Metabolites

15 pages, 2971 KiB

Open AccessArticle

L-Carnitine Stimulates In Vivo Carbohydrate Metabolism in the Type 1 Diabetic Heart as Demonstrated by Hyperpolarized MRI

by Dragana Savic, Vicky Ball, M. Kate Curtis, Maria da Luz Sousa Fialho, Kerstin N. Timm, David Hauton, James West, Julian Griffin, Lisa C. Heather and Damian J. Tyler

Metabolites 2021, 11(3), 191; https://doi.org/10.3390/metabo11030191 - 23 Mar 2021

Cited by 7 | Viewed by 3246

Abstract

The diabetic heart is energetically and metabolically abnormal, with increased fatty acid oxidation and decreased glucose oxidation. One factor contributing to the metabolic dysfunction in diabetes may be abnormal handling of acetyl and acyl groups by the mitochondria. L-carnitine is responsible for their [...] Read more.

The diabetic heart is energetically and metabolically abnormal, with increased fatty acid oxidation and decreased glucose oxidation. One factor contributing to the metabolic dysfunction in diabetes may be abnormal handling of acetyl and acyl groups by the mitochondria. L-carnitine is responsible for their transfer across the mitochondrial membrane, therefore, supplementation with L-carnitine may provide a route to improve the metabolic state of the diabetic heart. The primary aim of this study was to use hyperpolarized magnetic resonance imaging (MRI) to investigate the effects of L-carnitine supplementation on the in vivo metabolism of [1-¹³C]pyruvate in diabetes. Male Wistar rats were injected with either vehicle or streptozotocin (55 mg/kg) to induce type-1 diabetes. Three weeks of daily i.p. treatment with either saline or L-carnitine (3 g/kg/day) was subsequently undertaken. In vivo cardiac function and metabolism were assessed with CINE and hyperpolarized MRI, respectively. L-carnitine supplementation prevented the progression of hyperglycemia, which was observed in untreated streptozotocin injected animals and led to reductions in plasma triglyceride and ß-hydroxybutyrate concentrations. Hyperpolarized MRI revealed that L-carnitine treatment elevated pyruvate dehydrogenase flux by 3-fold in the diabetic animals, potentially through increased buffering of excess acetyl-CoA units in the mitochondria. Improved functional recovery following ischemia was also observed in the L-carnitine treated diabetic animals. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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11 pages, 1978 KiB

Open AccessArticle

The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1

by Mohammed Hamed Alqarni, Ahmed Ibrahim Foudah, Magdy Mohamed Muharram and Nikolaos E. Labrou

Metabolites 2021, 11(3), 190; https://doi.org/10.3390/metabo11030190 - 23 Mar 2021

Cited by 10 | Viewed by 2764

Abstract

Glutathione transferases (GSTs) are a family of Phase II detoxification enzymes that are involved in the development of the multidrug resistance (MDR) mechanism in cancer cells and therefore affect the clinical outcome of cancer chemotherapy. The discovery of nontoxic natural compounds as inhibitors [...] Read more.

Glutathione transferases (GSTs) are a family of Phase II detoxification enzymes that are involved in the development of the multidrug resistance (MDR) mechanism in cancer cells and therefore affect the clinical outcome of cancer chemotherapy. The discovery of nontoxic natural compounds as inhibitors for GSTs is a promising approach for chemosensitizing and reversing MDR. Fisetin (7,3′,4′-flavon-3-ol) is a plant flavonol present in many plants and fruits. In the present work, the interaction of fisetin with human glutathione transferase A1-1 (hGSTA1-1) was investigated. Kinetic analysis revealed that fisetin is a reversible inhibitor for hGSTA1-1 with IC₅₀ 1.2 ± 0.1 μΜ. It functions as a mixed-type inhibitor toward glutathione (GSH) and as a noncompetitive inhibitor toward the electrophile substrate 1-chloro-2,4-dinitrobenzene (CDNB). In silico molecular modeling and docking predicted that fisetin binds at a distinct location, in the solvent channel of the enzyme, and occupies the entrance of the substrate-binding sites. Treatment of proliferating human epithelial colorectal adenocarcinoma cells (CaCo-2) with fisetin causes a reduction in the expression of hGSTA1-1 at the mRNA and protein levels. In addition, fisetin inhibits GST activity in CaCo-2 cell crude extract with an IC₅₀ (2.5 ± 0.1 μΜ), comparable to that measured using purified recombinant hGSTA1-1. These actions of fisetin can provide a synergistic role toward the suppression and chemosensitization of cancer cells. The results of the present study provide insights into the development of safe and effective GST-targeted cancer chemosensitizers. Full article

(This article belongs to the Special Issue Advances in Plant Specialized Metabolites: How to Take Full Advantages of the Properties of Specialized Metabolites?)

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23 pages, 1773 KiB

Open AccessArticle

The Role of Risk or Contributory Death Factors in Methadone-Related Fatalities: A Review and Pooled Analysis

by Arianna Giorgetti, Jennifer Pascali, Massimo Montisci, Irene Amico, Barbara Bonvicini, Paolo Fais, Alessia Viero, Raffaele Giorgetti, Giovanni Cecchetto and Guido Viel

Metabolites 2021, 11(3), 189; https://doi.org/10.3390/metabo11030189 - 22 Mar 2021

Cited by 4 | Viewed by 3375

Abstract

Methadone-related deaths are characterized by a wide range of post-mortem blood concentrations, due to the high pharmacokinetic/dynamic inter-individual variability, the potential subjective tolerance state and to other risk factors or comorbidities, which might enhance methadone acute toxicity. In the present study, the association [...] Read more.

Methadone-related deaths are characterized by a wide range of post-mortem blood concentrations, due to the high pharmacokinetic/dynamic inter-individual variability, the potential subjective tolerance state and to other risk factors or comorbidities, which might enhance methadone acute toxicity. In the present study, the association among pre-existing and external conditions and diseases and the resultant methadone death capacity have been investigated. Beside a systematic literature review, a retrospective case-control study was done, dividing cases in which methadone was the only cause of death (controls), and those with associated clinical-circumstantial (naive/non-tolerant state), pathological (pulmonary or cardiovascular diseases) or toxicological (other drugs detected) conditions. Methadone concentrations were compared between the two groups and the association with conditions/diseases was assessed by multiple linear and binomial logistic regressions. Literature cases were 139, in house 35, consisting of 22 controls and 152 cases with associated conditions/diseases. Mean methadone concentrations were 2122 ng/mL and 715 ng/mL in controls and cases respectively, with a statistically significant difference (p < 0.05). Lower methadone concentrations (by 24, 19 and 33% respectively) were detected in association with naive/non-tolerant state, pulmonary diseases and presence of other drugs, and low levels of methadone (<600 ng/mL) might lead to death in the presence of the above conditions/diseases. Full article

(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)

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18 pages, 3326 KiB

Open AccessArticle

Stable Isotopic Tracer Phospholipidomics Reveals Contributions of Key Phospholipid Biosynthetic Pathways to Low Hepatocyte Phosphatidylcholine to Phosphatidylethanolamine Ratio Induced by Free Fatty Acids

by Kang-Yu Peng, Christopher K Barlow, Helene Kammoun, Natalie A Mellett, Jacquelyn M Weir, Andrew J Murphy, Mark A Febbraio and Peter J Meikle

Metabolites 2021, 11(3), 188; https://doi.org/10.3390/metabo11030188 - 22 Mar 2021

Cited by 6 | Viewed by 3141

Abstract

There is a strong association between hepatocyte phospholipid homeostasis and non-alcoholic fatty liver disease (NAFLD). The phosphatidylcholine to phosphatidylethanolamine ratio (PC/PE) often draws special attention as genetic and dietary disruptions to this ratio can provoke steatohepatitis and other signs of NAFLD. Here we [...] Read more.

There is a strong association between hepatocyte phospholipid homeostasis and non-alcoholic fatty liver disease (NAFLD). The phosphatidylcholine to phosphatidylethanolamine ratio (PC/PE) often draws special attention as genetic and dietary disruptions to this ratio can provoke steatohepatitis and other signs of NAFLD. Here we demonstrated that excessive free fatty acid (1:2 mixture of palmitic and oleic acid) alone was able to significantly lower the phosphatidylcholine to phosphatidylethanolamine ratio, along with substantial alterations to phospholipid composition in rat hepatocytes. This involved both a decrease in hepatocyte phosphatidylcholine (less prominent) and an increase in phosphatidylethanolamine, with the latter contributing more to the lowered ratio. Stable isotopic tracer phospholipidomic analysis revealed several previously unidentified changes that were triggered by excessive free fatty acid. Importantly, the enhanced cytidine diphosphate (CDP)-ethanolamine pathway activity appeared to be driven by the increased supply of preferred fatty acid substrates. By contrast, the phosphatidylethanolamine N-methyl transferase (PEMT) pathway was restricted by low endogenous methionine and consequently low S-adenosylmethionine, which resulted in a concomitant decrease in phosphatidylcholine and accumulation of phosphatidylethanolamine. Overall, our study identified several previously unreported links in the relationship between hepatocyte free fatty acid overload, phospholipid homeostasis, and the development of NAFLD. Full article

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

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17 pages, 1341 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Goldfish Response to Chronic Hypoxia: Mitochondrial Respiration, Fuel Preference and Energy Metabolism

by Elie Farhat, Hang Cheng, Caroline Romestaing, Matthew Pamenter and Jean-Michel Weber

Metabolites 2021, 11(3), 187; https://doi.org/10.3390/metabo11030187 - 22 Mar 2021

Cited by 32 | Viewed by 6282

Abstract

Hypometabolism is a hallmark strategy of hypoxia tolerance. To identify potential mechanisms of metabolic suppression, we have used the goldfish to quantify the effects of chronically low oxygen (4 weeks; 10% air saturation) on mitochondrial respiration capacity and fuel preference. The responses of [...] Read more.

Hypometabolism is a hallmark strategy of hypoxia tolerance. To identify potential mechanisms of metabolic suppression, we have used the goldfish to quantify the effects of chronically low oxygen (4 weeks; 10% air saturation) on mitochondrial respiration capacity and fuel preference. The responses of key enzymes from glycolysis, β-oxidation and the tricarboxylic acid (TCA) cycle, and Na⁺/K⁺-ATPase were also monitored in various tissues of this champion of hypoxia tolerance. Results show that mitochondrial respiration of individual tissues depends on oxygen availability as well as metabolic fuel oxidized. All the respiration parameters measured in this study (LEAK, OXPHOS, Respiratory Control Ratio, CCCP-uncoupled, and COX) are affected by hypoxia, at least for one of the metabolic fuels. However, no common pattern of changes in respiration states is observed across tissues, except for the general downregulation of COX that may help metabolic suppression. Hypoxia causes the brain to switch from carbohydrates to lipids, with no clear fuel preference in other tissues. It also downregulates brain Na⁺/K⁺-ATPase (40%) and causes widespread tissue-specific effects on glycolysis and beta-oxidation. This study shows that hypoxia-acclimated goldfish mainly promote metabolic suppression by adjusting the glycolytic supply of pyruvate, reducing brain Na⁺/K⁺-ATPase, and downregulating COX, most likely decreasing mitochondrial density. Full article

(This article belongs to the Special Issue Ectotherms Metabolism: Plasticity and Adaptation)

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12 pages, 1258 KiB

Open AccessArticle

Elemental and Isotopic Characterization of Tobacco from Umbria

by Luana Bontempo, Daniela Bertoldi, Pietro Franceschi, Fabio Rossi and Roberto Larcher

Metabolites 2021, 11(3), 186; https://doi.org/10.3390/metabo11030186 - 22 Mar 2021

Cited by 6 | Viewed by 2586

Abstract

Umbrian tobacco of the Virginia Bright variety is one of the most appreciated tobaccos in Europe, and one characterized by an excellent yield. In recent years, the Umbria region and local producers have invested in introducing novel practices (for production and processing) focused [...] Read more.

Umbrian tobacco of the Virginia Bright variety is one of the most appreciated tobaccos in Europe, and one characterized by an excellent yield. In recent years, the Umbria region and local producers have invested in introducing novel practices (for production and processing) focused on environmental, social, and economic sustainability. Due to this, tobacco from Umbria is a leading commodity in the global tobacco industry, and it claims a high economic value. The aim of this study is then to assess if elemental and isotopic compositions can be used to protect the quality and geographical traceability of this particular tobacco. For the first time the characteristic value ranges of the stable isotope ratios of the bio-elements as a whole (δ²H, δ¹³C, δ¹⁵N, δ¹⁸O, and δ³⁴S) and of the concentration of 56 macro- and micro-elements are now available, determined in Virginia Bright tobacco produced in two different areas of Italy (Umbria and Veneto), and from other worldwide geographical regions. The ranges of variability of elements and stable isotope ratios had slightly different results, according to the three geographical origins considered. In particular, Umbria samples presented significantly lower content of metals potentially dangerous for human health. The results of this first exploratory work highlight the possibility of characterizing tobacco from Umbria, and suggest widening the scope of the survey throughout Italy and foreign regions, in order to be used to describe the geographical origin of tobacco in general and verify the origin of the products on the market. Full article

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13 pages, 2361 KiB

Open AccessArticle

Galantamine Quantity and Alkaloid Profile in the Bulbs of Narcissus tazetta and daffodil cultivars (Amaryllidaceae) Grown in Israel

by Dana Atrahimovich, Raviv Harris, Ron Eitan, Menashe Cohen and Soliman Khatib

Metabolites 2021, 11(3), 185; https://doi.org/10.3390/metabo11030185 - 21 Mar 2021

Viewed by 3107

Abstract

Alkaloids produced by the bulbs of the Amaryllidaceae are a source of pharmaceutical compounds. The main alkaloid, galantamine, is a reversible acetylcholinesterase inhibitor and allosteric nicotinic receptor modulator, which slows cognitive and functional decline in mild to moderate dementia due to Alzheimer’s disease. [...] Read more.

Alkaloids produced by the bulbs of the Amaryllidaceae are a source of pharmaceutical compounds. The main alkaloid, galantamine, is a reversible acetylcholinesterase inhibitor and allosteric nicotinic receptor modulator, which slows cognitive and functional decline in mild to moderate dementia due to Alzheimer’s disease. Having a complex stereochemistry, the organic synthesis of galantamine for pharmaceutical uses is highly challenging and not always economically viable, and it is therefore isolated from Amaryllidaceae bulbs. In the present study, galantamine was extracted and quantified in Narcissus bulbs from five cultivars (cvs.), Fortune, Carlton, Ice Follies, Galilee and Ziva, which were grown in Israel under various conditions. Results show that the cvs. Fortune, Carlton and Ice Follies bulbs contained 285 ± 47, 452 ± 73 and 69 ± 17 µg g⁻¹ galantamine, respectively, while the Galilee and Ziva bulbs contained relatively low concentrations of galantamine (1–20 µg g⁻¹). Irrigation levels and pruning conditions did not affect the galantamine contents. Additionally, the alkaloids profile of the five cvs. was analyzed and characterized using LC-MS/MS showing that galantamine-type alkaloids were mainly detected in the Fortune and Carlton bulbs, lycorine-type alkaloids were mainly detected at the Galilee and Ziva bulbs and vittatine-type alkaloids were mainly detected in the Ice Follies bulbs. The present research is the first to characterize the alkaloids profile in the Narcissus bulbs of Galilee and Ziva, indigenous cvs. grown in Israel. The antiviral and anticancer alkaloids lycorine and lycorinine were the main alkaloids detected in the bulbs of those cultivars. Full article

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18 pages, 552 KiB

Open AccessReview

Approaches to Integrating Metabolomics and Multi-Omics Data: A Primer

by Takoua Jendoubi

Metabolites 2021, 11(3), 184; https://doi.org/10.3390/metabo11030184 - 21 Mar 2021

Cited by 62 | Viewed by 9098

Abstract

Metabolomics deals with multiple and complex chemical reactions within living organisms and how these are influenced by external or internal perturbations. It lies at the heart of omics profiling technologies not only as the underlying biochemical layer that reflects information expressed by the [...] Read more.

Metabolomics deals with multiple and complex chemical reactions within living organisms and how these are influenced by external or internal perturbations. It lies at the heart of omics profiling technologies not only as the underlying biochemical layer that reflects information expressed by the genome, the transcriptome and the proteome, but also as the closest layer to the phenome. The combination of metabolomics data with the information available from genomics, transcriptomics, and proteomics offers unprecedented possibilities to enhance current understanding of biological functions, elucidate their underlying mechanisms and uncover hidden associations between omics variables. As a result, a vast array of computational tools have been developed to assist with integrative analysis of metabolomics data with different omics. Here, we review and propose five criteria—hypothesis, data types, strategies, study design and study focus— to classify statistical multi-omics data integration approaches into state-of-the-art classes under which all existing statistical methods fall. The purpose of this review is to look at various aspects that lead the choice of the statistical integrative analysis pipeline in terms of the different classes. We will draw particular attention to metabolomics and genomics data to assist those new to this field in the choice of the integrative analysis pipeline. Full article

(This article belongs to the Special Issue Development and Application of Statistical Methods for Analyzing Metabolomics Data)

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13 pages, 314 KiB

Open AccessArticle

Association of Human Plasma Metabolomics with Delayed Dark Adaptation in Age-Related Macular Degeneration

by Kevin M. Mendez, Janice Kim, Inês Laíns, Archana Nigalye, Raviv Katz, Shrinivas Pundik, Ivana K. Kim, Liming Liang, Demetrios G. Vavvas, John B. Miller, Joan W. Miller, Jessica A. Lasky-Su and Deeba Husain

Metabolites 2021, 11(3), 183; https://doi.org/10.3390/metabo11030183 - 21 Mar 2021

Cited by 8 | Viewed by 3036

Abstract

The purpose of this study was to analyze the association between plasma metabolite levels and dark adaptation (DA) in age-related macular degeneration (AMD). This was a cross-sectional study including patients with AMD (early, intermediate, and late) and control subjects older than 50 years [...] Read more.

The purpose of this study was to analyze the association between plasma metabolite levels and dark adaptation (DA) in age-related macular degeneration (AMD). This was a cross-sectional study including patients with AMD (early, intermediate, and late) and control subjects older than 50 years without any vitreoretinal disease. Fasting blood samples were collected and used for metabolomic profiling with ultra-performance liquid chromatography–mass spectrometry (LC-MS). Patients were also tested with the AdaptDx (MacuLogix, Middletown, PA, USA) DA extended protocol (20 min). Two measures of dark adaptation were calculated and used: rod-intercept time (RIT) and area under the dark adaptation curve (AUDAC). Associations between dark adaption and metabolite levels were tested using multilevel mixed-effects linear modelling, adjusting for age, gender, body mass index (BMI), smoking, race, AMD stage, and Age-Related Eye Disease Study (AREDS) formulation supplementation. We included a total of 71 subjects: 53 with AMD (13 early AMD, 31 intermediate AMD, and 9 late AMD) and 18 controls. Our results revealed that fatty acid-related lipids and amino acids related to glutamate and leucine, isoleucine and valine metabolism were associated with RIT (p < 0.01). Similar results were found when AUDAC was used as the outcome. Fatty acid-related lipids and amino acids are associated with DA, thus suggesting that oxidative stress and mitochondrial dysfunction likely play a role in AMD and visual impairment in this condition. Full article

(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism)

19 pages, 1816 KiB

Open AccessReview

Phloroglucinol Derivatives in Plant-Beneficial Pseudomonas spp.: Biosynthesis, Regulation, and Functions

by Adrien Biessy and Martin Filion

Metabolites 2021, 11(3), 182; https://doi.org/10.3390/metabo11030182 - 20 Mar 2021

Cited by 38 | Viewed by 4330

Abstract

Plant-beneficial Pseudomonas spp. aggressively colonize the rhizosphere and produce numerous secondary metabolites, such as 2,4-diacetylphloroglucinol (DAPG). DAPG is a phloroglucinol derivative that contributes to disease suppression, thanks to its broad-spectrum antimicrobial activity. A famous example of this biocontrol activity has been previously described [...] Read more.

Plant-beneficial Pseudomonas spp. aggressively colonize the rhizosphere and produce numerous secondary metabolites, such as 2,4-diacetylphloroglucinol (DAPG). DAPG is a phloroglucinol derivative that contributes to disease suppression, thanks to its broad-spectrum antimicrobial activity. A famous example of this biocontrol activity has been previously described in the context of wheat monoculture where a decline in take-all disease (caused by the ascomycete Gaeumannomyces tritici) has been shown to be associated with rhizosphere colonization by DAPG-producing Pseudomonas spp. In this review, we discuss the biosynthesis and regulation of phloroglucinol derivatives in the genus Pseudomonas, as well as investigate the role played by DAPG-producing Pseudomonas spp. in natural soil suppressiveness. We also tackle the mode of action of phloroglucinol derivatives, which can act as antibiotics, signalling molecules and, in some cases, even as pathogenicity factors. Finally, we discuss the genetic and genomic diversity of DAPG-producing Pseudomonas spp. as well as its importance for improving the biocontrol of plant pathogens. Full article

(This article belongs to the Special Issue Metabolism in Molecular Plant–Insect and Plant–Microbe Interactions)

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28 pages, 1452 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Advances and Perspectives in Prostate Cancer Biomarker Discovery in the Last 5 Years through Tissue and Urine Metabolomics

by Ana Rita Lima, Joana Pinto, Filipa Amaro, Maria de Lourdes Bastos, Márcia Carvalho and Paula Guedes de Pinho

Metabolites 2021, 11(3), 181; https://doi.org/10.3390/metabo11030181 - 19 Mar 2021

Cited by 50 | Viewed by 5365

Abstract

Prostate cancer (PCa) is the second most diagnosed cancer in men worldwide. For its screening, serum prostate specific antigen (PSA) test has been largely performed over the past decade, despite its lack of accuracy and inability to distinguish indolent from aggressive disease. Metabolomics [...] Read more.

Prostate cancer (PCa) is the second most diagnosed cancer in men worldwide. For its screening, serum prostate specific antigen (PSA) test has been largely performed over the past decade, despite its lack of accuracy and inability to distinguish indolent from aggressive disease. Metabolomics has been widely applied in cancer biomarker discovery due to the well-known metabolic reprogramming characteristic of cancer cells. Most of the metabolomic studies have reported alterations in urine of PCa patients due its noninvasive collection, but the analysis of prostate tissue metabolome is an ideal approach to disclose specific modifications in PCa development. This review aims to summarize and discuss the most recent findings from tissue and urine metabolomic studies applied to PCa biomarker discovery. Eighteen metabolites were found consistently altered in PCa tissue among different studies, including alanine, arginine, uracil, glutamate, fumarate, and citrate. Urine metabolomic studies also showed consistency in the dysregulation of 15 metabolites and, interestingly, alterations in the levels of valine, taurine, leucine and citrate were found in common between urine and tissue studies. These findings unveil that the impact of PCa development in human metabolome may offer a promising strategy to find novel biomarkers for PCa diagnosis. Full article

(This article belongs to the Special Issue Cancer Metabolomic 2020)

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19 pages, 4459 KiB

Open AccessArticle

Iron-Bound Lipocalin-2 from Tumor-Associated Macrophages Drives Breast Cancer Progression Independent of Ferroportin

by Christina Mertens, Matthias Schnetz, Claudia Rehwald, Stephan Grein, Eiman Elwakeel, Andreas Weigert, Bernhard Brüne and Michaela Jung

Metabolites 2021, 11(3), 180; https://doi.org/10.3390/metabo11030180 - 19 Mar 2021

Cited by 17 | Viewed by 3358

Abstract

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, [...] Read more.

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2^−/− PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2^−/− compared to wildtype tumors stored more iron. In contrast, Lcn-2^−/− tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2^−/− tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches. Full article

(This article belongs to the Special Issue Iron Metabolism and Cancer)

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15 pages, 4867 KiB

Open AccessArticle

Untargeted Metabolomics Analysis by UHPLC-MS/MS of Soybean Plant in a Compatible Response to Phakopsora pachyrhizi Infection

by Evandro Silva, José Perez da Graça, Carla Porto, Rodolpho Martin do Prado, Estela Nunes, Francismar Corrêa Marcelino-Guimarães, Mauricio Conrado Meyer and Eduardo Jorge Pilau

Metabolites 2021, 11(3), 179; https://doi.org/10.3390/metabo11030179 - 19 Mar 2021

Cited by 21 | Viewed by 5063

Abstract

Phakopsora pachyrhizi is a biotrophic fungus, causer of the disease Asian Soybean Rust, a severe crop disease of soybean and one that demands greater investment from producers. Thus, research efforts to control this disease are still needed. We investigated the expression of metabolites [...] Read more.

Phakopsora pachyrhizi is a biotrophic fungus, causer of the disease Asian Soybean Rust, a severe crop disease of soybean and one that demands greater investment from producers. Thus, research efforts to control this disease are still needed. We investigated the expression of metabolites in soybean plants presenting a resistant genotype inoculated with P. pachyrhizi through the untargeted metabolomics approach. The analysis was performed in control and inoculated plants with P. pachyrhizi using UHPLC-MS/MS. Principal component analysis (PCA) and the partial least squares discriminant analysis (PLS-DA), was applied to the data analysis. PCA and PLS-DA resulted in a clear separation and classification of groups between control and inoculated plants. The metabolites were putative classified and identified using the Global Natural Products Social Molecular Networking platform in flavonoids, isoflavonoids, lipids, fatty acyls, terpenes, and carboxylic acids. Flavonoids and isoflavonoids were up-regulation, while terpenes were down-regulated in response to the soybean–P. pachyrhizi interaction. Our data provide insights into the potential role of some metabolites as flavonoids and isoflavonoids in the plant resistance to ASR. This information could result in the development of resistant genotypes of soybean to P. pachyrhizi, and effective and specific products against the pathogen. Full article

(This article belongs to the Section Plant Metabolism)

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12 pages, 2408 KiB

Open AccessArticle

Alterations in Pattern Baldness According to Sex: Hair Metabolomics Approach

by Yu Ra Lee, Bark Lynn Lew, Woo Young Sim, Jongki Hong and Bong Chul Chung

Metabolites 2021, 11(3), 178; https://doi.org/10.3390/metabo11030178 - 18 Mar 2021

Cited by 7 | Viewed by 2736

Abstract

Pattern baldness has been associated with the male hormone, dihydrotestosterone. In this study, we tried to determine how the overall metabolic pathways of pattern baldness differ in patients and in normal controls. Our study aimed to identify alterations in hair metabolomic profiles in [...] Read more.

Pattern baldness has been associated with the male hormone, dihydrotestosterone. In this study, we tried to determine how the overall metabolic pathways of pattern baldness differ in patients and in normal controls. Our study aimed to identify alterations in hair metabolomic profiles in order to identify possible markers of pattern baldness according to sex. Untargeted metabolomics profiling in pattern baldness patients and control subjects was conducted using ultra-performance liquid chromatography-mass spectrometry. To identify significantly altered metabolic pathways, partial least squares discriminant analysis was performed. Our analysis indicated differences in steroid biosynthesis pathway in both males and females. However, there was a remarkable difference in the androgen metabolic pathway in males, and the estrogen metabolic and arachidonic acid pathways in females. For the first time, we were able to confirm the metabolic pathway in pattern baldness patients using hair samples. Our finding improves understanding of pattern baldness and highlights the need to link pattern baldness and sex-related differences. Full article

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17 pages, 4659 KiB

Open AccessEditor’s ChoiceArticle

Lung Metabolomics Profiling of Congenital Diaphragmatic Hernia in Fetal Rats

by Maria del Mar Romero-Lopez, Marc Oria, Miki Watanabe-Chailland, Maria Florencia Varela, Lindsey Romick-Rosendale and Jose L. Peiro

Metabolites 2021, 11(3), 177; https://doi.org/10.3390/metabo11030177 - 18 Mar 2021

Cited by 7 | Viewed by 3032

Abstract

Congenital diaphragmatic hernia (CDH) is characterized by the herniation of abdominal contents into the thoracic cavity during the fetal period. This competition for fetal thoracic space results in lung hypoplasia and vascular maldevelopment that can generate severe pulmonary hypertension (PH). The detailed mechanisms [...] Read more.

Congenital diaphragmatic hernia (CDH) is characterized by the herniation of abdominal contents into the thoracic cavity during the fetal period. This competition for fetal thoracic space results in lung hypoplasia and vascular maldevelopment that can generate severe pulmonary hypertension (PH). The detailed mechanisms of CDH pathogenesis are yet to be understood. Acknowledgment of the lung metabolism during the in-utero CDH development can help to discern the CDH pathophysiology changes. Timed-pregnant dams received nitrofen or vehicle (olive oil) on E9.5 day of gestation. All fetal lungs exposed to nitrofen or vehicle control were harvested at day E21.5 by C-section and processed for metabolomics analysis using nuclear magnetic resonance (NMR) spectroscopy. The three groups analyzed were nitrofen-CDH (NCDH), nitrofen-control (NC), and vehicle control (VC). A total of 64 metabolites were quantified and subjected to statistical analysis. The multivariate analysis identified forty-four metabolites that were statistically different between the three groups. The highest Variable importance in projection (VIP) score (>2) metabolites were lactate, glutamate, and adenosine 5′-triphosphate (ATP). Fetal CDH lungs have changes related to oxidative stress, nucleotide synthesis, amino acid metabolism, glycerophospholipid metabolism, and glucose metabolism. This work provides new insights into the molecular mechanisms behind the CDH pathophysiology and can explore potential novel treatment targets for CDH patients. Full article

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

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11 pages, 3330 KiB

Open AccessFeature PaperArticle

Implantable NMR Microcoils in Rats: A New Tool for Exploring Tumor Metabolism at Sub-Microliter Scale?

by Justine Deborne, Noël Pinaud and Yannick Crémillieux

Metabolites 2021, 11(3), 176; https://doi.org/10.3390/metabo11030176 - 17 Mar 2021

Cited by 3 | Viewed by 2702

Abstract

The aim of this study was to evaluate the potential of a miniaturized implantable nuclear magnetic resonance (NMR) coil to acquire in vivo proton NMR spectra in sub-microliter regions of interest and to obtain metabolic information using magnetic resonance spectroscopy (MRS) in these [...] Read more.

The aim of this study was to evaluate the potential of a miniaturized implantable nuclear magnetic resonance (NMR) coil to acquire in vivo proton NMR spectra in sub-microliter regions of interest and to obtain metabolic information using magnetic resonance spectroscopy (MRS) in these small volumes. For this purpose, the NMR microcoils were implanted in the right cortex of healthy rats and in C6 glioma-bearing rats. The dimensions of the microcoil were 450 micrometers wide and 3 mm long. The MRS acquisitions were performed at 7 Tesla using volume coil for RF excitation and microcoil for signal reception. The detection volume of the microcoil was measured equal to 450 nL. A gain in sensitivity equal to 76 was found in favor of implanted microcoil as compared to external surface coil. Nine resonances from metabolites were assigned in the spectra acquired in healthy rats (n = 5) and in glioma-bearing rat (n = 1). The differences in relative amplitude of choline, lactate and creatine resonances observed in glioma-bearing animal were in agreement with published findings on this tumor model. In conclusion, the designed implantable microcoil is suitable for in vivo MRS and can be used for probing the metabolism in localized and very small regions of interest in a tumor. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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12 pages, 1970 KiB

Open AccessReview

Salt Sensation and Regulation

by Sonali Puri and Youngseok Lee

Metabolites 2021, 11(3), 175; https://doi.org/10.3390/metabo11030175 - 17 Mar 2021

Cited by 7 | Viewed by 3654

Abstract

Taste sensation and regulation are highly conserved in insects and mammals. Research conducted over recent decades has yielded major advances in our understanding of the molecular mechanisms underlying the taste sensors for a variety of taste sensations and the processes underlying regulation of [...] Read more.

Taste sensation and regulation are highly conserved in insects and mammals. Research conducted over recent decades has yielded major advances in our understanding of the molecular mechanisms underlying the taste sensors for a variety of taste sensations and the processes underlying regulation of ingestion depending on our internal state. Salt (NaCl) is an essential ingested nutrient. The regulation of internal sodium concentrations for physiological processes, including neuronal activity, fluid volume, acid–base balance, and muscle contraction, are extremely important issues in animal health. Both mammals and flies detect low and high NaCl concentrations as attractive and aversive tastants, respectively. These attractive or aversive behaviors can be modulated by the internal nutrient state. However, the differential encoding of the tastes underlying low and high salt concentrations in the brain remain unclear. In this review, we discuss the current view of taste sensation and modulation in the brain with an emphasis on recent advances in this field. This work presents new questions that include but are not limited to, “How do the fly’s neuronal circuits process this complex salt code?” and “Why do high concentrations of salt induce a negative valence only when the need for salt is low?” A better understanding of regulation of salt homeostasis could improve our understanding of why our brains enjoy salty food so much. Full article

(This article belongs to the Special Issue Metabolic Research in Drosophila melanogaster)

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18 pages, 3111 KiB

Open AccessArticle

HPTLC-Based Chemical Profiling: An Approach to Monitor Plant Metabolic Expansion Caused by Fungal Endophytes

by Luis F. Salomé-Abarca, Cees A. M. J. J. van den Hondel, Özlem Erol, Peter G. L. Klinkhamer, Hye Kyong Kim and Young Hae Choi

Metabolites 2021, 11(3), 174; https://doi.org/10.3390/metabo11030174 - 17 Mar 2021

Cited by 7 | Viewed by 3018

Abstract

Fungal endophytes isolated from two latex bearing species were chosen as models to show their potential to expand their host plant chemical diversity. Thirty-three strains were isolated from Alstonia scholaris (Apocynaceae) and Euphorbia myrsinites (Euphorbiaceae). High performance thin layer chromatography (HPTLC) was used [...] Read more.

Fungal endophytes isolated from two latex bearing species were chosen as models to show their potential to expand their host plant chemical diversity. Thirty-three strains were isolated from Alstonia scholaris (Apocynaceae) and Euphorbia myrsinites (Euphorbiaceae). High performance thin layer chromatography (HPTLC) was used to metabolically profile samples. The selected strains were well clustered in three major groups by hierarchical clustering analysis (HCA) of the HPTLC data, and the chemical profiles were strongly correlated with the strains’ colony size. This correlation was confirmed by orthogonal partial least squares (OPLS) modeling using colony size as “Y” variable. Based on the multivariate data analysis of the HPTLC data, the fastest growing strains of each cluster were selected and used for subsequent experiments: co-culturing to investigate interactions between endophytes-phytopathogens, and biotransformation of plant metabolites by endophytes. The strains exhibited a high capacity to fight against fungal pathogens. Moreover, there was an increase in the antifungal activity after being fed with host-plant metabolites. These results suggest that endophytes play a role in plant defense mechanisms either directly or by biotransformation/induction of metabolites. Regarding HPTLC-based metabolomics, it has proved to be a robust approach to monitor the interactions among fungal endophytes, the host plant and potential phytopathogens. Full article

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

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10 pages, 5287 KiB

Open AccessArticle

Does DDI-Predictor Help Pharmacists to Detect Drug-Drug Interactions and Resolve Medication Issues More Effectively?

by Fanny Moreau, Nicolas Simon, Julia Walther, Mathilde Dambrine, Gaetan Kosmalski, Stéphanie Genay, Maxime Perez, Dominique Lecoutre, Stéphanie Belaiche, Chloé Rousselière, Michel Tod, Bertrand Décaudin and Pascal Odou

Metabolites 2021, 11(3), 173; https://doi.org/10.3390/metabo11030173 - 17 Mar 2021

Cited by 11 | Viewed by 3301

Abstract

The characterization of drug-drug interactions (DDIs) may require the use of several different tools, such as the thesaurus issued by our national health agency (i.e., ANSM), the metabolic pathways table from the Geneva University Hospital (GUH), and DDI-Predictor (DDI-P). We sought to (i) [...] Read more.

The characterization of drug-drug interactions (DDIs) may require the use of several different tools, such as the thesaurus issued by our national health agency (i.e., ANSM), the metabolic pathways table from the Geneva University Hospital (GUH), and DDI-Predictor (DDI-P). We sought to (i) compare the three tools’ respective abilities to detect DDIs in routine clinical practice and (ii) measure the pharmacist intervention rate (PIR) and physician acceptance rate (PAR) associated with the use of DDI-P. The three tools’ respective DDI detection rates (in %) were measured. The PIRs and PARs were compared by using the area under the curve ratio given by DDI-P (R_AUC) and applying a chi-squared test. The DDI detection rates differed significantly: 40.0%, 76.5%, and 85.2% for ANSM (The National Agency for the Safety of Medicines and Health Products), GUH and DDI-P, respectively (p < 0.0001). The PIR differed significantly according to the DDI-P’s R_AUC: 90.0%, 44.2% and 75.0% for R_AUC ≤ 0.5; R_AUC 0.5–2 and R_AUC > 2, respectively (p < 0.001). The overall PAR was 85.1% and did not appear to depend on the R_AUC category (p = 0.729). Our results showed that more pharmacist interventions were issued when details of the strength of the DDI were available. The three tools can be used in a complementary manner, with a view to refining medication adjustments. Full article

(This article belongs to the Special Issue Pharmaceutical Sciences and Metabolism)

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16 pages, 4520 KiB

Open AccessArticle

The Importance of Objective Stool Classification in Fecal 1H-NMR Metabolomics: Exponential Increase in Stool Crosslinking Is Mirrored in Systemic Inflammation and Associated to Fecal Acetate and Methionine

by Leon Deutsch and Blaz Stres

Metabolites 2021, 11(3), 172; https://doi.org/10.3390/metabo11030172 - 16 Mar 2021

Cited by 11 | Viewed by 3362

Abstract

Past studies strongly connected stool consistency—as measured by Bristol Stool Scale (BSS)—with microbial gene richness and intestinal inflammation, colonic transit time and metabolome characteristics that are of clinical relevance in numerous gastro intestinal conditions. While retention time, defecation rate, BSS but not water [...] Read more.

Past studies strongly connected stool consistency—as measured by Bristol Stool Scale (BSS)—with microbial gene richness and intestinal inflammation, colonic transit time and metabolome characteristics that are of clinical relevance in numerous gastro intestinal conditions. While retention time, defecation rate, BSS but not water activity have been shown to account for BSS-associated inflammatory effects, the potential correlation with the strength of a gel in the context of intestinal forces, abrasion, mucus imprinting, fecal pore clogging remains unexplored as a shaping factor for intestinal inflammation and has yet to be determined. Our study introduced a minimal pressure approach (MP) by probe indentation as measure of stool material crosslinking in fecal samples. Results reported here were obtained from 170 samples collected in two independent projects, including males and females, covering a wide span of moisture contents and BSS. MP values increased exponentially with increasing consistency (i.e., lower BSS) and enabled stratification of samples exhibiting mixed BSS classes. A trade-off between lowest MP and highest dry matter content delineated the span of intermediate healthy density of gel crosslinks. The crossectional transects identified fecal surface layers with exceptionally high MP and of <5 mm thickness followed by internal structures with an order of magnitude lower MP, characteristic of healthy stool consistency. The MP and BSS values reported in this study were coupled to reanalysis of the PlanHab data and fecal 1H-NMR metabolomes reported before. The exponential association between stool consistency and MP determined in this study was mirrored in the elevated intestinal and also systemic inflammation and other detrimental physiological deconditioning effects observed in the PlanHab participants reported before. The MP approach described in this study can be used to better understand fecal hardness and its relationships to human health as it provides a simple, fine scale and objective stool classification approach for the characterization of the exact sampling locations in future microbiome and metabolome studies. Full article

(This article belongs to the Special Issue Metabolites: From Physiology to Pathology)

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23 pages, 2170 KiB

Open AccessReview

Rapid Evaporative Ionization Mass Spectrometry: A Review on Its Application to the Red Meat Industry with an Australian Context

by Robert S. Barlow, Adam G. Fitzgerald, Joanne M. Hughes, Kate E. McMillan, Sean C. Moore, Anita L. Sikes, Aarti B. Tobin and Peter J. Watkins

Metabolites 2021, 11(3), 171; https://doi.org/10.3390/metabo11030171 - 15 Mar 2021

Cited by 15 | Viewed by 3920

Abstract

The red meat supply chain is a complex network transferring product from producers to consumers in a safe and secure way. There can be times when fragmentation can arise within the supply chain, which could be exploited. This risk needs reduction so that [...] Read more.

The red meat supply chain is a complex network transferring product from producers to consumers in a safe and secure way. There can be times when fragmentation can arise within the supply chain, which could be exploited. This risk needs reduction so that meat products enter the market with the desired attributes. Rapid Evaporative Ionisation Mass Spectrometry (REIMS) is a novel ambient mass spectrometry technique originally developed for rapid and accurate classification of biological tissue which is now being considered for use in a range of additional applications. It has subsequently shown promise for a range of food provenance, quality and safety applications with its ability to conduct ex vivo and in situ analysis. These are regarded as critical characteristics for technologies which can enable real-time decision making in meat processing plants and more broadly throughout the sector. This review presents an overview of the REIMS technology, and its application to the areas of provenance, quality and safety to the red meat industry, particularly in an Australian context. Full article

(This article belongs to the Special Issue Development of Metabolomics Technologies and Their Applications in Food Science)

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18 pages, 2522 KiB

Open AccessArticle

Improved Sensitivity in Hydrophilic Interaction Liquid Chromatography-Electrospray-Mass Spectrometry after Removal of Sodium and Potassium Ions from Biological Samples

by Ida Erngren, Marika Nestor, Curt Pettersson and Mikael Hedeland

Metabolites 2021, 11(3), 170; https://doi.org/10.3390/metabo11030170 - 15 Mar 2021

Cited by 5 | Viewed by 2854

Abstract

Inorganic ions, such as sodium and potassium, are present in all biological matrices and are sometimes also added during sample preparation. However, these inorganic ions are known to hamper electrospray ionization -mass spectrometry (ESI-MS) applications, especially in hydrophilic interaction liquid chromatography (HILIC) where [...] Read more.

Inorganic ions, such as sodium and potassium, are present in all biological matrices and are sometimes also added during sample preparation. However, these inorganic ions are known to hamper electrospray ionization -mass spectrometry (ESI-MS) applications, especially in hydrophilic interaction liquid chromatography (HILIC) where they are retained and can be detected as adducts and clusters with mobile phase components or analytes. The retention of inorganic ions leads to co-elution with analytes and as a result ion-suppression, extensive adduct formation and problems with reproducibility. In the presented work, a sample preparation method using cation exchange solid phase extraction (SPE) was developed to trap Na⁺ and K⁺ ions from human blood plasma and head and neck cancer cells for the analysis of small cationic, anionic as well as neutral organic analytes. The investigated analytes were small, hydrophilic compounds typically in focus in metabolomics studies. The samples were analyzed using full-scan HILIC-ESI-quadrupole time of flight (QTOF)-MS with an untargeted, screening approach. Method performance was evaluated using multivariate data analysis as well as relative quantifications, spiking of standards to evaluate linearity of response and post-column infusion to study ion-suppression. In blood plasma, the reduction of sodium and potassium ion concentration resulted in improved sensitivity increased signal intensity for 19 out of 28 investigated analytes, improved linearity of response, reduced ion-suppression and reduced cluster formation as well as adduct formation. Thus, the presented method has significant potential to improve data quality in metabolomics studies. Full article

(This article belongs to the Section Metabolomic Profiling Technology)

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11 pages, 634 KiB

Open AccessArticle

Comparing Levels of Metabolic Predictors of Coronary Heart Disease between Healthy Lean and Overweight Females

by Rasha Abu-El-Ruz, Manar E. Abdel-Rahman, Stephen L. Atkin and Mohamed A. Elrayess

Metabolites 2021, 11(3), 169; https://doi.org/10.3390/metabo11030169 - 15 Mar 2021

Cited by 2 | Viewed by 2417

Abstract

Screening for the metabolomic signature of coronary heart disease (CHD) before disease onset could help in early diagnosis and potentially disease prevention. In this study, the levels of 17 CHD metabolic biomarkers in apparently healthy overweight females were compared to lean counterparts, and [...] Read more.

Screening for the metabolomic signature of coronary heart disease (CHD) before disease onset could help in early diagnosis and potentially disease prevention. In this study, the levels of 17 CHD metabolic biomarkers in apparently healthy overweight females were compared to lean counterparts, and their associations with conventional clinical risk factors were determined. Clinical and metabolic data from 200 apparently healthy non-obese Qatari females were collected from Qatar Biobank (discovery cohort). Logistic regression was used to assess the association between body mass index (BMI) groups and 17 CHD metabolic biomarkers, and receiver operating characteristic (ROC) analysis was used to evaluate the prognostic value of CHD metabolic biomarkers in overweight. Stepwise linear regression was performed to identify the classical risk factors associated with CHD metabolites differentiating the two BMI groups. Validation of the association of CHD metabolic biomarkers with BMI groups was performed in 107 subjects (replication cohort). Out of the tested CHD metabolic biomarkers, five were significantly different between lean and overweight females in the discovery cohort (AUC = 0.73). Among these, the association of mannose, asparagine, and linoleate with BMI groups was confirmed in the replication cohort (AUC = 0.97). Significant correlations between predictors of CHD in overweight healthy women and classical risk factors were observed, including serum levels of cholesterol, testosterone, triiodothyronine, thyroxine, creatinine, albumin, bilirubin, glucose, c-peptide, uric acid, calcium and chloride. Apparently, healthy overweight females exhibit significantly different levels of specific CHD metabolites compared to their lean counterparts, offering a prognostic potential with preventative value. Full article

(This article belongs to the Special Issue Metabolic Profiling of Cardiovascular Disease)

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17 pages, 1205 KiB

Open AccessArticle

A Genome-Scale Metabolic Model of Anabaena 33047 to Guide Genetic Modifications to Overproduce Nylon Monomers

by John I. Hendry, Hoang V. Dinh, Debolina Sarkar, Lin Wang, Anindita Bandyopadhyay, Himadri B. Pakrasi and Costas D. Maranas

Metabolites 2021, 11(3), 168; https://doi.org/10.3390/metabo11030168 - 15 Mar 2021

Cited by 5 | Viewed by 3088

Abstract

Nitrogen fixing-cyanobacteria can significantly improve the economic feasibility of cyanobacterial production processes by eliminating the requirement for reduced nitrogen. Anabaena sp. ATCC 33047 is a marine, heterocyst forming, nitrogen fixing cyanobacteria with a very short doubling time of 3.8 h. We developed a [...] Read more.

Nitrogen fixing-cyanobacteria can significantly improve the economic feasibility of cyanobacterial production processes by eliminating the requirement for reduced nitrogen. Anabaena sp. ATCC 33047 is a marine, heterocyst forming, nitrogen fixing cyanobacteria with a very short doubling time of 3.8 h. We developed a comprehensive genome-scale metabolic (GSM) model, iAnC892, for this organism using annotations and content obtained from multiple databases. iAnC892 describes both the vegetative and heterocyst cell types found in the filaments of Anabaena sp. ATCC 33047. iAnC892 includes 953 unique reactions and accounts for the annotation of 892 genes. Comparison of iAnC892 reaction content with the GSM of Anabaena sp. PCC 7120 revealed that there are 109 reactions including uptake hydrogenase, pyruvate decarboxylase, and pyruvate-formate lyase unique to iAnC892. iAnC892 enabled the analysis of energy production pathways in the heterocyst by allowing the cell specific deactivation of light dependent electron transport chain and glucose-6-phosphate metabolizing pathways. The analysis revealed the importance of light dependent electron transport in generating ATP and NADPH at the required ratio for optimal N₂ fixation. When used alongside the strain design algorithm, OptForce, iAnC892 recapitulated several of the experimentally successful genetic intervention strategies that over produced valerolactam and caprolactam precursors. Full article

(This article belongs to the Special Issue Genome-Scale Metabolic Models)

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19 pages, 4209 KiB

Open AccessEditor’s ChoiceArticle

Inhibition of Ganglioside Synthesis Suppressed Liver Cancer Cell Proliferation through Targeting Kinetochore Metaphase Signaling

by Ting Su, Xian-Yang Qin, Naoshi Dohmae, Feifei Wei, Yutaka Furutani, Soichi Kojima and Wenkui Yu

Metabolites 2021, 11(3), 167; https://doi.org/10.3390/metabo11030167 - 15 Mar 2021

Cited by 12 | Viewed by 4017

Abstract

The incidence and mortality of liver cancer, mostly hepatocellular carcinoma (HCC), have increased during the last two decades, partly due to persistent inflammation in the lipid-rich microenvironment associated with lifestyle diseases, such as obesity. Gangliosides are sialic acid-containing glycosphingolipids known to be important [...] Read more.

The incidence and mortality of liver cancer, mostly hepatocellular carcinoma (HCC), have increased during the last two decades, partly due to persistent inflammation in the lipid-rich microenvironment associated with lifestyle diseases, such as obesity. Gangliosides are sialic acid-containing glycosphingolipids known to be important in the organization of the membrane and membrane protein-mediated signal transduction. Ganglioside synthesis is increased in several types of cancers and has been proposed as a promising target for cancer therapy. Here, we provide evidence that ganglioside synthesis was increased in the livers of an animal model recapitulating the features of activation and expansion of liver progenitor-like cells and liver cancer (stem) cells. Chemical inhibition of ganglioside synthesis functionally suppressed proliferation and sphere growth of liver cancer cells, but had no impact on apoptotic and necrotic cell death. Proteome-based mechanistic analysis revealed that inhibition of ganglioside synthesis downregulated the expression of AURKA, AURKB, TTK, and NDC80 involved in the regulation of kinetochore metaphase signaling, which is essential for chromosome segregation and mitotic progression and probably under the control of activation of TP53-dependent cell cycle arrest. These data suggest that targeting ganglioside synthesis holds promise for the development of novel preventive/therapeutic strategies for HCC treatment. Full article

(This article belongs to the Special Issue The Emerging Role of Cancer Metabolism in the Development and Progression of Malignancy)

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16 pages, 7394 KiB

Open AccessArticle

Towards Extending the Detection Window of Gamma-Hydroxybutyric Acid—An Untargeted Metabolomics Study in Serum and Urine Following Controlled Administration in Healthy Men

by Andrea E. Steuer, Justine Raeber, Fabio Simbuerger, Dario A. Dornbierer, Oliver G. Bosch, Boris B. Quednow, Erich Seifritz and Thomas Kraemer

Metabolites 2021, 11(3), 166; https://doi.org/10.3390/metabo11030166 - 12 Mar 2021

Cited by 15 | Viewed by 3508

Abstract

In forensic toxicology, gamma-hydroxybutyrate (GHB) still represents one of the most challenging drugs of abuse in terms of analytical detection and interpretation. Given its rapid elimination, the detection window of GHB in common matrices is short (maximum 12 h in urine). Additionally, the [...] Read more.

In forensic toxicology, gamma-hydroxybutyrate (GHB) still represents one of the most challenging drugs of abuse in terms of analytical detection and interpretation. Given its rapid elimination, the detection window of GHB in common matrices is short (maximum 12 h in urine). Additionally, the differentiation from naturally occurring endogenous GHB, is challenging. Thus, novel biomarkers to extend the detection window of GHB are urgently needed. The present study aimed at searching new potential biomarkers of GHB use by means of mass spectrometry (MS) metabolomic profiling in serum (up to 16.5 h) and urine samples (up to 8 h after intake) collected during a placebo-controlled crossover study in healthy men. MS data acquired by different analytical methods (reversed phase and hydrophilic interaction liquid chromatography; positive and negative electrospray ionization each) were filtered for significantly changed features applying univariate and mixed-effect model statistics. Complementary to a former study, conjugates of GHB with glycine, glutamate, taurine, carnitine and pentose (ribose) were identified in urine, with particularly GHB-pentose being promising for longer detection. None of the conjugates were detectable in serum. Therein, mainly energy metabolic substrates were identified, which may be useful for more detailed interpretation of underlying pathways but are too unspecific as biomarkers. Full article

(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)

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25 pages, 6875 KiB

Open AccessArticle

Metabolomics for Biomarker Discovery: Key Signatory Metabolic Profiles for the Identification and Discrimination of Oat Cultivars

by Chanel J. Pretorius, Fidele Tugizimana, Paul A. Steenkamp, Lizelle A. Piater and Ian A. Dubery

Metabolites 2021, 11(3), 165; https://doi.org/10.3390/metabo11030165 - 12 Mar 2021

Cited by 27 | Viewed by 4075

Abstract

The first step in crop introduction—or breeding programmes—requires cultivar identification and characterisation. Rapid identification methods would therefore greatly improve registration, breeding, seed, trade and inspection processes. Metabolomics has proven to be indispensable in interrogating cellular biochemistry and phenotyping. Furthermore, metabolic fingerprints are chemical [...] Read more.

The first step in crop introduction—or breeding programmes—requires cultivar identification and characterisation. Rapid identification methods would therefore greatly improve registration, breeding, seed, trade and inspection processes. Metabolomics has proven to be indispensable in interrogating cellular biochemistry and phenotyping. Furthermore, metabolic fingerprints are chemical maps that can provide detailed insights into the molecular composition of a biological system under consideration. Here, metabolomics was applied to unravel differential metabolic profiles of various oat (Avena sativa) cultivars (Magnifico, Dunnart, Pallinup, Overberg and SWK001) and to identify signatory biomarkers for cultivar identification. The respective cultivars were grown under controlled conditions up to the 3-week maturity stage, and leaves and roots were harvested for each cultivar. Metabolites were extracted using 80% methanol, and extracts were analysed on an ultra-high performance liquid chromatography (UHPLC) system coupled to a quadrupole time-of-flight (qTOF) high-definition mass spectrometer analytical platform. The generated data were processed and analysed using multivariate statistical methods. Principal component analysis (PCA) models were computed for both leaf and root data, with PCA score plots indicating cultivar-related clustering of the samples and pointing to underlying differential metabolic profiles of these cultivars. Further multivariate analyses were performed to profile differential signatory markers, which included carboxylic acids, amino acids, fatty acids, phenolic compounds (hydroxycinnamic and hydroxybenzoic acids, and associated derivatives) and flavonoids, among the respective cultivars. Based on the key signatory metabolic markers, the cultivars were successfully distinguished from one another in profiles derived from both leaves and roots. The study demonstrates that metabolomics can be used as a rapid phenotyping tool for cultivar differentiation. Full article

(This article belongs to the Special Issue Metabolomics in Agriculture Volume 2)

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12 pages, 2874 KiB

Open AccessArticle

Cross-Species Comparison of Metabolomics to Decipher the Metabolic Diversity in Ten Fruits

by Jinwei Qi, Kang Li, Yunxia Shi, Yufei Li, Long Dong, Ling Liu, Mingyang Li, Hui Ren, Xianqing Liu, Chuanying Fang and Jie Luo

Metabolites 2021, 11(3), 164; https://doi.org/10.3390/metabo11030164 - 12 Mar 2021

Cited by 15 | Viewed by 3456

Abstract

Fruits provide humans with multiple kinds of nutrients and protect humans against worldwide nutritional deficiency. Therefore, it is essential to understand the nutrient composition of various fruits in depth. In this study, we performed LC-MS-based non-targeted metabolomic analyses with ten kinds of fruit, [...] Read more.

Fruits provide humans with multiple kinds of nutrients and protect humans against worldwide nutritional deficiency. Therefore, it is essential to understand the nutrient composition of various fruits in depth. In this study, we performed LC-MS-based non-targeted metabolomic analyses with ten kinds of fruit, including passion fruit, mango, starfruit, mangosteen, guava, mandarin orange, grape, apple, blueberry, and strawberry. In total, we detected over 2500 compounds and identified more than 300 nutrients. Although the ten fruits shared 909 common-detected compounds, each species accumulated a variety of species-specific metabolites. Additionally, metabolic profiling analyses revealed a constant variation in each metabolite’s content across the ten fruits. Moreover, we constructed a neighbor-joining tree using metabolomic data, which resembles the single-copy protein-based phylogenetic tree. This indicates that metabolome data could reflect the genetic relationship between different species. In conclusion, our work enriches knowledge on the metabolomics of fruits, and provides metabolic evidence for the genetic relationships among these fruits. Full article

(This article belongs to the Special Issue Metabolomic Analysis in Food Science)

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16 pages, 3407 KiB

Open AccessArticle

The mwtab Python Library for RESTful Access and Enhanced Quality Control, Deposition, and Curation of the Metabolomics Workbench Data Repository

by Christian D. Powell and Hunter N.B. Moseley

Metabolites 2021, 11(3), 163; https://doi.org/10.3390/metabo11030163 - 12 Mar 2021

Cited by 8 | Viewed by 3259

Abstract

The Metabolomics Workbench (MW) is a public scientific data repository consisting of experimental data and metadata from metabolomics studies collected with mass spectroscopy (MS) and nuclear magnetic resonance (NMR) analyses. MW has been constantly evolving; updating its ‘mwTab’ text file format, adding a [...] Read more.

The Metabolomics Workbench (MW) is a public scientific data repository consisting of experimental data and metadata from metabolomics studies collected with mass spectroscopy (MS) and nuclear magnetic resonance (NMR) analyses. MW has been constantly evolving; updating its ‘mwTab’ text file format, adding a JavaScript Object Notation (JSON) file format, implementing a REpresentational State Transfer (REST) interface, and nearly quadrupling the number of datasets hosted on the repository within the last three years. In order to keep up with the quickly evolving state of the MW repository, the ‘mwtab’ Python library and package have been continuously updated to mirror the changes in the ‘mwTab’ and JSONized formats and contain many new enhancements including methods for interacting with the MW REST interface, enhanced format validation features, and advanced features for parsing and searching for specific metabolite data and metadata. We used the enhanced format validation features to evaluate all available datasets in MW to facilitate improved curation and FAIRness of the repository. The ‘mwtab’ Python package is now officially released as version 1.0.1 and is freely available on GitHub and the Python Package Index (PyPI) under a Clear Berkeley Software Distribution (BSD) license with documentation available on ReadTheDocs. Full article

(This article belongs to the Special Issue Data Science in Metabolomics)

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23 pages, 3181 KiB

Open AccessEditor’s ChoiceArticle

Metabolites Secreted by Bovine Embryos In Vitro Predict Pregnancies That the Recipient Plasma Metabolome Cannot, and Vice Versa

by Enrique Gomez, Nuria Canela, Pol Herrero, Adrià Cereto, Isabel Gimeno, Susana Carrocera, David Martin-Gonzalez, Antonio Murillo and Marta Muñoz

Metabolites 2021, 11(3), 162; https://doi.org/10.3390/metabo11030162 - 11 Mar 2021

Cited by 12 | Viewed by 3283

Abstract

This work describes the use of mass spectrometry-based metabolomics as a non-invasive approach to accurately predict birth prior to embryo transfer (ET) starting from embryo culture media and plasma recipient. Metabolomics was used here as a predictive platform. Day-6 in vitro produced embryos [...] Read more.

This work describes the use of mass spectrometry-based metabolomics as a non-invasive approach to accurately predict birth prior to embryo transfer (ET) starting from embryo culture media and plasma recipient. Metabolomics was used here as a predictive platform. Day-6 in vitro produced embryos developed singly in modified synthetic oviduct fluid culture medium (CM) drops for 24 h were vitrified as Day-7 blastocysts and transferred to recipients. Day-0 and Day-7 recipient plasma (N = 36 × 2) and CM (N = 36) were analyzed by gas chromatography coupled to the quadrupole time of flight mass spectrometry (GC-qTOF). Metabolites quantified in CM and plasma were analyzed as a function to predict pregnancy at Day-40, Day-62, and birth (univariate and multivariate statistics). Subsequently, a Boolean matrix (F1 score) was constructed with metabolite pairs (one from the embryo, and one from the recipient) to combine the predictive power of embryos and recipients. Validation was performed in independent cohorts of ETs analyzed. Embryos that did not reach birth released more stearic acid, capric acid, palmitic acid, and glyceryl monostearate in CM (i.e., (p < 0.05, FDR < 0.05, Receiver Operator Characteristic—area under curve (ROC-AUC) > 0.669)). Within Holstein recipients, hydrocinnamic acid, alanine, and lysine predicted birth (ROC-AUC > 0.778). Asturiana de los Valles recipients that reached birth showed lower concentrations of 6-methyl-5-hepten-2-one, stearic acid, palmitic acid, and hippuric acid (ROC-AUC > 0.832). Embryonal capric acid and glyceryl-monostearate formed F1 scores generally >0.900, with metabolites found both to differ (e.g., hippuric acid, hydrocinnamic acid) or not (e.g., heptadecanoic acid, citric acid) with pregnancy in plasmas, as hypothesized. Efficient lipid metabolism in the embryo and the recipient can allow pregnancy to proceed. Changes in phenolics from plasma suggest that microbiota and liver metabolism influence the pregnancy establishment in cattle. Full article

(This article belongs to the Special Issue Metabolomic Applications in Animal Science Volume 2)

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