10.3390/metabo10020056 - 1 Feb 2020

Cited by 5 | Viewed by 3772

Abstract

We have previously reported that squalene overproducing yeast self-downregulate the expression of the ethanol pathway (non-essential pathway) to divert the metabolic flux to the squalene pathway. In this study, the effect of co-production of squalene and ethanol on other non-essential pathways (fusel alcohol [...] Read more.

We have previously reported that squalene overproducing yeast self-downregulate the expression of the ethanol pathway (non-essential pathway) to divert the metabolic flux to the squalene pathway. In this study, the effect of co-production of squalene and ethanol on other non-essential pathways (fusel alcohol pathway, FA) of Saccharomyces cerevisiae was evaluated. However, before that, 13 constitutive promoters, like IRA1p, PET9p, RHO1p, CMD1p, ATP16p, USA3p, RER2p, COQ1p, RIM1p, GRS1p, MAK5p, and BRN1p, were engineered using transcription factor bindings sites from strong promoters HHF2p (−300 to −669 bp) and TEF1p (−300 to −579 bp), and employed to co-overexpress squalene and ethanol pathways in S. cerevisiae. The FSE strain overexpressing the key genes of the squalene pathway accumulated 56.20 mg/L squalene, a 16.43-fold higher than wild type strain (WS). The biogenesis of lipid droplets was stimulated by overexpressing DGA1 and produced 106 mg/L squalene in the FSE strain. AFT1p and CTR1p repressible promoters were also characterized and employed to downregulate the expression of ERG1, which also enhanced the production of squalene in FSE strain up to 42.85- (148.67 mg/L) and 73.49-fold (255.11 mg/L) respectively. The FSE strain was further engineered by overexpressing the key genes of the ethanol pathway and produced 40.2 mg/mL ethanol in the FSE1 strain, 3.23-fold higher than the WS strain. The FSE1 strain also self-downregulated the expression of the FA pathway up to 73.9%, perhaps by downregulating the expression of GCN4 by 2.24-fold. We demonstrate the successful tuning of the strength of yeast promoters and highest coproduction of squalene and ethanol in yeast, and present GCN4 as a novel metabolic regulator that can be manipulated to divert the metabolic flux from the non-essential pathway to engineered pathways. Full article

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13 pages, 1648 KiB

Open AccessArticle

Identification of the Main Metabolites of a Marine-Derived Strain of Penicillium brevicompactum Using LC and GC MS Techniques

by Francesco Vinale, Maria Michela Salvatore, Rosario Nicoletti, Alessia Staropoli, Gelsomina Manganiello, Tommaso Venneri, Francesca Borrelli, Marina DellaGreca, Francesco Salvatore and Anna Andolfi

Metabolites 2020, 10(2), 55; https://doi.org/10.3390/metabo10020055 - 30 Jan 2020

Cited by 13 | Viewed by 3292

Abstract

Marine-derived fungi are an important source of many valuable compounds with original structures and diverse physico-chemical properties. In this work, the metabolomic profile of a strain of Penicillium brevicompactum, recovered from a snakelocks sea anemone (Anemonia sulcata), was investigated through [...] Read more.

Marine-derived fungi are an important source of many valuable compounds with original structures and diverse physico-chemical properties. In this work, the metabolomic profile of a strain of Penicillium brevicompactum, recovered from a snakelocks sea anemone (Anemonia sulcata), was investigated through the parallel application of LC-ESI-HRMS, GC-MS, and NMR. Our strategy allowed the identification of mycophenolic acid, brevianamide A, and several compounds belonging to the thiosilvatins. Among the latter, five products are reported for the first time in this species. The main product of this series, cis-bis(methylthio)silvatin, was also tested for antiproliferative activity on both cancer and non-tumoral colon cell lines. Full article

(This article belongs to the Special Issue Metabolomics in Multicomponent Interactions)

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10 pages, 1617 KiB

Open AccessArticle

General Guidelines for Sample Preparation Strategies in HR-µMAS NMR-based Metabolomics of Microscopic Specimens

by Covadonga Lucas-Torres, Thierry Bernard, Gaspard Huber, Patrick Berthault, Yusuke Nishiyama, Pancham S. Kandiyal, Bénédicte Elena-Herrmann, Laurent Molin, Florence Solari, Anne-Karine Bouzier-Sore and Alan Wong

Metabolites 2020, 10(2), 54; https://doi.org/10.3390/metabo10020054 - 30 Jan 2020

Cited by 11 | Viewed by 4019

Abstract

The study of the metabolome within tissues, organisms, cells or biofluids can be carried out by several bioanalytical techniques. Among them, nuclear magnetic resonance (NMR) is one of the principal spectroscopic methods. This is due to a sample rotation technique, high-resolution magic angle [...] Read more.

The study of the metabolome within tissues, organisms, cells or biofluids can be carried out by several bioanalytical techniques. Among them, nuclear magnetic resonance (NMR) is one of the principal spectroscopic methods. This is due to a sample rotation technique, high-resolution magic angle spinning (HR-MAS), which targets the analysis of heterogeneous specimens with a bulk sample mass from 5 to 10 mg. Recently, a new approach, high-resolution micro-magic angle spinning (HR-μMAS), has been introduced. It opens, for the first time, the possibility of investigating microscopic specimens (<500 μg) with NMR spectroscopy, strengthening the concept of homogeneous sampling in a heterogeneous specimen. As in all bioanalytical approaches, a clean and reliable sample preparation strategy is a significant component in designing metabolomics (or -omics, in general) studies. The sample preparation for HR-μMAS is consequentially complicated by the μg-scale specimen and has yet to be addressed. This report details the strategies for three specimen types: biofluids, fluid matrices and tissues. It also provides the basis for designing future μMAS NMR studies of microscopic specimens. Full article

(This article belongs to the Special Issue Sample Preparation in Metabolomics)

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14 pages, 1858 KiB

Open AccessArticle

Metabolomic Profiling of Wildtype and Transgenic Giardia lamblia Strains by ¹H HR-MAS NMR Spectroscopy

by Joachim Müller, Martina Vermathen, David Leitsch, Peter Vermathen and Norbert Müller

Metabolites 2020, 10(2), 53; https://doi.org/10.3390/metabo10020053 - 30 Jan 2020

Cited by 6 | Viewed by 3657

Abstract

Giardia lamblia, a causative agent of persistent diarrhea in humans, domestic animals, and cattle, is usually treated with nitro compounds. Consequently, enzymes involved in anaerobic nitro reduction have been investigated in detail as potential targets. Their role within the normal metabolic context [...] Read more.

Giardia lamblia, a causative agent of persistent diarrhea in humans, domestic animals, and cattle, is usually treated with nitro compounds. Consequently, enzymes involved in anaerobic nitro reduction have been investigated in detail as potential targets. Their role within the normal metabolic context is, however, not understood. Using ¹H high-resolution magic angle spinning (HR-MAS) NMR spectroscopy, we analyzed the metabolomes of G. lamblia trophozoites overexpressing three nitroreductases (NR1–NR3) and thioredoxin reductase (TrxR), most likely a scavenger of reactive oxygen species, as suggested by the results published in this study. We compared the patterns to convenient controls and to the situation in the nitro drug resistant strain C4 where NR1 is downregulated. We identified 27 metabolites in G. lamblia trophozoites. Excluding metabolites of high variability among different wildtype populations, only trophozoites overexpressing NR1 presented a distinct pattern of nine metabolites, in particular arginine catabolites, differing from the respective controls. This pattern matched a differential pattern between wildtype and strain C4. This suggests that NR1 interferes with arginine and thus energy metabolism. The exact metabolic function of NR1 (and the other nitroreductases) remains to be elucidated. Full article

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23 pages, 1227 KiB

Open AccessEditor’s ChoiceReview

Metabolomics as an Emerging Tool for the Study of Plant–Pathogen Interactions

by Fernanda R. Castro-Moretti, Irene N. Gentzel, David Mackey and Ana P. Alonso

Metabolites 2020, 10(2), 52; https://doi.org/10.3390/metabo10020052 - 29 Jan 2020

Cited by 143 | Viewed by 13122

Abstract

Plants defend themselves from most microbial attacks via mechanisms including cell wall fortification, production of antimicrobial compounds, and generation of reactive oxygen species. Successful pathogens overcome these host defenses, as well as obtain nutrients from the host. Perturbations of plant metabolism play a [...] Read more.

Plants defend themselves from most microbial attacks via mechanisms including cell wall fortification, production of antimicrobial compounds, and generation of reactive oxygen species. Successful pathogens overcome these host defenses, as well as obtain nutrients from the host. Perturbations of plant metabolism play a central role in determining the outcome of attempted infections. Metabolomic analyses, for example between healthy, newly infected and diseased or resistant plants, have the potential to reveal perturbations to signaling or output pathways with key roles in determining the outcome of a plant–microbe interaction. However, application of this -omic and its tools in plant pathology studies is lagging relative to genomic and transcriptomic methods. Thus, it is imperative to bring the power of metabolomics to bear on the study of plant resistance/susceptibility. This review discusses metabolomics studies that link changes in primary or specialized metabolism to the defense responses of plants against bacterial, fungal, nematode, and viral pathogens. Also examined are cases where metabolomics unveils virulence mechanisms used by pathogens. Finally, how integrating metabolomics with other -omics can advance plant pathology research is discussed. Full article

(This article belongs to the Special Issue Metabolomic and Flux Analysis in Plants)

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28 pages, 1201 KiB

Open AccessReview

Toward a Standardized Strategy of Clinical Metabolomics for the Advancement of Precision Medicine

by Nguyen Phuoc Long, Tran Diem Nghi, Yun Pyo Kang, Nguyen Hoang Anh, Hyung Min Kim, Sang Ki Park and Sung Won Kwon

Metabolites 2020, 10(2), 51; https://doi.org/10.3390/metabo10020051 - 29 Jan 2020

Cited by 54 | Viewed by 9456

Abstract

Despite the tremendous success, pitfalls have been observed in every step of a clinical metabolomics workflow, which impedes the internal validity of the study. Furthermore, the demand for logistics, instrumentations, and computational resources for metabolic phenotyping studies has far exceeded our expectations. In [...] Read more.

Despite the tremendous success, pitfalls have been observed in every step of a clinical metabolomics workflow, which impedes the internal validity of the study. Furthermore, the demand for logistics, instrumentations, and computational resources for metabolic phenotyping studies has far exceeded our expectations. In this conceptual review, we will cover inclusive barriers of a metabolomics-based clinical study and suggest potential solutions in the hope of enhancing study robustness, usability, and transferability. The importance of quality assurance and quality control procedures is discussed, followed by a practical rule containing five phases, including two additional “pre-pre-” and “post-post-” analytical steps. Besides, we will elucidate the potential involvement of machine learning and demonstrate that the need for automated data mining algorithms to improve the quality of future research is undeniable. Consequently, we propose a comprehensive metabolomics framework, along with an appropriate checklist refined from current guidelines and our previously published assessment, in the attempt to accurately translate achievements in metabolomics into clinical and epidemiological research. Furthermore, the integration of multifaceted multi-omics approaches with metabolomics as the pillar member is in urgent need. When combining with other social or nutritional factors, we can gather complete omics profiles for a particular disease. Our discussion reflects the current obstacles and potential solutions toward the progressing trend of utilizing metabolomics in clinical research to create the next-generation healthcare system. Full article

(This article belongs to the Special Issue 10th Anniversary of Metabolites: The Changing Landscape of Metabolomics)

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58 pages, 1598 KiB

Open AccessReview

Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy

by Diren Beyoğlu and Jeffrey R. Idle

Metabolites 2020, 10(2), 50; https://doi.org/10.3390/metabo10020050 - 28 Jan 2020

Cited by 58 | Viewed by 8936

Abstract

In recent years, there has been a plethora of attempts to discover biomarkers that are more reliable than α-fetoprotein for the early prediction and prognosis of hepatocellular carcinoma (HCC). Efforts have involved such fields as genomics, transcriptomics, epigenetics, microRNA, exosomes, proteomics, glycoproteomics, and [...] Read more.

In recent years, there has been a plethora of attempts to discover biomarkers that are more reliable than α-fetoprotein for the early prediction and prognosis of hepatocellular carcinoma (HCC). Efforts have involved such fields as genomics, transcriptomics, epigenetics, microRNA, exosomes, proteomics, glycoproteomics, and metabolomics. HCC arises against a background of inflammation, steatosis, and cirrhosis, due mainly to hepatic insults caused by alcohol abuse, hepatitis B and C virus infection, adiposity, and diabetes. Metabolomics offers an opportunity, without recourse to liver biopsy, to discover biomarkers for premalignant liver disease, thereby alerting the potential of impending HCC. We have reviewed metabolomic studies in alcoholic liver disease (ALD), cholestasis, fibrosis, cirrhosis, nonalcoholic fatty liver (NAFL), and nonalcoholic steatohepatitis (NASH). Specificity was our major criterion in proposing clinical evaluation of indole-3-lactic acid, phenyllactic acid, N-lauroylglycine, decatrienoate, N-acetyltaurine for ALD, urinary sulfated bile acids for cholestasis, cervonoyl ethanolamide for fibrosis, 16α-hydroxyestrone for cirrhosis, and the pattern of acyl carnitines for NAFL and NASH. These examples derive from a large body of published metabolomic observations in various liver diseases in adults, adolescents, and children, together with animal models. Many other options have been tabulated. Metabolomic biomarkers for premalignant liver disease may help reduce the incidence of HCC. Full article

(This article belongs to the Special Issue Metabolism and Metabolomics of Liver in Health and Disease)

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