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Metabolites, Volume 9, Issue 3 (March 2019)

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Cover Story (view full-size image) In this article, we explore the hypothesis that there are metabolic differences between children on [...] Read more.
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Open AccessArticle Metabolic Analysis of Four Cultivars of Liriope platyphylla
Metabolites 2019, 9(3), 59; https://doi.org/10.3390/metabo9030059
Received: 13 February 2019 / Revised: 23 March 2019 / Accepted: 25 March 2019 / Published: 26 March 2019
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Abstract
Liriope platyphylla (Liliaceae), a medical plant distributed mainly in China, Taiwan, and Korea, has been used traditionally for the treatment of cough, sputum, asthma, and neurodegenerative diseases. The present study involved the metabolic profiling of this plant and reports spicatoside A accumulation in [...] Read more.
Liriope platyphylla (Liliaceae), a medical plant distributed mainly in China, Taiwan, and Korea, has been used traditionally for the treatment of cough, sputum, asthma, and neurodegenerative diseases. The present study involved the metabolic profiling of this plant and reports spicatoside A accumulation in four different varieties of L. platyphylla (Cheongyangjaerae, Seongsoo, Cheongsim, and Liriope Tuber No. 1) using HPLC and gas chromatography time-of-flight mass spectrometry (GC–TOFMS). A total of 47 metabolites were detected in the different cultivars using GC–TOFMS-based metabolic profiling. The resulting data were subjected to principal component analysis (PCA) for determining the whole experimental variation, and the different cultivars were separated by score plots. Furthermore, hierarchical clustering, Pearson’s correlation, and partial least-squares discriminant analyses (PLS-DA) were subsequently performed to determine significant differences in the various metabolites of the cultivars. The HPLC data revealed that the presence of spicatoside A was detected in all four cultivars, with the amount of spicatoside A varying among them. Among the cultivars, Liriope Tuber No. 1 contained the highest amount of spicatoside A (1.83 ± 0.13 mg/g dry weight), followed by Cheongyangjaerae (1.25 ± 0.01 mg/g dry weight), Cheongsim (1.09 ± 0.04 mg/g dry weight), and Seongsoo (1.01 ± 0.02 mg/g dry weight). The identification of spicatoside A was confirmed by comparing the retention time of the sample with the retention time of the standard. Moreover, the Cheongsim cultivar contained higher levels of phenolic compounds—including vanillic acid, quinic acid, gallic acid, chlorogenic acid, caffeic acid, and benzoic acid—than those of the other two cultivars. On the other hand, the levels of amino acids were higher in the Seongsoo cultivar. Therefore, this study may help breeders produce new varieties with improved nutraceutical and nutritional qualities. Full article
(This article belongs to the Special Issue Metabolomics in Agriculture)
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Open AccessReview Non-Volatile Metabolites from Trichoderma spp.
Metabolites 2019, 9(3), 58; https://doi.org/10.3390/metabo9030058
Received: 5 March 2019 / Revised: 19 March 2019 / Accepted: 20 March 2019 / Published: 22 March 2019
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Abstract
The genus Trichoderma is comprised of many common fungi species that are distributed worldwide across many ecosystems. Trichoderma species are well-known producers of secondary metabolites with a variety of biological activities. Their potential use as biocontrol agents has been known for many years. [...] Read more.
The genus Trichoderma is comprised of many common fungi species that are distributed worldwide across many ecosystems. Trichoderma species are well-known producers of secondary metabolites with a variety of biological activities. Their potential use as biocontrol agents has been known for many years. Several reviews about metabolites from Trichoderma have been published. These reviews are based on their structural type, biological activity, or fungal origin. In this review, we summarize the secondary metabolites per Trichoderma species and elaborate on approximately 390 non-volatile compounds from 20 known species and various unidentified species. Full article
(This article belongs to the Special Issue Fungal and Mycotoxin Metabolism)
Open AccessFeature PaperArticle MetaboAnalystR 2.0: From Raw Spectra to Biological Insights
Metabolites 2019, 9(3), 57; https://doi.org/10.3390/metabo9030057
Received: 5 March 2019 / Revised: 20 March 2019 / Accepted: 21 March 2019 / Published: 22 March 2019
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Abstract
Global metabolomics based on high-resolution liquid chromatography mass spectrometry (LC-MS) has been increasingly employed in recent large-scale multi-omics studies. Processing and interpretation of these complex metabolomics datasets have become a key challenge in current computational metabolomics. Here, we introduce MetaboAnalystR 2.0 for comprehensive [...] Read more.
Global metabolomics based on high-resolution liquid chromatography mass spectrometry (LC-MS) has been increasingly employed in recent large-scale multi-omics studies. Processing and interpretation of these complex metabolomics datasets have become a key challenge in current computational metabolomics. Here, we introduce MetaboAnalystR 2.0 for comprehensive LC-MS data processing, statistical analysis, and functional interpretation. Compared to the previous version, this new release seamlessly integrates XCMS and CAMERA to support raw spectral processing and peak annotation, and also features high-performance implementations of mummichog and GSEA approaches for predictions of pathway activities. The application and utility of the MetaboAnalystR 2.0 workflow were demonstrated using a synthetic benchmark dataset and a clinical dataset. In summary, MetaboAnalystR 2.0 offers a unified and flexible workflow that enables end-to-end analysis of LC-MS metabolomics data within the open-source R environment. Full article
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Open AccessArticle Flavan-3-ols Content in Red Raspberry Leaves Increases under Blue Led-Light Irradiation
Metabolites 2019, 9(3), 56; https://doi.org/10.3390/metabo9030056
Received: 22 February 2019 / Revised: 18 March 2019 / Accepted: 20 March 2019 / Published: 21 March 2019
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Abstract
Berry fruits are well known to contain large amounts of polyphenol compounds. Among them, flavan-3-ol derivatives are a group of secondary metabolism compounds currently attracting a great deal of attention owing to their health benefits. Not only the fruits, but also the leaves [...] Read more.
Berry fruits are well known to contain large amounts of polyphenol compounds. Among them, flavan-3-ol derivatives are a group of secondary metabolism compounds currently attracting a great deal of attention owing to their health benefits. Not only the fruits, but also the leaves of raspberry plants, are highly esteemed for tea making around the world and are largely used for food. In this report, we discuss the results of our study on the effect of light and temperature on polyphenol accumulation in raspberry leaves. When raspberry was cultivated in a plant factory unit and light intensity, wavelength, and temperature were varied, the amount of total polyphenol increased under blue light. Quantitative determination of (+)-catechin, (–)-epicatechin, procyanidin B4, flavan-3-ol trimer, which are flavan-3-ol derivatives, was carried out using HPLC, whereby we confirmed their increase under blue light. Semi-quantitative RT-PCR showed correlation between chalcone synthase (CHS) gene expression and the amounts of the compounds measured in the leaves. Full article
(This article belongs to the Special Issue Natural Products Metabolomics)
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Open AccessProtocol Efficient Extraction from Mice Feces for NMR Metabolomics Measurements with Special Emphasis on SCFAs
Metabolites 2019, 9(3), 55; https://doi.org/10.3390/metabo9030055
Received: 14 January 2019 / Revised: 15 March 2019 / Accepted: 17 March 2019 / Published: 21 March 2019
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Abstract
Nuclear magnetic resonance (NMR) spectroscopy is one of the most promising methods for use in metabolomics studies as it is able to perform non targeted measurement of metabolites in a quantitative and non-destructive way. Sample preparation of liquid samples like urine or blood [...] Read more.
Nuclear magnetic resonance (NMR) spectroscopy is one of the most promising methods for use in metabolomics studies as it is able to perform non targeted measurement of metabolites in a quantitative and non-destructive way. Sample preparation of liquid samples like urine or blood serum is comparatively easy in NMR metabolomics, because mainly buffer and chemical shift reference substance are added. For solid samples like feces suitable extraction protocols need to be defined as initial step, where the exact protocol depends on sample type and features. Focusing on short chain fatty acids (SCFAs) in mice feces, we describe here a set of extraction protocols developed with the aim to suppress changes in metabolite composition within 24 h after extraction. Feces are obtained from mice fed on either standard rodent diet or high fat diet. The protocols presented in this manuscript are straightforward for application, and successfully minimize residual bacterial and enzymatic activities. Additionally, they are able to minimize the lipid background originating from the high fat diet. Full article
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Open AccessArticle Using Expert Driven Machine Learning to Enhance Dynamic Metabolomics Data Analysis
Metabolites 2019, 9(3), 54; https://doi.org/10.3390/metabo9030054
Received: 18 January 2019 / Revised: 5 March 2019 / Accepted: 18 March 2019 / Published: 20 March 2019
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Abstract
Data analysis for metabolomics is undergoing rapid progress thanks to the proliferation of novel tools and the standardization of existing workflows. As untargeted metabolomics datasets and experiments continue to increase in size and complexity, standardized workflows are often not sufficiently sophisticated. In addition, [...] Read more.
Data analysis for metabolomics is undergoing rapid progress thanks to the proliferation of novel tools and the standardization of existing workflows. As untargeted metabolomics datasets and experiments continue to increase in size and complexity, standardized workflows are often not sufficiently sophisticated. In addition, the ground truth for untargeted metabolomics experiments is intrinsically unknown and the performance of tools is difficult to evaluate. Here, the problem of dynamic multi-class metabolomics experiments was investigated using a simulated dataset with a known ground truth. This simulated dataset was used to evaluate the performance of tinderesting, a new and intuitive tool based on gathering expert knowledge to be used in machine learning. The results were compared to EDGE, a statistical method for time series data. This paper presents three novel outcomes. The first is a way to simulate dynamic metabolomics data with a known ground truth based on ordinary differential equations. This method is made available through the MetaboLouise R package. Second, the EDGE tool, originally developed for genomics data analysis, is highly performant in analyzing dynamic case vs. control metabolomics data. Third, the tinderesting method is introduced to analyse more complex dynamic metabolomics experiments. This tool consists of a Shiny app for collecting expert knowledge, which in turn is used to train a machine learning model to emulate the decision process of the expert. This approach does not replace traditional data analysis workflows for metabolomics, but can provide additional information, improved performance or easier interpretation of results. The advantage is that the tool is agnostic to the complexity of the experiment, and thus is easier to use in advanced setups. All code for the presented analysis, MetaboLouise and tinderesting are freely available. Full article
(This article belongs to the Special Issue Signal Processing and Machine Learning for Metabolomics)
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Open AccessArticle The Effect of Exercise Training on Myocardial and Skeletal Muscle Metabolism by MR Spectroscopy in Rats with Heart Failure
Metabolites 2019, 9(3), 53; https://doi.org/10.3390/metabo9030053
Received: 22 January 2019 / Revised: 12 March 2019 / Accepted: 14 March 2019 / Published: 19 March 2019
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Abstract
The metabolism and performance of myocardial and skeletal muscle are impaired in heart failure (HF) patients. Exercise training improves the performance and benefits the quality of life in HF patients. The purpose of the present study was to determine the metabolic profiles in [...] Read more.
The metabolism and performance of myocardial and skeletal muscle are impaired in heart failure (HF) patients. Exercise training improves the performance and benefits the quality of life in HF patients. The purpose of the present study was to determine the metabolic profiles in myocardial and skeletal muscle in HF and exercise training using MRS, and thus to identify targets for clinical MRS in vivo. After surgically establishing HF in rats, we randomized the rats to exercise training programs of different intensities. After the final training session, rats were sacrificed and tissues from the myocardial and skeletal muscle were extracted. Magnetic resonance spectra were acquired from these extracts, and principal component and metabolic enrichment analysis were used to assess the differences in metabolic profiles. The results indicated that HF affected myocardial metabolism by changing multiple metabolites, whereas it had a limited effect on skeletal muscle metabolism. Moreover, exercise training mainly altered the metabolite distribution in skeletal muscle, indicating regulation of metabolic pathways of taurine and hypotaurine metabolism and carnitine synthesis. Full article
(This article belongs to the Special Issue Exercise Metabonomics)
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Open AccessReview Critical Review of Volatile Organic Compound Analysis in Breath and In Vitro Cell Culture for Detection of Lung Cancer
Metabolites 2019, 9(3), 52; https://doi.org/10.3390/metabo9030052
Received: 10 January 2019 / Revised: 11 March 2019 / Accepted: 13 March 2019 / Published: 18 March 2019
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Abstract
Breath analysis is a promising technique for lung cancer screening. Despite the rapid development of breathomics in the last four decades, no consistent, robust, and validated volatile organic compound (VOC) signature for lung cancer has been identified. This review summarizes the identified VOC [...] Read more.
Breath analysis is a promising technique for lung cancer screening. Despite the rapid development of breathomics in the last four decades, no consistent, robust, and validated volatile organic compound (VOC) signature for lung cancer has been identified. This review summarizes the identified VOC biomarkers from both exhaled breath analysis and in vitro cultured lung cell lines. Both clinical and in vitro studies have produced inconsistent, and even contradictory, results. Methodological issues that lead to these inconsistencies are reviewed and discussed in detail. Recommendations on addressing specific issues for more accurate biomarker studies have also been made. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2018)
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Open AccessArticle PLS2 in Metabolomics
Metabolites 2019, 9(3), 51; https://doi.org/10.3390/metabo9030051
Received: 23 January 2018 / Revised: 4 March 2019 / Accepted: 6 March 2019 / Published: 15 March 2019
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Abstract
Metabolomics is the systematic study of the small-molecule profiles of biological samples produced by specific cellular processes. The high-throughput technologies used in metabolomic investigations generate datasets where variables are strongly correlated and redundancy is present in the data. Discovering the hidden information is [...] Read more.
Metabolomics is the systematic study of the small-molecule profiles of biological samples produced by specific cellular processes. The high-throughput technologies used in metabolomic investigations generate datasets where variables are strongly correlated and redundancy is present in the data. Discovering the hidden information is a challenge, and suitable approaches for data analysis must be employed. Projection to latent structures regression (PLS) has successfully solved a large number of problems, from multivariate calibration to classification, becoming a basic tool of metabolomics. PLS2 is the most used implementation of PLS. Despite its success, PLS2 showed some limitations when the so called ‘structured noise’ affects the data. Suitable methods have been recently introduced to patch up these limitations. In this study, a comprehensive and up-to-date presentation of PLS2 focused on metabolomics is provided. After a brief discussion of the mathematical framework of PLS2, the post-transformation procedure is introduced as a basic tool for model interpretation. Orthogonally-constrained PLS2 is presented as strategy to include constraints in the model according to the experimental design. Two experimental datasets are investigated to show how PLS2 and its improvements work in practice. Full article
(This article belongs to the Special Issue Bioinformatics in Metabolomics)
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Open AccessArticle Delta-Tocotrienol Modulates Glutamine Dependence by Inhibiting ASCT2 and LAT1 Transporters in Non-Small Cell Lung Cancer (NSCLC) Cells: A Metabolomic Approach
Metabolites 2019, 9(3), 50; https://doi.org/10.3390/metabo9030050
Received: 30 November 2018 / Revised: 1 March 2019 / Accepted: 4 March 2019 / Published: 13 March 2019
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Abstract
The growth and development of non-small cell lung cancer (NSCLC) primarily depends on glutamine. Both glutamine and essential amino acids (EAAs) have been reported to upregulate mTOR in NSCLC, which is a bioenergetics sensor involved in the regulation of cell growth, cell survival, [...] Read more.
The growth and development of non-small cell lung cancer (NSCLC) primarily depends on glutamine. Both glutamine and essential amino acids (EAAs) have been reported to upregulate mTOR in NSCLC, which is a bioenergetics sensor involved in the regulation of cell growth, cell survival, and protein synthesis. Seen as novel concepts in cancer development, ASCT2 and LAT transporters allow glutamine and EAAs to enter proliferating tumors as well as send a regulatory signal to mTOR. Blocking or downregulating these glutamine transporters in order to inhibit glutamine uptake would be an excellent therapeutic target for treatment of NSCLC. This study aimed to validate the metabolic dysregulation of glutamine and its derivatives in NSCLC using cellular 1H-NMR metabolomic approach while exploring the mechanism of delta-tocotrienol (δT) on glutamine transporters, and mTOR pathway. Cellular metabolomics analysis showed significant inhibition in the uptake of glutamine, its derivatives glutamate and glutathione, and some EAAs in both cell lines with δT treatment. Inhibition of glutamine transporters (ASCT2 and LAT1) and mTOR pathway proteins (P-mTOR and p-4EBP1) was evident in Western blot analysis in a dose-dependent manner. Our findings suggest that δT inhibits glutamine transporters, thus inhibiting glutamine uptake into proliferating cells, which results in the inhibition of cell proliferation and induction of apoptosis via downregulation of the mTOR pathway. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2018)
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Open AccessCommunication The Bacterial Phytoene Desaturase-Encoding Gene (CRTI) is an Efficient Selectable Marker for the Genetic Transformation of Eukaryotic Microalgae
Metabolites 2019, 9(3), 49; https://doi.org/10.3390/metabo9030049
Received: 7 February 2019 / Revised: 27 February 2019 / Accepted: 5 March 2019 / Published: 12 March 2019
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Abstract
Genetic manipulation shows great promise to further boost the productivity of microalgae-based compounds. However, selection of microalgal transformants depends mainly on the use of antibiotics, which have raised concerns about their potential impacts on human health and the environment. We propose the use [...] Read more.
Genetic manipulation shows great promise to further boost the productivity of microalgae-based compounds. However, selection of microalgal transformants depends mainly on the use of antibiotics, which have raised concerns about their potential impacts on human health and the environment. We propose the use of a synthetic phytoene desaturase-encoding gene (CRTIop) as a selectable marker and the bleaching herbicide norflurazon as a selective agent for the genetic transformation of microalgae. Bacterial phytoene desaturase (CRTI), which, unlike plant and algae phytoene desaturase (PDS), is not sensitive to norflurazon, catalyzes the conversion of the colorless carotenoid phytoene into lycopene. Although the expression of CRTI has been described to increase the carotenoid content in plant cells, its use as a selectable marker has never been testedin algae or in plants. In this study, a version of the CRTI gene adapted to the codon usage of Chlamydomonas has been synthesized, and its suitability to be used as selectable marker has been shown. The microalgae were transformed by the glass bead agitation method and selected in the presence of norflurazon. Average transformation efficiencies of 550 colonies µg−1 DNA were obtained. All the transformants tested had incorporated the CRTIop gene in their genomes and were able to synthesize colored carotenoids. Full article
(This article belongs to the Special Issue Metabolites from Phototrophic Prokaryotes and Algae Volume 2)
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Open AccessReview Metabolomics Contributions to the Discovery of Prostate Cancer Biomarkers
Metabolites 2019, 9(3), 48; https://doi.org/10.3390/metabo9030048
Received: 31 January 2019 / Revised: 1 March 2019 / Accepted: 4 March 2019 / Published: 8 March 2019
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Abstract
Prostate cancer (PCa) is one of the most frequently diagnosed cancers and a leading cause of death among men worldwide. Despite extensive efforts in biomarker discovery during the last years, currently used clinical biomarkers are still lacking enough specificity and sensitivity for PCa [...] Read more.
Prostate cancer (PCa) is one of the most frequently diagnosed cancers and a leading cause of death among men worldwide. Despite extensive efforts in biomarker discovery during the last years, currently used clinical biomarkers are still lacking enough specificity and sensitivity for PCa early detection, patient prognosis, and monitoring. Therefore, more precise biomarkers are required to improve the clinical management of PCa patients. In this context, metabolomics has shown to be a promising and powerful tool to identify novel PCa biomarkers in biofluids. Thus, changes in polyamines, tricarboxylic acid (TCA) cycle, amino acids, and fatty acids metabolism have been reported in different studies analyzing PCa patients’ biofluids. The review provides an up-to-date summary of the main metabolic alterations that have been described in biofluid-based studies of PCa patients, as well as a discussion regarding their potential to improve clinical PCa diagnosis and prognosis. Furthermore, a summary of the most significant findings reported in these studies and the connections and interactions between the different metabolic changes described has also been included, aiming to better describe the specific metabolic signature associated to PCa. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2018)
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Open AccessArticle Defining Metabolic Rewiring in Lung Squamous Cell Carcinoma
Metabolites 2019, 9(3), 47; https://doi.org/10.3390/metabo9030047
Received: 8 February 2019 / Revised: 26 February 2019 / Accepted: 2 March 2019 / Published: 7 March 2019
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Abstract
Metabolomics based on untargeted flow infusion electrospray ionization high-resolution mass spectrometry (FIE-HRMS) can provide a snap-shot of metabolism in living cells. Lung Squamous Cell Carcinoma (SCC) is one of the predominant subtypes of Non-Small Cell Lung Cancers (NSCLCs), which usually shows a poor [...] Read more.
Metabolomics based on untargeted flow infusion electrospray ionization high-resolution mass spectrometry (FIE-HRMS) can provide a snap-shot of metabolism in living cells. Lung Squamous Cell Carcinoma (SCC) is one of the predominant subtypes of Non-Small Cell Lung Cancers (NSCLCs), which usually shows a poor prognosis. We analysed lung SCC samples and matched histologically normal lung tissues from eight patients. Metabolites were profiled by FIE-HRMS and assessed using t-test and principal component analysis (PCA). Differentially accumulating metabolites were mapped to pathways using the mummichog algorithm in R, and biologically meaningful patterns were indicated by Metabolite Set Enrichment Analysis (MSEA). We identified metabolic rewiring networks, including the suppression of the oxidative pentose pathway and found that the normal tricarboxylic acid (TCA) cycle were decoupled from increases in glycolysis and glutamine reductive carboxylation. Well-established associated effects on nucleotide, amino acid and thiol metabolism were also seen. Novel aspects in SCC tissue were increased in Vitamin B complex cofactors, serotonin and a reduction of γ-aminobutyric acid (GABA). Our results show the value of FIE-HRMS as a high throughput screening method that could be exploited in clinical contexts. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2019)
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Open AccessArticle Ozone and Wounding Stresses Differently Alter the Temporal Variation in Formylated Phloroglucinols in Eucalyptus globulus Leaves
Metabolites 2019, 9(3), 46; https://doi.org/10.3390/metabo9030046
Received: 30 January 2019 / Revised: 28 February 2019 / Accepted: 28 February 2019 / Published: 6 March 2019
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Abstract
Formylated phloroglucinol compounds (FPCs) are a class of plant specialized metabolite present in the Myrtaceae family, especially in the genus Eucalyptus. FPCs are widely investigated due to their herbivore deterrence properties and various bioactivities of pharmaceutical relevance. Despite the increasing number of [...] Read more.
Formylated phloroglucinol compounds (FPCs) are a class of plant specialized metabolite present in the Myrtaceae family, especially in the genus Eucalyptus. FPCs are widely investigated due to their herbivore deterrence properties and various bioactivities of pharmaceutical relevance. Despite the increasing number of studies elucidating new FPCs structures and bioactivity, little is known about the role of those compounds in planta, and the effects of environmental stresses on FPC concentration. Ozone (O3) and wounding are key stress factors regularly confronted by plants. In this study, we investigated how O3, wounding, and their combination affected individual and total FPC foliar concentration of the economically important species Eucalyptus globulus. Six individual FPCs, including five macrocarpals and one sideroxylonal, showed different response patterns to the single and combined stresses. Total macrocarpals only increased under single O3 treatment, whereas total sideroxylonals only increased in response to wounding treatment, suggesting different physiological roles played by the two groups of FPCs predominantly existing in E. globulus foliage. Total FPCs increased significantly under individual wounding and O3 treatments but not under the combined treatment. A principal component analysis indicated that all different treatments had unique FPC fingerprints. Total phenolic contents increased in all O3 and wounding treatments, and a marginally positive correlation was found between total FPCs and total phenolic contents. We suggest that, depending on the concentration and composition, FPCs play multiple physiological roles in planta, including serving as antioxidants to scavenge the reactive oxygen species brought about by O3 and wounding stresses. Full article
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Open AccessProtocol An UPLC-MS/MS Assay to Measure Glutathione as Marker for Oxidative Stress in Cultured Cells
Metabolites 2019, 9(3), 45; https://doi.org/10.3390/metabo9030045
Received: 21 January 2019 / Revised: 15 February 2019 / Accepted: 28 February 2019 / Published: 5 March 2019
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Abstract
Oxidative stress plays a role in the onset and progression of a number of diseases, such as Alzheimer’s disease, diabetes and cancer, as well as ageing. Oxidative stress is caused by an increased production of reactive oxygen species and reduced antioxidant activity, resulting [...] Read more.
Oxidative stress plays a role in the onset and progression of a number of diseases, such as Alzheimer’s disease, diabetes and cancer, as well as ageing. Oxidative stress is caused by an increased production of reactive oxygen species and reduced antioxidant activity, resulting in the oxidation of glutathione. The ratio of reduced to oxidised glutathione is often used as a marker of the redox state in the cell. Whereas a variety of methods have been developed to measure glutathione in blood samples, methods to measure glutathione in cultured cells are scarce. Here we present a protocol to measure glutathione levels in cultured human and yeast cells using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). Full article
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Open AccessArticle Ageing Investigation Using Two-Time-Point Metabolomics Data from KORA and CARLA Studies
Metabolites 2019, 9(3), 44; https://doi.org/10.3390/metabo9030044
Received: 13 December 2018 / Revised: 26 February 2019 / Accepted: 28 February 2019 / Published: 5 March 2019
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Abstract
Ageing, one of the largest risk factors for many complex diseases, is highly interconnected to metabolic processes. Investigating the changes in metabolite concentration during ageing among healthy individuals offers us unique insights to healthy ageing. We aim to identify ageing-associated metabolites that are [...] Read more.
Ageing, one of the largest risk factors for many complex diseases, is highly interconnected to metabolic processes. Investigating the changes in metabolite concentration during ageing among healthy individuals offers us unique insights to healthy ageing. We aim to identify ageing-associated metabolites that are independent from chronological age to deepen our understanding of the long-term changes in metabolites upon ageing. Sex-stratified longitudinal analyses were performed using fasting serum samples of 590 healthy KORA individuals (317 women and 273 men) who participated in both baseline (KORA S4) and seven-year follow-up (KORA F4) studies. Replication was conducted using serum samples of 386 healthy CARLA participants (195 women and 191 men) in both baseline (CARLA-0) and four-year follow-up (CARLA-1) studies. Generalized estimation equation models were performed on each metabolite to identify ageing-associated metabolites after adjusting for baseline chronological age, body mass index, physical activity, smoking status, alcohol intake and systolic blood pressure. Literature researches were conducted to understand their biochemical relevance. Out of 122 metabolites analysed, we identified and replicated five (C18, arginine, ornithine, serine and tyrosine) and four (arginine, ornithine, PC aa C36:3 and PC ae C40:5) significant metabolites in women and men respectively. Arginine decreased, while ornithine increased in both sexes. These metabolites are involved in several ageing processes: apoptosis, mitochondrial dysfunction, inflammation, lipid metabolism, autophagy and oxidative stress resistance. The study reveals several significant ageing-associated metabolite changes with two-time-point measurements on healthy individuals. Larger studies are required to confirm our findings. Full article
(This article belongs to the Special Issue Metabolomics of Complex Traits)
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Open AccessConcept Paper A Tool to Encourage Minimum Reporting Guideline Uptake for Data Analysis in Metabolomics
Metabolites 2019, 9(3), 43; https://doi.org/10.3390/metabo9030043
Received: 22 January 2019 / Revised: 23 February 2019 / Accepted: 27 February 2019 / Published: 5 March 2019
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Abstract
Despite the proposal of minimum reporting guidelines for metabolomics over a decade ago, reporting on the data analysis step in metabolomics studies has been shown to be unclear and incomplete. Major omissions and a lack of logical flow render the data analysis’ sections [...] Read more.
Despite the proposal of minimum reporting guidelines for metabolomics over a decade ago, reporting on the data analysis step in metabolomics studies has been shown to be unclear and incomplete. Major omissions and a lack of logical flow render the data analysis’ sections in metabolomics studies impossible to follow, and therefore replicate or even imitate. Here, we propose possible reasons why the original reporting guidelines have had poor adherence and present an approach to improve their uptake. We present in this paper an R markdown reporting template file that guides the production of text and generates workflow diagrams based on user input. This R Markdown template contains, as an example in this instance, a set of minimum information requirements specifically for the data pre-treatment and data analysis section of biomarker discovery metabolomics studies, (gleaned directly from the original proposed guidelines by Goodacre at al). These minimum requirements are presented in the format of a questionnaire checklist in an R markdown template file. The R Markdown reporting template proposed here can be presented as a starting point to encourage the data analysis section of a metabolomics manuscript to have a more logical presentation and to contain enough information to be understandable and reusable. The idea is that these guidelines would be open to user feedback, modification and updating by the metabolomics community via GitHub. Full article
(This article belongs to the Special Issue Metabolomics — Workflows, Methods and Applications)
Open AccessArticle Metabolomics and Communication Skills Development in Children; Evidence from the Ages and Stages Questionnaire
Metabolites 2019, 9(3), 42; https://doi.org/10.3390/metabo9030042
Received: 14 January 2019 / Revised: 14 February 2019 / Accepted: 28 February 2019 / Published: 5 March 2019
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Abstract
We hypothesized metabolomic profiling could be utilized to identify children who scored poorly on the communication component of the Ages and Stages Questionnaire (ASQ); which assesses development in childhood, and to provide candidate biomarkers for autism spectrum disorders (ASD). In a population of [...] Read more.
We hypothesized metabolomic profiling could be utilized to identify children who scored poorly on the communication component of the Ages and Stages Questionnaire (ASQ); which assesses development in childhood, and to provide candidate biomarkers for autism spectrum disorders (ASD). In a population of three-year-old children, 15 plasma metabolites, were significantly (p < 0.05) different between children who were categorized as having communication skills that were “on schedule” (n = 365 (90.6%)) as compared to those “requiring further monitoring/evaluation” (n = 38 (9.4%)) according to multivariable regression models. Five of these metabolites, including three endocannabinoids, were also dysregulated at age one (n = 204 “on schedule”, n = 24 “further monitoring/evaluation”) in the same children. Stool metabolomic profiling identified 11 significant metabolites. Both the plasma and stool results implicated a role for tryptophan and tyrosine metabolism; in particular, higher levels of N-formylanthranilic acid were associated with an improved communication score in both biosample types. A model based on the significant plasma metabolites demonstrated high sensitivity (88.9%) and specificity (84.5%) for the prediction of autism by age 8. These results provide evidence that ASQ communication score and metabolomic profiling of plasma and/or stool may provide alternative approaches for early diagnosis of ASD, as well as insights into the pathobiology of these conditions. Full article
(This article belongs to the Special Issue Metabolomics in Epidemiological Studies)
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Open AccessArticle Characterization of Yak Common Biofluids Metabolome by Means of Proton Nuclear Magnetic Resonance Spectroscopy
Metabolites 2019, 9(3), 41; https://doi.org/10.3390/metabo9030041
Received: 14 February 2019 / Accepted: 25 February 2019 / Published: 2 March 2019
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Abstract
The aim of this study was to evaluate the metabolic profiles of yak (Bos grunniens) serum, feces, and urine by using proton nuclear magnetic resonance (1H-NMR), to serve as a reference guide for the healthy yak milieu. A total [...] Read more.
The aim of this study was to evaluate the metabolic profiles of yak (Bos grunniens) serum, feces, and urine by using proton nuclear magnetic resonance (1H-NMR), to serve as a reference guide for the healthy yak milieu. A total of 108 metabolites, giving information about diet, protein digestion, and energy generation or gut-microbial co-metabolism, were assigned across the three biological matrices. A core metabolome of 15 metabolites was ubiquitous across all biofluids. Lactate, acetate, and creatinine could be regarded as the most abundant metabolites in the metabolome of serum, feces, and urine, respectively. Metabolic pathway analysis showed that the molecules identified could be able to give thorough information about four main metabolic pathways, namely valine, leucine, and isoleucine biosynthesis; phenylalanine, tyrosine, and tryptophan biosynthesis; glutamine and glutamate metabolism; and taurine and hypotaurine metabolism. Full article
(This article belongs to the Special Issue NMR-based Metabolomics and Its Applications Volume 2)
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Open AccessArticle Maternal Dietary Docosahexaenoic Acid Alters Lipid Peroxidation Products and (n-3)/(n-6) Fatty Acid Balance in Offspring Mice
Metabolites 2019, 9(3), 40; https://doi.org/10.3390/metabo9030040
Received: 31 January 2019 / Revised: 24 February 2019 / Accepted: 26 February 2019 / Published: 1 March 2019
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Abstract
The abundance of docosahexaenoic acid (DHA) in the mammalian brain has generated substantial interest in the search for its roles in regulating brain functions. Our recent study with a gene/stress mouse model provided evidence to support the ability for the maternal supplement of [...] Read more.
The abundance of docosahexaenoic acid (DHA) in the mammalian brain has generated substantial interest in the search for its roles in regulating brain functions. Our recent study with a gene/stress mouse model provided evidence to support the ability for the maternal supplement of DHA to alleviate autism-associated behavior in the offspring. DHA and arachidonic acid (ARA) are substrates of enzymatic and non-enzymatic reactions, and lipid peroxidation results in the production of 4-hydroxyhexenal (4-HHE) and 4-hydroxynonenal (4-HNE), respectively. In this study, we examine whether a maternal DHA-supplemented diet alters fatty acids (FAs), as well as lipid peroxidation products in the pup brain, heart and plasma by a targeted metabolite approach. Pups in the maternal DHA-supplemented diet group showed an increase in DHA and a concomitant decrease in ARA in all brain regions examined. However, significant increases in 4-HHE, and not 4-HNE, were found mainly in the cerebral cortex and hippocampus. Analysis of heart and plasma showed large increases in DHA and 4-HHE, but a significant decrease in 4-HNE levels only in plasma. Taken together, the DHA-supplemented maternal diet alters the (n-3)/(n-6) FA ratio, and increases 4-HHE levels in pup brain, heart and plasma. These effects may contribute to the beneficial effects of DHA on neurodevelopment, as well as functional changes in other body organs. Full article
(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics and Its Applications)
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Open AccessArticle Modulation of Polar Lipid Profiles in Chlorella sp. in Response to Nutrient Limitation
Metabolites 2019, 9(3), 39; https://doi.org/10.3390/metabo9030039
Received: 16 January 2019 / Revised: 21 February 2019 / Accepted: 22 February 2019 / Published: 28 February 2019
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Abstract
We evaluate the effects of nutrient limitation on cellular composition of polar lipid classes/species in Chlorella sp. using modern polar lipidomic profiling methods (liquid chromatography–tandem mass spectrometry; LC-MS/MS). Total polar lipid concentration was highest in nutrient-replete (HN) cultures with a significant reduction in [...] Read more.
We evaluate the effects of nutrient limitation on cellular composition of polar lipid classes/species in Chlorella sp. using modern polar lipidomic profiling methods (liquid chromatography–tandem mass spectrometry; LC-MS/MS). Total polar lipid concentration was highest in nutrient-replete (HN) cultures with a significant reduction in monogalactosyldiacylglycerol (MGDG), phosphatidylglycerol (PG), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) class concentrations for nutrient-deplete (LN) cultures. Moreover, reductions in the abundance of MGDG relative to total polar lipids versus an increase in the relative abundance of digalactosyldiacylglycerol (DGDG) were recorded in LN cultures. In HN cultures, polar lipid species composition remained relatively constant throughout culture with high degrees of unsaturation associated with acyl moieties. Conversely, in LN cultures lipid species composition shifted towards greater saturation of acyl moieties. Multivariate analyses revealed that changes in the abundance of a number of species contributed to the dissimilarity between LN and HN cultures but with dominant effects from certain species, e.g., reduction in MGDG 34:7 (18:3/16:4). Results demonstrate that Chlorella sp. significantly alters its polar lipidome in response to nutrient limitation, and this is discussed in terms of physiological significance and polar lipids production for applied microalgal production systems. Full article
(This article belongs to the Special Issue Metabolites from Phototrophic Prokaryotes and Algae Volume 2)
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