Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
6.9
3.7
Journals
Metabolites
Editor’s Choice
share announcement

Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

Order results
Result details
Results per page
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
11 pages, 430 KB  
Article
Relationship between Fasting and Postprandial Glucose Levels and the Gut Microbiota
by Yui Mineshita, Hiroyuki Sasaki, Hyeon-ki Kim and Shigenobu Shibata
Metabolites 2022, 12(7), 669; https://doi.org/10.3390/metabo12070669 - 20 Jul 2022
Cited by 3 | Viewed by 2692
Abstract
Postprandial hyperglycemia increases the risk of mortality among patients with type 2 diabetes and cardiovascular diseases. Additionally, the gut microbiota and type 2 diabetes and cardio-vascular disease are known to be correlated. Currently, fasting blood glucose is the primary in-dex for the clinical [...] Read more.
Postprandial hyperglycemia increases the risk of mortality among patients with type 2 diabetes and cardiovascular diseases. Additionally, the gut microbiota and type 2 diabetes and cardio-vascular disease are known to be correlated. Currently, fasting blood glucose is the primary in-dex for the clinical diagnosis of diabetes; however, postprandial blood glucose is associated with the risk of developing type 2 diabetes and cardiovascular disease and mortality. Therefore, the dynamic change in blood glucose levels under free-living conditions is considered an important and better marker than fasting glucose levels to study the relationship between glucose levels and microbiota. Here, we investigated the relationship between fasting and postprandial glucose levels and microbiota under free-living conditions for one week in older adults. In addition, in order to clarify the relationship between blood glucose level and intestinal bacteria, postprandial 4-h AUC was calculated and the correlation with gut bacteria was investigated. As a result of the present study, we observed many of the most significant correlations between the gut bacteria and the peak glucose levels after dinner and the 4-h AUC after dinner. Together, these findings suggest that the individual pattern of microbiota may help to predict post-dinner hyperglycemia and the risk of abnormal glucose metabolism, such as diabetes. Full article
(This article belongs to the Section Nutrition and Metabolism)
►▼ Show Figures

Figure 1

15 pages, 3008 KB  
Article
Molecular Network-Based Identification of Tramadol Metabolites in a Fatal Tramadol Poisoning
by Romain Magny, Nicolas Auzeil, Bertrand Lefrère, Bruno Mégarbane, Pascal Houzé and Laurence Labat
Metabolites 2022, 12(7), 665; https://doi.org/10.3390/metabo12070665 - 19 Jul 2022
Cited by 19 | Viewed by 2947
Abstract
Identification of xenobiotics and their phase I/II metabolites in poisoned patients remains challenging. Systematic approaches using bioinformatic tools are needed to detect all compounds as exhaustively as possible. Here, we aimed to assess an analytical workflow using liquid chromatography coupled to high-resolution mass [...] Read more.
Identification of xenobiotics and their phase I/II metabolites in poisoned patients remains challenging. Systematic approaches using bioinformatic tools are needed to detect all compounds as exhaustively as possible. Here, we aimed to assess an analytical workflow using liquid chromatography coupled to high-resolution mass spectrometry with data processing based on a molecular network to identify tramadol metabolites in urine and plasma in poisoned patients. The generated molecular network from liquid chromatography coupled to high-resolution tandem mass spectrometry data acquired in both positive and negative ion modes allowed for the identification of 25 tramadol metabolites in urine and plasma, including four methylated metabolites that have not been previously reported in humans or in vitro models. While positive ion mode is reliable for generating a network of tramadol metabolites displaying a dimethylamino radical in their structure, negative ion mode was useful to cluster phase II metabolites. In conclusion, the combined use of molecular networks in positive and negative ion modes is a suitable and robust tool to identify a broad range of metabolites in poisoned patients, as shown in a fatal tramadol-poisoned patient. Full article
(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics as Tools in Pharmaceutical and Biological Analysis)
►▼ Show Figures

Figure 1

13 pages, 9965 KB  
Article
Discovery of Synergistic Drug Combinations for Colorectal Cancer Driven by Tumor Barcode Derived from Metabolomics “Big Data”
by Bo Lv, Ruijie Xu, Xinrui Xing, Chuyao Liao, Zunjian Zhang, Pei Zhang and Fengguo Xu
Metabolites 2022, 12(6), 494; https://doi.org/10.3390/metabo12060494 - 30 May 2022
Cited by 1 | Viewed by 3929
Abstract
The accumulation of cancer metabolomics data in the past decade provides exceptional opportunities for deeper investigations into cancer metabolism. However, integrating a large amount of heterogeneous metabolomics data to draw a full picture of the metabolic reprogramming and to discover oncometabolites of certain [...] Read more.
The accumulation of cancer metabolomics data in the past decade provides exceptional opportunities for deeper investigations into cancer metabolism. However, integrating a large amount of heterogeneous metabolomics data to draw a full picture of the metabolic reprogramming and to discover oncometabolites of certain cancers remains challenging. In this study, a tumor barcode constructed based upon existing metabolomics “big data” using the Bayesian vote-counting method is proposed to identify oncometabolites in colorectal cancer (CRC). Specifically, a panel of oncometabolites of CRC was generated from 39 clinical studies with 3202 blood samples (1332 CRC vs. 1870 controls) and 990 tissue samples (495 CRC vs. 495 controls). Next, an oncometabolite-protein network was constructed by combining the tumor barcode and its involved proteins/enzymes. The effect of anti-cancer drugs or drug combinations was then mapped into this network by the random walk with restart process. Utilizing this network, potential Irinotecan (CPT-11)-sensitizing agents for CRC treatment were discovered by random forest and Xgboost. Finally, a compound named MK-2206 was highlighted and its synergy with CPT-11 was validated on two CRC cell lines. To summarize, we demonstrate in the present study that the metabolomics “big data”-based tumor barcodes and the subsequent network analyses are potentially useful for drug combination discovery or drug repositioning. Full article
(This article belongs to the Special Issue Advanced Strategies and Tools for Metabolomics Data Analysis, Metabolite Annotation and Identification)
►▼ Show Figures

Figure 1

29 pages, 934 KB  
Article
Structural Thermokinetic Modelling
by Wolfram Liebermeister
Metabolites 2022, 12(5), 434; https://doi.org/10.3390/metabo12050434 - 11 May 2022
Cited by 4 | Viewed by 3323
Abstract
To translate metabolic networks into dynamic models, the Structural Kinetic Modelling framework (SKM) assumes a given reference state and replaces the reaction elasticities in this state by random numbers. A new variant, called Structural Thermokinetic Modelling (STM), accounts for reversible reactions and thermodynamics. [...] Read more.
To translate metabolic networks into dynamic models, the Structural Kinetic Modelling framework (SKM) assumes a given reference state and replaces the reaction elasticities in this state by random numbers. A new variant, called Structural Thermokinetic Modelling (STM), accounts for reversible reactions and thermodynamics. STM relies on a dependence schema in which some basic variables are sampled, fitted to data, or optimised, while all other variables can be easily computed. Correlated elasticities follow from enzyme saturation values and thermodynamic forces, which are physically independent. Probability distributions in the dependence schema define a model ensemble, which allows for probabilistic predictions even if data are scarce. STM highlights the importance of variabilities, dependencies, and covariances of biological variables. By varying network structure, fluxes, thermodynamic forces, regulation, or types of rate laws, the effects of these model features can be assessed. By choosing the basic variables, metabolic networks can be converted into kinetic models with consistent reversible rate laws. Metabolic control coefficients obtained from these models can tell us about metabolic dynamics, including responses and optimal adaptations to perturbations, enzyme synergies and metabolite correlations, as well as metabolic fluctuations arising from chemical noise. To showcase STM, I study metabolic control, metabolic fluctuations, and enzyme synergies, and how they are shaped by thermodynamic forces. Considering thermodynamics can improve predictions of flux control, enzyme synergies, correlated flux and metabolite variations, and the emergence and propagation of metabolic noise. Full article
(This article belongs to the Section Bioinformatics and Data Analysis)
►▼ Show Figures

Figure 1

42 pages, 823 KB  
Review
Patient Stratification in Sepsis: Using Metabolomics to Detect Clinical Phenotypes, Sub-Phenotypes and Therapeutic Response
by Humma Hussain, Kritchai Vutipongsatorn, Beatriz Jiménez and David B. Antcliffe
Metabolites 2022, 12(5), 376; https://doi.org/10.3390/metabo12050376 - 21 Apr 2022
Cited by 27 | Viewed by 6239
Abstract
Infections are common and need minimal treatment; however, occasionally, due to inappropriate immune response, they can develop into a life-threatening condition known as sepsis. Sepsis is a global concern with high morbidity and mortality. There has been little advancement in the treatment of [...] Read more.
Infections are common and need minimal treatment; however, occasionally, due to inappropriate immune response, they can develop into a life-threatening condition known as sepsis. Sepsis is a global concern with high morbidity and mortality. There has been little advancement in the treatment of sepsis, outside of antibiotics and supportive measures. Some of the difficulty in identifying novel therapies is the heterogeneity of the condition. Metabolic phenotyping has great potential for gaining understanding of this heterogeneity and how the metabolic fingerprints of patients with sepsis differ based on survival, organ dysfunction, disease severity, type of infection, treatment or causative organism. Moreover, metabolomics offers potential for patient stratification as metabolic profiles obtained from analytical platforms can reflect human individuality and phenotypic variation. This article reviews the most relevant metabolomic studies in sepsis and aims to provide an overview of the metabolic derangements in sepsis and how metabolic phenotyping has been used to identify sub-groups of patients with this condition. Finally, we consider the new avenues that metabolomics could open, exploring novel phenotypes and untangling the heterogeneity of sepsis, by looking at advances made in the field with other -omics technologies. Full article
(This article belongs to the Special Issue Using Metabolomics to Subphenotype Disease and Therapeutic Response)
►▼ Show Figures

Figure 1

19 pages, 3218 KB  
Article
Matching Drug Metabolites from Non-Targeted Metabolomics to Self-Reported Medication in the Qatar Biobank Study
by Karsten Suhre, Nisha Stephan, Shaza Zaghlool, Chris R. Triggle, Richard J. Robinson, Anne M. Evans and Anna Halama
Metabolites 2022, 12(3), 249; https://doi.org/10.3390/metabo12030249 - 16 Mar 2022
Cited by 12 | Viewed by 4309
Abstract
Modern metabolomics platforms are able to identify many drug-related metabolites in blood samples. Applied to population-based biobank studies, the detection of drug metabolites can then be used as a proxy for medication use or serve as a validation tool for questionnaire-based health assessments. [...] Read more.
Modern metabolomics platforms are able to identify many drug-related metabolites in blood samples. Applied to population-based biobank studies, the detection of drug metabolites can then be used as a proxy for medication use or serve as a validation tool for questionnaire-based health assessments. However, it is not clear how well detection of drug metabolites in blood samples matches information on self-reported medication provided by study participants. Here, we curate free-text responses to a drug-usage questionnaire from 6000 participants of the Qatar Biobank (QBB) using standardized WHO Anatomical Therapeutic Chemical (ATC) Classification System codes and compare the occurrence of these ATC terms to the detection of drug-related metabolites in matching blood plasma samples from 2807 QBB participants for which we collected non-targeted metabolomics data. We found that the detection of 22 drug-related metabolites significantly associated with the self-reported use of the corresponding medication. Good agreement of self-reported medication with non-targeted metabolomics was observed, with self-reported drugs and their metabolites being detected in a same blood sample in 79.4% of the cases. On the other hand, only 29.5% of detected drug metabolites matched to self-reported medication. Possible explanations for differences include under-reporting of over-the-counter medications from the study participants, such as paracetamol, misannotation of low abundance metabolites, such as metformin, and inability of the current methods to detect them. Taken together, our study provides a broad real-world view of what to expect from large non-targeted metabolomics measurements in population-based biobank studies and indicates areas where further improvements can be made. Full article
(This article belongs to the Special Issue Metabolomics Data Analysis and Quality Assessment)
►▼ Show Figures

Figure 1

27 pages, 6569 KB  
Article
Impact of Influenza A Virus Infection on Growth and Metabolism of Suspension MDCK Cells Using a Dynamic Model
by João Rodrigues Correia Ramos, Thomas Bissinger, Yvonne Genzel and Udo Reichl
Metabolites 2022, 12(3), 239; https://doi.org/10.3390/metabo12030239 - 12 Mar 2022
Cited by 4 | Viewed by 4655
Abstract
Cell cultured-based influenza virus production is a viable option for vaccine manufacturing. In order to achieve a high concentration of viable cells, is requirement to have not only optimal process conditions, but also an active metabolism capable of intracellular synthesis of viral components. [...] Read more.
Cell cultured-based influenza virus production is a viable option for vaccine manufacturing. In order to achieve a high concentration of viable cells, is requirement to have not only optimal process conditions, but also an active metabolism capable of intracellular synthesis of viral components. Experimental metabolic data collected in such processes are complex and difficult to interpret, for which mathematical models are an appropriate way to simulate and analyze the complex and dynamic interaction between the virus and its host cell. A dynamic model with 35 states was developed in this study to describe growth, metabolism, and influenza A virus production in shake flask cultivations of suspension Madin-Darby Canine Kidney (MDCK) cells. It considers cell growth (concentration of viable cells, mean cell diameters, volume of viable cells), concentrations of key metabolites both at the intracellular and extracellular level and virus titers. Using one set of parameters, the model accurately simulates the dynamics of mock-infected cells and correctly predicts the overall dynamics of virus-infected cells for up to 60 h post infection (hpi). The model clearly suggests that most changes observed after infection are related to cessation of cell growth and the subsequent transition to apoptosis and cell death. However, predictions do not cover late phases of infection, particularly for the extracellular concentrations of glutamate and ammonium after about 12 hpi. Results obtained from additional in silico studies performed indicated that amino acid degradation by extracellular enzymes resulting from cell lysis during late infection stages may contribute to this observed discrepancy. Full article
(This article belongs to the Section Bioinformatics and Data Analysis)
►▼ Show Figures

Graphical abstract

16 pages, 2108 KB  
Article
Systematic Evaluation of HILIC Stationary Phases for Global Metabolomics of Human Plasma
by Farideh Hosseinkhani, Luojiao Huang, Anne-Charlotte Dubbelman, Faisa Guled, Amy C. Harms and Thomas Hankemeier
Metabolites 2022, 12(2), 165; https://doi.org/10.3390/metabo12020165 - 9 Feb 2022
Cited by 32 | Viewed by 6204
Abstract
Polar hydrophilic metabolites have been identified as important actors in many biochemical pathways. Despite continuous improvement and refinement of hydrophilic interaction liquid chromatography (HILIC) platforms, its application in global polar metabolomics has been underutilized. In this study, we aimed to systematically evaluate polar [...] Read more.
Polar hydrophilic metabolites have been identified as important actors in many biochemical pathways. Despite continuous improvement and refinement of hydrophilic interaction liquid chromatography (HILIC) platforms, its application in global polar metabolomics has been underutilized. In this study, we aimed to systematically evaluate polar stationary phases for untargeted metabolomics by using HILIC columns (neutral and zwitterionic) that have been exploited widely in targeted approaches. To do so, high-resolution mass spectrometry was applied to thoroughly investigate selectivity, repeatability and matrix effect at three pH conditions for 9 classes of polar compounds using 54 authentic standards and plasma matrix. The column performance for utilization in untargeted metabolomics was assessed using plasma samples with diverse phenotypes. Our results indicate that the ZIC-c HILIC column operated at neutral pH exhibited several advantages, including superior performance for different classes of compounds, better isomer separation, repeatability and high metabolic coverage. Regardless of the column type, the retention of inorganic ions in plasma leads to extensive adduct formation and co-elution with analytes, which results in ion-suppression as part of the overall plasma matrix effect. In ZIC-c HILIC, the sodium chloride ion effect was particularly observed for amino acids and amine classes. Successful performance of HILIC for separation of plasma samples with different phenotypes highlights this mode of separation as a valuable approach in global profiling of plasma sample and discovering the metabolic changes associated with health and disease. Full article
(This article belongs to the Special Issue Metabolic Pathway Profiling and Untargeted/Targeted Analysis of Metabolites)
►▼ Show Figures

Graphical abstract

16 pages, 3240 KB  
Article
Comparative Evaluation of Plasma Metabolomic Data from Multiple Laboratories
by Shin Nishiumi, Yoshihiro Izumi, Akiyoshi Hirayama, Masatomo Takahashi, Motonao Nakao, Kosuke Hata, Daisuke Saigusa, Eiji Hishinuma, Naomi Matsukawa, Suzumi M. Tokuoka, Yoshihiro Kita, Fumie Hamano, Nobuyuki Okahashi, Kazutaka Ikeda, Hiroki Nakanishi, Kosuke Saito, Masami Yokota Hirai, Masaru Yoshida, Yoshiya Oda, Fumio Matsuda and Takeshi Bambaadd Show full author list remove Hide full author list
Metabolites 2022, 12(2), 135; https://doi.org/10.3390/metabo12020135 - 1 Feb 2022
Cited by 8 | Viewed by 3761
Abstract
In mass spectrometry-based metabolomics, the differences in the analytical results from different laboratories/machines are an issue to be considered because various types of machines are used in each laboratory. Moreover, the analytical methods are unique to each laboratory. It is important to understand [...] Read more.
In mass spectrometry-based metabolomics, the differences in the analytical results from different laboratories/machines are an issue to be considered because various types of machines are used in each laboratory. Moreover, the analytical methods are unique to each laboratory. It is important to understand the reality of inter-laboratory differences in metabolomics. Therefore, we have evaluated whether the differences in analytical methods, with the exception sample pretreatment and including metabolite extraction, are involved in the inter-laboratory differences or not. In this study, nine facilities are evaluated for inter-laboratory comparisons of metabolomic analysis. Identical dried samples prepared from human and mouse plasma are distributed to each laboratory, and the metabolites are measured without the pretreatment that is unique to each laboratory. In these measurements, hydrophilic and hydrophobic metabolites are analyzed using 11 and 7 analytical methods, respectively. The metabolomic data acquired at each laboratory are integrated, and the differences in the metabolomic data from the laboratories are evaluated. No substantial difference in the relative quantitative data (human/mouse) for a little less than 50% of the detected metabolites is observed, and the hydrophilic metabolites have fewer differences between the laboratories compared with hydrophobic metabolites. From evaluating selected quantitatively guaranteed metabolites, the proportion of metabolites without the inter-laboratory differences is observed to be slightly high. It is difficult to resolve the inter-laboratory differences in metabolomics because all laboratories cannot prepare the same analytical environments. However, the results from this study indicate that the inter-laboratory differences in metabolomic data are due to measurement and data analysis rather than sample preparation, which will facilitate the understanding of the problems in metabolomics studies involving multiple laboratories. Full article
(This article belongs to the Special Issue Metabolic Profiling of Biofluids and Tissues Using Multiplatform Approaches)
►▼ Show Figures

Graphical abstract

19 pages, 1922 KB  
Article
Automated Sample Preparation and Data Collection Workflow for High-Throughput In Vitro Metabolomics
by Julia M. Malinowska, Taina Palosaari, Jukka Sund, Donatella Carpi, Gavin R. Lloyd, Ralf J. M. Weber, Maurice Whelan and Mark R. Viant
Metabolites 2022, 12(1), 52; https://doi.org/10.3390/metabo12010052 - 8 Jan 2022
Cited by 7 | Viewed by 5118
Abstract
Regulatory bodies have started to recognise the value of in vitro screening and metabolomics as two types of new approach methodologies (NAMs) for chemical risk assessments, yet few high-throughput in vitro toxicometabolomics studies have been reported. A significant challenge is to implement automated [...] Read more.
Regulatory bodies have started to recognise the value of in vitro screening and metabolomics as two types of new approach methodologies (NAMs) for chemical risk assessments, yet few high-throughput in vitro toxicometabolomics studies have been reported. A significant challenge is to implement automated sample preparation of the low biomass samples typically used for in vitro screening. Building on previous work, we have developed, characterised and demonstrated an automated sample preparation and analysis workflow for in vitro metabolomics of HepaRG cells in 96-well microplates using a Biomek i7 Hybrid Workstation (Beckman Coulter) and Orbitrap Elite (Thermo Scientific) high-resolution nanoelectrospray direct infusion mass spectrometry (nESI-DIMS), across polar metabolites and lipids. The experimental conditions evaluated included the day of metabolite extraction, order of extraction of samples in 96-well microplates, position of the 96-well microplate on the instrument’s deck and well location within a microplate. By using the median relative standard deviation (mRSD (%)) of spectral features, we have demonstrated good repeatability of the workflow (final mRSD < 30%) with a low percentage of features outside the threshold applied for statistical analysis. To improve the quality of the automated workflow further, small method modifications were made and then applied to a large cohort study (4860 sample infusions across three nESI-DIMS assays), which confirmed very high repeatability of the whole workflow from cell culturing to metabolite measurements, whilst providing a significant improvement in sample throughput. It is envisioned that the automated in vitro metabolomics workflow will help to advance the application of metabolomics (as a part of NAMs) in chemical safety, primarily as an approach for high throughput screening and prioritisation. Full article
(This article belongs to the Special Issue Sample Preparation in Metabolomics Volume II)
►▼ Show Figures

Graphical abstract

18 pages, 1374 KB  
Article
Untargeted Metabolomics Reveals a Complex Impact on Different Metabolic Pathways in Scallop Mimachlamys varia (Linnaeus, 1758) after Short-Term Exposure to Copper at Environmental Dose
by Vincent Hamani, Pascaline Ory, Pierre-Edouard Bodet, Laurence Murillo and Marianne Graber
Metabolites 2021, 11(12), 862; https://doi.org/10.3390/metabo11120862 - 11 Dec 2021
Cited by 11 | Viewed by 3641
Abstract
Ports are a good example of how coastal environments, gathering a set of diverse ecosystems, are subjected to pollution factors coming from human activities both on land and at sea. Among them, trace element as copper represents a major factor. Abundant in port [...] Read more.
Ports are a good example of how coastal environments, gathering a set of diverse ecosystems, are subjected to pollution factors coming from human activities both on land and at sea. Among them, trace element as copper represents a major factor. Abundant in port ecosystem, copper is transported by runoff water and results from diverse port features (corrosion of structures, fuel, anti-fouling products, etc.). The variegated scallop Mimachlamys varia is common in the Atlantic port areas and is likely to be directly influenced by copper pollution, due to its sessile and filtering lifestyle. Thus, the aim of the present study is to investigate the disruption of the variegated scallop metabolism, under a short exposure (48 h) to a copper concentration frequently encountered in the waters of the largest marina in Europe (82 μg/L). For this, we chose a non-targeted metabolomic approach using ultra-high performance liquid chromatography coupled to high resolution mass spectrometry (UHPLC-HRMS), offering a high level of sensitivity and allowing the study without a priori of the entire metabolome. We described 28 metabolites clearly modulated by copper. They reflected the action of copper on several biological functions such as osmoregulation, oxidative stress, reproduction and energy metabolism. Full article
(This article belongs to the Special Issue Application of Metabolomic in Ecotoxicology)
►▼ Show Figures

Graphical abstract

23 pages, 2685 KB  
Article
Cascading Effects of Root Microbial Symbiosis on the Development and Metabolome of the Insect Herbivore Manduca sexta L.
by Dimitra Papantoniou, Fredd Vergara, Alexander Weinhold, Teresa Quijano, Bekzod Khakimov, David I. Pattison, Søren Bak, Nicole M. van Dam and Ainhoa Martínez-Medina
Metabolites 2021, 11(11), 731; https://doi.org/10.3390/metabo11110731 - 25 Oct 2021
Cited by 21 | Viewed by 5470
Abstract
Root mutualistic microbes can modulate the production of plant secondary metabolites affecting plant–herbivore interactions. Still, the main mechanisms underlying the impact of root mutualists on herbivore performance remain ambiguous. In particular, little is known about how changes in the plant metabolome induced by [...] Read more.
Root mutualistic microbes can modulate the production of plant secondary metabolites affecting plant–herbivore interactions. Still, the main mechanisms underlying the impact of root mutualists on herbivore performance remain ambiguous. In particular, little is known about how changes in the plant metabolome induced by root mutualists affect the insect metabolome and post-larval development. By using bioassays with tomato plants (Solanum lycopersicum), we analyzed the impact of the arbuscular mycorrhizal fungus Rhizophagus irregularis and the growth-promoting fungus Trichoderma harzianum on the plant interaction with the specialist insect herbivore Manduca sexta. We found that root colonization by the mutualistic microbes impaired insect development, including metamorphosis. By using untargeted metabolomics, we found that root colonization by the mutualistic microbes altered the secondary metabolism of tomato shoots, leading to enhanced levels of steroidal glycoalkaloids. Untargeted metabolomics further revealed that root colonization by the mutualists affected the metabolome of the herbivore, leading to an enhanced accumulation of steroidal glycoalkaloids and altered patterns of fatty acid amides and carnitine-derived metabolites. Our results indicate that the changes in the shoot metabolome triggered by root mutualistic microbes can cascade up altering the metabolome of the insects feeding on the colonized plants, thus affecting the insect development. Full article
(This article belongs to the Special Issue Metabolomics in Chemical Ecology)
►▼ Show Figures

Graphical abstract

13 pages, 5248 KB  
Article
Analytical Methodology for a Metabolome Atlas of Goat’s Plasma, Milk and Feces Using 1H-NMR and UHPLC-HRMS
by Cécile Martias, Julie Gatien, Léa Roch, Nadine Baroukh, Sylvie Mavel, Antoine Lefèvre, Frédéric Montigny, Laurent Schibler, Patrick Emond and Lydie Nadal-Desbarats
Metabolites 2021, 11(10), 681; https://doi.org/10.3390/metabo11100681 - 4 Oct 2021
Cited by 4 | Viewed by 2905
Abstract
Metabolomics has been increasingly used in animal and food sciences. Animal health is one of the most important factor that can also alter animal integrity and welfare. Some studies have already investigated the link between health and metabolic profile of dairy animals. These [...] Read more.
Metabolomics has been increasingly used in animal and food sciences. Animal health is one of the most important factor that can also alter animal integrity and welfare. Some studies have already investigated the link between health and metabolic profile of dairy animals. These studies in metabolomics often consider a single type of sample using a single analytical platform (nuclear magnetic resonance or mass spectrometry). Only few studies with multi-platform approaches are also used with a single or a multi type of sample, but they mainly consider dairy cows’ metabolome although dairy goats present similar diseases, that it could be interesting to detect early to preserve animal health and milk production. This study aims to create a metabolic atlas of goat plasma, milk and feces, based on healthy animals. Our study describes a standard operating procedure for three goat matrices: blood plasma, milk, and feces using multiple platforms (NMR (1H), UHPLC (RP)-MS and UHPLC (HILIC)-MS) that follows a unique sample preparation procedure for each sample type to be analyzed on multi-platforms basis. Our method was evaluated for its robustness and allowed a better characterization of goat metabolic profile in healthy conditions. Full article
(This article belongs to the Special Issue Metabolomic Applications in Animal Science Volume 2)
►▼ Show Figures

Figure 1

20 pages, 2247 KB  
Article
An Extensive Metabolomics Workflow to Discover Cardiotoxin-Induced Molecular Perturbations in Microtissues
by Tara J. Bowen, Andrew R. Hall, Gavin R. Lloyd, Ralf J. M. Weber, Amanda Wilson, Amy Pointon and Mark R. Viant
Metabolites 2021, 11(9), 644; https://doi.org/10.3390/metabo11090644 - 21 Sep 2021
Cited by 6 | Viewed by 3549
Abstract
Discovering modes of action and predictive biomarkers of drug-induced structural cardiotoxicity offers the potential to improve cardiac safety assessment of lead compounds and enhance preclinical to clinical translation during drug development. Cardiac microtissues are a promising, physiologically relevant, in vitro model, each composed [...] Read more.
Discovering modes of action and predictive biomarkers of drug-induced structural cardiotoxicity offers the potential to improve cardiac safety assessment of lead compounds and enhance preclinical to clinical translation during drug development. Cardiac microtissues are a promising, physiologically relevant, in vitro model, each composed of ca. 500 cells. While untargeted metabolomics is capable of generating hypotheses on toxicological modes of action and discovering metabolic biomarkers, applying this technology to low-biomass microtissues in suspension is experimentally challenging. Thus, we first evaluated a filtration-based approach for harvesting microtissues and assessed the sensitivity and reproducibility of nanoelectrospray direct infusion mass spectrometry (nESI-DIMS) measurements of intracellular extracts, revealing samples consisting of 28 pooled microtissues, harvested by filtration, are suitable for profiling the intracellular metabolome and lipidome. Subsequently, an extensive workflow combining nESI-DIMS untargeted metabolomics and lipidomics of intracellular extracts with ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) analysis of spent culture medium, to profile the metabolic footprint and quantify drug exposure concentrations, was implemented. Using the synthetic drug and model cardiotoxin sunitinib, time-resolved metabolic and lipid perturbations in cardiac microtissues were investigated, providing valuable data for generating hypotheses on toxicological modes of action and identifying putative biomarkers such as disruption of purine metabolism and perturbation of polyunsaturated fatty acid levels. Full article
(This article belongs to the Special Issue Toxicometabolomics)
►▼ Show Figures

Figure 1

12 pages, 706 KB  
Article
Significance of Metabolite Ratios in the Interpretation of Segmental Hair Testing Results—Differentiation of Single from Chronic Morphine Use in a Case Series
by Milena M. Madry, Sandra N. Poetzsch, Andrea E. Steuer, Thomas Kraemer and Markus R. Baumgartner
Metabolites 2021, 11(8), 557; https://doi.org/10.3390/metabo11080557 - 22 Aug 2021
Cited by 5 | Viewed by 3102
Abstract
In morphine intoxication cases, forensic toxicologists are frequently confronted with the question of if the individual was opioid-tolerant or opioid-naïve, which can be investigated by hair analysis. However, interpretation of results can be challenging. Here, we report on hair testing for morphine and [...] Read more.
In morphine intoxication cases, forensic toxicologists are frequently confronted with the question of if the individual was opioid-tolerant or opioid-naïve, which can be investigated by hair analysis. However, interpretation of results can be challenging. Here, we report on hair testing for morphine and its metabolite hydromorphone following morphine intoxication without tolerance and upon chronic use. Two consecutive hair samples were collected after a non-fatal intoxication. Analysis comprised short hair segments and their initial wash water solutions. In the intoxications, morphine and hydromorphone levels were 3.3 to 56 pg/mg and at maximum 9.8 pg/mg, respectively. Both levels and hydromorphone to morphine ratios were significantly lower compared to chronic morphine use. In the non-fatal intoxication, the highest hydromorphone to morphine ratio was obtained in the segment corresponding to the time of intoxication. Morphine ratios of wash to hair were significantly higher in the intoxications compared to chronic use, being indicative of sweat/sebum contamination. We recommend including the analysis of hydromorphone and the initial wash solution in cases of morphine intoxications. Our study demonstrates that hydromorphone to morphine ratios can help in distinguishing single from chronic morphine use and in estimating the period of exposure when a consecutive hair sample can be collected in survived intoxications. Full article
(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)
►▼ Show Figures

Figure 1

13 pages, 1506 KB  
Article
Acute Administration of Exogenous Lactate Increases Carbohydrate Metabolism during Exercise in Mice
by Inkwon Jang, Jisu Kim, Sunghwan Kyun, Deunsol Hwang and Kiwon Lim
Metabolites 2021, 11(8), 553; https://doi.org/10.3390/metabo11080553 - 21 Aug 2021
Cited by 9 | Viewed by 3833
Abstract
In this study, we investigated the effects of exogenous lactate administration before exercise on energy substrate utilization during exercise. Mice were divided into exercise control (EX) and exercise with lactate intake (EXLA) groups; saline/lactate was administered 30 min before exercise. Respiratory gas was [...] Read more.
In this study, we investigated the effects of exogenous lactate administration before exercise on energy substrate utilization during exercise. Mice were divided into exercise control (EX) and exercise with lactate intake (EXLA) groups; saline/lactate was administered 30 min before exercise. Respiratory gas was measured during moderate intensity treadmill exercise (30 min). Immediately after exercise, blood, liver, and skeletal muscle samples were collected and mRNA levels of energy metabolism-related and metabolic factors were analyzed. At 16–30 min of exercise, the respiratory exchange ratio (p = 0.045) and carbohydrate oxidation level (p = 0.014) were significantly higher in the EXLA than in the EX group. Immediately after exercise, the muscle and liver glycogen content and blood glucose level of the EXLA group were lower than those of the EX group. In addition, muscle mRNA levels of HK2 (hexokinase 2; p = 0.009), a carbohydrate oxidation-related factor, were higher in the EXLA than in the EX group, whereas the expression of PDK4 (pyruvate dehydrogenase kinase 4; p = 0.001), CS (citrate synthase; p = 0.045), and CD36 (cluster of differentiation 36; p = 0.002), factors related to oxidative metabolism, was higher in the EX than in the EXLA group. These results suggest that lactate can be used in various research fields to promote carbohydrate metabolism. Full article
(This article belongs to the Section Animal Metabolism)
►▼ Show Figures

Figure 1

17 pages, 2265 KB  
Article
Enantioselective Quantification of Amphetamine and Metabolites in Serum Samples: Forensic Evaluation and Estimation of Consumption Time
by Moritz Losacker, Michael Kraemer, Alexandra Philipsen, Kristina Duecker, Nadine Dreimueller, Jan Engelmann, Joerg Roehrich and Cornelius Hess
Metabolites 2021, 11(8), 521; https://doi.org/10.3390/metabo11080521 - 6 Aug 2021
Cited by 15 | Viewed by 4061
Abstract
In forensic toxicology, amphetamine intoxications represent one of the most common case groups and present difficult questions for toxicologists. Estimating the time of consumption and the current influence of the stimulant is particularly difficult when only total amphetamine concentrations are considered. Stereoselective analysis [...] Read more.
In forensic toxicology, amphetamine intoxications represent one of the most common case groups and present difficult questions for toxicologists. Estimating the time of consumption and the current influence of the stimulant is particularly difficult when only total amphetamine concentrations are considered. Stereoselective analysis and the consideration of metabolites can provide valuable information to facilitate interpretation. An enantioselective liquid chromatography−tandem mass spectrometry (LC-MS/MS) method for detection of amphetamine, norephedrine and 4-hydroxyamphetamine was developed. Validation showed satisfactory selectivity, sensitivity, linearity (0.5–250 ng/mL), precision and accuracy for all enantiomers. The method was applied to a collective of 425 forensic serum samples and 30 serum samples from psychiatric inpatients stating their last time of amphetamine consumption. Norephedrine and 4-hydroxyamphetamine were detected more frequently at higher amphetamine concentrations and at lower amphetamine (R)/(S) concentration ratios, possibly indicating recent consumption. Mean (R)/(S) ratio of amphetamine was 1.14, whereas higher ratios (mean 1.36) were found for amphetamine concentrations below 100 ng/mL. The (R)/(S) ratios of psychiatric inpatients significantly correlated with the reported time intervals to last consumption. The use of amphetamine (R)/(S) ratios and the simultaneous detection of metabolites are promising factors that can facilitate estimation of consumption time and current impairment. Full article
(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)
►▼ Show Figures

Figure 1

13 pages, 1542 KB  
Article
Proline as a Sparker Metabolite of Oxidative Metabolism during the Flight of the Bumblebee, Bombus impatiens
by Nadia Stec, Ammar Saleem and Charles-A. Darveau
Metabolites 2021, 11(8), 511; https://doi.org/10.3390/metabo11080511 - 4 Aug 2021
Cited by 21 | Viewed by 3584
Abstract
Several insect species use the amino acid proline as a major energy substrate. Although initially thought to be limited to blood-feeding dipterans, studies have revealed this capability is more widespread. Recent work with isolated flight muscle showed that the bumblebee Bombus impatiens can [...] Read more.
Several insect species use the amino acid proline as a major energy substrate. Although initially thought to be limited to blood-feeding dipterans, studies have revealed this capability is more widespread. Recent work with isolated flight muscle showed that the bumblebee Bombus impatiens can oxidize proline at a high rate. However, its role as a metabolic fuel to power flight is unclear. To elucidate the extent to which proline is oxidized to power flight and how its contribution changes during flight, we profiled 14 metabolites central to energy and proline metabolism at key time points in flight muscle and abdominal tissues. Ultra-high performance liquid chromatography-electrospray ionization-quadrupole time of flight mass spectrometry (UPLC-ESI-QTOF MS) analysis revealed that proline is likely used as a sparker metabolite of the tricarboxylic acid cycle at the onset of flight, whereby it supplements the intermediates of the cycle. Carbohydrates are the major energy substrates, which is evidenced by marked decreases in abdominal glycogen stores and a lack of alanine accumulation to replenish flight muscle proline. The time course of fuel stores and metabolites changes during flight highlights homeostatic regulation of energy substrates and patterns of changes in metabolic intermediates within pathways. This study clarifies the role of proline and carbohydrate metabolism during flight in hymenopterans, such as B. impatiens. Full article
(This article belongs to the Special Issue Ectotherms Metabolism: Plasticity and Adaptation)
►▼ Show Figures

Figure 1

14 pages, 3236 KB  
Article
In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity
by Matthias J. Richter, Lea Wagmann, Tanja M. Gampfer, Simon D. Brandt and Markus R. Meyer
Metabolites 2021, 11(8), 509; https://doi.org/10.3390/metabo11080509 - 3 Aug 2021
Cited by 8 | Viewed by 3073
Abstract
Quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate (QMPSB) and quinolin-8-yl 4-methyl-3-(piperidine-1-carbonyl)benzoate (QMPCB, SGT-11) are synthetic cannabinoid receptor agonists (SCRAs). Knowing their metabolic fate is crucial for the identification of toxicological screening targets and to predict possible drug interactions. The presented study aimed to identify the in vitro phase [...] Read more.
Quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate (QMPSB) and quinolin-8-yl 4-methyl-3-(piperidine-1-carbonyl)benzoate (QMPCB, SGT-11) are synthetic cannabinoid receptor agonists (SCRAs). Knowing their metabolic fate is crucial for the identification of toxicological screening targets and to predict possible drug interactions. The presented study aimed to identify the in vitro phase I/II metabolites of QMPSB and QMPCB and to study the contribution of different monooxygenases and human carboxylesterases by using pooled human liver S9 fraction (pHLS9), recombinant human monooxygenases, three recombinant human carboxylesterases, and pooled human liver microsomes. Analyses were carried out by liquid chromatography high-resolution tandem mass spectrometry. QMPSB and QMPCB showed ester hydrolysis, and hydroxy and carboxylic acid products were detected in both cases. Mono/dihydroxy metabolites were formed, as were corresponding glucuronides and sulfates. Most of the metabolites could be detected in positive ionization mode with the exception of some QMPSB metabolites, which could only be found in negative mode. Monooxygenase activity screening revealed that CYP2B6/CYP2C8/CYP2C9/CYP2C19/CYP3A4/CYP3A5 were involved in hydroxylations. Esterase screening showed the involvement of all investigated isoforms. Additionally, extensive non-enzymatic ester hydrolysis was observed. Considering the results of the in vitro experiments, inclusion of the ester hydrolysis products and their glucuronides and monohydroxy metabolites into toxicological screening procedures is recommended. Full article
(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)
►▼ Show Figures

Figure 1

16 pages, 3065 KB  
Article
High Throughput Procedure for Comparative Analysis of In Vivo Cardiac Glucose or Amino Acids Use in Cardiovascular Pathologies and Pharmacological Treatments
by Marta Tomczyk, Mariola Olkowicz, Ewa M. Slominska and Ryszard T. Smolenski
Metabolites 2021, 11(8), 497; https://doi.org/10.3390/metabo11080497 - 30 Jul 2021
Cited by 3 | Viewed by 3509
Abstract
The heart is characterized by the prominent flexibility of its energy metabolism and is able to use diverse carbon substrates, including carbohydrates and amino acids. Cardiac substrate preference could have a major impact on the progress of cardiac pathologies. However, the majority of [...] Read more.
The heart is characterized by the prominent flexibility of its energy metabolism and is able to use diverse carbon substrates, including carbohydrates and amino acids. Cardiac substrate preference could have a major impact on the progress of cardiac pathologies. However, the majority of methods to investigate changes in substrates’ use in cardiac metabolism in vivo are complex and not suitable for high throughput testing necessary to understand and reverse these pathologies. Thus, this study aimed to develop a simple method that would allow for the analysis of cardiac metabolic substrate use. The developed methods involved the subcutaneous injection of stable 13C isotopomers of glucose, valine, or leucine with mass spectrometric analysis for the investigation of its entry into cardiac metabolic pathways that were deducted from 13C alanine and glutamate enrichments in heart extracts. The procedures were validated by confirming the known effects of treatments that modify glucose, free fatty acids, and amino acid metabolism. Furthermore, we studied changes in the energy metabolism of CD73 knock-out mice to demonstrate the potential of our methods in experimental research. The methods created allowed for fast estimation of cardiac glucose and amino acid use in mice and had the potential for high-throughput analysis of changes in pathology and after pharmacological treatments. Full article
(This article belongs to the Special Issue Insights into the Bioenergetics and Metabolism in Normal and Failing Heart)
►▼ Show Figures

Graphical abstract

21 pages, 5054 KB  
Article
Short Duration Alagebrium Chloride Therapy Prediabetes Does Not Inhibit Progression to Autoimmune Diabetes in an Experimental Model
by Danielle J. Borg, Pouya Faridi, Kai Lin Giam, Peta Reeves, Amelia K. Fotheringham, Domenica A. McCarthy, Sherman Leung, Micheal S. Ward, Brooke E. Harcourt, Rochelle Ayala, Jean L. Scheijen, David Briskey, Nadine L. Dudek, Casper G. Schalkwijk, Raymond Steptoe, Anthony W. Purcell and Josephine M. Forbes
Metabolites 2021, 11(7), 426; https://doi.org/10.3390/metabo11070426 - 28 Jun 2021
Cited by 2 | Viewed by 4265
Abstract
Mechanisms by which advanced glycation end products (AGEs) contribute to type 1 diabetes (T1D) pathogenesis are poorly understood. Since life-long pharmacotherapy with alagebrium chloride (ALT) slows progression to experimental T1D, we hypothesized that acute ALT therapy delivered prediabetes, may be effective. However, in [...] Read more.
Mechanisms by which advanced glycation end products (AGEs) contribute to type 1 diabetes (T1D) pathogenesis are poorly understood. Since life-long pharmacotherapy with alagebrium chloride (ALT) slows progression to experimental T1D, we hypothesized that acute ALT therapy delivered prediabetes, may be effective. However, in female, non-obese diabetic (NODShiLt) mice, ALT administered prediabetes (day 50–100) did not protect against experimental T1D. ALT did not decrease circulating AGEs or their precursors. Despite this, pancreatic β-cell function was improved, and insulitis and pancreatic CD45.1+ cell infiltration was reduced. Lymphoid tissues were unaffected. ALT pre-treatment, prior to transfer of primed GC98 CD8+ T cell receptor transgenic T cells, reduced blood glucose concentrations and delayed diabetes, suggesting islet effects rather than immune modulation by ALT. Indeed, ALT did not reduce interferon-γ production by leukocytes from ovalbumin-pre-immunised NODShiLt mice and NODscid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate β-cell effects, NOD-derived MIN6N8 β-cell major histocompatibility complex (MHC) Class Ia surface antigens were examined using immunopeptidomics. Overall, no major changes in the immunopeptidome were observed during the various treatments with all peptides exhibiting allele specific consensus binding motifs. As expected, longer MHC Class Ia peptides were captured bound to H-2Db than H-2Kb under all conditions. Moreover, more 10–12 mer peptides were isolated from H-2Db after AGE modified bovine serum albumin (AGE-BSA) treatment, compared with bovine serum albumin (BSA) or AGE-BSA+ALT treatment. Proteomics of MIN6N8 cells showed enrichment of processes associated with catabolism, the immune system, cell cycling and presynaptic endocytosis with AGE-BSA compared with BSA treatments. These data show that short-term ALT intervention, given prediabetes, does not arrest experimental T1D but transiently impacts β-cell function. Full article
(This article belongs to the Special Issue Islet Biology and Metabolism)
►▼ Show Figures

Figure 1

14 pages, 4165 KB  
Article
Lipidomic Analysis to Assess Oxidative Stress in Acute Coronary Syndrome and Acute Stroke Patients
by Martin Malý, Martin Hajšl, Kamila Bechyňská, Ondřej Kučerka, Martin Šrámek, Jiří Suttnar, Alžběta Hlaváčková, Jana Hajšlová and Vít Kosek
Metabolites 2021, 11(7), 412; https://doi.org/10.3390/metabo11070412 - 23 Jun 2021
Cited by 17 | Viewed by 3823
Abstract
Alterations in lipid metabolism mediated by oxidative stress play a key role in the process of atherosclerosis and superimposed thrombosis; these can lead to acute coronary syndrome (ACS) and acute ischemic stroke (AIS). Multiple studies have shown that the formation of atheromatous lesions [...] Read more.
Alterations in lipid metabolism mediated by oxidative stress play a key role in the process of atherosclerosis and superimposed thrombosis; these can lead to acute coronary syndrome (ACS) and acute ischemic stroke (AIS). Multiple studies have shown that the formation of atheromatous lesions is initiated by oxidation of low-density lipoproteins incorporated into the intima of the vessel wall. Here, we studied lipids in plasma samples from three cohorts: 61 patients with ACS (group A), 49 patients with AIS (group D), and 82 controls (group K). Untargeted lipidomics based on high-performance liquid chromatography coupled to mass spectrometry (UHPLC-HRMS) was employed to obtain comprehensive information on whether relationships exist between these patient categories based on lipid patterns. In addition, malondialdehyde (MDA) as a standard marker of oxidative stress was monitored. The most characteristic lipids in group K were fatty acyls of hydroxyfatty acids (FAHFAs). As expected, MDA concentrations were the lowest in group K. Our findings can better explain ongoing pathologies, both acute and chronic, with the potential for future diagnosis and treatment. Full article
(This article belongs to the Special Issue Thrombosis and Metabolism)
►▼ Show Figures

Figure 1

13 pages, 779 KB  
Review
Measurement of Pulsatile Insulin Secretion: Rationale and Methodology
by Marcello C. Laurenti, Aleksey Matveyenko and Adrian Vella
Metabolites 2021, 11(7), 409; https://doi.org/10.3390/metabo11070409 - 22 Jun 2021
Cited by 13 | Viewed by 3956
Abstract
Pancreatic β-cells are responsible for the synthesis and exocytosis of insulin in response to an increase in circulating glucose. Insulin secretion occurs in a pulsatile manner, with oscillatory pulses superimposed on a basal secretion rate. Insulin pulses are a marker of β-cell health, [...] Read more.
Pancreatic β-cells are responsible for the synthesis and exocytosis of insulin in response to an increase in circulating glucose. Insulin secretion occurs in a pulsatile manner, with oscillatory pulses superimposed on a basal secretion rate. Insulin pulses are a marker of β-cell health, and secretory parameters, such as pulse amplitude, time interval and frequency distribution, are impaired in obesity, aging and type 2 diabetes. In this review, we detail the mechanisms of insulin production and β-cell synchronization that regulate pulsatile insulin secretion, and we discuss the challenges to consider when measuring fast oscillatory secretion in vivo. These include the anatomical difficulties of measuring portal vein insulin noninvasively in humans before the hormone is extracted by the liver and quickly removed from the circulation. Peripheral concentrations of insulin or C-peptide, a peptide cosecreted with insulin, can be used to estimate their secretion profile, but mathematical deconvolution is required. Parametric and nonparametric approaches to the deconvolution problem are evaluated, alongside the assumptions and trade-offs required for their application in the quantification of unknown insulin secretory rates from known peripheral concentrations. Finally, we discuss the therapeutical implication of targeting impaired pulsatile secretion and its diagnostic value as an early indicator of β-cell stress. Full article
(This article belongs to the Special Issue Insulin: A Life-Saving Hormone and Key Regulator of Metabolism)
►▼ Show Figures

Figure 1

37 pages, 1443 KB  
Review
What We Know So Far about the Metabolite-Mediated Microbiota-Intestinal Immunity Dialogue and How to Hear the Sound of This Crosstalk
by Clément Caffaratti, Caroline Plazy, Geoffroy Mery, Abdoul-Razak Tidjani, Federica Fiorini, Sarah Thiroux, Bertrand Toussaint, Dalil Hannani and Audrey Le Gouellec
Metabolites 2021, 11(6), 406; https://doi.org/10.3390/metabo11060406 - 21 Jun 2021
Cited by 24 | Viewed by 10290
Abstract
Trillions of microorganisms, termed the “microbiota”, reside in the mammalian gastrointestinal tract, and collectively participate in regulating the host phenotype. It is now clear that the gut microbiota, metabolites, and intestinal immune function are correlated, and that alterations of the complex and dynamic [...] Read more.
Trillions of microorganisms, termed the “microbiota”, reside in the mammalian gastrointestinal tract, and collectively participate in regulating the host phenotype. It is now clear that the gut microbiota, metabolites, and intestinal immune function are correlated, and that alterations of the complex and dynamic host-microbiota interactions can have deep consequences for host health. However, the mechanisms by which the immune system regulates the microbiota and by which the microbiota shapes host immunity are still not fully understood. This article discusses the contribution of metabolites in the crosstalk between gut microbiota and immune cells. The identification of key metabolites having a causal effect on immune responses and of the mechanisms involved can contribute to a deeper insight into host-microorganism relationships. This will allow a better understanding of the correlation between dysbiosis, microbial-based dysmetabolism, and pathogenesis, thus creating opportunities to develop microbiota-based therapeutics to improve human health. In particular, we systematically review the role of soluble and membrane-bound microbial metabolites in modulating host immunity in the gut, and of immune cells-derived metabolites affecting the microbiota, while discussing evidence of the bidirectional impact of this crosstalk. Furthermore, we discuss the potential strategies to hear the sound of such metabolite-mediated crosstalk. Full article
(This article belongs to the Special Issue Reviews and Advances in Microbial Metabolomics)
►▼ Show Figures

Graphical abstract

19 pages, 9214 KB  
Article
Metabolomic Study of High-Fat Diet-Induced Obese (DIO) and DIO Plus CCl4-Induced NASH Mice and the Effect of Obeticholic Acid
by Nanlin Zhu, Suling Huang, Qingli Zhang, Zhuohui Zhao, Hui Qu, Mengmeng Ning, Ying Leng and Jia Liu
Metabolites 2021, 11(6), 374; https://doi.org/10.3390/metabo11060374 - 10 Jun 2021
Cited by 12 | Viewed by 5243
Abstract
The pathophysiology of nonalcoholic fatty liver disease (NAFLD) is a complex process involving metabolic and inflammatory changes in livers and other organs, but the pathogenesis is still not well clarified. Two mouse models were established to study metabolic alteration of nonalcoholic fatty liver [...] Read more.
The pathophysiology of nonalcoholic fatty liver disease (NAFLD) is a complex process involving metabolic and inflammatory changes in livers and other organs, but the pathogenesis is still not well clarified. Two mouse models were established to study metabolic alteration of nonalcoholic fatty liver and nonalcoholic steatohepatitis, respectively. The concentrations of metabolites in serum, liver and intestine content were measured by the AbsoluteIDQ® p180 Kit (Biocrates Life Sciences, Innsbruck, Austria). Multivariate statistical methods, pathway analysis, enrichment analysis and correlation analysis were performed to analyze metabolomic data. The metabolic characteristics of liver, serum and intestine content could be distinctly distinguished from each group, indicating the occurrence of metabolic disturbance. Among them, metabolic alteration of liver and intestine content was more significant. Based on the metabolic data of liver, 19 differential metabolites were discovered between DIO and control, 12 between DIO-CCl4 and DIO, and 47 between DIO-CCl4 and normal. These metabolites were mainly associated with aminoacyl-tRNA biosynthesis, nitrogen metabolism, lipid metabolism, glyoxylate and dicarboxylate metabolism, and amino metabolism. Further study revealed that the intervention of obeticholic acid (OCA) could partly reverse the damage of CCl4. The correlation analysis of metabolite levels and clinical parameters showed that phosphatidylcholines were negatively associated with serum alanine aminotransferase, aspartate aminotransferase, NAFLD activity score, and fibrosis score, while lysophosphatidylcholines, sphingomyelins, amino acids, and acylcarnitines shared the reverse pattern. Our study investigated metabolic alteration among control, NAFLD model, and OCA treatment groups, providing preclinical information to understand the mechanism of NAFLD and amelioration of OCA. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
►▼ Show Figures

Figure 1

15 pages, 3480 KB  
Article
Hypothalamic Expression of Neuropeptide Y (NPY) and Pro-OpioMelanoCortin (POMC) in Adult Male Mice Is Affected by Chronic Exposure to Endocrine Disruptors
by Marilena Marraudino, Elisabetta Bo, Elisabetta Carlini, Alice Farinetti, Giovanna Ponti, Isabella Zanella, Diego Di Lorenzo, Gian Carlo Panzica and Stefano Gotti
Metabolites 2021, 11(6), 368; https://doi.org/10.3390/metabo11060368 - 9 Jun 2021
Cited by 16 | Viewed by 4657
Abstract
In the arcuate nucleus, neuropeptide Y (NPY) neurons, increase food intake and decrease energy expenditure, and control the activity of pro-opiomelanocortin (POMC) neurons, that decrease food intake and increase energy expenditure. Both systems project to other hypothalamic nuclei such as the paraventricular and [...] Read more.
In the arcuate nucleus, neuropeptide Y (NPY) neurons, increase food intake and decrease energy expenditure, and control the activity of pro-opiomelanocortin (POMC) neurons, that decrease food intake and increase energy expenditure. Both systems project to other hypothalamic nuclei such as the paraventricular and dorsomedial hypothalamic nuclei. Endocrine disrupting chemicals (EDCs) are environmental contaminants that alter the endocrine system causing adverse health effects in an intact organism or its progeny. We investigated the effects of long-term exposure to some EDCs on the hypothalamic NPY and POMC systems of adult male mice that had been previously demonstrated to be a target of some of these EDCs after short-term exposure. Animals were chronically fed for four months with a phytoestrogen-free diet containing two different concentrations of bisphenol A, diethylstilbestrol, tributyltin, or E2. At the end, brains were processed for NPY and POMC immunohistochemistry and quantitatively analyzed. In the arcuate and dorsomedial nuclei, both NPY and POMC immunoreactivity showed a statistically significant decrease. In the paraventricular nucleus, only the NPY system was affected, while the POMC system was not affected. Finally, in the VMH the NPY system was affected whereas no POMC immunoreactive material was observed. These results indicate that adult exposure to different EDCs may alter the hypothalamic circuits that control food intake and energy metabolism. Full article
(This article belongs to the Special Issue Neuroendocrine Control of Energy Metabolism)
►▼ Show Figures

Graphical abstract

13 pages, 1792 KB  
Article
Identification of Circulating Diagnostic Biomarkers for Coronary Microvascular Disease in Postmenopausal Women Using Machine-Learning Techniques
by Alicia Arredondo Eve, Elif Tunc, Yu-Jeh Liu, Saumya Agrawal, Huriye Erbak Yilmaz, Sadık Volkan Emren, Filiz Akyıldız Akçay, Luidmila Mainzer, Justina Žurauskienė and Zeynep Madak Erdogan
Metabolites 2021, 11(6), 339; https://doi.org/10.3390/metabo11060339 - 25 May 2021
Cited by 6 | Viewed by 5303
Abstract
Coronary microvascular disease (CMD) is a common form of heart disease in postmenopausal women. It is not due to plaque formation but dysfunction of microvessels that feed the heart muscle. The majority of the patients do not receive a proper diagnosis, are discharged [...] Read more.
Coronary microvascular disease (CMD) is a common form of heart disease in postmenopausal women. It is not due to plaque formation but dysfunction of microvessels that feed the heart muscle. The majority of the patients do not receive a proper diagnosis, are discharged prematurely and must go back to the hospital with persistent symptoms. Because of the lack of diagnostic biomarkers, in the current study, we focused on identifying novel circulating biomarkers of CMV that could potentially be used for developing a diagnostic test. We hypothesized that plasma metabolite composition is different for postmenopausal women with no heart disease, CAD, or CMD. A total of 70 postmenopausal women, 26 healthy individuals, 23 individuals with CMD and 21 individuals with CAD were recruited. Their full health screening and tests were completed. Basic cardiac examination, including detailed clinical history, additional disease and prescribed drugs, were noted. Electrocardiograph, transthoracic echocardiography and laboratory analysis were also obtained. Additionally, we performed full metabolite profiling of plasma samples from these individuals using gas chromatography-mass spectrometry (GC–MS) analysis, identified and classified circulating biomarkers using machine learning approaches. Stearic acid and ornithine levels were significantly higher in postmenopausal women with CMD. In contrast, valine levels were higher for women with CAD. Our research identified potential circulating plasma biomarkers of this debilitating heart disease in postmenopausal women, which will have a clinical impact on diagnostic test design in the future. Full article
(This article belongs to the Special Issue Biomarkers for Metabolism and Cardiometabolic Diseases)
►▼ Show Figures

Figure 1

26 pages, 1764 KB  
Review
Thromboembolic Complications of SARS-CoV-2 and Metabolic Derangements: Suggestions from Clinical Practice Evidence to Causative Agents
by Francesco Nappi, Adelaide Iervolino and Sanjeet Singh Avtaar Singh
Metabolites 2021, 11(6), 341; https://doi.org/10.3390/metabo11060341 - 25 May 2021
Cited by 12 | Viewed by 4771
Abstract
Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2 is a recently identified positive sense single-strand RNA (ssRNA) β-coronavirus. The viral spike proteins infect human hosts by binding to the cellular receptor angiotensin-converting enzyme 2 (ACE2). The infection causes a systemic illness involving cell metabolism. [...] Read more.
Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2 is a recently identified positive sense single-strand RNA (ssRNA) β-coronavirus. The viral spike proteins infect human hosts by binding to the cellular receptor angiotensin-converting enzyme 2 (ACE2). The infection causes a systemic illness involving cell metabolism. This widespread involvement is implicated in the pathophysiology of the illness which ranges from mild to severe, requiring multi organ support, ranging from oxygen supplementation to full cardiovascular and respiratory support. Patients with multiple co-existing comorbidities are also at a higher risk. The aim of this review is to explore the exact mechanisms by which COVID-19 affects patients systemically with a primary focus on the bleeding and thrombotic complications linked with the disease. Issues surrounding the thrombotic complications following administration of the ChAdOx1 nCoV-19 (Astra-Zeneca-Oxford) vaccine have also been illustrated. Risk stratification and treatment options in these patients should be tailored according to clinical severity with input from a multidisciplinary team. Full article
(This article belongs to the Special Issue Thrombosis and Metabolism)
►▼ Show Figures

Graphical abstract

21 pages, 6204 KB  
Article
Iron-Bound Lipocalin-2 Protects Renal Cell Carcinoma from Ferroptosis
by Julia K. Meier, Matthias Schnetz, Susanne Beck, Tobias Schmid, Monica Dominguez, Sanela Kalinovic, Andreas Daiber, Bernhard Brüne and Michaela Jung
Metabolites 2021, 11(5), 329; https://doi.org/10.3390/metabo11050329 - 19 May 2021
Cited by 31 | Viewed by 5729
Abstract
While the importance of the iron-load of lipocalin-2 (Lcn-2) in promoting tumor progression is widely appreciated, underlying molecular mechanisms largely remain elusive. Considering its role as an iron-transporter, we aimed at clarifying iron-loaded, holo-Lcn-2 (hLcn-2)-dependent signaling pathways in affecting renal cancer cell viability. [...] Read more.
While the importance of the iron-load of lipocalin-2 (Lcn-2) in promoting tumor progression is widely appreciated, underlying molecular mechanisms largely remain elusive. Considering its role as an iron-transporter, we aimed at clarifying iron-loaded, holo-Lcn-2 (hLcn-2)-dependent signaling pathways in affecting renal cancer cell viability. Applying RNA sequencing analysis in renal CAKI1 tumor cells to explore highly upregulated molecular signatures in response to hLcn-2, we identified a cluster of genes (SLC7A11, GCLM, GLS), which are implicated in regulating ferroptosis. Indeed, hLcn-2-stimulated cells are protected from erastin-induced ferroptosis. We also noticed a rapid increase in reactive oxygen species (ROS) with subsequent activation of the antioxidant Nrf2 pathway. However, knocking down Nrf2 by siRNA was not sufficient to induce erastin-dependent ferroptotic cell death in hLcn-2-stimulated tumor cells. In contrast, preventing oxidative stress through N-acetyl-l-cysteine (NAC) supplementation was still able to induce erastin-dependent ferroptotic cell death in hLcn-2-stimulated tumor cells. Besides an oxidative stress response, we noticed activation of the integrated stress response (ISR), shown by enhanced phosphorylation of eIF-2α and induction of ATF4 after hLcn-2 addition. ATF4 knockdown as well as inhibition of the ISR sensitized hLcn-2-treated renal tumor cells to ferroptosis, thus linking the ISR to pro-tumor characteristics of hLcn-2. Our study provides mechanistic details to better understand tumor pro-survival pathways initiated by iron-loaded Lcn-2. Full article
(This article belongs to the Section Cell Metabolism)
►▼ Show Figures

Figure 1

16 pages, 2807 KB  
Article
Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway
by Jiling Liang, Hu Zhang, Zhengzhong Zeng, Liangwen Wu, Ying Zhang, Yanju Guo, Jun Lv, Cenyi Wang, Jingjing Fan and Ning Chen
Metabolites 2021, 11(5), 323; https://doi.org/10.3390/metabo11050323 - 18 May 2021
Cited by 62 | Viewed by 7496
Abstract
Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular [...] Read more.
Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular dystrophy. As a publicly recognized strategy for extending lifespan and improving the health of the elderly, the underlying mechanisms of lifelong regular aerobic exercise for the prevention of sarcopenia have not been fully elucidated. To explore the role of lifelong aerobic exercise in the beneficial regulation of autophagic signaling pathways in senescent skeletal muscle, the natural aging mice were used as the sarcopenia model and subjected to lifelong treadmill running to evaluate corresponding parameters related to skeletal muscle atrophy and autophagic signaling pathways. Compared with the young control mice, the aged mice showed a significant reduction in skeletal muscle mass, gastrocnemius muscle weight/body weight (GMW/BW) ratio, and cross-sectional areas (CSA) of skeletal muscle fibers (p < 0.01). In contrast, lifelong aerobic exercise effectively rescued these reduced biomarkers associated with muscle atrophy. Moreover, as shown in the activated AMPK/PGC-1α signaling pathway, lifelong aerobic exercise successfully prevented the aging-induced impairment of the ubiquitin-proteasome system (UPS), excessive apoptosis, defective autophagy, and mitochondrial dysfunction. The exercise-induced autophagy suppressed the key regulatory components of the UPS, inhibited excessive apoptosis, and optimized mitochondrial quality control, thereby preventing and delaying aging-induced skeletal muscle atrophy. Full article
(This article belongs to the Special Issue Skeletal Muscle Atrophy and Metabolic Adaptation)
►▼ Show Figures

Graphical abstract

28 pages, 3076 KB  
Article
Exploration of Blood Lipoprotein and Lipid Fraction Profiles in Healthy Subjects through Integrated Univariate, Multivariate, and Network Analysis Reveals Association of Lipase Activity and Cholesterol Esterification with Sex and Age
by Yasmijn Balder, Alessia Vignoli, Leonardo Tenori, Claudio Luchinat and Edoardo Saccenti
Metabolites 2021, 11(5), 326; https://doi.org/10.3390/metabo11050326 - 18 May 2021
Cited by 7 | Viewed by 5460
Abstract
In this study, we investigated blood lipoprotein and lipid fraction profiles, quantified using nuclear magnetic resonance, in a cohort of 844 healthy blood donors, integrating standard univariate and multivariate analysis with predictive modeling and network analysis. We observed a strong association of lipoprotein [...] Read more.
In this study, we investigated blood lipoprotein and lipid fraction profiles, quantified using nuclear magnetic resonance, in a cohort of 844 healthy blood donors, integrating standard univariate and multivariate analysis with predictive modeling and network analysis. We observed a strong association of lipoprotein and lipid main fraction profiles with sex and age. Our results suggest an age-dependent remodulation of lipase lipoprotein activity in men and a change in the mechanisms controlling the ratio between esterified and non-esterified cholesterol in both men and women. Full article
(This article belongs to the Collection Advances in Metabolomics)
►▼ Show Figures

Figure 1

20 pages, 2398 KB  
Review
Browning of White Adipose Tissue as a Therapeutic Tool in the Fight against Atherosclerosis
by Christel L. Roth, Filippo Molica and Brenda R. Kwak
Metabolites 2021, 11(5), 319; https://doi.org/10.3390/metabo11050319 - 14 May 2021
Cited by 27 | Viewed by 5874
Abstract
Despite continuous medical advances, atherosclerosis remains the prime cause of mortality worldwide. Emerging findings on brown and beige adipocytes highlighted that these fat cells share the specific ability of non-shivering thermogenesis due to the expression of uncoupling protein 1. Brown fat is established [...] Read more.
Despite continuous medical advances, atherosclerosis remains the prime cause of mortality worldwide. Emerging findings on brown and beige adipocytes highlighted that these fat cells share the specific ability of non-shivering thermogenesis due to the expression of uncoupling protein 1. Brown fat is established during embryogenesis, and beige cells emerge from white adipose tissue exposed to specific stimuli like cold exposure into a process called browning. The consecutive energy expenditure of both thermogenic adipose tissues has shown therapeutic potential in metabolic disorders like obesity and diabetes. The latest data suggest promising effects on atherosclerosis development as well. Upon cold exposure, mice and humans have a physiological increase in brown adipose tissue activation and browning of white adipocytes is promoted. The use of drugs like β3-adrenergic agonists in murine models induces similar effects. With respect to atheroprotection, thermogenic adipose tissue activation has beneficial outcomes in mice by decreasing plasma triglycerides, total cholesterol and low-density lipoproteins, by increasing high-density lipoproteins, and by inducing secretion of atheroprotective adipokines. Atheroprotective effects involve an unaffected hepatic clearance. Latest clinical data tend to find thinner atherosclerotic lesions in patients with higher brown adipose tissue activity. Strategies for preserving healthy arteries are a major concern for public health. Full article
(This article belongs to the Special Issue Cardiovascular Risk Biomarkers: Deciphering the Metabolism and Interaction Networks)
►▼ Show Figures

Figure 1

10 pages, 1304 KB  
Article
Correcting for Naturally Occurring Mass Isotopologue Abundances in Stable-Isotope Tracing Experiments with PolyMID
by Heesoo Jeong, Yan Yu, Henrik J. Johansson, Frank C. Schroeder, Janne Lehtiö and Nathaniel M. Vacanti
Metabolites 2021, 11(5), 310; https://doi.org/10.3390/metabo11050310 - 12 May 2021
Cited by 6 | Viewed by 5565
Abstract
Stable-isotope tracing is a method to measure intracellular metabolic pathway utilization by feeding a cellular system a stable-isotope-labeled tracer nutrient. The power of the method to resolve differential pathway utilization is derived from the enrichment of metabolites in heavy isotopes that are synthesized [...] Read more.
Stable-isotope tracing is a method to measure intracellular metabolic pathway utilization by feeding a cellular system a stable-isotope-labeled tracer nutrient. The power of the method to resolve differential pathway utilization is derived from the enrichment of metabolites in heavy isotopes that are synthesized from the tracer nutrient. However, the readout is complicated by the presence of naturally occurring heavy isotopes that are not derived from the tracer nutrient. Herein we present an algorithm, and a tool that applies it (PolyMID-Correct, part of the PolyMID software package), to computationally remove the influence of naturally occurring heavy isotopes. The algorithm is applicable to stable-isotope tracing data collected on low- and high- mass resolution mass spectrometers. PolyMID-Correct is open source and available under an MIT license. Full article
(This article belongs to the Special Issue Mitochondrial Metabolism and Bioenergetics)
►▼ Show Figures

Figure 1

15 pages, 671 KB  
Review
FFAR from the Gut Microbiome Crowd: SCFA Receptors in T1D Pathology
by Medha Priyadarshini, Kristen Lednovich, Kai Xu, Sophie Gough, Barton Wicksteed and Brian T. Layden
Metabolites 2021, 11(5), 302; https://doi.org/10.3390/metabo11050302 - 11 May 2021
Cited by 12 | Viewed by 5366
Abstract
The gut microbiome has emerged as a novel determinant of type 1 diabetes (T1D), but the underlying mechanisms are unknown. In this context, major gut microbial metabolites, short-chain fatty acids (SCFAs), are considered to be an important link between the host and gut [...] Read more.
The gut microbiome has emerged as a novel determinant of type 1 diabetes (T1D), but the underlying mechanisms are unknown. In this context, major gut microbial metabolites, short-chain fatty acids (SCFAs), are considered to be an important link between the host and gut microbiome. We, along with other laboratories, have explored how SCFAs and their cognate receptors affect various metabolic conditions, including obesity, type 2 diabetes, and metabolic syndrome. Though gut microbiome and SCFA-level changes have been reported in T1D and in mouse models of the disease, the role of SCFA receptors in T1D remains under explored. In this review article, we will highlight the existing and possible roles of these receptors in T1D pathology. We conclude with a discussion of SCFA receptors as therapeutic targets for T1D, exploring an exciting new potential for novel treatments of glucometabolic disorders. Full article
(This article belongs to the Special Issue Islet Biology and Metabolism)
►▼ Show Figures

Figure 1

16 pages, 1754 KB  
Article
Untargeted Lipidomic Profiling of Dry Blood Spots Using SFC-HRMS
by Pauline Le Faouder, Julia Soullier, Marie Tremblay-Franco, Anthony Tournadre, Jean-François Martin, Yann Guitton, Caroline Carlé, Sylvie Caspar-Bauguil, Pierre-Damien Denechaud and Justine Bertrand-Michel
Metabolites 2021, 11(5), 305; https://doi.org/10.3390/metabo11050305 - 11 May 2021
Cited by 18 | Viewed by 4282
Abstract
Lipids are essential cellular constituents that have many critical roles in physiological functions. They are notably involved in energy storage and cell signaling as second messengers, and they are major constituents of cell membranes, including lipid rafts. As a consequence, they are implicated [...] Read more.
Lipids are essential cellular constituents that have many critical roles in physiological functions. They are notably involved in energy storage and cell signaling as second messengers, and they are major constituents of cell membranes, including lipid rafts. As a consequence, they are implicated in a large number of heterogeneous diseases, such as cancer, diabetes, neurological disorders, and inherited metabolic diseases. Due to the high structural diversity and complexity of lipid species, the presence of isomeric and isobaric lipid species, and their occurrence at a large concentration scale, a complete lipidomic profiling of biological matrices remains challenging, especially in clinical contexts. Using supercritical fluid chromatography coupled with high-resolution mass spectrometry, we have developed and validated an untargeted lipidomic approach to the profiling of plasma and blood. Moreover, we have tested the technique using the Dry Blood Spot (DBS) method and found that it allows for the easy collection of blood for analysis. To develop the method, we performed the optimization of the separation and detection of lipid species on pure standards, reference human plasma (SRM1950), whole blood, and DBS. These analyses allowed an in-house lipid data bank to be built. Using the MS-Dial software, we developed an automatic process for the relative quantification of around 500 lipids species belonging to the 6 main classes of lipids (including phospholipids, sphingolipids, free fatty acids, sterols, and fatty acyl-carnitines). Then, we compared the method using the published data for SRM 1950 and a mouse blood sample, along with another sample of the same blood collected using the DBS method. In this study, we provided a method for blood lipidomic profiling that can be used for the easy sampling of dry blood spots. Full article
(This article belongs to the Special Issue Mass Spectrometry-Based Lipidomics)
►▼ Show Figures

Figure 1

22 pages, 5682 KB  
Article
Metabolic View on Human Healthspan: A Lipidome-Wide Association Study
by Justin Carrard, Hector Gallart-Ayala, Denis Infanger, Tony Teav, Jonathan Wagner, Raphael Knaier, Flora Colledge, Lukas Streese, Karsten Königstein, Timo Hinrichs, Henner Hanssen, Julijana Ivanisevic and Arno Schmidt-Trucksäss
Metabolites 2021, 11(5), 287; https://doi.org/10.3390/metabo11050287 - 30 Apr 2021
Cited by 24 | Viewed by 6811
Abstract
As ageing is a major risk factor for the development of non-communicable diseases, extending healthspan has become a medical and societal necessity. Precise lipid phenotyping that captures metabolic individuality could support healthspan extension strategies. This study applied ‘omic-scale lipid profiling to characterise sex-specific [...] Read more.
As ageing is a major risk factor for the development of non-communicable diseases, extending healthspan has become a medical and societal necessity. Precise lipid phenotyping that captures metabolic individuality could support healthspan extension strategies. This study applied ‘omic-scale lipid profiling to characterise sex-specific age-related differences in the serum lipidome composition of healthy humans. A subset of the COmPLETE-Health study, composed of 73 young (25.2 ± 2.6 years, 43% female) and 77 aged (73.5 ± 2.3 years, 48% female) clinically healthy individuals, was investigated, using an untargeted liquid chromatography high-resolution mass spectrometry approach. Compared to their younger counterparts, aged females and males exhibited significant higher levels in 138 and 107 lipid species representing 15 and 13 distinct subclasses, respectively. Percentage of difference ranged from 5.8% to 61.7% (females) and from 5.3% to 46.0% (males), with sphingolipid and glycerophophospholipid species displaying the greatest amplitudes. Remarkably, specific sphingolipid and glycerophospholipid species, previously described as cardiometabolically favourable, were found elevated in aged individuals. Furthermore, specific ether-glycerophospholipid and lyso-glycerophosphocholine species displayed higher levels in aged females only, revealing a more favourable lipidome evolution in females. Altogether, age determined the circulating lipidome composition, while lipid species analysis revealed additional findings that were not observed at the subclass level. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
►▼ Show Figures

Graphical abstract

16 pages, 2024 KB  
Review
Isolation and Proteomics of the Insulin Secretory Granule
by Nicholas Norris, Belinda Yau and Melkam Alamerew Kebede
Metabolites 2021, 11(5), 288; https://doi.org/10.3390/metabo11050288 - 30 Apr 2021
Cited by 19 | Viewed by 6778
Abstract
Insulin, a vital hormone for glucose homeostasis is produced by pancreatic beta-cells and when secreted, stimulates the uptake and storage of glucose from the blood. In the pancreas, insulin is stored in vesicles termed insulin secretory granules (ISGs). In Type 2 diabetes (T2D), [...] Read more.
Insulin, a vital hormone for glucose homeostasis is produced by pancreatic beta-cells and when secreted, stimulates the uptake and storage of glucose from the blood. In the pancreas, insulin is stored in vesicles termed insulin secretory granules (ISGs). In Type 2 diabetes (T2D), defects in insulin action results in peripheral insulin resistance and beta-cell compensation, ultimately leading to dysfunctional ISG production and secretion. ISGs are functionally dynamic and many proteins present either on the membrane or in the lumen of the ISG may modulate and affect different stages of ISG trafficking and secretion. Previously, studies have identified few ISG proteins and more recently, proteomics analyses of purified ISGs have uncovered potential novel ISG proteins. This review summarizes the proteins identified in the current ISG proteomes from rat insulinoma INS-1 and INS-1E cell lines. Here, we also discuss techniques of ISG isolation and purification, its challenges and potential future directions. Full article
(This article belongs to the Special Issue Islet Biology and Metabolism)
►▼ Show Figures

Figure 1

33 pages, 2516 KB  
Review
Vitamin D Sources, Metabolism, and Deficiency: Available Compounds and Guidelines for Its Treatment
by Ligia J. Dominguez, Mario Farruggia, Nicola Veronese and Mario Barbagallo
Metabolites 2021, 11(4), 255; https://doi.org/10.3390/metabo11040255 - 20 Apr 2021
Cited by 177 | Viewed by 35852
Abstract
Studies on vitamin/hormone D deficiency have received a vast amount of attention in recent years, particularly concerning recommendations, guidelines, and treatments. Moreover, vitamin D’s role as a hormone has been confirmed in various enzymatic, metabolic, physiological, and pathophysiological processes related to many organs [...] Read more.
Studies on vitamin/hormone D deficiency have received a vast amount of attention in recent years, particularly concerning recommendations, guidelines, and treatments. Moreover, vitamin D’s role as a hormone has been confirmed in various enzymatic, metabolic, physiological, and pathophysiological processes related to many organs and systems in the human body. This growing interest is mostly due to the evidence that modest-to-severe vitamin D deficiency is widely prevalent around the world. There is broad agreement that optimal vitamin D status is necessary for bones, muscles, and one’s general health, as well as for the efficacy of antiresorptive and anabolic bone-forming treatments. Food supplementation with vitamin D, or the use of vitamin D supplements, are current strategies to improve vitamin D levels and treat deficiency. This article reviews consolidated and emerging concepts about vitamin D/hormone D metabolism, food sources, deficiency, as well as the different vitamin D supplements available, and current recommendations on the proper use of these compounds. Full article
(This article belongs to the Special Issue Vitamin D and Bone Metabolism)
►▼ Show Figures

Figure 1

15 pages, 2645 KB  
Article
Serum Zinc, Copper, and Other Biometals Are Associated with COVID-19 Severity Markers
by Anatoly V. Skalny, Peter S. Timashev, Michael Aschner, Jan Aaseth, Lyubov N. Chernova, Vladimir E. Belyaev, Andrey R. Grabeklis, Svetlana V. Notova, Ryszard Lobinski, Aristides Tsatsakis, Andrey A. Svistunov, Victor V. Fomin, Alexey A. Tinkov and Peter V. Glybochko
Metabolites 2021, 11(4), 244; https://doi.org/10.3390/metabo11040244 - 15 Apr 2021
Cited by 66 | Viewed by 6662
Abstract
The objective of the present study was to evaluate of serum metal levels in COVID-19 patients with different disease severity, and to investigate the independent association between serum metal profile and markers of lung damage. The cohort of COVID-19 patients consisted of groups [...] Read more.
The objective of the present study was to evaluate of serum metal levels in COVID-19 patients with different disease severity, and to investigate the independent association between serum metal profile and markers of lung damage. The cohort of COVID-19 patients consisted of groups of subjects with mild, moderate, and severe illness, 50 examinees each. Forty-four healthy subjects of the respective age were involved in the current study as the control group. Serum metal levels were evaluated using inductively-coupled plasma mass-spectrometry. Examination of COVID-19 patients demonstrated that heart rate, respiratory rate, body temperature, C-reactive protein levels, as well as lung damage increased significantly with COVID-19 severity, whereas SpO2 decreased gradually. Increasing COVID-19 severity was also associated with a significant gradual decrease in serum Ca, Fe, Se, Zn levels as compared to controls, whereas serum Cu and especially Cu/Zn ratio were elevated. No significant group differences in serum Mg and Mn levels were observed. Serum Ca, Fe, Se, Zn correlated positively with SpO2, being inversely associated with fever, lung damage, and C-reactive protein concentrations. Opposite correlations were observed for Cu and Cu/Zn ratio. In regression models, serum Se levels were inversely associated with lung damage independently of other markers of disease severity, anthropometric, biochemical, and hemostatic parameters. Cu/Zn ratio was also considered as a significant predictor of lower SpO2 in adjusted regression models. Taken together, these findings demonstrated that metal metabolism significantly interferes with COVID-19 pathogenesis, although the causal relations as well as precise mechanisms are yet to be characterized. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
►▼ Show Figures

Graphical abstract

24 pages, 2182 KB  
Review
Clinical Insights into Mitochondrial Neurodevelopmental and Neurodegenerative Disorders: Their Biosignatures from Mass Spectrometry-Based Metabolomics
by Haorong Li, Martine Uittenbogaard, Ling Hao and Anne Chiaramello
Metabolites 2021, 11(4), 233; https://doi.org/10.3390/metabo11040233 - 10 Apr 2021
Cited by 13 | Viewed by 5653
Abstract
Mitochondria are dynamic multitask organelles that function as hubs for many metabolic pathways. They produce most ATP via the oxidative phosphorylation pathway, a critical pathway that the brain relies on its energy need associated with its numerous functions, such as synaptic homeostasis and [...] Read more.
Mitochondria are dynamic multitask organelles that function as hubs for many metabolic pathways. They produce most ATP via the oxidative phosphorylation pathway, a critical pathway that the brain relies on its energy need associated with its numerous functions, such as synaptic homeostasis and plasticity. Therefore, mitochondrial dysfunction is a prevalent pathological hallmark of many neurodevelopmental and neurodegenerative disorders resulting in altered neurometabolic coupling. With the advent of mass spectrometry (MS) technology, MS-based metabolomics provides an emerging mechanistic understanding of their global and dynamic metabolic signatures. In this review, we discuss the pathogenetic causes of mitochondrial metabolic disorders and the recent MS-based metabolomic advances on their metabolomic remodeling. We conclude by exploring the MS-based metabolomic functional insights into their biosignatures to improve diagnostic platforms, stratify patients, and design novel targeted therapeutic strategies. Full article
(This article belongs to the Special Issue The Role of Metabolism in Brain Diseases)
►▼ Show Figures

Graphical abstract

16 pages, 676 KB  
Article
Metabolomic Analysis of Small Extracellular Vesicles Derived from Pancreatic Cancer Cells Cultured under Normoxia and Hypoxia
by Ryosuke Hayasaka, Sho Tabata, Masako Hasebe, Satsuki Ikeda, Sumiko Ohnuma, Masaru Mori, Tomoyoshi Soga, Masaru Tomita and Akiyoshi Hirayama
Metabolites 2021, 11(4), 215; https://doi.org/10.3390/metabo11040215 - 1 Apr 2021
Cited by 25 | Viewed by 4821
Abstract
Extracellular vesicles (EVs) released from cancer cells contribute to various malignant phenotypes of cancer, including metastasis, cachexia, and angiogenesis. Although DNA, mRNAs, miRNAs, and proteins contained in EVs have been extensively studied, the function of metabolites in EVs remains unclear. In this study, [...] Read more.
Extracellular vesicles (EVs) released from cancer cells contribute to various malignant phenotypes of cancer, including metastasis, cachexia, and angiogenesis. Although DNA, mRNAs, miRNAs, and proteins contained in EVs have been extensively studied, the function of metabolites in EVs remains unclear. In this study, we performed a comprehensive metabolomic analysis of pancreatic cancer cells, PANC-1, cultured under different oxygen concentrations, and small EVs (sEVs) released from them, considering the fact that hypoxia contributes to the malignant behavior of cells in pancreatic cancer, which is a poorly diagnosed cancer. sEVs were collected by ultracentrifugation, and hydrophilic metabolites were analyzed using capillary ion chromatography-mass spectrometry and liquid chromatography-mass spectrometry, and lipids were analyzed by supercritical fluid chromatography-tandem mass spectrometry. A total of 140 hydrophilic metabolites and 494 lipids were detected in sEVs, and their profiles were different from those in cells. In addition, the metabolomic profile of sEVs was observed to change under hypoxic stress, and an increase in metabolites involved in angiogenesis was also detected. We reveal the hallmark of the metabolites contained in sEVs and the effect of tumor hypoxia on their profiles, which may help in understanding EV-mediated cancer malignancy. Full article
(This article belongs to the Section Cell Metabolism)
►▼ Show Figures

Figure 1

15 pages, 3680 KB  
Article
Optical Microscopy-Guided Laser Ablation Electrospray Ionization Ion Mobility Mass Spectrometry: Ambient Single Cell Metabolomics with Increased Confidence in Molecular Identification
by Michael J. Taylor, Sara Mattson, Andrey Liyu, Sylwia A. Stopka, Yehia M. Ibrahim, Akos Vertes and Christopher R. Anderton
Metabolites 2021, 11(4), 200; https://doi.org/10.3390/metabo11040200 - 27 Mar 2021
Cited by 32 | Viewed by 5233
Abstract
Single cell analysis is a field of increasing interest as new tools are continually being developed to understand intercellular differences within large cell populations. Laser-ablation electrospray ionization mass spectrometry (LAESI-MS) is an emerging technique for single cell metabolomics. Over the years, it has [...] Read more.
Single cell analysis is a field of increasing interest as new tools are continually being developed to understand intercellular differences within large cell populations. Laser-ablation electrospray ionization mass spectrometry (LAESI-MS) is an emerging technique for single cell metabolomics. Over the years, it has been validated that this ionization technique is advantageous for probing the molecular content of individual cells in situ. Here, we report the integration of a microscope into the optical train of the LAESI source to allow for visually informed ambient in situ single cell analysis. Additionally, we have coupled this ‘LAESI microscope’ to a drift-tube ion mobility mass spectrometer to enable separation of isobaric species and allow for the determination of ion collision cross sections in conjunction with accurate mass measurements. This combined information helps provide higher confidence for structural assignment of molecules ablated from single cells. Here, we show that this system enables the analysis of the metabolite content of Allium cepa epidermal cells with high confidence structural identification together with their spatial locations within a tissue. Full article
(This article belongs to the Special Issue Imaging Mass Spectrometry in Metabolome)
►▼ Show Figures

Figure 1

17 pages, 1341 KB  
Article
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 38 | Viewed by 7287
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)
►▼ Show Figures

Graphical abstract

28 pages, 1452 KB  
Review
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 54 | Viewed by 6331
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)
►▼ Show Figures

Figure 1

17 pages, 4659 KB  
Article
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 8 | Viewed by 3638
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)
►▼ Show Figures

Graphical abstract

19 pages, 4209 KB  
Article
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 14 | Viewed by 4665
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)
►▼ Show Figures

Graphical abstract

23 pages, 3181 KB  
Article
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 15 | Viewed by 3958
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)
►▼ Show Figures

Graphical abstract

10 pages, 250 KB  
Article
Pre-Diagnostic Circulating Metabolites and Colorectal Cancer Risk in the Cancer Prevention Study-II Nutrition Cohort
by Marjorie L. McCullough, Rebecca A. Hodge, Peter T. Campbell, Victoria L. Stevens and Ying Wang
Metabolites 2021, 11(3), 156; https://doi.org/10.3390/metabo11030156 - 9 Mar 2021
Cited by 19 | Viewed by 3700
Abstract
Untargeted metabolomic studies have identified potential biomarkers of colorectal cancer risk, but evidence is still limited and broadly inconsistent. Among 39,239 Cancer Prevention Study II Nutrition cohort participants who provided a blood sample between 1998–2001, 517 newly diagnosed colorectal cancers were identified through [...] Read more.
Untargeted metabolomic studies have identified potential biomarkers of colorectal cancer risk, but evidence is still limited and broadly inconsistent. Among 39,239 Cancer Prevention Study II Nutrition cohort participants who provided a blood sample between 1998–2001, 517 newly diagnosed colorectal cancers were identified through 30 June 2015. In this nested case–control study, controls were matched 1:1 to cases on age, sex, race and date of blood draw. Mass spectroscopy-based metabolomic analyses of pre-diagnostic plasma identified 886 named metabolites, after quality control exclusions. Conditional logistic regression models estimated multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) for 1 standard deviation (SD) increase in each metabolite with risk of colorectal cancer. Six metabolites were associated with colorectal cancer risk at a false discovery rate < 0.20. These metabolites were of several classes, including cofactors and vitamins, nucleotides, xenobiotics, lipids and amino acids. Five metabolites (guanidinoacetate, 2’-O-methylcytidine, vanillylmandelate, bilirubin (E,E) and N-palmitoylglycine) were positively associated (OR per 1 SD = 1.29 to 1.32), and one (3-methylxanthine) was inversely associated with CRC risk (OR = 0.79, 95% CI, 0.69–0.89). We did not replicate findings from two earlier prospective studies of 250 cases each after adjusting for multiple comparisons. Large pooled prospective analyses are warranted to confirm or refute these findings and to discover and replicate metabolites associated with colorectal cancer risk. Full article
(This article belongs to the Special Issue Metabolomics Meets Epidemiology)
►▼ Show Figures

Graphical abstract

34 pages, 2754 KB  
Review
Metabolomics and Lipidomics: Expanding the Molecular Landscape of Exercise Biology
by Mehdi R. Belhaj, Nathan G. Lawler and Nolan J. Hoffman
Metabolites 2021, 11(3), 151; https://doi.org/10.3390/metabo11030151 - 7 Mar 2021
Cited by 82 | Viewed by 11274
Abstract
Dynamic changes in circulating and tissue metabolites and lipids occur in response to exercise-induced cellular and whole-body energy demands to maintain metabolic homeostasis. The metabolome and lipidome in a given biological system provides a molecular snapshot of these rapid and complex metabolic perturbations. [...] Read more.
Dynamic changes in circulating and tissue metabolites and lipids occur in response to exercise-induced cellular and whole-body energy demands to maintain metabolic homeostasis. The metabolome and lipidome in a given biological system provides a molecular snapshot of these rapid and complex metabolic perturbations. The application of metabolomics and lipidomics to map the metabolic responses to an acute bout of aerobic/endurance or resistance exercise has dramatically expanded over the past decade thanks to major analytical advancements, with most exercise-related studies to date focused on analyzing human biofluids and tissues. Experimental and analytical considerations, as well as complementary studies using animal model systems, are warranted to help overcome challenges associated with large human interindividual variability and decipher the breadth of molecular mechanisms underlying the metabolic health-promoting effects of exercise. In this review, we provide a guide for exercise researchers regarding analytical techniques and experimental workflows commonly used in metabolomics and lipidomics. Furthermore, we discuss advancements in human and mammalian exercise research utilizing metabolomic and lipidomic approaches in the last decade, as well as highlight key technical considerations and remaining knowledge gaps to continue expanding the molecular landscape of exercise biology. Full article
(This article belongs to the Special Issue 10th Anniversary of Metabolites: The Changing Landscape of Metabolomics)
►▼ Show Figures

Graphical abstract

11 pages, 751 KB  
Article
Metabolomics of Cerebrospinal Fluid from Healthy Subjects Reveal Metabolites Associated with Ageing
by Henrik Carlsson, Niclas Rollborn, Stephanie Herman, Eva Freyhult, Anders Svenningsson, Joachim Burman and Kim Kultima
Metabolites 2021, 11(2), 126; https://doi.org/10.3390/metabo11020126 - 23 Feb 2021
Cited by 19 | Viewed by 4170
Abstract
To increase our understanding of age-related diseases affecting the central nervous system (CNS) it is important to understand the molecular processes of biological ageing. Metabolomics of cerebrospinal fluid (CSF) is a promising methodology to increase our understanding of naturally occurring processes of ageing [...] Read more.
To increase our understanding of age-related diseases affecting the central nervous system (CNS) it is important to understand the molecular processes of biological ageing. Metabolomics of cerebrospinal fluid (CSF) is a promising methodology to increase our understanding of naturally occurring processes of ageing of the brain and CNS that could be reflected in CSF. In the present study the CSF metabolomes of healthy subjects aged 30–74 years (n = 23) were studied using liquid chromatography high-resolution mass spectrometry (LC-HRMS), and investigated in relation to age. Ten metabolites were identified with high confidence as significantly associated with ageing, eight with increasing levels with ageing: isoleucine, acetylcarnitine, pipecolate, methionine, glutarylcarnitine, 5-hydroxytryptophan, ketoleucine, and hippurate; and two decreasing with ageing: methylthioadenosine and 3-methyladenine. To our knowledge, this is the first time the CSF metabolomes of healthy subjects are assessed in relation to ageing. The present study contributes to the field of ageing metabolomics by presenting a number of metabolites present in CSF with potential relevance for ageing and the results motivate further studies. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying article 351-400 on page 8 of 9.
Back to TopTop