Metabolites

15 pages, 4954 KiB

Open AccessArticle

Involvement of Spermidine in the Reduced Lifespan of Caenorhabditis elegans During Vitamin B₁₂ Deficiency

by Tomohiro Bito, Naho Okamoto, Kenji Otsuka, Yukinori Yabuta, Jiro Arima, Tsuyoshi Kawano and Fumio Watanabe

Metabolites 2019, 9(9), 192; https://doi.org/10.3390/metabo9090192 - 19 Sep 2019

Cited by 3 | Viewed by 3225

Abstract

Vitamin B₁₂ deficiency leads to various symptoms such as neuropathy, growth retardation, and infertility. Vitamin B₁₂ functions as a coenzyme for two enzymes involved in amino acid metabolisms. However, there is limited information available on whether amino acid disorders caused by [...] Read more.

Vitamin B₁₂ deficiency leads to various symptoms such as neuropathy, growth retardation, and infertility. Vitamin B₁₂ functions as a coenzyme for two enzymes involved in amino acid metabolisms. However, there is limited information available on whether amino acid disorders caused by vitamin B₁₂ deficiency induce such symptoms. First, free amino acid levels were determined in vitamin B₁₂-deficient Caenorhabditis elegans to clarify the mechanisms underlying the symptoms caused by vitamin B₁₂ deficiency. Various amino acids (valine, leucine, isoleucine, methionine, and cystathionine, among others) metabolized by vitamin B₁₂-dependent enzymes were found to be significantly changed during conditions of B₁₂ deficiency, which indirectly affected certain amino acids metabolized by vitamin B₁₂-independent enzymes. For example, ornithine was significantly increased during vitamin B₁₂ deficiency, which also significantly increased arginase activity. The accumulation of ornithine during vitamin B₁₂ deficiency constitutes the first report. In addition, the biosynthesis of spermidine from ornithine was significantly decreased during vitamin B₁₂ deficiency, likely due to the reduction of S-adenosylmethionine as a substrate for S-adenosylmethionine decarboxylase, which catalyzes the formation of spermidine. Moreover, vitamin B₁₂ deficiency also demonstrated a significant reduction in worm lifespan, which was partially recovered by the addition of spermidine. Collectively, our findings suggest that decreased spermidine is one factor responsible for reduced lifespan in vitamin B₁₂-deficient worms. Full article

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16 pages, 2951 KiB

Open AccessArticle

Associations between Blood Metabolic Profile at 7 Years Old and Eating Disorders in Adolescence: Findings from the Avon Longitudinal Study of Parents and Children

by Diana L. Santos Ferreira, Christopher Hübel, Moritz Herle, Mohamed Abdulkadir, Ruth J. F. Loos, Rachel Bryant-Waugh, Cynthia M. Bulik, Bianca L. De Stavola, Deborah A. Lawlor and Nadia Micali

Metabolites 2019, 9(9), 191; https://doi.org/10.3390/metabo9090191 - 19 Sep 2019

Cited by 6 | Viewed by 4168

Abstract

Eating disorders are severe illnesses characterized by both psychiatric and metabolic factors. We explored the prospective role of metabolic risk in eating disorders in a UK cohort (n = 2929 participants), measuring 158 metabolic traits in non-fasting EDTA-plasma by nuclear magnetic resonance. [...] Read more.

Eating disorders are severe illnesses characterized by both psychiatric and metabolic factors. We explored the prospective role of metabolic risk in eating disorders in a UK cohort (n = 2929 participants), measuring 158 metabolic traits in non-fasting EDTA-plasma by nuclear magnetic resonance. We associated metabolic markers at 7 years (exposure) with risk for anorexia nervosa and binge-eating disorder (outcomes) at 14, 16, and 18 years using logistic regression adjusted for maternal education, child’s sex, age, body mass index, and calorie intake at 7 years. Elevated very low-density lipoproteins, triglycerides, apolipoprotein-B/A, and monounsaturated fatty acids ratio were associated with lower odds of anorexia nervosa at age 18, while elevated high-density lipoproteins, docosahexaenoic acid and polyunsaturated fatty acids ratio, and fatty acid unsaturation were associated with higher risk for anorexia nervosa at 18 years. Elevated linoleic acid and n-6 fatty acid ratios were associated with lower odds of binge-eating disorder at 16 years, while elevated saturated fatty acid ratio was associated with higher odds of binge-eating disorder. Most associations had large confidence intervals and showed, for anorexia nervosa, different directions across time points. Overall, our results show some evidence for a role of metabolic factors in eating disorders development in adolescence. Full article

(This article belongs to the Special Issue Metabolomics in Epidemiological Studies)

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19 pages, 5274 KiB

Open AccessArticle

Differences in Pregnancy Metabolic Profiles and Their Determinants between White European and South Asian Women: Findings from the Born in Bradford Cohort

by Kurt Taylor, Diana L. Santos Ferreira, Jane West, Tiffany Yang, Massimo Caputo and Deborah A. Lawlor

Metabolites 2019, 9(9), 190; https://doi.org/10.3390/metabo9090190 - 18 Sep 2019

Cited by 32 | Viewed by 4404

Abstract

There is widespread metabolic disruption in women upon becoming pregnant. South Asians (SA) compared to White Europeans (WE) have more fat mass and are more insulin-resistant at a given body mass index (BMI). Whether these are reflected in other gestational metabolomic differences is [...] Read more.

There is widespread metabolic disruption in women upon becoming pregnant. South Asians (SA) compared to White Europeans (WE) have more fat mass and are more insulin-resistant at a given body mass index (BMI). Whether these are reflected in other gestational metabolomic differences is unclear. Our aim was to compare gestational metabolic profiles and their determinants between WE and SA women. We used data from a United Kingdom (UK) cohort to compare metabolic profiles and associations of maternal age, education, parity, height, BMI, tricep skinfold thickness, gestational diabetes (GD), pre-eclampsia, and gestational hypertension with 156 metabolic measurements in WE (n = 4072) and SA (n = 4702) women. Metabolic profiles, measured in fasting serum taken between 26–28 weeks gestation, were quantified by nuclear magnetic resonance. Distributions of most metabolic measures differed by ethnicity. WE women had higher levels of most lipoprotein subclasses, cholesterol, glycerides and phospholipids, monosaturated fatty acids, and creatinine but lower levels of glucose, linoleic acid, omega-6 and polyunsaturated fatty acids, and most amino acids. Higher BMI and having GD were associated with higher levels of several lipoprotein subclasses, triglycerides, and other metabolites, mostly with stronger associations in WEs. We have shown differences in gestational metabolic profiles between WE and SA women and demonstrated that associations of exposures with these metabolites differ by ethnicity. Full article

(This article belongs to the Special Issue Metabolomics in Epidemiological Studies)

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15 pages, 2901 KiB

Open AccessArticle

Comprehensive Evaluation of Parameters Affecting One-Step Method for Quantitative Analysis of Fatty Acids in Meat

by Michael P. Agnew, Cameron R. Craigie, Gayani Weralupitiya, Marlon M. Reis, Patricia L. Johnson and Mariza G. Reis

Metabolites 2019, 9(9), 189; https://doi.org/10.3390/metabo9090189 - 18 Sep 2019

Cited by 25 | Viewed by 3344

Abstract

Despite various direct transmethylation methods having been published and applied to analysis of meat fatty acid (FA) composition, there are still conflicting ideas about the best method for overcoming all the difficulties posed by analysis of complex mixtures of FA in meat. This [...] Read more.

Despite various direct transmethylation methods having been published and applied to analysis of meat fatty acid (FA) composition, there are still conflicting ideas about the best method for overcoming all the difficulties posed by analysis of complex mixtures of FA in meat. This study performed a systematic investigation of factors affecting a one-step method for quantitative analysis of fatty acids in freeze-dried animal tissue. Approximately 280 reactions, selected using factorial design, were performed to investigate the effect of temperature, reaction time, acid concentration, solvent volume, sample weight and sample moisture. The reaction yield for different types of fatty acids, including saturated, unsaturated (cis, trans and conjugated) and long-chain polyunsaturated fatty acids was determined. The optimised condition for one-step transmethylation was attained with four millilitres 5% sulfuric acid in methanol (as acid catalyst), four millilitres toluene (as co-solvent), 300 mg of freeze-dried meat and incubation at 70 °C for 2 h, with interim mixing by inversion at 30, 60 and 90 min for 15 s. The optimised condition was applied to meat samples from different species, covering a broad range of fat content and offers a simplified and reliable method for analysis of fatty acids from meat samples. Full article

(This article belongs to the Special Issue Compound Identification of Small Molecules)

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19 pages, 5331 KiB

Open AccessArticle

2-Deoxy-d-Glucose-Induced Metabolic Alteration in Human Oral Squamous SCC15 Cells: Involvement of N-Glycosylation of Axl and Met

by Naeun Lee, Won-Jun Jang, Ji Hae Seo, Sooyeun Lee and Chul-Ho Jeong

Metabolites 2019, 9(9), 188; https://doi.org/10.3390/metabo9090188 - 17 Sep 2019

Cited by 13 | Viewed by 3782

Abstract

One of the most prominent hallmarks of cancer cells is their dependency on the glycolytic pathway for energy production. As a potent inhibitor of glycolysis, 2-deoxy-d-glucose (2DG) has been proposed for cancer treatment and extensively investigated in clinical studies. Moreover, 2DG [...] Read more.

One of the most prominent hallmarks of cancer cells is their dependency on the glycolytic pathway for energy production. As a potent inhibitor of glycolysis, 2-deoxy-d-glucose (2DG) has been proposed for cancer treatment and extensively investigated in clinical studies. Moreover, 2DG has been reported to interfere with other biological processes including glycosylation. To further understand the overall effect of and metabolic alteration by 2DG, we performed biochemical and metabolomics analyses on oral squamous cell carcinoma cell lines. In this study, we found that 2DG more effectively reduced glucose consumption and lactate level in SCC15 cells than in SCC4 cells, which are less dependent on glycolysis. Coincidentally, 2DG impaired N-linked glycosylation of the key oncogenic receptors Axl and Met in SCC15 cells, thereby reducing the cell viability and colony formation ability. The impaired processes of glycolysis and N-linked glycosylation were restored by exogenous addition of pyruvate and mannose, respectively. Additionally, our targeted metabolomics analysis revealed significant alterations in the metabolites, including amino acids, biogenic amines, glycerophospholipids, and sphingolipids, caused by the impairment of glycolysis and N-linked glycosylation. These observations suggest that alterations of these metabolites may be responsible for the phenotypic and metabolic changes in SCC15 cells induced by 2DG. Moreover, our data suggest that N-linked glycosylation of Axl and Met may contribute to the maintenance of cancer properties in SCC15 cells. Further studies are needed to elucidate the roles of these altered metabolites to provide novel therapeutic targets for treating human oral cancer. Full article

(This article belongs to the Special Issue Metabolomics 2019)

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16 pages, 1594 KiB

Open AccessArticle

R-MetaboList 2: A Flexible Tool for Metabolite Annotation from High-Resolution Data-Independent Acquisition Mass Spectrometry Analysis

by Manuel D. Peris-Díaz, Shannon R. Sweeney, Olga Rodak, Enrique Sentandreu and Stefano Tiziani

Metabolites 2019, 9(9), 187; https://doi.org/10.3390/metabo9090187 - 17 Sep 2019

Cited by 9 | Viewed by 4719

Abstract

Technological advancements have permitted the development of innovative multiplexing strategies for data independent acquisition (DIA) mass spectrometry (MS). Software solutions and extensive compound libraries facilitate the efficient analysis of MS¹ data, regardless of the analytical platform. However, the development of comparable tools [...] Read more.

Technological advancements have permitted the development of innovative multiplexing strategies for data independent acquisition (DIA) mass spectrometry (MS). Software solutions and extensive compound libraries facilitate the efficient analysis of MS¹ data, regardless of the analytical platform. However, the development of comparable tools for DIA data analysis has significantly lagged. This research introduces an update to the former MetaboList R package and a workflow for full-scan MS¹ and MS/MS DIA processing of metabolomic data from multiplexed liquid chromatography high-resolution mass spectrometry (LC-HRMS) experiments. When compared to the former version, new functions have been added to address isolated MS¹ and MS/MS workflows, processing of MS/MS data from stepped collision energies, performance scoring of metabolite annotations, and batch job analysis were incorporated into the update. The flexibility and efficiency of this strategy were assessed through the study of the metabolite profiles of human urine, leukemia cell culture, and medium samples analyzed by either liquid chromatography quadrupole time-of-flight (q-TOF) or quadrupole orbital (q-Orbitrap) instruments. This open-source alternative was designed to promote global metabolomic strategies based on recursive retrospective research of multiplexed DIA analysis. Full article

(This article belongs to the Special Issue Metabolomics Data Processing and Data Analysis—Current Best Practices)

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18 pages, 2174 KiB

Open AccessArticle

Untargeted Metabolomics Toward Systematic Characterization of Antioxidant Compounds in Betulaceae Family Plant Extracts

by Sunmin Lee, Dong-Gu Oh, Digar Singh, Hye Jin Lee, Ga Ryun Kim, Sarah Lee, Jong Seok Lee and Choong Hwan Lee

Metabolites 2019, 9(9), 186; https://doi.org/10.3390/metabo9090186 - 16 Sep 2019

Cited by 13 | Viewed by 3183

Abstract

Plant species have traditionally been revered for their unparalleled pharmacognostic applications. We outline a non-iterative multi-parallel metabolomic-cum-bioassay-guided methodology toward the functional characterization of ethanol extracts from the Betulaceae family plants (n = 10). We performed mass spectrometry (MS)-based multivariate analyses and bioassay-guided [...] Read more.

Plant species have traditionally been revered for their unparalleled pharmacognostic applications. We outline a non-iterative multi-parallel metabolomic-cum-bioassay-guided methodology toward the functional characterization of ethanol extracts from the Betulaceae family plants (n = 10). We performed mass spectrometry (MS)-based multivariate analyses and bioassay-guided (ABTS antioxidant activity and cytoprotective effects against H₂O₂-induced cell damage) analyses of SPE fractions. A clearly distinct metabolomic pattern coupled with significantly higher bioactivities was observed for 40% methanol SPE eluate. Further, the 40% SPE eluate was subjected to preparative high-performance liquid chromatography (prep-HPLC) analysis, yielding 72 sub-fractions (1 min⁻¹), with the highest antioxidant activities observed for the 15 min and 31 min sub-fractions. We simultaneously performed hyphenated-MS-based metabolite characterization of bioactive components for both the 40% methanol SPE fraction and its prep-HPLC sub-fraction (15 min and 31 min). Altogether, 19 candidate metabolites were mainly observed to contribute toward the observed bioactivities. In particular, ethyl gallate was mainly observed to affect the antioxidant activities of SPE and prep-HPLC fractions of Alnus firma extracts. We propose an integrated metabolomic-cum-bioassay-guided approach for the expeditious selection and characterization of discriminant metabolites with desired phenotypes or bioactivities. Full article

(This article belongs to the Special Issue Plant Metabolomics)

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16 pages, 1140 KiB

Open AccessArticle

Neonatal Urine Metabolic Profiling and Development of Childhood Asthma

by Bo L. Chawes, Giuseppe Giordano, Paola Pirillo, Daniela Rago, Morten A. Rasmussen, Jakob Stokholm, Klaus Bønnelykke, Hans Bisgaard and Eugenio Baraldi

Metabolites 2019, 9(9), 185; https://doi.org/10.3390/metabo9090185 - 16 Sep 2019

Cited by 18 | Viewed by 2905

Abstract

Urine metabolomics case-control studies of childhood asthma have demonstrated a discriminative ability. Here, we investigated whether urine metabolic profiles from healthy neonates were associated with the development of asthma in childhood. Untargeted metabolomics by liquid chromatography-mass spectrometry was applied to urine samples collected [...] Read more.

Urine metabolomics case-control studies of childhood asthma have demonstrated a discriminative ability. Here, we investigated whether urine metabolic profiles from healthy neonates were associated with the development of asthma in childhood. Untargeted metabolomics by liquid chromatography-mass spectrometry was applied to urine samples collected at age 4 weeks in 171 and 161 healthy neonates born from mothers with asthma from the COPSAC2000 and COPSAC2010 cohorts, respectively, where persistent wheeze/asthma was prospectively diagnosed using a symptom-based algorithm. Univariate and multivariate analyses were applied to investigate differences in metabolic profiles between children who developed asthma and healthy children. Univariate analysis showed 63 and 87 metabolites (q-value < 0.15) in COPSAC2000 and COPSAC2010, respectively, which is promising for discriminating between asthmatic and healthy children. Of those, 14 metabolites were common among the two cohorts. Multivariate random forest and projection to latent structures discriminant analyses confirmed the discriminatory capacity of the metabolic profiles in both cohorts with estimated errors in prediction equal to 35% and AUCpred > 0.60. Database search enabled annotation of three discriminative features: a glucoronidated compound (steroid), 3-hydroxytetradecanedioic acid (fatty acid), and taurochenodeoxycholate-3-sulfate (bile acid). The urine metabolomics profiles from healthy neonates were associated with the development of childhood asthma, but further research is needed to understand underlying metabolic pathways. Full article

(This article belongs to the Special Issue Metabolomics and Chronic Obstructive Lung Diseases)

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21 pages, 918 KiB

Open AccessArticle

Targeted Clinical Metabolite Profiling Platform for the Stratification of Diabetic Patients

by Linda Ahonen, Sirkku Jäntti, Tommi Suvitaival, Simone Theilade, Claudia Risz, Risto Kostiainen, Peter Rossing, Matej Orešič and Tuulia Hyötyläinen

Metabolites 2019, 9(9), 184; https://doi.org/10.3390/metabo9090184 - 14 Sep 2019

Cited by 18 | Viewed by 4609

Abstract

Several small molecule biomarkers have been reported in the literature for prediction and diagnosis of (pre)diabetes, its co-morbidities, and complications. Here, we report the development and validation of a novel, quantitative method for the determination of a selected panel of 34 metabolite biomarkers [...] Read more.

Several small molecule biomarkers have been reported in the literature for prediction and diagnosis of (pre)diabetes, its co-morbidities, and complications. Here, we report the development and validation of a novel, quantitative method for the determination of a selected panel of 34 metabolite biomarkers from human plasma. We selected a panel of metabolites indicative of various clinically-relevant pathogenic stages of diabetes. We combined these candidate biomarkers into a single ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method and optimized it, prioritizing simplicity of sample preparation and time needed for analysis, enabling high-throughput analysis in clinical laboratory settings. We validated the method in terms of limits of detection (LOD) and quantitation (LOQ), linearity (R²), and intra- and inter-day repeatability of each metabolite. The method’s performance was demonstrated in the analysis of selected samples from a diabetes cohort study. Metabolite levels were associated with clinical measurements and kidney complications in type 1 diabetes (T1D) patients. Specifically, both amino acids and amino acid-related analytes, as well as specific bile acids, were associated with macro-albuminuria. Additionally, specific bile acids were associated with glycemic control, anti-hypertensive medication, statin medication, and clinical lipid measurements. The developed analytical method is suitable for robust determination of selected plasma metabolites in the diabetes clinic. Full article

(This article belongs to the Special Issue Metabolomics 2019)

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14 pages, 2674 KiB

Open AccessArticle

Comparative Evaluation of Six Traditional Fermented Soybean Products in East Asia: A Metabolomics Approach

by Yong Sung Kwon, Sunmin Lee, Seung Hwa Lee, Hae Jin Kim and Choong Hwan Lee

Metabolites 2019, 9(9), 183; https://doi.org/10.3390/metabo9090183 - 13 Sep 2019

Cited by 33 | Viewed by 4400

Abstract

Many ethnic fermented soybean products (FSPs) have long been consumed as seasoning and protein sources in East Asia. To evaluate the quality of various FSPs in East Asia, non-targeted metabolite profiling with multivariate analysis of six traditional FSPs (Natto; NT, Cheonggukjang; CG, Doenjang; [...] Read more.

Many ethnic fermented soybean products (FSPs) have long been consumed as seasoning and protein sources in East Asia. To evaluate the quality of various FSPs in East Asia, non-targeted metabolite profiling with multivariate analysis of six traditional FSPs (Natto; NT, Cheonggukjang; CG, Doenjang; DJ, Miso; MS, Doubanjiang; DB, Tianmianjiang; TM) was performed. Six FSPs could be clearly distinguished by principle component analysis (PCA) and partial least square-discriminant analysis (PLS-DA). Amino acid contents were relatively higher in NT and CG, sugar and sugar alcohol contents were relatively higher in MS and TM, isoflavone glycoside contents were relatively highest in CG, isoflavone aglycon contents were the highest in DJ, and soyasaponin contents were the highest in CG. Antioxidant activity and physicochemical properties were determined to examine the relationships between the FSPs and their antioxidant activities. We observed a negative correlation between isoflavone aglycon contents and 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) activity. Furthermore, the order of ABTS activity of FSPs has a positive correlation with the order of soybean content in the six FSPs. Herein it was found that primary metabolites were affected by the main ingredients and secondary metabolites were most influenced by the fermentation time, and that soybean content contributed more to antioxidant activity than fermentation time. Full article

(This article belongs to the Special Issue Metabolomics in Yeast and Fermentation)

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23 pages, 2389 KiB

Open AccessArticle

Production of Active Poly- and Oligosaccharidic Fractions from Ulva sp. by Combining Enzyme-Assisted Extraction (EAE) and Depolymerization

by Mathilde Fournière, Thomas Latire, Marie Lang, Nolwenn Terme, Nathalie Bourgougnon and Gilles Bedoux

Metabolites 2019, 9(9), 182; https://doi.org/10.3390/metabo9090182 - 12 Sep 2019

Cited by 16 | Viewed by 3958

Abstract

Data on fractionation and depolymerization of the matrix ulvan polysaccharides, and studies on the biological activities on skin cells, are very scarce. In this work, crude ulvans were produced by using EAE (enzyme-assisted extraction) and compared to maceration (an established procedure). After different [...] Read more.

Data on fractionation and depolymerization of the matrix ulvan polysaccharides, and studies on the biological activities on skin cells, are very scarce. In this work, crude ulvans were produced by using EAE (enzyme-assisted extraction) and compared to maceration (an established procedure). After different fractionation procedures—ethanolic precipitation, dialysis, or ammonium sulfate precipitation—the biochemical composition showed that EAE led to an increased content in ulvans. Coupling EAE to sulfate ammonium precipitation led to protein enrichment. Oligosaccharides were obtained by using radical depolymerization by H₂O₂ and ion-exchange resin depolymerization. Sulfate groups were partially cleaved during these chemical treatments. The potential bioactivity of the fractions was assessed using a lipoxygenase inhibition assay for anti-inflammatory activity and a WST-1 assay for human dermal fibroblast viability and proliferation. All ulvans extracts, poly- and oligosaccharidic fractions from EAE, expanded the fibroblast proliferation rate up to 62%. Our research emphasizes the potential use of poly- and oligosaccharidic fractions of Ulva sp. for further development in cosmetic applications. Full article

(This article belongs to the Special Issue Seaweeds Metabolites)

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14 pages, 18881 KiB

Open AccessArticle

An Isotopic Ratio Outlier Analysis Approach for Global Metabolomics of Biosynthetically Talented Actinomycetes

by Jordan Carey, Thanh Nguyen, Jennifer Korchak, Christopher Beecher, Felice de Jong and Amy L. Lane

Metabolites 2019, 9(9), 181; https://doi.org/10.3390/metabo9090181 - 10 Sep 2019

Cited by 2 | Viewed by 4045

Abstract

Actinomycetes are powerhouses of natural product biosynthesis. Full realization of this biosynthetic potential requires approaches for recognizing novel metabolites and determining mediators of metabolite production. Herein, we develop an isotopic ratio outlier analysis (IROA) ultra-high performance liquid chromatography-mass spectrometry (UHPLC/MS) global metabolomics strategy [...] Read more.

Actinomycetes are powerhouses of natural product biosynthesis. Full realization of this biosynthetic potential requires approaches for recognizing novel metabolites and determining mediators of metabolite production. Herein, we develop an isotopic ratio outlier analysis (IROA) ultra-high performance liquid chromatography-mass spectrometry (UHPLC/MS) global metabolomics strategy for actinomycetes that facilitates recognition of novel metabolites and evaluation of production mediators. We demonstrate this approach by determining impacts of the iron chelator 2,2′-bipyridyl on the Nocardiopsis dassonvillei metabolome. Experimental and control cultures produced metabolites with isotopic carbon signatures that were distinct from corresponding “standard” culture metabolites, which were used as internal standards for LC/MS. This provided an isotopic MS peak pair for each metabolite, which revealed the number of carbon atoms and relative concentrations of metabolites and distinguished biosynthetic products from artifacts. Principal component analysis (PCA) and random forest (RF) differentiated bipyridyl-treated samples from controls. RF mean decrease accuracy (MDA) values supported perturbation of metabolites from multiple amino acid pathways and novel natural products. Evaluation of bipyridyl impacts on the nocazine/XR334 diketopiperazine (DKP) pathway revealed upregulation of amino acid precursors and downregulation of late stage intermediates and products. These results establish IROA as a tool in the actinomycete natural product chemistry arsenal and support broad metabolic consequences of bipyridyl. Full article

(This article belongs to the Special Issue Natural Products Metabolomics)

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17 pages, 659 KiB

Open AccessReview

Nicotinamide and NAFLD: Is There Nothing New Under the Sun?

by Maria Guarino and Jean-François Dufour

Metabolites 2019, 9(9), 180; https://doi.org/10.3390/metabo9090180 - 10 Sep 2019

Cited by 16 | Viewed by 4122

Abstract

Nicotinamide adenine dinucleotide (NAD) has a critical role in cellular metabolism and energy homeostasis. Its importance has been established early with the discovery of NAD’s therapeutic role for pellagra. This review addresses some of the recent findings on NAD physiopathology and their effects [...] Read more.

Nicotinamide adenine dinucleotide (NAD) has a critical role in cellular metabolism and energy homeostasis. Its importance has been established early with the discovery of NAD’s therapeutic role for pellagra. This review addresses some of the recent findings on NAD physiopathology and their effects on nonalcoholic fatty liver disease (NAFLD) pathogenesis, which need to be considered in the search for a better therapeutic approach. Reduced NAD concentrations contribute to the dysmetabolic imbalance and consequently to the pathogenesis of NAFLD. In this perspective, the dietary supplementation or the pharmacological modulation of NAD levels appear to be an attractive strategy. These reviewed studies open the doors to growing interest in NAD metabolism for NAFLD diagnosis, prevention, and treatment. Future rigorous clinical studies in humans will be necessary to validate these preliminary but promising results. Full article

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

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16 pages, 872 KiB

Open AccessArticle

Pharmacometabolomics of Bronchodilator Response in Asthma and the Role of Age-Metabolite Interactions

by Rachel S. Kelly, Joanne E. Sordillo, Sharon M. Lutz, Lydiana Avila, Manuel Soto-Quiros, Juan C. Celedón, Michael J. McGeachie, Amber Dahlin, Kelan Tantisira, Mengna Huang, Clary B. Clish, Scott T. Weiss, Jessica Lasky-Su and Ann Chen Wu

Metabolites 2019, 9(9), 179; https://doi.org/10.3390/metabo9090179 - 07 Sep 2019

Cited by 13 | Viewed by 2970

Abstract

The role of metabolism in modifying age-related differential responses to asthma medications is insufficiently understood. The objective of this study was to determine the role of the metabolome in modifying the effect of age on bronchodilator response (BDR) in individuals with asthma. We [...] Read more.

The role of metabolism in modifying age-related differential responses to asthma medications is insufficiently understood. The objective of this study was to determine the role of the metabolome in modifying the effect of age on bronchodilator response (BDR) in individuals with asthma. We used longitudinal measures of BDR and plasma metabolomic profiling in 565 children with asthma from the Childhood Asthma Management Program (CAMP) to identify age by metabolite interactions on BDR. The mean ages at the three studied time-points across 16 years of follow-up in CAMP were 8.8, 12.8, and 16.8 years; the mean BDRs were 11%, 9% and 8%, respectively. Of 501 identified metabolites, 39 (7.8%) demonstrated a significant interaction with age on BDR (p-value < 0.05). We were able to validate two significant interactions in 320 children with asthma from the Genetics of Asthma in Costa Rica Study; 2-hydroxyglutarate, a compound involved in butanoate metabolism (interaction; CAMP: β = −0.004, p = 1.8 × 10⁻⁴; GACRS: β = −0.015, p = 0.018), and a cholesterol ester; CE C18:1 (CAMP: β = 0.005, p = 0.006; GACRS: β = 0.023, p = 0.041) Five additional metabolites had a p-value < 0.1 in GACRS, including Gammaminobutyric acid (GABA), C16:0 CE, C20:4 CE, C18.0 CE and ribothymidine. These findings suggest Cholesterol esters and GABA may modify the estimated effect of age on bronchodilator response. Full article

(This article belongs to the Special Issue Metabolomics and Chronic Obstructive Lung Diseases)

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22 pages, 2485 KiB

Open AccessArticle

Multiplatform Urinary Metabolomics Profiling to Discriminate Cachectic from Non-Cachectic Colorectal Cancer Patients: Pilot Results from the ColoCare Study

by Jennifer Ose, Biljana Gigic, Tengda Lin, David B. Liesenfeld, Jürgen Böhm, Johanna Nattenmüller, Dominique Scherer, Lin Zielske, Petra Schrotz-King, Nina Habermann, Heather M. Ochs-Balcom, Anita R. Peoples, Sheetal Hardikar, Christopher I. Li, David Shibata, Jane Figueiredo, Adetunji T. Toriola, Erin M. Siegel, Stephanie Schmit, Martin Schneider, Alexis Ulrich, Hans-Ulrich Kauczor and Cornelia M. Ulrich Show full author list Hide full author list

Metabolites 2019, 9(9), 178; https://doi.org/10.3390/metabo9090178 - 06 Sep 2019

Cited by 12 | Viewed by 3477

Abstract

Cachexia is a multifactorial syndrome that is characterized by loss of skeletal muscle mass in cancer patients. The biological pathways involved remain poorly characterized. Here, we compare urinary metabolic profiles in newly diagnosed colorectal cancer patients (stage I–IV) from the ColoCare Study in [...] Read more.

Cachexia is a multifactorial syndrome that is characterized by loss of skeletal muscle mass in cancer patients. The biological pathways involved remain poorly characterized. Here, we compare urinary metabolic profiles in newly diagnosed colorectal cancer patients (stage I–IV) from the ColoCare Study in Heidelberg, Germany. Patients were classified as cachectic (n = 16), pre-cachectic (n = 13), or non-cachectic (n = 23) based on standard criteria on weight loss over time at two time points. Urine samples were collected pre-surgery, and 6 and 12 months thereafter. Fat and muscle mass area were assessed utilizing computed tomography scans at the time of surgery. N = 152 compounds were detected using untargeted metabolomics with gas chromatography–mass spectrometry and n = 154 features with proton nuclear magnetic resonance spectroscopy. Thirty-four metabolites were overlapping across platforms. We calculated differences across groups and performed discriminant and overrepresentation enrichment analysis. We observed a trend for 32 compounds that were nominally significantly different across groups, although not statistically significant after adjustment for multiple testing. Nineteen compounds could be identified, including acetone, hydroquinone, and glycine. Comparing cachectic to non-cachectic patients, higher levels of metabolites such as acetone (Fold change (FC) = 3.17; p = 0.02) and arginine (FC = 0.33; p = 0.04) were observed. The two top pathways identified were glycerol phosphate shuttle metabolism and glycine and serine metabolism pathways. Larger subsequent studies are needed to replicate and validate these results. Full article

(This article belongs to the Special Issue Metabolomics in Epidemiological Studies)

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16 pages, 1273 KiB

Open AccessArticle

Oxylipin Profiling of Alzheimer’s Disease in Nondiabetic and Type 2 Diabetic Elderly

by Jill K. Morris, Brian D. Piccolo, Casey S. John, Zachary D. Green, John P. Thyfault and Sean H. Adams

Metabolites 2019, 9(9), 177; https://doi.org/10.3390/metabo9090177 - 05 Sep 2019

Cited by 19 | Viewed by 3405

Abstract

Oxygenated lipids, called “oxylipins,” serve a variety of important signaling roles within the cell. Oxylipins have been linked to inflammation and vascular function, and blood patterns have been shown to differ in type 2 diabetes (T2D). Because these factors (inflammation, vascular function, diabetes) [...] Read more.

Oxygenated lipids, called “oxylipins,” serve a variety of important signaling roles within the cell. Oxylipins have been linked to inflammation and vascular function, and blood patterns have been shown to differ in type 2 diabetes (T2D). Because these factors (inflammation, vascular function, diabetes) are also associated with Alzheimer’s disease (AD) risk, we set out to characterize the serum oxylipin profile in elderly and AD subjects to understand if there are shared patterns between AD and T2D. We obtained serum from 126 well-characterized, overnight-fasted elderly individuals who underwent a stringent cognitive evaluation and were determined to be cognitively healthy or AD. Because the oxylipin profile may also be influenced by T2D, we assessed nondiabetic and T2D subjects separately. Within nondiabetic individuals, cognitively healthy subjects had higher levels of the nitrolipid 10-nitrooleate (16.8% higher) compared to AD subjects. AD subjects had higher levels of all four dihydroxyeicosatrienoic acid (DiHETrE) species: 14,15-DiHETrE (18% higher), 11,12 DiHETrE (18% higher), 8,9-DiHETrE (23% higher), and 5,6-DiHETrE (15% higher). Within T2D participants, we observed elevations in 14,15-dihydroxyeicosa-5,8,11-trienoic acid (14,15-DiHETE; 66% higher), 17,18-dihydroxyeicosa-5,8,11,14-tetraenoic acid (17,18-DiHETE; 29% higher) and 17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid (17-HDoHE; 105% higher) and summed fatty acid diols (85% higher) in subjects with AD compared to cognitively healthy elderly, with no differences in the DiHETrE species between groups. Although these effects were no longer significant following stringent adjustment for multiple comparisons, the consistent effects on groups of molecules with similar physiological roles, as well as clear differences in the AD-related profiles within nondiabetic and T2D individuals, warrant further research into these molecules in the context of AD. Full article

(This article belongs to the Special Issue Metabolomics to Probe Metabolism in Ageing and Age-related Neurodegenerative Diseases)

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14 pages, 3144 KiB

Open AccessArticle

Comparison of Differential Flavor Metabolites in Meat of Lubei White Goat, Jining Gray Goat and Boer Goat

by Weiting Wang, Bei Sun, Peng Hu, Meng Zhou, Sujun Sun, Pengfei Du, Yi Ru, Alexander Suvorov, Yongsheng Li, Yaobo Liu and Shoujing Wang

Metabolites 2019, 9(9), 176; https://doi.org/10.3390/metabo9090176 - 05 Sep 2019

Cited by 20 | Viewed by 3980

Abstract

Flavor is one of the most important sensory characteristics of meat. The development of taste and aroma can be attributed to thousands of flavor molecules and precursors that are present in meat tissues. As a result, the identification of these flavor compounds and [...] Read more.

Flavor is one of the most important sensory characteristics of meat. The development of taste and aroma can be attributed to thousands of flavor molecules and precursors that are present in meat tissues. As a result, the identification of these flavor compounds and an improved understanding of their roles are necessary for improving the sensory quality and customer appeal of meat products. In the current study, we compared the metabolic profiles of meat specimens from the Lubei white goats (LBB), Boer goats (BE) and Jining grey goats (JNQ) by untargeted liquid chromatography-mass spectrometry. Our metabolomic data revealed that the three types of goat meat showed significantly different profiles of fatty acids, aldehydes, ketones, lactones, alkaloids, flavonoids, phenolics and drug residues, which could underpin the nuances of their flavors. Taken together, our results provided insights into the molecular basis for sensory variations between different goat meat products. Full article

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1 pages, 145 KiB

Open AccessErratum

Erratum: Chen, F. et al. Advances of Metabolomics in Fungal Pathogen–Plant Interactions. Metabolites 2019, 9, 169

by Fangfang Chen, Ruijing Ma and Xiao-Lin Chen

Metabolites 2019, 9(9), 175; https://doi.org/10.3390/metabo9090175 - 04 Sep 2019

Cited by 13 | Viewed by 1769

Abstract

The authors wish to make the following corrections to this paper [...] Full article

21 pages, 6623 KiB

Open AccessArticle

Non-Targeted UHPLC-Q-TOF/MS-Based Metabolomics Reveals a Metabolic Shift from Glucose to Glutamine in CPB Cells during ISKNV Infection Cycle

by Xiaozhe Fu, Xixi Guo, Shiwei Wu, Qiang Lin, Lihui Liu, Hongru Liang, Yinjie Niu and Ningqiu Li

Metabolites 2019, 9(9), 174; https://doi.org/10.3390/metabo9090174 - 04 Sep 2019

Cited by 20 | Viewed by 3517

Abstract

Infectious spleen and kidney necrosis virus (ISKNV) has caused serious economic losses in the cultured mandarin fish (Siniperca chuatsi) industry in China. Host metabolism alteration induced by disease infection may be the core problem of pathogenesis. However, to date, little is [...] Read more.

Infectious spleen and kidney necrosis virus (ISKNV) has caused serious economic losses in the cultured mandarin fish (Siniperca chuatsi) industry in China. Host metabolism alteration induced by disease infection may be the core problem of pathogenesis. However, to date, little is known about the disease-induced fish metabolism changes. In this study, we first reported ISKNV, the fish virus, induced metabolism alteration. The metabolomics profiles of Chinese perch brain cells (CPB) post-ISKNV infection at progressive time points were analyzed using the UHPLC-Q-TOF/MS technique. A total of 98 differential metabolites were identified. In the samples harvested at 24 hours post-infection (hpi; the early stage of ISKNV infection), 49 differential metabolites were identified comparing with control cells, including 31 up-regulated and 18 down-regulated metabolites. And in the samples harvested at 72 hpi (the late stage of ISKNV infection), 49 differential metabolites were identified comparing with control cells, including 27 up-regulated and 22 down-regulated metabolites. These differential metabolites were involved in many pathways related with viral pathogenesis. Further analysis on the major differential metabolites related to glucose metabolism and amino acid metabolism revealed that both glucose metabolism and glutamine metabolism were altered and a metabolic shift was determined from glucose to glutamine during ISKNV infection cycle. In ISKNV-infected cells, CPB cells prefer to utilize glucose for ISKNV replication at the early stage of infection, while they prefer to utilize glutamine to synthetize lipid for ISKNV maturation at the late stage of infection. These findings may improve the understanding of the interaction between ISKNV and host, as well as provide a new insight for elucidating the ISKNV pathogenic mechanism. Full article

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11 pages, 2477 KiB

Open AccessArticle

A Facile Profiling Method of Short Chain Fatty Acids Using Liquid Chromatography-Mass Spectrometry

by Ha Eun Song, Hyo Yeong Lee, Su Jung Kim, Sung Hoon Back and Hyun Ju Yoo

Metabolites 2019, 9(9), 173; https://doi.org/10.3390/metabo9090173 - 28 Aug 2019

Cited by 32 | Viewed by 5066

Abstract

Short chain fatty acids (SCFAs) are the main products of dietary fibers that are not digested by the human body, and they have been shown to affect human metabolism and inflammation. The amount of SCFAs in the body is related to many human [...] Read more.

Short chain fatty acids (SCFAs) are the main products of dietary fibers that are not digested by the human body, and they have been shown to affect human metabolism and inflammation. The amount of SCFAs in the body is related to many human diseases, and studies have focused on elucidating their roles and target molecules in both metabolic and immune responses. Thus, the quantitation of SCFAs in biological samples becomes crucial in understanding their important roles in the human body. Herein, a facile profiling method of SCFAs using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and then applied to biological samples. C2-C6 SCFAs were derivatized while using 4-acetamido-7-mercapto-2,1,3-benzoxadiazole for 5 min. at room temperature prior to LC-MS/MS analysis, and characteristic fragmentation patterns and increased hydrophobicity after chemical derivatization enabled specific discrimination among 12 SCFAs. Derivatization was fast and reliable, and the reaction products were stable for a week at 4 °C. The developed method was applied to measure SCFAs in mouse feces, plasma, and human exhaled breath condensates. This fast and simple method can save labor and effort to profile SCFAs from various biological samples. Full article

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11 pages, 2561 KiB

Open AccessArticle

Optimal Regimen of N-Acetylcysteine on Chromium-Induced Renal Cell Damage

by I-Jeng Yeh, Tzu-Yi Wang, Jhong-Ching Lin, Tzeng-Jih Lin, Jung-San Chang, Meng-Chi Yen, Yao-Hua Liu, Pei-Lin Wu, Fen-Wei Chen, Yueh-Lun Shih and Chiung-Yu Peng

Metabolites 2019, 9(9), 172; https://doi.org/10.3390/metabo9090172 - 28 Aug 2019

Cited by 4 | Viewed by 2571

Abstract

Chromium (Cr) is a well-known heavy metal that can cause renal damage. The production of reactive oxygen species (ROS) due to chromium-induced toxicity induces cell dysfunction, apoptosis, and death. N-acetylcysteine (NAC) is an antioxidant used as an antidote for chromium-induced toxicity. However, the [...] Read more.

Chromium (Cr) is a well-known heavy metal that can cause renal damage. The production of reactive oxygen species (ROS) due to chromium-induced toxicity induces cell dysfunction, apoptosis, and death. N-acetylcysteine (NAC) is an antioxidant used as an antidote for chromium-induced toxicity. However, the optimal regimen and protective mechanisms of NAC are not fully understood in human renal cells. Our results showed that exposure to 10 μM K₂Cr₂O₇, a toxic Cr(VI) compound, induced apoptosis and production of intracellular ROS in the human proximal tubular epithelial cell line HK-2. Supplements of 600 or 1000 µg/mL NAC inhibited intracellular ROS in HK-2 cells exposed to Cr(VI) and significantly increased cell viability within 2 h of Cr(VI)-induced cytotoxicity. Moreover, Cr(VI) induced the expression of apoptosis markers, including cleaved-caspase-3, cleaved-poly (ADP-ribose) polymerase, cleaved-caspase 8, and cleaved-caspase 9, and altered the expression ratio of Bax/Bcl-xL. Expression of apoptosis markers within 2 h of Cr(VI)-induced cytotoxicity in cells treated with 600 µg/mL NAC was significantly suppressed. However, delayed treatment with NAC at 4 h and 8 h after exposure to Cr did not suppress the activation of apoptotic pathways. In summary, our study reports the optimum timing and dose of NAC for the protection of human renal proximal tubular cells from Cr(VI)-induced cell death. The NAC treatment strategy described could be applied in clinical practice to suppress renal cell apoptosis, which in turn could rescue renal function. Full article

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15 pages, 2112 KiB

Open AccessArticle

WiPP: Workflow for Improved Peak Picking for Gas Chromatography-Mass Spectrometry (GC-MS) Data

by Nico Borgsmüller, Yoann Gloaguen, Tobias Opialla, Eric Blanc, Emilie Sicard, Anne-Lise Royer, Bruno Le Bizec, Stéphanie Durand, Carole Migné, Mélanie Pétéra, Estelle Pujos-Guillot, Franck Giacomoni, Yann Guitton, Dieter Beule and Jennifer Kirwan

Metabolites 2019, 9(9), 171; https://doi.org/10.3390/metabo9090171 - 21 Aug 2019

Cited by 18 | Viewed by 6008

Abstract

Lack of reliable peak detection impedes automated analysis of large-scale gas chromatography-mass spectrometry (GC-MS) metabolomics datasets. Performance and outcome of individual peak-picking algorithms can differ widely depending on both algorithmic approach and parameters, as well as data acquisition method. Therefore, comparing and contrasting [...] Read more.

Lack of reliable peak detection impedes automated analysis of large-scale gas chromatography-mass spectrometry (GC-MS) metabolomics datasets. Performance and outcome of individual peak-picking algorithms can differ widely depending on both algorithmic approach and parameters, as well as data acquisition method. Therefore, comparing and contrasting between algorithms is difficult. Here we present a workflow for improved peak picking (WiPP), a parameter optimising, multi-algorithm peak detection for GC-MS metabolomics. WiPP evaluates the quality of detected peaks using a machine learning-based classification scheme based on seven peak classes. The quality information returned by the classifier for each individual peak is merged with results from different peak detection algorithms to create one final high-quality peak set for immediate down-stream analysis. Medium- and low-quality peaks are kept for further inspection. By applying WiPP to standard compound mixes and a complex biological dataset, we demonstrate that peak detection is improved through the novel way to assign peak quality, an automated parameter optimisation, and results in integration across different embedded peak picking algorithms. Furthermore, our approach can provide an impartial performance comparison of different peak picking algorithms. WiPP is freely available on GitHub (https://github.com/bihealth/WiPP) under MIT licence. Full article

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