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Metabolites, Volume 9, Issue 4 (April 2019)

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Cover Story (view full-size image) CFM-ID is a freely available software tool that implements the Competitive Fragmentation Modeling [...] Read more.
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Open AccessArticle
Surfactant Lipidomics of Alveolar Lavage Fluid in Mice Based on Ultra-High-Performance Liquid Chromatography Coupled to Hybrid Quadrupole-Exactive Orbitrap Mass Spectrometry
Metabolites 2019, 9(4), 80; https://doi.org/10.3390/metabo9040080
Received: 20 December 2018 / Revised: 18 April 2019 / Accepted: 23 April 2019 / Published: 25 April 2019
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Abstract
Surfactant lipid metabolism is closely related to pulmonary diseases. Lipid metabolism disorder can cause lung diseases, vice versa. With this rationale, a useful method was established in this study to determine the lipidome in bronchoalveolar lavage fluid (BALF) of mice. The lipid components [...] Read more.
Surfactant lipid metabolism is closely related to pulmonary diseases. Lipid metabolism disorder can cause lung diseases, vice versa. With this rationale, a useful method was established in this study to determine the lipidome in bronchoalveolar lavage fluid (BALF) of mice. The lipid components in BALF were extracted by liquid–liquid extraction (methanol and methyl tert-butyl ether, and water). Ultra-high-performance liquid chromatography coupled to hybrid Quadrupole-Exactive Orbitrap mass spectrometry was used to analyze the extracted samples, which showed a broad scanning range of 215–1800 m/z. With MS-DIAL software and built-in LipidBlast database, we identified 38 lipids in positive, and 31 lipids in negative, ion mode, including lysophosphatidylcholine (lysoPC), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), etc. Then, the changes of lipids in BALF of mice with acute lung injury (ALI) induced by lipopolysaccharide (LPS) was investigated, which may contribute to further exploration of the pathogenesis of ALI. Full article
(This article belongs to the Special Issue Compound Identification of Small Molecules)
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Open AccessArticle
An Integrative Multi-Omics Workflow to Address Multifactorial Toxicology Experiments
Metabolites 2019, 9(4), 79; https://doi.org/10.3390/metabo9040079
Received: 19 March 2019 / Revised: 3 April 2019 / Accepted: 21 April 2019 / Published: 24 April 2019
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Abstract
Toxicology studies can take advantage of omics approaches to better understand the phenomena underlying the phenotypic alterations induced by different types of exposure to certain toxicants. Nevertheless, in order to analyse the data generated from multifactorial omics studies, dedicated data analysis tools are [...] Read more.
Toxicology studies can take advantage of omics approaches to better understand the phenomena underlying the phenotypic alterations induced by different types of exposure to certain toxicants. Nevertheless, in order to analyse the data generated from multifactorial omics studies, dedicated data analysis tools are needed. In this work, we propose a new workflow comprising both factor deconvolution and data integration from multiple analytical platforms. As a case study, 3D neural cell cultures were exposed to trimethyltin (TMT) and the relevance of the culture maturation state, the exposure duration, as well as the TMT concentration were simultaneously studied using a metabolomic approach combining four complementary analytical techniques (reversed-phase LC and hydrophilic interaction LC, hyphenated to mass spectrometry in positive and negative ionization modes). The ANOVA multiblock OPLS (AMOPLS) method allowed us to decompose and quantify the contribution of the different experimental factors on the outcome of the TMT exposure. Results showed that the most important contribution to the overall metabolic variability came from the maturation state and treatment duration. Even though the contribution of TMT effects represented the smallest observed modulation among the three factors, it was highly statistically significant. The MetaCore™ pathway analysis tool revealed TMT-induced alterations in biosynthetic pathways and in neuronal differentiation and signaling processes, with a predominant deleterious effect on GABAergic and glutamatergic neurons. This was confirmed by combining proteomic data, increasing the confidence on the mechanistic understanding of such a toxicant exposure. Full article
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Open AccessArticle
Polyphenol Microbial Metabolites Exhibit Gut and Blood–Brain Barrier Permeability and Protect Murine Microglia against LPS-Induced Inflammation
Metabolites 2019, 9(4), 78; https://doi.org/10.3390/metabo9040078
Received: 28 March 2019 / Revised: 16 April 2019 / Accepted: 17 April 2019 / Published: 19 April 2019
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Abstract
Increasing evidence supports the beneficial effects of polyphenol-rich diets, including the traditional Mediterranean diet, for the management of cardiovascular disease, obesity and neurodegenerative diseases. However, a common concern when discussing the protective effects of polyphenol-rich diets against diseases is whether these compounds are [...] Read more.
Increasing evidence supports the beneficial effects of polyphenol-rich diets, including the traditional Mediterranean diet, for the management of cardiovascular disease, obesity and neurodegenerative diseases. However, a common concern when discussing the protective effects of polyphenol-rich diets against diseases is whether these compounds are present in systemic circulation in their intact/parent forms in order to exert their beneficial effects in vivo. Here, we explore two common classes of dietary polyphenols, namely isoflavones and lignans, and their gut microbial-derived metabolites for gut and blood–brain barrier predicted permeability, as well as protection against neuroinflammatory stimuli in murine BV-2 microglia. Polyphenol microbial metabolites (PMMs) generally showed greater permeability through artificial gut and blood–brain barriers compared to their parent compounds. The parent polyphenols and their corresponding PMMs were evaluated for protective effects against lipopolysaccharide-induced inflammation in BV-2 microglia. The lignan-derived PMMs, equol and enterolactone, exhibited protective effects against nitric oxide production, as well as against pro-inflammatory cytokines (IL-6 and TNF-α) in BV-2 microglia. Therefore, PMMs may contribute, in large part, to the beneficial effects attributed to polyphenol-rich diets, further supporting the important role of gut microbiota in human health and disease prevention. Full article
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Open AccessArticle
Biomarker Discovery for Cytochrome P450 1A2 Activity Assessment in Rats, Based on Metabolomics
Metabolites 2019, 9(4), 77; https://doi.org/10.3390/metabo9040077
Received: 1 April 2019 / Revised: 15 April 2019 / Accepted: 15 April 2019 / Published: 18 April 2019
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Abstract
Cytochrome P450 1A2 (CYP1A2) is one of the major CYP450 enzymes (CYPs) in the liver, and participates in the biotransformation of various xenobiotics and endogenous signaling molecules. The expression and activity of CYP1A2 show large individual differences, due to genetic and environmental factors. [...] Read more.
Cytochrome P450 1A2 (CYP1A2) is one of the major CYP450 enzymes (CYPs) in the liver, and participates in the biotransformation of various xenobiotics and endogenous signaling molecules. The expression and activity of CYP1A2 show large individual differences, due to genetic and environmental factors. In order to discover non-invasive serum biomarkers associated with hepatic CYP1A2, mass spectrometry-based, untargeted metabolomics were first conducted, in order to dissect the metabolic differences in the serum and liver between control rats and β-naphthoflavone (an inducer of CYP1A2)-treated rats. Real-time reverse transcription polymerase chain reaction and pharmacokinetic analysis of phenacetin and paracetamol were performed, in order to determine the changes of mRNA levels and activity of CYP1A2 in these two groups, respectively. Branched-chain amino acids phenylalanine and tyrosine were ultimately focalized, as they were detected in both the serum and liver with the same trends. These findings were further confirmed by absolute quantification via a liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based targeted metabolomics approach. Furthermore, the ratio of phenylalanine to tyrosine concentration was also found to be highly correlated with CYP1A2 activity and gene expression. This study demonstrates that metabolomics can be a potentially useful tool for biomarker discovery associated with CYPs. Our findings contribute to explaining interindividual variations in CYP1A2-mediated drug metabolism. Full article
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Open AccessPerspective
Systems Biology and Multi-Omics Integration: Viewpoints from the Metabolomics Research Community
Metabolites 2019, 9(4), 76; https://doi.org/10.3390/metabo9040076
Received: 25 March 2019 / Revised: 15 April 2019 / Accepted: 16 April 2019 / Published: 18 April 2019
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Abstract
The use of multiple omics techniques (i.e., genomics, transcriptomics, proteomics, and metabolomics) is becoming increasingly popular in all facets of life science. Omics techniques provide a more holistic molecular perspective of studied biological systems compared to traditional approaches. However, due to their inherent [...] Read more.
The use of multiple omics techniques (i.e., genomics, transcriptomics, proteomics, and metabolomics) is becoming increasingly popular in all facets of life science. Omics techniques provide a more holistic molecular perspective of studied biological systems compared to traditional approaches. However, due to their inherent data differences, integrating multiple omics platforms remains an ongoing challenge for many researchers. As metabolites represent the downstream products of multiple interactions between genes, transcripts, and proteins, metabolomics, the tools and approaches routinely used in this field could assist with the integration of these complex multi-omics data sets. The question is, how? Here we provide some answers (in terms of methods, software tools and databases) along with a variety of recommendations and a list of continuing challenges as identified during a peer session on multi-omics integration that was held at the recent ‘Australian and New Zealand Metabolomics Conference’ (ANZMET 2018) in Auckland, New Zealand (Sept. 2018). We envisage that this document will serve as a guide to metabolomics researchers and other members of the community wishing to perform multi-omics studies. We also believe that these ideas may allow the full promise of integrated multi-omics research and, ultimately, of systems biology to be realized. Full article
(This article belongs to the Special Issue Agribio and Food Metabolomics)
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Open AccessArticle
Propolis Exerts an Anti-Inflammatory Effect on PMA-Differentiated THP-1 Cells via Inhibition of Purine Nucleoside Phosphorylase
Metabolites 2019, 9(4), 75; https://doi.org/10.3390/metabo9040075
Received: 11 March 2019 / Revised: 9 April 2019 / Accepted: 15 April 2019 / Published: 16 April 2019
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Abstract
Previous research has shown that propolis has immunomodulatory activity. Propolis extracts from different geographic origins were assessed for their anti-inflammatory activities by investigating their ability to alter the production of tumour necrosis factor-α (TNF-α) and the cytokines interleukin-1β (IL-1β), IL-6 and IL-10 in [...] Read more.
Previous research has shown that propolis has immunomodulatory activity. Propolis extracts from different geographic origins were assessed for their anti-inflammatory activities by investigating their ability to alter the production of tumour necrosis factor-α (TNF-α) and the cytokines interleukin-1β (IL-1β), IL-6 and IL-10 in THP-1-derived macrophage cells co-stimulated with lipopolysaccharide (LPS). All the propolis extracts suppressed the TNF-α and IL-6 LPS-stimulated levels. Similar suppression effects were detected for IL-1β, but the release of this cytokine was synergised by propolis samples from Ghana and Indonesia when compared with LPS. Overall, the Cameroonian propolis extract (P-C) was the most active and this was evaluated for its effects on the metabolic profile of unstimulated macrophages or macrophages activated by LPS. The levels of 81 polar metabolites were identified by liquid chromatography (LC) coupled with mass spectrometry (MS) on a ZIC-pHILIC column. LPS altered the energy, amino acid and nucleotide metabolism in THP-1 cells, and interpretation of the metabolic pathways showed that P-C reversed some of the effects of LPS. Overall, the results showed that propolis extracts exert an anti-inflammatory effect by inhibition of pro-inflammatory cytokines and by metabolic reprogramming of LPS activity in macrophage cells, suggesting an immunomodulatory effect. Full article
(This article belongs to the Special Issue Metabolomics in the Study of Disease)
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Open AccessArticle
Intracellular and Extracellular Metabolites from the Cyanobacterium Chlorogloeopsis fritschii, PCC 6912, During 48 Hours of UV-B Exposure
Metabolites 2019, 9(4), 74; https://doi.org/10.3390/metabo9040074
Received: 12 March 2019 / Revised: 12 April 2019 / Accepted: 13 April 2019 / Published: 16 April 2019
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Abstract
Cyanobacteria have many defence strategies to overcome harmful ultraviolet (UV) stress including the production of secondary metabolites. Metabolomics can be used to investigate this altered metabolism via targeted and untargeted techniques. In this study we assessed the changes in the intra- and extracellular [...] Read more.
Cyanobacteria have many defence strategies to overcome harmful ultraviolet (UV) stress including the production of secondary metabolites. Metabolomics can be used to investigate this altered metabolism via targeted and untargeted techniques. In this study we assessed the changes in the intra- and extracellular low molecular weight metabolite levels of Chlorogloeopsis fritschii (C. fritschii) during 48 h of photosynthetically active radiation (PAR) supplemented with UV-B (15 µmol m−2 s−1 of PAR plus 3 µmol m−2 s−1 of UV-B) and intracellular levels during 48 h of PAR only (15 µmol m−2 s−1) with sampling points at 0, 2, 6, 12, 24 and 48 h. Gas chromatography–mass spectrometry (GC–MS) was used as a metabolite profiling tool to investigate the global changes in metabolite levels. The UV-B time series experiment showed an overall significant reduction in intracellular metabolites involved with carbon and nitrogen metabolism such as the amino acids tyrosine and phenylalanine which have a role in secondary metabolite production. Significant accumulation of proline was observed with a potential role in stress mitigation as seen in other photosynthetic organisms. 12 commonly identified metabolites were measured in both UV-B exposed (PAR + UV-B) and PAR only experiments with differences in significance observed. Extracellular metabolites (PAR + UV-B) showed accumulation of sugars as seen in other cyanobacterial species as a stress response to UV-B. In conclusion, a snapshot of the metabolome of C. fritschii was measured. Little work has been undertaken on C. fritschii, a novel candidate for use in industrial biotechnology, with, to our knowledge, no previous literature on combined intra- and extracellular analysis during a UV-B treatment time-series. This study is important to build on experimental data already available for cyanobacteria and other photosynthetic organisms exposed to UV-B. Full article
(This article belongs to the Special Issue Metabolites from Phototrophic Prokaryotes and Algae Volume 2)
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Open AccessReview
Carbonic Anhydrases in Photosynthesizing Cells of C3 Higher Plants
Metabolites 2019, 9(4), 73; https://doi.org/10.3390/metabo9040073
Received: 19 March 2019 / Revised: 13 April 2019 / Accepted: 15 April 2019 / Published: 16 April 2019
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Abstract
The review presents data on the location, nature, properties, number, and expression of carbonic anhydrase genes in the photosynthesizing cells of C3 plants. The available data about the presence of carbonic anhydrases in plasma membrane, cytoplasm, mitochondria, chloroplast stroma and thylakoids are scrutinized. [...] Read more.
The review presents data on the location, nature, properties, number, and expression of carbonic anhydrase genes in the photosynthesizing cells of C3 plants. The available data about the presence of carbonic anhydrases in plasma membrane, cytoplasm, mitochondria, chloroplast stroma and thylakoids are scrutinized. Special attention was paid to the presence of carbonic anhydrase activities in the different parts of thylakoids, and on collation of sources of these activities with enzymes encoded by the established genes of carbonic anhydrases. The data are presented to show that the consistent incorporation of carbonic anhydrases belonging to different families of these enzymes forms a coherent system of CO2 molecules transport from air to chloroplasts in photosynthesizing cells, where they are included in organic molecules in the carboxylation reaction. It is discussed that the manifestation of the activity of a certain carbonic anhydrase depends on environmental conditions and the stage of ontogenesis. Full article
(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism Volume 2)
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Open AccessArticle
CFM-ID 3.0: Significantly Improved ESI-MS/MS Prediction and Compound Identification
Metabolites 2019, 9(4), 72; https://doi.org/10.3390/metabo9040072
Received: 4 March 2019 / Revised: 31 March 2019 / Accepted: 8 April 2019 / Published: 13 April 2019
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Abstract
Metabolite identification for untargeted metabolomics is often hampered by the lack of experimentally collected reference spectra from tandem mass spectrometry (MS/MS). To circumvent this problem, Competitive Fragmentation Modeling-ID (CFM-ID) was developed to accurately predict electrospray ionization-MS/MS (ESI-MS/MS) spectra from chemical structures and to [...] Read more.
Metabolite identification for untargeted metabolomics is often hampered by the lack of experimentally collected reference spectra from tandem mass spectrometry (MS/MS). To circumvent this problem, Competitive Fragmentation Modeling-ID (CFM-ID) was developed to accurately predict electrospray ionization-MS/MS (ESI-MS/MS) spectra from chemical structures and to aid in compound identification via MS/MS spectral matching. While earlier versions of CFM-ID performed very well, CFM-ID’s performance for predicting the MS/MS spectra of certain classes of compounds, including many lipids, was quite poor. Furthermore, CFM-ID’s compound identification capabilities were limited because it did not use experimentally available MS/MS spectra nor did it exploit metadata in its spectral matching algorithm. Here, we describe significant improvements to CFM-ID’s performance and speed. These include (1) the implementation of a rule-based fragmentation approach for lipid MS/MS spectral prediction, which greatly improves the speed and accuracy of CFM-ID; (2) the inclusion of experimental MS/MS spectra and other metadata to enhance CFM-ID’s compound identification abilities; (3) the development of new scoring functions that improves CFM-ID’s accuracy by 21.1%; and (4) the implementation of a chemical classification algorithm that correctly classifies unknown chemicals (based on their MS/MS spectra) in >80% of the cases. This improved version called CFM-ID 3.0 is freely available as a web server. Its source code is also accessible online. Full article
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Open AccessArticle
Plasma Free Fatty Acids Metabolic Profile with LC-MS and Appetite-Related Hormones in South Asian and White European Men in Relation to Adiposity, Physical Activity and Cardiorespiratory Fitness: A Cross-Sectional Study
Metabolites 2019, 9(4), 71; https://doi.org/10.3390/metabo9040071
Received: 21 March 2019 / Revised: 10 April 2019 / Accepted: 11 April 2019 / Published: 13 April 2019
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Abstract
South Asians have a greater cardiovascular disease (CVD) and type 2 diabetes (T2D) risk than white Europeans, but the mechanisms are poorly understood. This study examined ethnic differences in free fatty acids (FFAs) metabolic profile (assessed using liquid chromatography-mass spectrometry), appetite-related hormones and [...] Read more.
South Asians have a greater cardiovascular disease (CVD) and type 2 diabetes (T2D) risk than white Europeans, but the mechanisms are poorly understood. This study examined ethnic differences in free fatty acids (FFAs) metabolic profile (assessed using liquid chromatography-mass spectrometry), appetite-related hormones and traditional CVD and T2D risk markers in blood samples collected from 16 South Asian and 16 white European men and explored associations with body composition, objectively-measured physical activity and cardiorespiratory fitness. South Asians exhibited higher concentrations of five FFAs (laurate, myristate, palmitate, linolenic, linoleate; p ≤ 0.040), lower acylated ghrelin (ES = 1.00, p = 0.008) and higher leptin (ES = 1.11, p = 0.004) than white Europeans; total peptide YY was similar between groups (p = 0.381). South Asians exhibited elevated fasting insulin, C-reactive protein, interleukin-6, triacylglycerol and ratio of total cholesterol to high-density lipoprotein cholesterol (HDL-C) and lower fasting HDL-C (all ES ≥ 0.74, p ≤ 0.053). Controlling for body fat percentage (assessed using air displacement plethysmography) attenuated these differences. Despite similar habitual moderate-to-vigorous physical activity (ES = 0.18, p = 0.675), V ˙ O2max was lower in South Asians (ES = 1.36, p = 0.001). Circulating FFAs in South Asians were positively correlated with body fat percentage (r2 = 0.92), body mass (r2 = 0.86) and AUC glucose (r2 = 0.89) whereas in white Europeans FFAs were negatively correlated with total step counts (r2 = 0.96). In conclusion, South Asians exhibited a different FFA profile, lower ghrelin, higher leptin, impaired CVD and T2D risk markers and lower cardiorespiratory fitness than white Europeans. Full article
(This article belongs to the Special Issue Exercise Metabonomics)
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Open AccessRetraction
Retraction: Carulli, L. et al. The OMICs Window into Nonalcoholic Fatty Liver Disease (NAFLD). Metabolites 2019, 9(2), 25
Metabolites 2019, 9(4), 70; https://doi.org/10.3390/metabo9040070
Received: 9 April 2019 / Accepted: 9 April 2019 / Published: 11 April 2019
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Abstract
As the authors of the title paper [...] Full article
Open AccessArticle
Role of Intestinal Microbiota in Metabolism of Gastrodin In Vitro and In Vivo
Metabolites 2019, 9(4), 69; https://doi.org/10.3390/metabo9040069
Received: 9 March 2019 / Revised: 1 April 2019 / Accepted: 4 April 2019 / Published: 8 April 2019
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Abstract
Alteration in the number and composition of intestinal microbiota affects the metabolism of several xenobiotics. Gastrodin, isolated from Gastrodia elata, is prone to be hydrolyzed by intestinal microbiota. In the present study, the role of intestinal microbiota in gastrodin metabolism was investigated in [...] Read more.
Alteration in the number and composition of intestinal microbiota affects the metabolism of several xenobiotics. Gastrodin, isolated from Gastrodia elata, is prone to be hydrolyzed by intestinal microbiota. In the present study, the role of intestinal microbiota in gastrodin metabolism was investigated in vitro and in vivo. Gastrodin was incubated in an anaerobic condition with intestinal contents prepared from vehicle- and antibiotics-treated rats and the disappearance of gastrodin and formation of 4-hydroxybenzyl alcohol (4-HBA) was measured by liquid chromatography coupled to mass spectroscopy (LC-MS/MS). The results showed that almost all gastrodin incubated with control intestinal contents was metabolized to its aglycone in time- and concentration-dependent manners. In contrast, much less formation of 4-HBA was detected in intestinal contents from antibiotics-treated rats. Subsequently, in vivo pharmacokinetic study revealed that the antibiotic pretreatment of rats significantly affected the metabolism of gastrodin to 4-HBA. When administered orally, gastrodin was rapidly absorbed rapidly into plasma, metabolized to 4-HBA, and disappeared from the body within six hours. Interestingly, the pharmacokinetic parameters of 4-HBA were changed remarkably in antibiotics-treated rats, compared to control rats. The results clearly indicated that the antibiotics treatment of rats suppressed the ability of intestinal microbiota to metabolize gastrodin to 4-HBA and that, thereby, the pharmacodynamic action was significantly modulated. Full article
(This article belongs to the Special Issue Gut Metabolism of Natural Products)
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Open AccessCommunication
Drying Enhances Signal Intensities for Global GC–MS Metabolomics
Metabolites 2019, 9(4), 68; https://doi.org/10.3390/metabo9040068
Received: 13 March 2019 / Revised: 3 April 2019 / Accepted: 4 April 2019 / Published: 5 April 2019
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Abstract
We report here that a straightforward change of the standard derivatization procedure for GC–MS metabolomics is leading to a strong increase in metabolite signal intensity. Drying samples between methoxymation and trimethylsilylation significantly increased signals by two- to tenfold in extracts of yeast cells, [...] Read more.
We report here that a straightforward change of the standard derivatization procedure for GC–MS metabolomics is leading to a strong increase in metabolite signal intensity. Drying samples between methoxymation and trimethylsilylation significantly increased signals by two- to tenfold in extracts of yeast cells, plant and animal tissue, and human urine. This easy step reduces the cost of sample material and the need for expensive new hardware. Full article
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Open AccessReview
The Metabolomic Signatures of Weight Change
Metabolites 2019, 9(4), 67; https://doi.org/10.3390/metabo9040067
Received: 30 January 2019 / Revised: 18 March 2019 / Accepted: 3 April 2019 / Published: 4 April 2019
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Abstract
Obesity represents a major health concern, not just in the West but increasingly in low and middle income countries. In order to develop successful strategies for losing weight, it is essential to understand the molecular pathogenesis of weight change. A number of pathways, [...] Read more.
Obesity represents a major health concern, not just in the West but increasingly in low and middle income countries. In order to develop successful strategies for losing weight, it is essential to understand the molecular pathogenesis of weight change. A number of pathways, implicating oxidative stress but also the fundamental regulatory of insulin, have been implicated in weight gain and in the regulation of energy expenditure. In addition, a considerable body of work has highlighted the role of metabolites generated by the gut microbiome, in particular short chain fatty acids, in both processes. The current review provides a brief understanding of the mechanisms underlying the associations of weight change with changes in lipid and amino acid metabolism, energy metabolism, dietary composition and insulin dynamics, as well as the influence of the gut microbiome. The changes in metabolomic profiles and the models outlined can be used as an accurate predictor for obesity and obesity related disorders. Full article
(This article belongs to the Special Issue Metabolomics of Complex Traits)
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Open AccessReview
Computational Methods for the Discovery of Metabolic Markers of Complex Traits
Metabolites 2019, 9(4), 66; https://doi.org/10.3390/metabo9040066
Received: 1 February 2019 / Revised: 19 March 2019 / Accepted: 1 April 2019 / Published: 4 April 2019
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Abstract
Metabolomics uses quantitative analyses of metabolites from tissues or bodily fluids to acquire a functional readout of the physiological state. Complex diseases arise from the influence of multiple factors, such as genetics, environment and lifestyle. Since genes, RNAs and proteins converge onto the [...] Read more.
Metabolomics uses quantitative analyses of metabolites from tissues or bodily fluids to acquire a functional readout of the physiological state. Complex diseases arise from the influence of multiple factors, such as genetics, environment and lifestyle. Since genes, RNAs and proteins converge onto the terminal downstream metabolome, metabolomics datasets offer a rich source of information in a complex and convoluted presentation. Thus, powerful computational methods capable of deciphering the effects of many upstream influences have become increasingly necessary. In this review, the workflow of metabolic marker discovery is outlined from metabolite extraction to model interpretation and validation. Additionally, current metabolomics research in various complex disease areas is examined to identify gaps and trends in the use of several statistical and computational algorithms. Then, we highlight and discuss three advanced machine-learning algorithms, specifically ensemble learning, artificial neural networks, and genetic programming, that are currently less visible, but are budding with high potential for utility in metabolomics research. With an upward trend in the use of highly-accurate, multivariate models in the metabolomics literature, diagnostic biomarker panels of complex diseases are more recently achieving accuracies approaching or exceeding traditional diagnostic procedures. This review aims to provide an overview of computational methods in metabolomics and promote the use of up-to-date machine-learning and computational methods by metabolomics researchers. Full article
(This article belongs to the Special Issue Metabolomics of Complex Traits)
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Open AccessArticle
Extra-Virgin Olive Oils from Nine Italian Regions: An 1H NMR-Chemometric Characterization
Metabolites 2019, 9(4), 65; https://doi.org/10.3390/metabo9040065
Received: 18 February 2019 / Revised: 29 March 2019 / Accepted: 29 March 2019 / Published: 3 April 2019
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Abstract
Extra-virgin olive oil (383 samples; EVOOs) of three consecutive harvesting years from nine Italian regions were collected and submitted to an 1H NMR-chemometric protocol to characterize the samples according to their origin (geographical area and variety). A more complete assignment of the [...] Read more.
Extra-virgin olive oil (383 samples; EVOOs) of three consecutive harvesting years from nine Italian regions were collected and submitted to an 1H NMR-chemometric protocol to characterize the samples according to their origin (geographical area and variety). A more complete assignment of the olive oil 1H spectrum in CDCl3 and DMSOd6 was reported identifying 24-methylencycolartanol. A single classification model provided the discrimination of EVOOs among the three geographical macro-areas (North, Islands, Center-South), whereas a hierarchical approach based on breaking the overall classification problem into a series of smaller linear discriminant analysis (LDA) sub-models was tested to differentiate olive oils according to their geographical regions. Specific compounds responsible for olive oil characterization were identified. Full article
(This article belongs to the Special Issue NMR-based Metabolomics and Its Applications Volume 2)
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Open AccessArticle
The Effect of Pre-Analytical Conditions on Blood Metabolomics in Epidemiological Studies
Metabolites 2019, 9(4), 64; https://doi.org/10.3390/metabo9040064
Received: 11 February 2019 / Revised: 22 March 2019 / Accepted: 27 March 2019 / Published: 3 April 2019
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Abstract
Serum and plasma are commonly used in metabolomic-epidemiology studies. Their metabolome is susceptible to differences in pre-analytical conditions and the impact of this is unclear. Participant-matched EDTA-plasma and serum samples were collected from 37 non-fasting volunteers and profiled using a targeted nuclear magnetic [...] Read more.
Serum and plasma are commonly used in metabolomic-epidemiology studies. Their metabolome is susceptible to differences in pre-analytical conditions and the impact of this is unclear. Participant-matched EDTA-plasma and serum samples were collected from 37 non-fasting volunteers and profiled using a targeted nuclear magnetic resonance (NMR) metabolomics platform (n = 151 traits). Correlations and differences in mean of metabolite concentrations were compared between reference (pre-storage: 4 °C, 1.5 h; post-storage: no buffer addition delay or NMR analysis delay) and four pre-storage blood processing conditions, where samples were incubated at (i) 4 °C, 24 h; (ii) 4 °C, 48 h; (iii) 21 °C, 24 h; and (iv) 21 °C, 48 h, before centrifugation; and two post-storage sample processing conditions in which samples thawed overnight (i) then left for 24 h before addition of sodium buffer followed by immediate NMR analysis; and (ii) addition of sodium buffer, then left for 24 h before NMR profiling. We used multilevel linear regression models and Spearman’s rank correlation coefficients to analyse the data. Most metabolic traits had high rank correlation and minimal differences in mean concentrations between samples subjected to reference and the different conditions tested, that may commonly occur in studies. However, glycolysis metabolites, histidine, acetate and diacylglycerol concentrations may be compromised and this could bias results in association/causal analyses. Full article
(This article belongs to the Special Issue Metabolomics in Epidemiological Studies)
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Open AccessArticle
HILIC-Enabled 13C Metabolomics Strategies: Comparing Quantitative Precision and Spectral Accuracy of QTOF High- and QQQ Low-Resolution Mass Spectrometry
Metabolites 2019, 9(4), 63; https://doi.org/10.3390/metabo9040063
Received: 29 January 2019 / Revised: 21 March 2019 / Accepted: 28 March 2019 / Published: 2 April 2019
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Abstract
Dynamic 13C-tracer-based flux analyses of in vivo reaction networks still require a continuous development of advanced quantification methods applying state-of-the-art mass spectrometry platforms. Utilizing alkaline HILIC chromatography, we adapt strategies for a systematic quantification study in non- and 13C-labeled multicomponent endogenous [...] Read more.
Dynamic 13C-tracer-based flux analyses of in vivo reaction networks still require a continuous development of advanced quantification methods applying state-of-the-art mass spectrometry platforms. Utilizing alkaline HILIC chromatography, we adapt strategies for a systematic quantification study in non- and 13C-labeled multicomponent endogenous Corynebacterium glutamicum extracts by LC-QTOF high resolution (HRMS) and LC-QQQ tandem mass spectrometry (MS/MS). Without prior derivatization, a representative cross-section of 17 central carbon and anabolic key intermediates were analyzed with high selectivity and sensitivity under optimized ESI-MS settings. In column detection limits for the absolute quantification range were between 6.8–304.7 (QQQ) and 28.7–881.5 fmol (QTOF) with comparable linearities (3–5 orders of magnitude) and enhanced precision using QQQ-MRM detection. Tailor-made preparations of uniformly (U)13C-labeled cultivation extracts for isotope dilution mass spectrometry enabled the accurate quantification in complex sample matrices and extended linearities without effect on method parameters. Furthermore, evaluation of metabolite-specific m+1-to-m+0 ratios (ISR1:0) in non-labeled extracts exhibited sufficient methodical spectral accuracies with mean deviations of 3.89 ± 3.54% (QTOF) and 4.01 ± 3.01% (QQQ). Based on the excellent HILIC performance, conformity analysis of time-resolved isotopic enrichments in 13C-tracer experiments revealed sufficient spectral accuracy for QQQ-SIM detection. However, only QTOF-HRMS ensures determination of the full isotopologue space in complex matrices without mass interferences. Full article
(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics and Its Applications)
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Open AccessArticle
Identification of N-Oxide-Containing Aromatic Heterocycles as Pharmacophores for Rumen Fermentation Modifiers
Metabolites 2019, 9(4), 62; https://doi.org/10.3390/metabo9040062
Received: 31 January 2019 / Revised: 5 March 2019 / Accepted: 8 March 2019 / Published: 2 April 2019
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Abstract
Different strategies have been used to mitigate greenhouse gas emissions from domesticated ruminants, including the removal of protozoa (defaunation). The objective of the present work was to analyze the potential of different N-oxide-containing aromatic heterocycles with known antiprotozoal activity as rumen-gas-abating agents. [...] Read more.
Different strategies have been used to mitigate greenhouse gas emissions from domesticated ruminants, including the removal of protozoa (defaunation). The objective of the present work was to analyze the potential of different N-oxide-containing aromatic heterocycles with known antiprotozoal activity as rumen-gas-abating agents. Nineteen pure compounds, belonging to seven different N-oxide chemotypes from our chemo-library were studied together with monensin in an in vitro rumen simulation assay. Fermentation profiles, i.e., gas production, pH, and short carboxylic acid concentrations, were compared to an untreated control at 96 h post inoculation. In our study, we investigated whole-ruminal fluid, with and without compound treatments, by NMR spectroscopy focusing on concentrations of the metabolites acetate, propionate, butyrate, and lactate. From data analysis, three of the compounds from different N-oxide chemotypes, including quinoxaline dioxide, benzofuroxan, and methylfuroxan, were able to diminish the production of gases such as monensin with similar gas production lag times for each of them. Additionally, unlike monensin, one methylfuroxan did not decrease the rumen pH during the analyzed incubation time, shifting rumen fermentation to increase the molar concentrations of propionate and butyrate. These facts suggest interesting alternatives as feed supplements to control gas emissions from dairy ruminants. Full article
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Open AccessArticle
Metabolomics Identifies Novel Blood Biomarkers of Pulmonary Function and COPD in the General Population
Metabolites 2019, 9(4), 61; https://doi.org/10.3390/metabo9040061
Received: 8 February 2019 / Revised: 21 March 2019 / Accepted: 26 March 2019 / Published: 1 April 2019
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Abstract
Determination of metabolomic signatures of pulmonary function and chronic obstructive pulmonary disease (COPD) in the general population could aid in identification and understanding of early disease processes. Metabolome measurements were performed on serum from 4742 individuals (2354 African-Americans and 1529 European-Americans from the [...] Read more.
Determination of metabolomic signatures of pulmonary function and chronic obstructive pulmonary disease (COPD) in the general population could aid in identification and understanding of early disease processes. Metabolome measurements were performed on serum from 4742 individuals (2354 African-Americans and 1529 European-Americans from the Atherosclerosis Risk in Communities study and 859 Europeans from the Cooperative Health Research in the Region of Augsburg study). We examined 368 metabolites in relation to cross-sectional measures of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), their ratio (FEV1/FVC) and COPD using multivariable regression followed by meta-analysis. At a false discovery rate of 0.05, 95 metabolites were associated with FEV1 and 100 with FVC (73 overlapping), including inverse associations with branched-chain amino acids and positive associations with glutamine. Ten metabolites were associated with FEV1/FVC and seventeen with COPD (393 cases). Enriched pathways of amino acid metabolism were identified. Associations with FEV1 and FVC were not driven by individuals with COPD. We identified novel metabolic signatures of pulmonary function and COPD in African and European ancestry populations. These may allow development of biomarkers in the general population of early disease pathogenesis, before pulmonary function has decreased to levels diagnostic for COPD. Full article
(This article belongs to the Special Issue Metabolomics and Chronic Obstructive Lung Diseases)
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Open AccessArticle
Deciphering the Resistance Mechanism of Tomato Plants Against Whitefly-Mediated Tomato Curly Stunt Virus Infection through Ultra-High-Performance Liquid Chromatography Coupled to Mass Spectrometry (UHPLC-MS)-Based Metabolomics Approaches
Metabolites 2019, 9(4), 60; https://doi.org/10.3390/metabo9040060
Received: 22 February 2019 / Revised: 18 March 2019 / Accepted: 25 March 2019 / Published: 28 March 2019
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Abstract
Begomoviruses, such as the Tomato curly stunt virus (ToCSV), pose serious economic consequences due to severe crop losses. Therefore, the development and screening of possible resistance markers is imperative. While some tomato cultivars exhibit differential resistance to different begomovirus species, in most cases, [...] Read more.
Begomoviruses, such as the Tomato curly stunt virus (ToCSV), pose serious economic consequences due to severe crop losses. Therefore, the development and screening of possible resistance markers is imperative. While some tomato cultivars exhibit differential resistance to different begomovirus species, in most cases, the mechanism of resistance is not fully understood. In this study, the response of two near-isogenic lines of tomato (Solanum lycopersicum), differing in resistance against whitefly-mediated ToCSV infection were investigated using untargeted ultra-high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS)-based metabolomics. The responses of the two lines were deciphered using multivariate statistics models. Principal component analysis (PCA) scores plots from various time intervals revealed that the resistant line responded more rapidly with changes to the metabolome than the susceptible counterpart. Moreover, the metabolic reprogramming of chemically diverse metabolites that span a range of metabolic pathways was associated with the defence response. Biomarkers primarily included hydroxycinnamic acids conjugated to quinic acid, galactaric acid, and glucose. Minor constituents included benzenoids, flavonoids, and steroidal glycoalkaloids. Interestingly, when reduced to the level of metabolites, the phytochemistry of the infected plants’ responses was very similar. However, the resistant phenotype was strongly associated with the hydroxycinnamic acid derivatives deployed in response to infection. In addition, the resistant line was able to mount a stronger and quicker response. Full article
(This article belongs to the Special Issue Metabolomics in Agriculture)
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