Metabolites

21 pages, 4958 KiB

Open AccessArticle

The Urine Metabolome of Young Autistic Children Correlates with Their Clinical Profile Severity

by Michele Mussap, Martina Siracusano, Antonio Noto, Claudia Fattuoni, Assia Riccioni, Hema Sekhar Reddy Rajula, Vassilios Fanos, Paolo Curatolo, Luigi Barberini and Luigi Mazzone

Metabolites 2020, 10(11), 476; https://doi.org/10.3390/metabo10110476 - 23 Nov 2020

Cited by 25 | Viewed by 5084

Abstract

Autism diagnosis is moving from the identification of common inherited genetic variants to a systems biology approach. The aims of the study were to explore metabolic perturbations in autism, to investigate whether the severity of autism core symptoms may be associated with specific [...] Read more.

Autism diagnosis is moving from the identification of common inherited genetic variants to a systems biology approach. The aims of the study were to explore metabolic perturbations in autism, to investigate whether the severity of autism core symptoms may be associated with specific metabolic signatures; and to examine whether the urine metabolome discriminates severe from mild-to-moderate restricted, repetitive, and stereotyped behaviors. We enrolled 57 children aged 2–11 years; thirty-one with idiopathic autism and twenty-six neurotypical (NT), matched for age and ethnicity. The urine metabolome was investigated by gas chromatography-mass spectrometry (GC-MS). The urinary metabolome of autistic children was largely distinguishable from that of NT children; food selectivity induced further significant metabolic differences. Severe autism spectrum disorder core deficits were marked by high levels of metabolites resulting from diet, gut dysbiosis, oxidative stress, tryptophan metabolism, mitochondrial dysfunction. The hierarchical clustering algorithm generated two metabolic clusters in autistic children: 85–90% of children with mild-to-moderate abnormal behaviors fell in cluster II. Our results open up new perspectives for the more general understanding of the correlation between the clinical phenotype of autistic children and their urine metabolome. Adipic acid, palmitic acid, and 3-(3-hydroxyphenyl)-3-hydroxypropanoic acid can be proposed as candidate biomarkers of autism severity. Full article

(This article belongs to the Special Issue Metabolomics and Its Application in Human Diseases Volume 2)

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16 pages, 3573 KiB

Open AccessArticle

Anti-Adipogenic Effect of Theabrownin Is Mediated by Bile Acid Alternative Synthesis via Gut Microbiota Remodeling

by Junliang Kuang, Xiaojiao Zheng, Fengjie Huang, Shouli Wang, Mengci Li, Mingliang Zhao, Chao Sang, Kun Ge, Yitao Li, Jiufeng Li, Cynthia Rajani, Xiaohui Ma, Shuiping Zhou, Aihua Zhao and Wei Jia

Metabolites 2020, 10(11), 475; https://doi.org/10.3390/metabo10110475 - 23 Nov 2020

Cited by 48 | Viewed by 4238

Abstract

Theabrownin is one of the most bioactive compounds in Pu-erh tea. Our previous study revealed that the hypocholesterolemic effect of theabrownin was mediated by the modulation of bile salt hydrolase (BSH)-enriched gut microbiota and bile acid metabolism. In this study, we demonstrated that [...] Read more.

Theabrownin is one of the most bioactive compounds in Pu-erh tea. Our previous study revealed that the hypocholesterolemic effect of theabrownin was mediated by the modulation of bile salt hydrolase (BSH)-enriched gut microbiota and bile acid metabolism. In this study, we demonstrated that theabrownin ameliorated high-fat-diet (HFD)-induced obesity by modifying gut microbiota, especially those with 7α-dehydroxylation on the species level, and these changed microbes were positively correlated with secondary bile acid (BA) metabolism. Thus, altered intestinal BAs resulted in shifting bile acid biosynthesis from the classic to the alternative pathway. This shift changed the BA pool by increasing non-12α-hydroxylated-BAs (non-12OH-BAs) and decreasing 12α-hydroxylated BAs (12OH-BAs), which improved energy metabolism in white and brown adipose tissue. This study showed that theabrownin was a potential therapeutic modality for obesity and other metabolic disorders via gut microbiota-driven bile acid alternative synthesis. Full article

(This article belongs to the Special Issue Metabolite Markers of Phytochemicals II)

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14 pages, 3342 KiB

Open AccessArticle

Isotope Fractionation during Gas Chromatography Can Enhance Mass Spectrometry-Based Measures of ²H-Labeling of Small Molecules

by Daniel P. Downes, Takhar Kasumov, Natalie A. Daurio, Neil B. Wood, Michael J. Previs, Payal R. Sheth, David G. McLaren and Stephen F. Previs

Metabolites 2020, 10(11), 474; https://doi.org/10.3390/metabo10110474 - 20 Nov 2020

Cited by 3 | Viewed by 2360

Abstract

Stable isotope tracers can be used to quantify the activity of metabolic pathways. Specifically, ²H-water is quite versatile, and its incorporation into various products can enable measurements of carbohydrate, lipid, protein and nucleic acid kinetics. However, since there are limits on how [...] Read more.

Stable isotope tracers can be used to quantify the activity of metabolic pathways. Specifically, ²H-water is quite versatile, and its incorporation into various products can enable measurements of carbohydrate, lipid, protein and nucleic acid kinetics. However, since there are limits on how much ²H-water can be administered and since some metabolic processes may be slow, it is possible that one may be challenged with measuring small changes in isotopic enrichment. We demonstrate an advantage of the isotope fractionation that occurs during gas chromatography, namely, setting tightly bounded integration regions yields a powerful approach for determining isotope ratios. We determined how the degree of isotope fractionation, chromatographic peak width and mass spectrometer dwell time can increase the apparent isotope labeling. Relatively simple changes in the logic surrounding data acquisition and processing can enhance gas chromatography-mass spectrometry measures of low levels of ²H-labeling, this is especially useful when asymmetrical peaks are recorded at low signal:background. Although we have largely focused attention on alanine (which is of interest in studies of protein synthesis), it should be possible to extend the concepts to other analytes and/or hardware configurations. Full article

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

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15 pages, 1744 KiB

Open AccessArticle

Sphingolipid Profiling Reveals Different Extent of Ceramide Accumulation in Bovine Retroperitoneal and Subcutaneous Adipose Tissues

by Yue Hei Leung, Sonja Christiane Bäßler, Christian Koch, Theresa Scheu, Ulrich Meyer, Sven Dänicke, Korinna Huber and Ákos Kenéz

Metabolites 2020, 10(11), 473; https://doi.org/10.3390/metabo10110473 - 19 Nov 2020

Cited by 9 | Viewed by 3424

Abstract

Sphingolipids are bioactive lipids that can modulate insulin sensitivity, cellular differentiation, and apoptosis in a tissue-specific manner. However, their comparative profiles in bovine retroperitoneal (RPAT) and subcutaneous adipose tissue (SCAT) are currently unknown. We aimed to characterize the sphingolipid profiles using a targeted [...] Read more.

Sphingolipids are bioactive lipids that can modulate insulin sensitivity, cellular differentiation, and apoptosis in a tissue-specific manner. However, their comparative profiles in bovine retroperitoneal (RPAT) and subcutaneous adipose tissue (SCAT) are currently unknown. We aimed to characterize the sphingolipid profiles using a targeted lipidomics approach and to assess whether potentially related sphingolipid pathways are different between SCAT and RPAT. Holstein bulls (n = 6) were slaughtered, and SCAT and RPAT samples were collected for sphingolipid profiling. A total of 70 sphingolipid species were detected and quantified by UPLC-MS/MS in multiple reaction monitoring (MRM) mode, including ceramide (Cer), dihydroceramide (DHCer), sphingomyelin (SM), dihydrosphingomyelin (DHSM), ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P), galactosylceramide (GalCer), glucosylceramide (GluCer), lactosylceramide (LacCer), sphinganine (DHSph), and sphingosine (Sph). Our results showed that sphingolipids of the de novo synthesis pathway, such as DHSph, DHCer, and Cer, were more concentrated in RPAT than in SCAT. Sphingolipids of the salvage pathway and the sphingomyelinase pathway, such as Sph, S1P, C1P, glycosphingolipid, and SM, were more concentrated in SCAT. Our results indicate that RPAT had a greater extent of ceramide accumulation, thereby increasing the concentration of further sphingolipid intermediates in the de novo synthesis pathway. This distinctive sphingolipid distribution pattern in RPAT and SCAT can potentially explain the tissue-specific activity in insulin sensitivity, proinflammation, and oxidative stress in RPAT and SCAT. Full article

(This article belongs to the Section Lipid Metabolism)

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14 pages, 3941 KiB

Open AccessArticle

Mouse Age Matters: How Age Affects the Murine Plasma Metabolome

by Patrick Pann, Martin Hrabě de Angelis, Cornelia Prehn and Jerzy Adamski

Metabolites 2020, 10(11), 472; https://doi.org/10.3390/metabo10110472 - 19 Nov 2020

Cited by 8 | Viewed by 3139

Abstract

A large part of metabolomics research relies on experiments involving mouse models, which are usually 6 to 20 weeks of age. However, in this age range mice undergo dramatic developmental changes. Even small age differences may lead to different metabolomes, which in turn [...] Read more.

A large part of metabolomics research relies on experiments involving mouse models, which are usually 6 to 20 weeks of age. However, in this age range mice undergo dramatic developmental changes. Even small age differences may lead to different metabolomes, which in turn could increase inter-sample variability and impair the reproducibility and comparability of metabolomics results. In order to learn more about the variability of the murine plasma metabolome, we analyzed male and female C57BL/6J, C57BL/6NTac, 129S1/SvImJ, and C3HeB/FeJ mice at 6, 10, 14, and 20 weeks of age, using targeted metabolomics (BIOCRATES AbsoluteIDQ™ p150 Kit). Our analysis revealed high variability of the murine plasma metabolome during adolescence and early adulthood. A general age range with minimal variability, and thus a stable metabolome, could not be identified. Age-related metabolomic changes as well as the metabolite profiles at specific ages differed markedly between mouse strains. This observation illustrates the fact that the developmental timing in mice is strain specific. We therefore stress the importance of deliberate strain choice, as well as consistency and precise documentation of animal age, in metabolomics studies. Full article

(This article belongs to the Section Animal Metabolism)

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27 pages, 2686 KiB

Open AccessReview

Control of Adipose Cell Browning and Its Therapeutic Potential

by Fernando Lizcano and Felipe Arroyave

Metabolites 2020, 10(11), 471; https://doi.org/10.3390/metabo10110471 - 19 Nov 2020

Cited by 20 | Viewed by 4603

Abstract

Adipose tissue is the largest endocrine organ in humans and has an important influence on many physiological processes throughout life. An increasing number of studies have described the different phenotypic characteristics of fat cells in adults. Perhaps one of the most important properties [...] Read more.

Adipose tissue is the largest endocrine organ in humans and has an important influence on many physiological processes throughout life. An increasing number of studies have described the different phenotypic characteristics of fat cells in adults. Perhaps one of the most important properties of fat cells is their ability to adapt to different environmental and nutritional conditions. Hypothalamic neural circuits receive peripheral signals from temperature, physical activity or nutrients and stimulate the metabolism of white fat cells. During this process, changes in lipid inclusion occur, and the number of mitochondria increases, giving these cells functional properties similar to those of brown fat cells. Recently, beige fat cells have been studied for their potential role in the regulation of obesity and insulin resistance. In this context, it is important to understand the embryonic origin of beige adipocytes, the response of adipocyte to environmental changes or modifications within the body and their ability to transdifferentiate to elucidate the roles of these cells for their potential use in therapeutic strategies for obesity and metabolic diseases. In this review, we discuss the origins of the different fat cells and the possible therapeutic properties of beige fat cells. Full article

(This article belongs to the Special Issue Neuroendocrine Control of Energy Metabolism)

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10 pages, 1509 KiB

Open AccessArticle

Variable Selection in Untargeted Metabolomics and the Danger of Sparsity

by Gerjen H. Tinnevelt, Udo F.H. Engelke, Ron A. Wevers, Stefanie Veenhuis, Michel A. Willemsen, Karlien L.M. Coene, Purva Kulkarni and Jeroen J. Jansen

Metabolites 2020, 10(11), 470; https://doi.org/10.3390/metabo10110470 - 17 Nov 2020

Cited by 5 | Viewed by 3063

Abstract

The goal of metabolomics is to measure as many metabolites as possible in order to capture biomarkers that may indicate disease mechanisms. Variable selection in chemometric methods can be divided into the following two groups: (1) sparse methods that find the minimal set [...] Read more.

The goal of metabolomics is to measure as many metabolites as possible in order to capture biomarkers that may indicate disease mechanisms. Variable selection in chemometric methods can be divided into the following two groups: (1) sparse methods that find the minimal set of variables to discriminate between groups and (2) methods that find all variables important for discrimination. Such important variables can be summarized into metabolic pathways using pathway analysis tools like Mummichog. As a test case, we studied the metabolic effects of treatment with nicotinamide riboside, a form of vitamin B3, in a cohort of patients with ataxia–telangiectasia. Vitamin B3 is an important co-factor for many enzymatic reactions in the human body. Thus, the variable selection method was expected to find vitamin B3 metabolites and also other secondary metabolic changes during treatment. However, sparse methods did not select any vitamin B3 metabolites despite the fact that these metabolites showed a large difference when comparing intensity before and during treatment. Univariate analysis or significance multivariate correlation (sMC) in combination with pathway analysis using Mummichog were able to select vitamin B3 metabolites. Moreover, sMC analysis found additional metabolites. Therefore, in our comparative study, sMC displayed the best performance for selection of relevant variables. 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, 524 KiB

Open AccessArticle

Altered Levels of Desaturation and ω-6 Fatty Acids in Breast Cancer Patients’ Red Blood Cell Membranes

by Javier Amézaga, Gurutze Ugartemendia, Aitziber Larraioz, Nerea Bretaña, Aizpea Iruretagoyena, Joana Camba, Ander Urruticoechea, Carla Ferreri and Itziar Tueros

Metabolites 2020, 10(11), 469; https://doi.org/10.3390/metabo10110469 - 17 Nov 2020

Cited by 10 | Viewed by 2655

Abstract

Red blood cell (RBC) membrane can reflect fatty acid (FA) contribution from diet and biosynthesis. In cancer, membrane FAs are involved in tumorigenesis and invasiveness, and are indicated as biomarkers to monitor the disease evolution as well as potential targets for therapies and [...] Read more.

Red blood cell (RBC) membrane can reflect fatty acid (FA) contribution from diet and biosynthesis. In cancer, membrane FAs are involved in tumorigenesis and invasiveness, and are indicated as biomarkers to monitor the disease evolution as well as potential targets for therapies and nutritional strategies. The present study provides RBC membrane FA profiles in recently diagnosed breast cancer patients before starting chemotherapy treatment. Patients and controls were recruited, and their dietary habits were collected. FA lipidomic analysis of mature erythrocyte membrane phospholipids in blood samples was performed. Data were adjusted to correct for the effects of diet, body mass index (BMI), and age, revealing that patients showed lower levels of saturated fatty acids (SFA) and higher levels of monounsaturated fatty acid, cis-vaccenic (25%) than controls, with consequent differences in desaturase enzymatic index (∆9 desaturase, –13.1%). In the case of polyunsaturated fatty acids (PUFA), patients had higher values of ω-6 FA (C18:2 (+11.1%); C20:4 (+7.4%)). RBC membrane lipidomic analysis in breast cancer revealed that ω-6 pathways are favored. These results suggest new potential targets for treatments and better nutritional guidelines. Full article

(This article belongs to the Section Cell Metabolism)

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17 pages, 770 KiB

Open AccessArticle

Blood Metabolomic Profiling Confirms and Identifies Biomarkers of Food Intake

by Julia Langenau, Kolade Oluwagbemigun, Christian Brachem, Wolfgang Lieb, Romina di Giuseppe, Anna Artati, Gabi Kastenmüller, Leonie Weinhold, Matthias Schmid and Ute Nöthlings

Metabolites 2020, 10(11), 468; https://doi.org/10.3390/metabo10110468 - 17 Nov 2020

Cited by 16 | Viewed by 3362

Abstract

Metabolomics can be a tool to identify dietary biomarkers. However, reported food-metabolite associations have been inconsistent, and there is a need to explore further associations. Our aims were to confirm previously reported food-metabolite associations and to identify novel food-metabolite associations. We conducted a [...] Read more.

Metabolomics can be a tool to identify dietary biomarkers. However, reported food-metabolite associations have been inconsistent, and there is a need to explore further associations. Our aims were to confirm previously reported food-metabolite associations and to identify novel food-metabolite associations. We conducted a cross-sectional analysis of data from 849 participants (57% men) of the PopGen cohort. Dietary intake was obtained using FFQ and serum metabolites were profiled by an untargeted metabolomics approach. We conducted a systematic literature search to identify previously reported food-metabolite associations and analyzed these associations using linear regression. To identify potential novel food-metabolite associations, datasets were split into training and test datasets and linear regression models were fitted to the training datasets. Significant food-metabolite associations were evaluated in the test datasets. Models were adjusted for covariates. In the literature, we identified 82 food-metabolite associations. Of these, 44 associations were testable in our data and confirmed associations of coffee with 12 metabolites, of fish with five, of chocolate with two, of alcohol with four, and of butter, poultry and wine with one metabolite each. We did not identify novel food-metabolite associations; however, some associations were sex-specific. Potential use of some metabolites as biomarkers should consider sex differences in metabolism. Full article

(This article belongs to the Special Issue Nutritional Metabolomics)

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4 pages, 214 KiB

Open AccessEditorial

Special Issue: Plant Metabolomics

by Sándor Gonda

Metabolites 2020, 10(11), 467; https://doi.org/10.3390/metabo10110467 - 16 Nov 2020

Cited by 6 | Viewed by 2749

Abstract

This Special Issue was initiated to collect a handful of studies on plant chemistry, utilizing metabolomics as the main technique, to show the diversity of possible applications of this approach [...] Full article

(This article belongs to the Special Issue Plant Metabolomics)

20 pages, 2806 KiB

Open AccessArticle

Concurrent Metabolic Profiling and Quantification of Aromatic Amino Acids and Phytohormones in Solanum lycopersicum Plants Responding to Phytophthora capsici

by Msizi I. Mhlongo, Lizelle A. Piater, Paul A. Steenkamp, Nico Labuschagne and Ian A. Dubery

Metabolites 2020, 10(11), 466; https://doi.org/10.3390/metabo10110466 - 16 Nov 2020

Cited by 15 | Viewed by 3193

Abstract

Pathogenic microorganisms account for large production losses in the agricultural sector. Phytophthora capsici is an oomycete that causes blight and fruit rot in important crops, especially those in the Solanaceae family. P. capsici infection is difficult to control due to genetic diversity, arising [...] Read more.

Pathogenic microorganisms account for large production losses in the agricultural sector. Phytophthora capsici is an oomycete that causes blight and fruit rot in important crops, especially those in the Solanaceae family. P. capsici infection is difficult to control due to genetic diversity, arising from sexual reproduction, and resistant spores that remain dormant in soil. In this study, the metabolomics of tomato plants responding to infection by P. capsici were investigated. Non-targeted metabolomics, based on liquid chromatography coupled to mass spectrometry (LC-MS), were used with multivariate data analyses to investigate time-dependent metabolic reprogramming in the roots, stems, and leaves of stem-infected plants, over an 8 day period. In addition, phytohormones and amino acids were determined using quantitative LC-MS. Methyl salicylate and 1-aminocyclopropane-1-carboxylate were detected as major signalling molecules in the defensive response to P. capsici. As aromatic amino acid precursors of secondary metabolic pathways, both phenylalanine and tryptophan showed a continuous increase over time in all tissues, whereas tyrosine peaked at day 4. Non-targeted metabolomic analysis revealed phenylpropanoids, benzoic acids, glycoalkaloids, flavonoids, amino acids, organic acids, and fatty acids as the major classes of reprogrammed metabolites. Correlation analysis showed that metabolites derived from the same pathway, or synthesised by different pathways, could either have a positive or negative correlation. Furthermore, roots, stems, and leaves showed contrasting time-dependent metabolic reprogramming, possibly related to the biotrophic vs. necrotrophic life-stages of the pathogen, and overlapping biotic and abiotic stress signaling. As such, the targeted and untargeted approaches complemented each other, to provide a detailed view of key time-dependent metabolic changes, occurring in both the asymptomatic and symptomatic stages of infection. Full article

(This article belongs to the Special Issue Metabolomics in Plant Defence)

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16 pages, 901 KiB

Open AccessReview

Metabolic Syndrome and Abnormal Peri-Organ or Intra-Organ Fat (APIFat) Deposition in Chronic Obstructive Pulmonary Disease: An Overview

by Niki Katsiki, Anca Pantea Stoian, Paschalis Steiropoulos, Nikolaos Papanas, Andra-Iulia Suceveanu and Dimitri P. Mikhailidis

Metabolites 2020, 10(11), 465; https://doi.org/10.3390/metabo10110465 - 15 Nov 2020

Cited by 10 | Viewed by 3243

Abstract

Chronic obstructive pulmonary disease (COPD) is a common disorder with an increasing prevalence, characterised by persistent respiratory symptoms and airflow limitation. Systemic inflammation is involved in the pathogenesis of COPD and can also predispose to metabolic disorders (e.g., metabolic syndrome (MetS) and non-alcoholic [...] Read more.

Chronic obstructive pulmonary disease (COPD) is a common disorder with an increasing prevalence, characterised by persistent respiratory symptoms and airflow limitation. Systemic inflammation is involved in the pathogenesis of COPD and can also predispose to metabolic disorders (e.g., metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD)). Such comorbidities can negatively affect COPD outcomes, cardiovascular risk, and quality of life. Apart from NAFLD, abnormal peri-organ or intra-organ fat (APIFat) could be considered as markers for cardiometabolic diseases and even for COPD. The present narrative review considers the associations of COPD with MetS, NAFLD, and other APIFat, including epicardial, perirenal, peripancreatic, and intramuscular adipose tissue. Further research is needed to define these relationships and identify any potential clinical implications. Full article

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

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17 pages, 1966 KiB

Open AccessArticle

Evaluation of Different Tandem MS Acquisition Modes to Support Metabolite Annotation in Human Plasma Using Ultra High-Performance Liquid Chromatography High-Resolution Mass Spectrometry for Untargeted Metabolomics

by Julian Pezzatti, Víctor González-Ruiz, Julien Boccard, Davy Guillarme and Serge Rudaz

Metabolites 2020, 10(11), 464; https://doi.org/10.3390/metabo10110464 - 15 Nov 2020

Cited by 12 | Viewed by 3795

Abstract

Ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) is a powerful and essential technique for metabolite annotation in untargeted metabolomic applications. The aim of this study was to evaluate the performance of diverse tandem MS (MS/MS) acquisition modes, i.e., all ion [...] Read more.

Ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) is a powerful and essential technique for metabolite annotation in untargeted metabolomic applications. The aim of this study was to evaluate the performance of diverse tandem MS (MS/MS) acquisition modes, i.e., all ion fragmentation (AIF) and data-dependent analysis (DDA), with and without ion mobility spectrometry (IM), to annotate metabolites in human plasma. The influence of the LC separation was also evaluated by comparing the performance of MS/MS acquisition in combination with three complementary chromatographic separation modes: reversed-phase chromatography (RPLC) and hydrophilic interaction chromatography (HILIC) with either an amide (aHILIC) or a zwitterionic (zHILIC) stationary phase. RPLC conditions were first chosen to investigate all the tandem MS modes, and we found out that DDA did not provide a significant additional amount of chemical coverage and that cleaner MS/MS spectra can be obtained by performing AIF acquisitions in combination with IM. Finally, we were able to annotate 338 unique metabolites and demonstrated that zHILIC was a powerful complementary approach to both the RPLC and aHILIC chromatographic modes. Moreover, a better analytical throughput was reached for an almost negligible loss of metabolite coverage when IM-AIF and AIF using ramped instead of fixed collision energies were used. Full article

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

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19 pages, 5412 KiB

Open AccessArticle

Influence of Indomethacin on Steroid Metabolism: Endocrine Disruption and Confounding Effects in Urinary Steroid Profiling of Anti-Doping Analyses

by Anna Stoll, Michele Iannone, Giuseppina De Gregorio, Francesco Molaioni, Xavier de la Torre, Francesco Botrè and Maria Kristina Parr

Metabolites 2020, 10(11), 463; https://doi.org/10.3390/metabo10110463 - 14 Nov 2020

Cited by 9 | Viewed by 3634

Abstract

Anabolic androgenic steroids (AAS) are prohibited as doping substances in sports by the World Anti-Doping Agency. Concentrations and concentration ratios of endogenous AAS (steroid profile markers) in urine samples collected from athletes are used to detect their administration. Certain (non-prohibited) drugs have been [...] Read more.

Anabolic androgenic steroids (AAS) are prohibited as doping substances in sports by the World Anti-Doping Agency. Concentrations and concentration ratios of endogenous AAS (steroid profile markers) in urine samples collected from athletes are used to detect their administration. Certain (non-prohibited) drugs have been shown to influence the steroid profile and thereby sophisticate anti-doping analysis. It was shown in vitro that the non-steroidal anti-inflammatory drug (NSAID) indomethacin inhibits selected steroid-biotransformations catalyzed by the aldo-keto reductase (AKR) 1C3, which plays a key role in the endogenous steroid metabolism. Kinetic parameters for the indomethacin-mediated inhibition of the AKR1C3 catalyzed reduction in etiocholanolone were determined in vitro using two comparing methods. As NSAIDs are very frequently used (not only) by athletes, the inhibitory impact of indomethacin intake on the steroid metabolism was evaluated, and steroid profile alterations were detected in vivo (one male and one female volunteer). Significant differences between samples collected before, during or after the intake of indomethacin for selected steroid profile markers were observed. The presented results are of relevance for the interpretation of results from doping control analysis. Additionally, the administration of NSAIDs should be carefully reconsidered due to their potential as endocrine disruptors. Full article

(This article belongs to the Section Pharmacology and Drug Metabolism)

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21 pages, 4200 KiB

Open AccessArticle

Impact of Long-Term HFD Intake on the Peripheral and Central IGF System in Male and Female Mice

by Santiago Guerra-Cantera, Laura M. Frago, María Jiménez-Hernaiz, Purificación Ros, Alejandra Freire-Regatillo, Vicente Barrios, Jesús Argente and Julie A. Chowen

Metabolites 2020, 10(11), 462; https://doi.org/10.3390/metabo10110462 - 13 Nov 2020

Cited by 8 | Viewed by 3214

Abstract

The insulin-like growth factor (IGF) system is responsible for growth, but also affects metabolism and brain function throughout life. New IGF family members (i.e., pappalysins and stanniocalcins) control the availability/activity of IGFs and are implicated in growth. However, how diet and obesity modify [...] Read more.

The insulin-like growth factor (IGF) system is responsible for growth, but also affects metabolism and brain function throughout life. New IGF family members (i.e., pappalysins and stanniocalcins) control the availability/activity of IGFs and are implicated in growth. However, how diet and obesity modify this system has been poorly studied. We explored how intake of a high-fat diet (HFD) or commercial control diet (CCD) affects the IGF system in the circulation, visceral adipose tissue (VAT) and hypothalamus. Male and female C57/BL6J mice received HFD (60% fat, 5.1 kcal/g), CCD (10% fat, 3.7 kcal/g) or chow (3.1 % fat, 3.4 kcal/g) for 8 weeks. After 7 weeks of HFD intake, males had decreased glucose tolerance (p < 0.01) and at sacrifice increased plasma insulin (p < 0.05) and leptin (p < 0.01). Circulating free IGF1 (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.05) and IGFBP3 (p < 0.01) were higher after HFD in both sexes, with CCD increasing IGFBP2 in males (p < 0.001). In VAT, HFD reduced mRNA levels of IGF2 (p < 0.05), PAPP-A (p < 0.001) and stanniocalcin (STC)-1 (p < 0.001) in males. HFD increased hypothalamic IGF1 (p < 0.01), IGF2 (p < 0.05) and IGFBP5 (p < 0.01) mRNA levels, with these changes more apparent in females. Our results show that diet-induced changes in the IGF system are tissue-, sex- and diet-dependent. Full article

(This article belongs to the Special Issue Neuroendocrine Control of Energy Metabolism)

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18 pages, 6820 KiB

Open AccessArticle

Divergent Impact of Glucose Availability on Human Virus-Specific and Generically Activated CD8 T Cells

by Jenifer Sanchez, Ian Jackson, Katie R. Flaherty, Tamara Muliaditan and Anna Schurich

Metabolites 2020, 10(11), 461; https://doi.org/10.3390/metabo10110461 - 13 Nov 2020

Cited by 5 | Viewed by 3310

Abstract

Upon activation T cells engage glucose metabolism to fuel the costly effector functions needed for a robust immune response. Consequently, the availability of glucose can impact on T cell function. The glucose concentrations used in conventional culture media and common metabolic assays are [...] Read more.

Upon activation T cells engage glucose metabolism to fuel the costly effector functions needed for a robust immune response. Consequently, the availability of glucose can impact on T cell function. The glucose concentrations used in conventional culture media and common metabolic assays are often artificially high, representing hyperglycaemic levels rarely present in vivo. We show here that reducing glucose concentration to physiological levels in culture differentially impacted on virus-specific compared to generically activated human CD8 T cell responses. In virus-specific T cells, limiting glucose availability significantly reduced the frequency of effector-cytokine producing T cells, but promoted the upregulation of CD69 and CD103 associated with an increased capacity for tissue retention. In contrast the functionality of generically activated T cells was largely unaffected and these showed reduced differentiation towards a residency phenotype. Furthermore, T cells being cultured at physiological glucose concentrations were more susceptible to viral infection. This setting resulted in significantly improved lentiviral transduction rates of primary cells. Our data suggest that CD8 T cells are exquisitely adapted to their niche and provide a reminder of the need to better mimic physiological conditions to study the complex nature of the human CD8 T cell immune response. Full article

(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)

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23 pages, 5534 KiB

Open AccessArticle

¹H-NMR-Based Analysis for Exploring Knee Synovial Fluid Metabolite Changes after Local Cryotherapy in Knee Arthritis Patients

by Wafa Douzi, Xavier Guillot, Delphine Bon, François Seguin, Nadège Boildieu, Daniel Wendling, Nicolas Tordi, Olivier Dupuy and Benoit Dugué

Metabolites 2020, 10(11), 460; https://doi.org/10.3390/metabo10110460 - 13 Nov 2020

Cited by 5 | Viewed by 2950

Abstract

Rehabilitation using cryotherapy has widely been used in inflammatory diseases to relieve pain and decrease the disease activity. The aim of this study was to explore the metabolite changes in inflammatory knee-joint synovial fluids following local cryotherapy treatment (ice or cold CO₂ [...] Read more.

Rehabilitation using cryotherapy has widely been used in inflammatory diseases to relieve pain and decrease the disease activity. The aim of this study was to explore the metabolite changes in inflammatory knee-joint synovial fluids following local cryotherapy treatment (ice or cold CO₂). We used proton nuclear magnetic resonance (¹H NMR) spectroscopy to assess the metabolite patterns in synovial fluid (SF) in patients with knee arthritis (n = 46) before (D0) and after (D1, 24 h later) two applications of local cryotherapy. Spectra from aqueous samples and organic extracts were obtained with an 11.75 Tesla spectrometer. The metabolite concentrations within the SF were compared between D1 and D0 using multiple comparisons with the application of a false discovery rate (FDR) adjusted at 10% for each metabolite. A total of 32 metabolites/chemical structures were identified including amino acids, organic acids, fatty acids or sugars. Pyruvate, alanine, citrate, threonine was significantly higher at D1 vs D0 (p < 0.05). Tyrosine concentration significantly decreases after cryotherapy application (p < 0.001). We did not observe any effect of gender and cooling technique on metabolite concentrations between D0 and D1 (p > 0.05). The present study provides new insight into a short-term effect of cold stimulus in synovial fluid from patients with knee arthritis. Our observations suggest that the increased level of metabolites involved in energy metabolism may explain the underlying molecular pathways that mediate the antioxidant and anti-inflammatory capacities of cryotherapy. Full article

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

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17 pages, 1762 KiB

Open AccessArticle

Potent Antifungal Properties of Dimeric Acylphloroglucinols from Hypericum mexicanum and Mechanism of Action of a Highly Active 3′Prenyl Uliginosin B

by Noemi Tocci, Tobias Weil, Daniele Perenzoni, Marco Moretto, Nicolai Nürk, Santiago Madriñán, Ruggero Ferrazza, Graziano Guella and Fulvio Mattivi

Metabolites 2020, 10(11), 459; https://doi.org/10.3390/metabo10110459 - 13 Nov 2020

Cited by 3 | Viewed by 2603

Abstract

The success of antifungal therapies is often hindered by the limited number of available drugs. To close the gap in the antifungal pipeline, the search of novel leads is of primary importance, and here the exploration of neglected plants has great promise for [...] Read more.

The success of antifungal therapies is often hindered by the limited number of available drugs. To close the gap in the antifungal pipeline, the search of novel leads is of primary importance, and here the exploration of neglected plants has great promise for the discovery of new principles. Through bioassay-guided isolation, uliginosin B and five new dimeric acylphloroglucinols (uliginosins C-D, and 3′prenyl uliginosins B-D), besides cembrenoids, have been isolated from the lipophilic extract of Hypericum mexicanum. Their structures were elucidated by a combination of Liquid Chromatography - Mass Spectrometry LC-MS and Nuclear Magnetic Resonance (NMR) measurements. The compounds showed strong anti-Candida activity, also against fluconazole-resistant strains, with fungal growth inhibition properties at concentrations ranging from 3 to 32 µM, and reduced or absent cytotoxicity against human cell lines. A chemogenomic screen of 3′prenyl uliginosin B revealed target genes that are important for cell cycle regulation and cytoskeleton assembly in fungi. Taken together, our study suggests dimeric acylphloroglucinols as potential candidates for the development of alternative antifungal therapies. Full article

(This article belongs to the Section Plant Metabolism)

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17 pages, 3061 KiB

Open AccessArticle

Streamlining the Analysis of Dynamic ¹³C-Labeling Patterns for the Metabolic Engineering of Corynebacterium glutamicum as l-Histidine Production Host

by André Feith, Andreas Schwentner, Attila Teleki, Lorenzo Favilli, Bastian Blombach and Ralf Takors

Metabolites 2020, 10(11), 458; https://doi.org/10.3390/metabo10110458 - 12 Nov 2020

Cited by 6 | Viewed by 2772

Abstract

Today’s possibilities of genome editing easily create plentitudes of strain mutants that need to be experimentally qualified for configuring the next steps of strain engineering. The application of design-build-test-learn cycles requires the identification of distinct metabolic engineering targets as design inputs for subsequent [...] Read more.

Today’s possibilities of genome editing easily create plentitudes of strain mutants that need to be experimentally qualified for configuring the next steps of strain engineering. The application of design-build-test-learn cycles requires the identification of distinct metabolic engineering targets as design inputs for subsequent optimization rounds. Here, we present the pool influx kinetics (PIK) approach that identifies promising metabolic engineering targets by pairwise comparison of up- and downstream ¹³C labeling dynamics with respect to a metabolite of interest. Showcasing the complex l-histidine production with engineered Corynebacterium glutamicuml-histidine-on-glucose yields could be improved to 8.6 ± 0.1 mol% by PIK analysis, starting from a base strain. Amplification of purA, purB, purH, and formyl recycling was identified as key targets only analyzing the signal transduction kinetics mirrored in the PIK values. Full article

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

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16 pages, 1687 KiB

Open AccessArticle

Towards a More Reliable Identification of Isomeric Metabolites Using Pattern Guided Retention Validation

by Tobias Opialla, Stefan Kempa and Matthias Pietzke

Metabolites 2020, 10(11), 457; https://doi.org/10.3390/metabo10110457 - 12 Nov 2020

Cited by 18 | Viewed by 2870

Abstract

Reliable analyte identification is critical in metabolomics experiments to ensure proper interpretation of data. Due to chemical similarity of metabolites (as isobars and isomers) identification by mass spectrometry or chromatography alone can be difficult. Here we show that isomeric compounds are quite common [...] Read more.

Reliable analyte identification is critical in metabolomics experiments to ensure proper interpretation of data. Due to chemical similarity of metabolites (as isobars and isomers) identification by mass spectrometry or chromatography alone can be difficult. Here we show that isomeric compounds are quite common in the metabolic space as given in common metabolite databases. Further, we show that retention information can shift dramatically between different experiments decreasing the value of external or even in-house compound databases. As a consequence the retention information in compound databases should be updated regularly, to allow a reliable identification. To do so we present a feasible and budget conscious method to guarantee updates of retention information on a regular basis using well designed compound mixtures. For this we combine compounds in “Ident-Mixes”, showing a way to distinctly identify chemically similar compounds through combinatorics and principle of exclusion. We illustrate the feasibility of this approach by comparing Gas chromatography (GC)–columns with identical properties from three different vendors and by creating a compound database from measuring these mixtures by Liquid chromatography–mass spectrometry (LC–MS). The results show the high influence of used materials on retention behavior and the ability of our approach to generate high quality identifications in a short time. Full article

(This article belongs to the Section Integrative Metabolomics)

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27 pages, 5091 KiB

Open AccessArticle

by Mihai V. Curtasu, Valeria Tafintseva, Zachary A. Bendiks, Maria L. Marco, Achim Kohler, Yetong Xu, Natalja P. Nørskov, Helle Nygaard Lærke, Knud Erik Bach Knudsen and Mette Skou Hedemann

Metabolites 2020, 10(11), 456; https://doi.org/10.3390/metabo10110456 - 12 Nov 2020

Cited by 17 | Viewed by 4989

Abstract

The metabolome and gut microbiota were investigated in a juvenile Göttingen minipig model. This study aimed to explore the metabolic effects of two carbohydrate sources with different degrees of risk in obesity development when associated with a high fat intake. A high-risk (HR) [...] Read more.

The metabolome and gut microbiota were investigated in a juvenile Göttingen minipig model. This study aimed to explore the metabolic effects of two carbohydrate sources with different degrees of risk in obesity development when associated with a high fat intake. A high-risk (HR) high-fat diet containing 20% fructose was compared to a control lower-risk (LR) high-fat diet where a similar amount of carbohydrate was provided as a mix of digestible and resistant starch from high amylose maize. Both diets were fed ad libitum. Non-targeted metabolomics was used to explore plasma, urine, and feces samples over five months. Plasma and fecal short-chain fatty acids were targeted and quantified. Fecal microbiota was analyzed using genomic sequencing. Data analysis was performed using sparse multi-block partial least squares regression. The LR diet increased concentrations of fecal and plasma total short-chain fatty acids, primarily acetate, and there was a higher relative abundance of microbiota associated with acetate production such as Bacteroidetes and Ruminococcus. A higher proportion of Firmicutes was measured with the HR diet, together with a lower alpha diversity compared to the LR diet. Irrespective of diet, the ad libitum exposure to the high-energy diets was accompanied by well-known biomarkers associated with obesity and diabetes, particularly branched-chain amino acids, keto acids, and other catabolism metabolites. Full article

(This article belongs to the Special Issue Nutrition, Microbiota and Metabolism)

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17 pages, 1180 KiB

Open AccessReview

Islet Health, Hormone Secretion, and Insulin Responsivity with Low-Carbohydrate Feeding in Diabetes

by Cassandra A. A. Locatelli and Erin E. Mulvihill

Metabolites 2020, 10(11), 455; https://doi.org/10.3390/metabo10110455 - 11 Nov 2020

Cited by 9 | Viewed by 4167

Abstract

Exploring new avenues to control daily fluctuations in glycemia has been a central theme for diabetes research since the Diabetes Control and Complications Trial (DCCT). Carbohydrate restriction has re-emerged as a means to control type 2 diabetes mellitus (T2DM), becoming increasingly popular and [...] Read more.

Exploring new avenues to control daily fluctuations in glycemia has been a central theme for diabetes research since the Diabetes Control and Complications Trial (DCCT). Carbohydrate restriction has re-emerged as a means to control type 2 diabetes mellitus (T2DM), becoming increasingly popular and supported by national diabetes associations in Canada, Australia, the USA, and Europe. This approval comes from many positive outcomes on HbA1c in human studies; yet mechanisms underlying their success have not been fully elucidated. In this review, we discuss the preclinical and clinical studies investigating the role of carbohydrate restriction and physiological elevations in ketone bodies directly on pancreatic islet health, islet hormone secretion, and insulin sensitivity. Included studies have clearly outlined diet compositions, including a diet with 30% or less of calories from carbohydrates. Full article

(This article belongs to the Special Issue Islet Inflammation and Metabolic Homeostasis)

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31 pages, 2671 KiB

Open AccessReview

Metabolic Signatures of the Exposome—Quantifying the Impact of Exposure to Environmental Chemicals on Human Health

by Matej Orešič, Aidan McGlinchey, Craig E. Wheelock and Tuulia Hyötyläinen

Metabolites 2020, 10(11), 454; https://doi.org/10.3390/metabo10110454 - 10 Nov 2020

Cited by 24 | Viewed by 7250

Abstract

Human health and well-being are intricately linked to environmental quality. Environmental exposures can have lifelong consequences. In particular, exposures during the vulnerable fetal or early development period can affect structure, physiology and metabolism, causing potential adverse, often permanent, health effects at any point [...] Read more.

Human health and well-being are intricately linked to environmental quality. Environmental exposures can have lifelong consequences. In particular, exposures during the vulnerable fetal or early development period can affect structure, physiology and metabolism, causing potential adverse, often permanent, health effects at any point in life. External exposures, such as the “chemical exposome” (exposures to environmental chemicals), affect the host’s metabolism and immune system, which, in turn, mediate the risk of various diseases. Linking such exposures to adverse outcomes, via intermediate phenotypes such as the metabolome, is one of the central themes of exposome research. Much progress has been made in this line of research, including addressing some key challenges such as analytical coverage of the exposome and metabolome, as well as the integration of heterogeneous, multi-omics data. There is strong evidence that chemical exposures have a marked impact on the metabolome, associating with specific disease risks. Herein, we review recent progress in the field of exposome research as related to human health as well as selected metabolic and autoimmune diseases, with specific emphasis on the impacts of chemical exposures on the host metabolome. Full article

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

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24 pages, 2572 KiB

Open AccessReview

Electrophile Modulation of Inflammation: A Two-Hit Approach

by James O’Brien and Stacy G. Wendell

Metabolites 2020, 10(11), 453; https://doi.org/10.3390/metabo10110453 - 10 Nov 2020

Cited by 6 | Viewed by 3383

Abstract

Electrophilic small molecules have gained significant attention over the last decade in the field of covalent drug discovery. Long recognized as mediators of the inflammatory process, recent evidence suggests that electrophiles may modulate the immune response through the regulation of metabolic networks. These [...] Read more.

Electrophilic small molecules have gained significant attention over the last decade in the field of covalent drug discovery. Long recognized as mediators of the inflammatory process, recent evidence suggests that electrophiles may modulate the immune response through the regulation of metabolic networks. These molecules function as pleiotropic signaling mediators capable of reversibly reacting with nucleophilic biomolecules, most notably at reactive cysteines. More specifically, electrophiles target critical cysteines in redox regulatory proteins to activate protective pathways such as the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1) antioxidant signaling pathway while also inhibiting Nuclear Factor κB (NF-κB). During inflammatory states, reactive species broadly alter cell signaling through the oxidation of lipids, amino acids, and nucleic acids, effectively propagating the inflammatory sequence. Subsequent changes in metabolic signaling inform immune cell maturation and effector function. Therapeutic strategies targeting inflammatory pathologies leverage electrophilic drug compounds, in part, because of their documented effect on the redox balance of the cell. With mounting evidence demonstrating the link between redox signaling and metabolism, electrophiles represent ideal therapeutic candidates for the treatment of inflammatory conditions. Through their pleiotropic signaling activity, electrophiles may be used strategically to both directly and indirectly target immune cell metabolism. Full article

(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)

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12 pages, 3552 KiB

Open AccessReview

Beta Cell Physiological Dynamics and Dysfunctional Transitions in Response to Islet Inflammation in Obesity and Diabetes

by Marlon E. Cerf

Metabolites 2020, 10(11), 452; https://doi.org/10.3390/metabo10110452 - 10 Nov 2020

Cited by 32 | Viewed by 3306

Abstract

Beta cells adapt their function to respond to fluctuating glucose concentrations and variable insulin demand. The highly specialized beta cells have well-established endoplasmic reticulum to handle their high metabolic load for insulin biosynthesis and secretion. Beta cell endoplasmic reticulum therefore recognize and remove [...] Read more.

Beta cells adapt their function to respond to fluctuating glucose concentrations and variable insulin demand. The highly specialized beta cells have well-established endoplasmic reticulum to handle their high metabolic load for insulin biosynthesis and secretion. Beta cell endoplasmic reticulum therefore recognize and remove misfolded proteins thereby limiting their accumulation. Beta cells function optimally when they sense glucose and, in response, biosynthesize and secrete sufficient insulin. Overnutrition drives the pathogenesis of obesity and diabetes, with adverse effects on beta cells. The interleukin signaling system maintains beta cell physiology and plays a role in beta cell inflammation. In pre-diabetes and compromised metabolic states such as obesity, insulin resistance, and glucose intolerance, beta cells biosynthesize and secrete more insulin, i.e., hyperfunction. Obesity is entwined with inflammation, characterized by compensatory hyperinsulinemia, for a defined period, to normalize glycemia. However, with chronic hyperglycemia and diabetes, there is a perpetual high demand for insulin, and beta cells become exhausted resulting in insufficient insulin biosynthesis and secretion, i.e., they hypofunction in response to elevated glycemia. Therefore, beta cell hyperfunction progresses to hypofunction, and may progressively worsen towards failure. Preserving beta cell physiology, through healthy nutrition and lifestyles, and therapies that are aligned with beta cell functional transitions, is key for diabetes prevention and management. Full article

(This article belongs to the Special Issue Islet Inflammation and Metabolic Homeostasis)

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15 pages, 1294 KiB

Open AccessArticle

Volatile Organic Compounds (VOCs) of Endophytic Fungi Growing on Extracts of the Host, Horseradish (Armoracia rusticana)

by Tamás Plaszkó, Zsolt Szűcs, Zoltán Kállai, Hajnalka Csoma, Gábor Vasas and Sándor Gonda

Metabolites 2020, 10(11), 451; https://doi.org/10.3390/metabo10110451 - 8 Nov 2020

Cited by 22 | Viewed by 3216

Abstract

The interaction between plant defensive metabolites and different plant-associated fungal species is of high interest to many disciplines. Volatile organic compounds (VOCs) are natural products that are easily evaporated under ambient conditions. They play a very important role in inter-species communication of microbes [...] Read more.

The interaction between plant defensive metabolites and different plant-associated fungal species is of high interest to many disciplines. Volatile organic compounds (VOCs) are natural products that are easily evaporated under ambient conditions. They play a very important role in inter-species communication of microbes and their hosts. In this study, the VOCs produced by 43 different fungal isolates of endophytic and soil fungi during growth on horseradish root (Armoracia rusticana) extract or malt extract agar were examined, by using headspace-gas chromatography-mass spectrometry (headspace-GC-MS) and a high relative surface agar film as a medium. The proposed technique enabled sensitive detection of several typical VOCs (acetone, methyl acetate, methyl formate, ethyl acetate, methyl butanol isomers, styrene, beta-phellandrene), along with glucosinolate decomposition products, including allyl cyanide and allyl isothiocyanate and other sulfur-containing compounds—carbon disulfide, dimethyl sulfide. The VOC patterns of fungi belonging to Setophoma, Paraphoma, Plectosphaerella, Pyrenochaeta, Volutella, Cadophora, Notophoma, and Curvularia genera were described for the first time. The VOC pattern was significantly different among the isolates. The pattern was indicative of putative myrosinase activity for many tested isolates. On the other hand, endophytes and soil fungi as groups could not be separated by VOC pattern or intensity. Full article

(This article belongs to the Special Issue Plant Metabolomics)

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20 pages, 983 KiB

Open AccessReview

Energy Metabolism Decline in the Aging Brain—Pathogenesis of Neurodegenerative Disorders

by Janusz Wiesław Błaszczyk

Metabolites 2020, 10(11), 450; https://doi.org/10.3390/metabo10110450 - 7 Nov 2020

Cited by 67 | Viewed by 7214

Abstract

There is a growing body of evidencethat indicates that the aging of the brain results from the decline of energy metabolism. In particular, the neuronal metabolism of glucose declines steadily, resulting in a growing deficit of adenosine triphosphate (ATP) production—which, in turn, limits [...] Read more.

There is a growing body of evidencethat indicates that the aging of the brain results from the decline of energy metabolism. In particular, the neuronal metabolism of glucose declines steadily, resulting in a growing deficit of adenosine triphosphate (ATP) production—which, in turn, limits glucose access. This vicious circle of energy metabolism at the cellular level is evoked by a rising deficiency of nicotinamide adenine dinucleotide (NAD) in the mitochondrial salvage pathway and subsequent impairment of the Krebs cycle. A decreasing NAD level also impoverishes the activity of NAD-dependent enzymes that augments genetic errors and initiate processes of neuronal degeneration and death.This sequence of events is characteristic of several brain structures in which neurons have the highest energy metabolism. Neurons of the cerebral cortex and basal ganglia with long unmyelinated axons and these with numerous synaptic junctions are particularly prone to senescence and neurodegeneration. Unfortunately, functional deficits of neurodegeneration are initially well-compensated, therefore, clinical symptoms are recognized too late when the damages to the brain structures are already irreversible. Therefore, future treatment strategies in neurodegenerative disorders should focus on energy metabolism and compensation age-related NAD deficit in neurons. This review summarizes the complex interrelationships between metabolic processes on the systemic and cellular levels and provides directions on how to reduce the risk of neurodegeneration and protect the elderly against neurodegenerative diseases. Full article

(This article belongs to the Special Issue Neurodegenerative Disorders and Metabolism of the Aging Brain)

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11 pages, 2358 KiB

Open AccessArticle

Robust Metabolite Quantification from J-Compensated 2D ¹H-¹³C-HSQC Experiments

by Alexander Weitzel, Claudia Samol, Peter J. Oefner and Wolfram Gronwald

Metabolites 2020, 10(11), 449; https://doi.org/10.3390/metabo10110449 - 7 Nov 2020

Cited by 5 | Viewed by 2450

Abstract

The spectral resolution of 2D

^{1}

H-

^{13}

C heteronuclear single quantum coherence (

^{1}

H-

^{13}

C-HSQC) nuclear magnetic resonance (NMR) spectra facilitates both metabolite identification and quantification in nuclear magnetic resonance-based metabolomics. However, quantification is complicated by variations in magnetization transfer, [...] Read more.

The spectral resolution of 2D

^{1}

H-

^{13}

C heteronuclear single quantum coherence (

^{1}

H-

^{13}

C-HSQC) nuclear magnetic resonance (NMR) spectra facilitates both metabolite identification and quantification in nuclear magnetic resonance-based metabolomics. However, quantification is complicated by variations in magnetization transfer, which among others originate mainly from scalar coupling differences. Methods that compensate for variation in scalar coupling include the generation of calibration factors for individual signals or the use of additional pulse sequence schemes such as quantitative HSQC (Q-HSQC) that suppress the J_CH-dependence by modulating the polarization transfer delays of HSQC or, additionally, employ a pure-shift homodecoupling approach in the

^{1}

H dimension, such as Quantitative, Perfected and Pure Shifted HSQC (QUIPU-HSQC). To test the quantitative accuracy of these three methods, employing a 600 MHz NMR spectrometer equipped with a helium cooled cryoprobe, a Latin-square design that covered the physiological concentration ranges of 10 metabolites was used. The results show the suitability of all three methods for the quantification of highly abundant metabolites. However, the substantially increased residual water signal observed in QUIPU-HSQC spectra impeded the quantification of low abundant metabolites located near the residual water signal, thus limiting its utility in high-throughput metabolite fingerprinting studies. Full article

(This article belongs to the Special Issue Advances in Cellular Metabolomics)

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10 pages, 813 KiB

Open AccessReview

NLRP3 Inflammasome Biomarker—Could Be the New Tool for Improved Cardiometabolic Syndrome Outcome

by Andra-Iulia Suceveanu, Laura Mazilu, Niki Katsiki, Irinel Parepa, Felix Voinea, Anca Pantea-Stoian, Manfredi Rizzo, Florin Botea, Vlad Herlea, Dragos Serban and Adrian-Paul Suceveanu

Metabolites 2020, 10(11), 448; https://doi.org/10.3390/metabo10110448 - 6 Nov 2020

Cited by 27 | Viewed by 3247

Abstract

Metabolomics, the research area studying chemical processes involving metabolites, finds its utility in inflammasome biomarker discovery, thus representing a novel approach for cardiometabolic syndrome pathogeny acknowledgements. Metabolite biomarkers discovery is expected to improve the disease evolution and outcome. The activation of abundantly expressed [...] Read more.

Metabolomics, the research area studying chemical processes involving metabolites, finds its utility in inflammasome biomarker discovery, thus representing a novel approach for cardiometabolic syndrome pathogeny acknowledgements. Metabolite biomarkers discovery is expected to improve the disease evolution and outcome. The activation of abundantly expressed NLRP3 inflammasome represents the background process of the diabetes mellitus disturbances like hyperglycemia and insulin resistance, as well as for myocardial cell death and fibrosis, all of them being features characteristic for cardiometabolic syndrome. Many molecules like troponins, brain natriuretic protein (BNP), ST2/IL-33, C-reactive protein (CRP), TNF, IL-1β, and IL-18 cytokines have been already examined as molecular markers for diagnosing or predicting different cardiac disturbances like myocardial infarction, heart failure, or myocarditis. In addition, metabolomics research comes with new findings arguing that NLRP3 inflammasome becomes a promising molecular tool to use for clinical and therapeutical management providing new targets for therapies in cardiometabolic syndrome. Inflammasome markers analyses, along with other molecular or genetic biomarkers, will result in a better understanding of cardiometabolic syndrome pathogenesis and therapeutic targets. Screening, diagnostic, and prognostic biomarkers resulted from inflammasome biomarker research will become standard of care in cardiometabolic syndrome management, their utility becoming the first magnitude. Full article

(This article belongs to the Special Issue Cardiometabolic Challenges-Present and Future)

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21 pages, 2832 KiB

Open AccessReview

Metabolic Flux Analysis—Linking Isotope Labeling and Metabolic Fluxes

by Yujue Wang, Fredric E. Wondisford, Chi Song, Teng Zhang and Xiaoyang Su

Metabolites 2020, 10(11), 447; https://doi.org/10.3390/metabo10110447 - 6 Nov 2020

Cited by 27 | Viewed by 5072

Abstract

Metabolic flux analysis (MFA) is an increasingly important tool to study metabolism quantitatively. Unlike the concentrations of metabolites, the fluxes, which are the rates at which intracellular metabolites interconvert, are not directly measurable. MFA uses stable isotope labeled tracers to reveal information related [...] Read more.

Metabolic flux analysis (MFA) is an increasingly important tool to study metabolism quantitatively. Unlike the concentrations of metabolites, the fluxes, which are the rates at which intracellular metabolites interconvert, are not directly measurable. MFA uses stable isotope labeled tracers to reveal information related to the fluxes. The conceptual idea of MFA is that in tracer experiments the isotope labeling patterns of intracellular metabolites are determined by the fluxes, therefore by measuring the labeling patterns we can infer the fluxes in the network. In this review, we will discuss the basic concept of MFA using a simplified upper glycolysis network as an example. We will show how the fluxes are reflected in the isotope labeling patterns. The central idea we wish to deliver is that under metabolic and isotopic steady-state the labeling pattern of a metabolite is the flux-weighted average of the substrates’ labeling patterns. As a result, MFA can tell the relative contributions of converging metabolic pathways only when these pathways make substrates in different labeling patterns for the shared product. This is the fundamental principle guiding the design of isotope labeling experiment for MFA including tracer selection. In addition, we will also discuss the basic biochemical assumptions of MFA, and we will show the flux-solving procedure and result evaluation. Finally, we will highlight the link between isotopically stationary and nonstationary flux analysis. Full article

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

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Metabolites, Volume 10, Issue 11 (November 2020) – 54 articles

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