Metabolites

17 pages, 2574 KiB

Open AccessArticle

Diagnostic Potential of the Plasma Lipidome in Infectious Disease: Application to Acute SARS-CoV-2 Infection

by Nicola Gray, Nathan G. Lawler, Annie Xu Zeng, Monique Ryan, Sze How Bong, Berin A. Boughton, Maider Bizkarguenaga, Chiara Bruzzone, Nieves Embade, Julien Wist, Elaine Holmes, Oscar Millet, Jeremy K. Nicholson and Luke Whiley

Metabolites 2021, 11(7), 467; https://doi.org/10.3390/metabo11070467 - 20 Jul 2021

Cited by 31 | Viewed by 4948

Abstract

Improved methods are required for investigating the systemic metabolic effects of SARS-CoV-2 infection and patient stratification for precision treatment. We aimed to develop an effective method using lipid profiles for discriminating between SARS-CoV-2 infection, healthy controls, and non-SARS-CoV-2 respiratory infections. Targeted liquid chromatography–mass [...] Read more.

Improved methods are required for investigating the systemic metabolic effects of SARS-CoV-2 infection and patient stratification for precision treatment. We aimed to develop an effective method using lipid profiles for discriminating between SARS-CoV-2 infection, healthy controls, and non-SARS-CoV-2 respiratory infections. Targeted liquid chromatography–mass spectrometry lipid profiling was performed on discovery (20 SARS-CoV-2-positive; 37 healthy controls; 22 COVID-19 symptoms but SARS-CoV-2negative) and validation (312 SARS-CoV-2-positive; 100 healthy controls) cohorts. Orthogonal projection to latent structure-discriminant analysis (OPLS-DA) and Kruskal–Wallis tests were applied to establish discriminant lipids, significance, and effect size, followed by logistic regression to evaluate classification performance. OPLS-DA reported separation of SARS-CoV-2 infection from healthy controls in the discovery cohort, with an area under the curve (AUC) of 1.000. A refined panel of discriminant features consisted of six lipids from different subclasses (PE, PC, LPC, HCER, CER, and DCER). Logistic regression in the discovery cohort returned a training ROC AUC of 1.000 (sensitivity = 1.000, specificity = 1.000) and a test ROC AUC of 1.000. The validation cohort produced a training ROC AUC of 0.977 (sensitivity = 0.855, specificity = 0.948) and a test ROC AUC of 0.978 (sensitivity = 0.948, specificity = 0.922). The lipid panel was also able to differentiate SARS-CoV-2-positive individuals from SARS-CoV-2-negative individuals with COVID-19-like symptoms (specificity = 0.818). Lipid profiling and multivariate modelling revealed a signature offering mechanistic insights into SARS-CoV-2, with strong predictive power, and the potential to facilitate effective diagnosis and clinical management. Full article

(This article belongs to the Special Issue Lipidomics: Insights into Lipid Metabolism and OMICS Research)

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14 pages, 1116 KiB

Open AccessArticle

Untargeted Plasma Metabolomic Profiling in Patients with Major Depressive Disorder Using Ultra-High Performance Liquid Chromatography Coupled with Mass Spectrometry

by Claudia Homorogan, Diana Nitusca, Virgil Enatescu, Philip Schubart, Corina Moraru, Carmen Socaciu and Catalin Marian

Metabolites 2021, 11(7), 466; https://doi.org/10.3390/metabo11070466 - 20 Jul 2021

Cited by 11 | Viewed by 3269

Abstract

Major depressive disorder (MDD) is a neuropsychiatric illness with an increasing incidence and a shortfall of efficient diagnostic tools. Interview-based diagnostic tools and clinical examination often lead to misdiagnosis and inefficient systematic treatment selection. Diagnostic and treatment monitoring biomarkers are warranted for MDD. [...] Read more.

Major depressive disorder (MDD) is a neuropsychiatric illness with an increasing incidence and a shortfall of efficient diagnostic tools. Interview-based diagnostic tools and clinical examination often lead to misdiagnosis and inefficient systematic treatment selection. Diagnostic and treatment monitoring biomarkers are warranted for MDD. Thus, the emerging field of metabolomics is a promising tool capable of portraying the metabolic repertoire of biomolecules from biological samples in a minimally invasive fashion. Herein, we report an untargeted metabolomic profiling performed in plasma samples of 11 MDD patients, at baseline (MDD1) and at 12 weeks following antidepressant therapy with escitalopram (MDD2), and in 11 healthy controls (C), using ultra-high performance liquid chromatography coupled with electrospray ionization-quadrupole-time of flight-mass spectrometry (UHPLC-QTOF-(ESI+)-MS). We found two putative metabolites ((phosphatidylserine PS (16:0/16:1) and phosphatidic acid PA (18:1/18:0)) as having statistically significant increased levels in plasma samples of MDD1 patients compared to healthy subjects. ROC analysis revealed an AUC value of 0.876 for PS (16:0/16:1), suggesting a potential diagnostic biomarker role. In addition, PS (18:3/20:4) was significantly decreased in MDD2 group compared to MDD1, with AUC value of 0.785. Full article

(This article belongs to the Section Advances in Metabolomics)

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26 pages, 5714 KiB

Open AccessReview

Deciphering Prunus Responses to PPV Infection: A Way toward the Use of Metabolomics Approach for the Diagnostic of Sharka Disease

by Christian Espinoza, Benoît Bascou, Christophe Calvayrac and Cédric Bertrand

Metabolites 2021, 11(7), 465; https://doi.org/10.3390/metabo11070465 - 19 Jul 2021

Cited by 9 | Viewed by 2721

Abstract

Sharka disease, caused by Plum pox virus (PPV), induces several changes in Prunus. In leaf tissues, the infection may cause oxidative stress and disrupt the photosynthetic process. Moreover, several defense responses can be activated after PPV infection and have been detected at [...] Read more.

Sharka disease, caused by Plum pox virus (PPV), induces several changes in Prunus. In leaf tissues, the infection may cause oxidative stress and disrupt the photosynthetic process. Moreover, several defense responses can be activated after PPV infection and have been detected at the phytohormonal, transcriptomic, proteomic, and even translatome levels. As proposed in this review, some responses may be systemic and earlier to the onset of symptoms. Nevertheless, these changes are highly dependent among species, variety, sensitivity, and tissue type. In the case of fruit tissues, PPV infection can modify the ripening process, induced by an alteration of the primary metabolism, including sugars and organic acids, and secondary metabolism, including phenolic compounds. Interestingly, metabolomics is an emerging tool to better understand Prunus–PPV interactions mainly in primary and secondary metabolisms. Moreover, through untargeted metabolomics analyses, specific and early candidate biomarkers of PPV infection can be detected. Nevertheless, these candidate biomarkers need to be validated before being selected for a diagnostic or prognosis by targeted analyses. The development of a new method for early detection of PPV-infected trees would be crucial for better management of the outbreak, especially since there is no curative treatment. Full article

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

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10 pages, 2780 KiB

Open AccessArticle

Changes in the Harpagide, Harpagoside, and Verbascoside Content of Field Grown Scrophularia lanceolata and Scrophularia marilandica in Response to Season and Shade

by Korey J. Brownstein, Andrew L. Thomas, Hien T. T. Nguyen, David R. Gang and William R. Folk

Metabolites 2021, 11(7), 464; https://doi.org/10.3390/metabo11070464 - 19 Jul 2021

Cited by 3 | Viewed by 2641

Abstract

Scrophularia lanceolata Pursh and Scrophularia marilandica L. are two common species within the Scrophulariaceae family that are endemic to North America. Historically, these species were used by indigenous peoples and colonialists to treat sunburn, sunstroke, frostbite, edema, as well as for blood purification, [...] Read more.

Scrophularia lanceolata Pursh and Scrophularia marilandica L. are two common species within the Scrophulariaceae family that are endemic to North America. Historically, these species were used by indigenous peoples and colonialists to treat sunburn, sunstroke, frostbite, edema, as well as for blood purification, and in women’s health. Several iridoid and phenylethanoid/phenylpropanoid glycosides detected in these species, such as harpagoside and verbascoside, possess anti-inflammatory and anti-nociceptive properties. Due to the presence of anti-inflammatory metabolites and the historical uses of these species, we performed a two-year field study to determine the optimal production of these important compounds. We subjected the plants to shade treatment and analyzed differences in the metabolite composition between the two species and each of their leaves, stems, and roots at various times throughout the growing seasons. We determined that S. lanceolata plants grown in full sun produced 0.63% harpagoside per dried weight in their leaves compared to shade-grown plants (0.43%). Furthermore, S. lanceolata accumulated more harpagoside than S. marilandica (0.24%). We also found that verbascoside accumulated in the leaves of S. lanceolata and S. marilandica as the growing season progressed, while the production of this metabolite remained mostly seasonally unchanged in the roots of both species. Full article

(This article belongs to the Section Plant Metabolism)

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24 pages, 2269 KiB

Open AccessArticle

Sex-Specific Relationship between the Cardiorespiratory Fitness and Plasma Metabolite Patterns in Healthy Humans—Results of the KarMeN Study

by Sina Kistner, Maik Döring, Ralf Krüger, Manuela J. Rist, Christoph H. Weinert, Diana Bunzel, Benedikt Merz, Katrin Radloff, Rainer Neumann, Sascha Härtel and Achim Bub

Metabolites 2021, 11(7), 463; https://doi.org/10.3390/metabo11070463 - 17 Jul 2021

Cited by 7 | Viewed by 4382

Abstract

Cardiorespiratory fitness (CRF) represents a strong predictor of all-cause mortality and is strongly influenced by regular physical activity (PA). However, the biological mechanisms involved in the body’s adaptation to PA remain to be fully elucidated. The aim of this study was to systematically [...] Read more.

Cardiorespiratory fitness (CRF) represents a strong predictor of all-cause mortality and is strongly influenced by regular physical activity (PA). However, the biological mechanisms involved in the body’s adaptation to PA remain to be fully elucidated. The aim of this study was to systematically examine the relationship between CRF and plasma metabolite patterns in 252 healthy adults from the cross-sectional Karlsruhe Metabolomics and Nutrition (KarMeN) study. CRF was determined by measuring the peak oxygen uptake during incremental exercise. Fasting plasma samples were analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry coupled to one- or two-dimensional gas chromatography or liquid chromatography. Based on this multi-platform metabolomics approach, 427 plasma analytes were detected. Bi- and multivariate association analyses, adjusted for age and menopausal status, showed that CRF was linked to specific sets of metabolites primarily indicative of lipid metabolism. However, CRF-related metabolite patterns largely differed between sexes. While several phosphatidylcholines were linked to CRF in females, single lyso-phosphatidylcholines and sphingomyelins were associated with CRF in males. When controlling for further assessed clinical and phenotypical parameters, sex-specific CRF tended to be correlated with a smaller number of metabolites linked to lipid, amino acid, or xenobiotics-related metabolism. Interestingly, sex-specific CRF explanation models could be improved when including selected plasma analytes in addition to clinical and phenotypical variables. In summary, this study revealed sex-related differences in CRF-associated plasma metabolite patterns and proved known associations between CRF and risk factors for cardiometabolic diseases such as fat mass, visceral adipose tissue mass, or blood triglycerides in metabolically healthy individuals. Our findings indicate that covariates like sex and, especially, body composition have to be considered when studying blood metabolic markers related to CRF. Full article

(This article belongs to the Special Issue Effect of Exercise on Energy Metabolism)

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14 pages, 742 KiB

Open AccessArticle

Metabolic Evidence Rather Than Amounts of Red or Processed Meat as a Risk on Korean Colorectal Cancer

by Eunbee Kim, Joon Seok Lee, Eunjae Kim, Myung-Ah Lee, Alfred N. Fonteh, Michael Kwong, Yoon Hee Cho, Un Jae Lee and Mihi Yang

Metabolites 2021, 11(7), 462; https://doi.org/10.3390/metabo11070462 - 16 Jul 2021

Cited by 4 | Viewed by 2922

Abstract

The incidence of colorectal cancer (CRC) has increased in Korea, a newly-industrialized Asian country, with the dramatic increase of meat intake. To assess the risks of red or processed meat consumption on CRC, we performed a case-control study with biological monitoring of [...] Read more.

The incidence of colorectal cancer (CRC) has increased in Korea, a newly-industrialized Asian country, with the dramatic increase of meat intake. To assess the risks of red or processed meat consumption on CRC, we performed a case-control study with biological monitoring of urinary1-OHP, PhIP, and MeIQx for the meat exposure; dG-C8 MeIQx and dG-C8 PhIP for HCA-induced DNA adducts; and homocysteine and C-reactive protein (CRP) in blood as well as malondialdehyde (MDA) and 31fatty acids in urine for inflammation and lipid alteration. We further analyzed global DNA methylation and expression of 15 CRC-related genes. As a result, the consumption of red or processed meat was not higher in the cases than in the controls. However, urinary MeIQx and PhIP were associated with the intake of red meat and urinary 1-OHP. MDA and multiple fatty acids were related to the exposure biomarkers. Most of the 31 fatty acids and multiple saturated fatty acids were higher in the cases than in the controls. Finally, the cases showed upregulation of PTGS2, which is related to pro-inflammatory fatty acids. This study describes indirect mechanisms of CRC via lipid alteration with a series of processes including exposure to red meat, alteration of fatty acids, and relevant gene expression. Full article

(This article belongs to the Section Nutrition and Metabolism)

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31 pages, 8876 KiB

Open AccessReview

Metabolomics-Based Evaluation of Crop Quality Changes as a Consequence of Climate Change

by Helena Romero, Delphine M. Pott, José G. Vallarino and Sonia Osorio

Metabolites 2021, 11(7), 461; https://doi.org/10.3390/metabo11070461 - 16 Jul 2021

Cited by 11 | Viewed by 3887

Abstract

Fruit composition determines the fruit quality and, consequently, consumer acceptance. As fruit quality can be modified by environmental conditions, it will be impacted by future alterations produced by global warming. Therefore, agricultural activities will be influenced by the changes in climatological conditions in [...] Read more.

Fruit composition determines the fruit quality and, consequently, consumer acceptance. As fruit quality can be modified by environmental conditions, it will be impacted by future alterations produced by global warming. Therefore, agricultural activities will be influenced by the changes in climatological conditions in cultivable areas, which could have a high socioeconomic impact if fruit production and quality decline. Currently, different stresses are being applied to several cultivated species to evaluate their impact on fruit metabolism and plant performance. With the use of metabolomic tools, these changes can be precisely measured, allowing us to determine changes in the patterns of individual compounds. As these changes depend on both the stress severity and the specific species involved and even on the specific cultivar, individual analysis must be conducted. To date, the most-studied crops have mainly been crops that are widely cultivated and have a high socioeconomic impact. In the near future, with the development of these metabolomic strategies, their implementation will be extended to other species, which will allow the adaptation of cultivation conditions and the development of varieties with high adaptability to climatological changes. Full article

(This article belongs to the Special Issue Metabolomics to Elucidate the Metabolic Mechanisms of Plant Responses to Variable Environmental Stresses)

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30 pages, 5528 KiB

Open AccessReview

Chronic Kidney Disease Cohort Studies: A Guide to Metabolome Analyses

by Ulla T. Schultheiss, Robin Kosch, Fruzsina Kotsis, Michael Altenbuchinger and Helena U. Zacharias

Metabolites 2021, 11(7), 460; https://doi.org/10.3390/metabo11070460 - 16 Jul 2021

Cited by 5 | Viewed by 3962

Abstract

Kidney diseases still pose one of the biggest challenges for global health, and their heterogeneity and often high comorbidity load seriously hinders the unraveling of their underlying pathomechanisms and the delivery of optimal patient care. Metabolomics, the quantitative study of small organic compounds, [...] Read more.

Kidney diseases still pose one of the biggest challenges for global health, and their heterogeneity and often high comorbidity load seriously hinders the unraveling of their underlying pathomechanisms and the delivery of optimal patient care. Metabolomics, the quantitative study of small organic compounds, called metabolites, in a biological specimen, is gaining more and more importance in nephrology research. Conducting a metabolomics study in human kidney disease cohorts, however, requires thorough knowledge about the key workflow steps: study planning, sample collection, metabolomics data acquisition and preprocessing, statistical/bioinformatics data analysis, and results interpretation within a biomedical context. This review provides a guide for future metabolomics studies in human kidney disease cohorts. We will offer an overview of important a priori considerations for metabolomics cohort studies, available analytical as well as statistical/bioinformatics data analysis techniques, and subsequent interpretation of metabolic findings. We will further point out potential research questions for metabolomics studies in the context of kidney diseases and summarize the main results and data availability of important studies already conducted in this field. Full article

(This article belongs to the Special Issue Metabolomics Approaches for the Understanding, Diagnosis and Monitoring of Chronic Kidney Diseases)

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13 pages, 930 KiB

Open AccessArticle

Lipoprotein Proteomics and Aortic Valve Transcriptomics Identify Biological Pathways Linking Lipoprotein(a) Levels to Aortic Stenosis

by Raphaëlle Bourgeois, Jérôme Bourgault, Audrey-Anne Despres, Nicolas Perrot, Jakie Guertin, Arnaud Girard, Patricia L. Mitchell, Clarisse Gotti, Sylvie Bourassa, Corey A. Scipione, Nathalie Gaudreault, Michael B. Boffa, Marlys L. Koschinsky, Philippe Pibarot, Arnaud Droit, Sébastien Thériault, Patrick Mathieu, Yohan Bossé and Benoit J. Arsenault

Metabolites 2021, 11(7), 459; https://doi.org/10.3390/metabo11070459 - 16 Jul 2021

Cited by 16 | Viewed by 4353

Abstract

Lipoprotein(a) (Lp(a)) is one of the most important risk factors for the development of calcific aortic valve stenosis (CAVS). However, the mechanisms through which Lp(a) causes CAVS are currently unknown. Our objectives were to characterize the Lp(a) proteome and to identify proteins that [...] Read more.

Lipoprotein(a) (Lp(a)) is one of the most important risk factors for the development of calcific aortic valve stenosis (CAVS). However, the mechanisms through which Lp(a) causes CAVS are currently unknown. Our objectives were to characterize the Lp(a) proteome and to identify proteins that may be differentially associated with Lp(a) in patients with versus without CAVS. Our second objective was to identify genes that may be differentially regulated by exposure to high versus low Lp(a) levels in explanted aortic valves from patients with CAVS. We isolated Lp(a) from the blood of 21 patients with CAVS and 22 volunteers and performed untargeted label-free analysis of the Lp(a) proteome. We also investigated the transcriptomic signature of calcified aortic valves from patients who underwent aortic valve replacement with high versus low Lp(a) levels (n = 118). Proteins involved in the protein activation cascade, platelet degranulation, leukocyte migration, and response to wounding may be associated with Lp(a) depending on CAVS status. The transcriptomic analysis identified genes involved in cardiac aging, chondrocyte development, and inflammation as potentially influenced by Lp(a). Our multi-omic analyses identified biological pathways through which Lp(a) may cause CAVS, as well as key molecular events that could be triggered by Lp(a) in CAVS development. Full article

(This article belongs to the Special Issue Metabolomics of Complex Traits II)

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15 pages, 862 KiB

Open AccessArticle

Differential Responses of Methionine Sulfoxide Reductases A and B to Anoxia and Oxidative Stress in the Freshwater Turtle Trachemys scripta

by Melissa Reiterer, Lynsey Bruce and Sarah Milton

Metabolites 2021, 11(7), 458; https://doi.org/10.3390/metabo11070458 - 16 Jul 2021

Cited by 2 | Viewed by 2714

Abstract

Oxidative stress has been acknowledged as a major factor in aging, senescence and neurodegenerative conditions. Mammalian models are susceptible to these stresses following the restoration of oxygen after anoxia; however, some organisms including the freshwater turtle Trachemys scripta can withstand repeated anoxia and [...] Read more.

Oxidative stress has been acknowledged as a major factor in aging, senescence and neurodegenerative conditions. Mammalian models are susceptible to these stresses following the restoration of oxygen after anoxia; however, some organisms including the freshwater turtle Trachemys scripta can withstand repeated anoxia and reoxygenation without apparent pathology. T. scripta thus provides us with an alternate vertebrate model to investigate physiological mechanisms of neuroprotection. The objective of this study was to investigate the antioxidant methionine sulfoxide reductase system (Msr) in turtle neuronal tissue. We examined brain transcript and protein levels of MsrA and MsrB and examined the potential for the transcription factor FOXO3a to regulate the oxygen-responsive changes in Msr in vitro. We found that Msr mRNA and protein levels are differentially upregulated during anoxia and reoxygenation, and when cells were exposed to chemical oxidative stress. However, while MsrA and MsrB3 levels increased when cell cultures were exposed to chemical oxidative stress, this induction was not enhanced by treatment with epigallocatechin gallate (EGCG), which has previously been shown to enhance FOXO3a levels in the turtle. These results suggest that FOXO3a and Msr protect the cells from oxidative stress through different molecular pathways, and that both the Msr pathway and EGCG may be therapeutic targets to treat diseases related to oxidative damage. Full article

(This article belongs to the Special Issue Metabolic Strategies in Hypoxia)

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31 pages, 2067 KiB

Open AccessReview

Plant Responses to Abiotic Stresses and Rhizobacterial Biostimulants: Metabolomics and Epigenetics Perspectives

by Motseoa M. Lephatsi, Vanessa Meyer, Lizelle A. Piater, Ian A. Dubery and Fidele Tugizimana

Metabolites 2021, 11(7), 457; https://doi.org/10.3390/metabo11070457 - 16 Jul 2021

Cited by 38 | Viewed by 6119

Abstract

In response to abiotic stresses, plants mount comprehensive stress-specific responses which mediate signal transduction cascades, transcription of relevant responsive genes and the accumulation of numerous different stress-specific transcripts and metabolites, as well as coordinated stress-specific biochemical and physiological readjustments. These natural mechanisms employed [...] Read more.

In response to abiotic stresses, plants mount comprehensive stress-specific responses which mediate signal transduction cascades, transcription of relevant responsive genes and the accumulation of numerous different stress-specific transcripts and metabolites, as well as coordinated stress-specific biochemical and physiological readjustments. These natural mechanisms employed by plants are however not always sufficient to ensure plant survival under abiotic stress conditions. Biostimulants such as plant growth-promoting rhizobacteria (PGPR) formulation are emerging as novel strategies for improving crop quality, yield and resilience against adverse environmental conditions. However, to successfully formulate these microbial-based biostimulants and design efficient application programs, the understanding of molecular and physiological mechanisms that govern biostimulant-plant interactions is imperatively required. Systems biology approaches, such as metabolomics, can unravel insights on the complex network of plant-PGPR interactions allowing for the identification of molecular targets responsible for improved growth and crop quality. Thus, this review highlights the current models on plant defence responses to abiotic stresses, from perception to the activation of cellular and molecular events. It further highlights the current knowledge on the application of microbial biostimulants and the use of epigenetics and metabolomics approaches to elucidate mechanisms of action of microbial biostimulants. Full article

(This article belongs to the Special Issue Metabolomics to Elucidate the Metabolic Mechanisms of Plant Responses to Variable Environmental Stresses)

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20 pages, 6329 KiB

Open AccessArticle

A Metabolic Model of Intestinal Secretions: The Link between Human Microbiota and Colorectal Cancer Progression

by Pejman Salahshouri, Modjtaba Emadi-Baygi, Mahdi Jalili, Faiz M. Khan, Olaf Wolkenhauer and Ali Salehzadeh-Yazdi

Metabolites 2021, 11(7), 456; https://doi.org/10.3390/metabo11070456 - 15 Jul 2021

Cited by 9 | Viewed by 5327

Abstract

The human gut microbiota plays a dual key role in maintaining human health or inducing disorders, for example, obesity, type 2 diabetes, and cancers such as colorectal cancer (CRC). High-throughput data analysis, such as metagenomics and metabolomics, have shown the diverse effects of [...] Read more.

The human gut microbiota plays a dual key role in maintaining human health or inducing disorders, for example, obesity, type 2 diabetes, and cancers such as colorectal cancer (CRC). High-throughput data analysis, such as metagenomics and metabolomics, have shown the diverse effects of alterations in dynamic bacterial populations on the initiation and progression of colorectal cancer. However, it is well established that microbiome and human cells constantly influence each other, so it is not appropriate to study them independently. Genome-scale metabolic modeling is a well-established mathematical framework that describes the dynamic behavior of these two axes at the system level. In this study, we created community microbiome models of three conditions during colorectal cancer progression, including carcinoma, adenoma and health status, and showed how changes in the microbial population influence intestinal secretions. Conclusively, our findings showed that alterations in the gut microbiome might provoke mutations and transform adenomas into carcinomas. These alterations include the secretion of mutagenic metabolites such as H₂S, NO compounds, spermidine and TMA (trimethylamine), as well as the reduction of butyrate. Furthermore, we found that the colorectal cancer microbiome can promote inflammation, cancer progression (e.g., angiogenesis) and cancer prevention (e.g., apoptosis) by increasing and decreasing certain metabolites such as histamine, glutamine and pyruvate. Thus, modulating the gut microbiome could be a promising strategy for the prevention and treatment of CRC. Full article

(This article belongs to the Special Issue Host-Microbe-Metabolite Interaction in Intestinal Health)

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22 pages, 2654 KiB

Open AccessArticle

Metabolomics and Dual RNA-Sequencing on Root Nodules Revealed New Cellular Functions Controlled by Paraburkholderia phymatum NifA

by Paula Bellés-Sancho, Martina Lardi, Yilei Liu, Leo Eberl, Nicola Zamboni, Aurélien Bailly and Gabriella Pessi

Metabolites 2021, 11(7), 455; https://doi.org/10.3390/metabo11070455 - 15 Jul 2021

Cited by 5 | Viewed by 3374

Abstract

Paraburkholderia phymatum STM815 is a nitrogen-fixing endosymbiont that nodulate the agriculturally important Phaseolus vulgaris and several other host plants. We previously showed that the nodules induced by a STM815 mutant of the gene encoding the master regulator of nitrogen fixation NifA showed no [...] Read more.

Paraburkholderia phymatum STM815 is a nitrogen-fixing endosymbiont that nodulate the agriculturally important Phaseolus vulgaris and several other host plants. We previously showed that the nodules induced by a STM815 mutant of the gene encoding the master regulator of nitrogen fixation NifA showed no nitrogenase activity (Fix⁻) and increased in number compared to P. vulgaris plants infected with the wild-type strain. To further investigate the role of NifA during symbiosis, nodules from P. phymatum wild-type and nifA mutants were collected and analyzed by metabolomics and dual RNA-Sequencing, allowing us to investigate both host and symbiont transcriptome. Using this approach, several metabolites’ changes could be assigned to bacterial or plant responses. While the amount of the C₄-dicarboxylic acid succinate and of several amino acids was lower in Fix⁻ nodules, the level of indole-acetamide (IAM) and brassinosteroids increased. Transcriptome analysis identified P. phymatum genes involved in transport of C₄-dicarboxylic acids, carbon metabolism, auxin metabolism and stress response to be differentially expressed in absence of NifA. Furthermore, P. vulgaris genes involved in autoregulation of nodulation (AON) are repressed in nodules in absence of NifA potentially explaining the hypernodulation phenotype of the nifA mutant. These results and additional validation experiments suggest that P. phymatum STM815 NifA is not only important to control expression of nitrogenase and related enzymes but is also involved in regulating its own auxin production and stress response. Finally, our data indicate that P. vulgaris does sanction the nifA nodules by depleting the local carbon allocation rather than by mounting a strong systemic immune response to the Fix⁻ rhizobia. Full article

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

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13 pages, 1556 KiB

Open AccessArticle

Progression of Postprandial Blood Plasma Phospholipids Following Acute Intake of Different Dairy Matrices: A Randomized Crossover Trial

by Rebekka Thøgersen, Ida Emilie I. Lindahl, Bekzod Khakimov, Louise Kjølbæk, Klaus Juhl Jensen, Arne Astrup, Marianne Hammershøj, Anne Raben and Hanne Christine Bertram

Metabolites 2021, 11(7), 454; https://doi.org/10.3390/metabo11070454 - 14 Jul 2021

Cited by 2 | Viewed by 2892

Abstract

Studies have indicated that the dairy matrix can affect postprandial responses of dairy products, but little is known about the effect on postprandial plasma phospholipid levels. This study investigated postprandial plasma phospholipid levels following consumption of four different dairy products that are similar [...] Read more.

Studies have indicated that the dairy matrix can affect postprandial responses of dairy products, but little is known about the effect on postprandial plasma phospholipid levels. This study investigated postprandial plasma phospholipid levels following consumption of four different dairy products that are similar in micro and macro nutrients, but different in texture and structure: cheddar cheese (Cheese), homogenized cheddar cheese (Hom. Cheese), micellar casein isolate with cream (MCI Drink) or a gel made from the MCI Drink (MCI Gel). The study was an acute randomized, crossover trial in human volunteers with four test days. Blood samples were collected during an 8 h postprandial period and the content of 53 plasma phospholipids was analysed using liquid chromatography-mass spectrometry (LC-MS). No meal–time interactions were revealed; however, for nine of the 53 phospholipids, a meal effect was found. Thus, the results indicated a lower plasma level of specific lyso-phosphatidylethanolamines (LPEs) and lyso-phosphatidylcholines (LPCs) following consumption of the MCI Gel compared to the MCI Drink and Hom. Cheese, which might be attributed to an effect of viscosity. However, further studies are needed in order to reveal more details on the effect of the dairy matrix on postprandial phospholipids. Full article

(This article belongs to the Section Food Metabolomics)

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14 pages, 271 KiB

Open AccessArticle

Plasma Bile Acid Profile in Patients with and without Type 2 Diabetes

by Alessandro Mantovani, Andrea Dalbeni, Denise Peserico, Filippo Cattazzo, Michele Bevilacqua, Gian Luca Salvagno, Giuseppe Lippi, Giovanni Targher, Elisa Danese and Cristiano Fava

Metabolites 2021, 11(7), 453; https://doi.org/10.3390/metabo11070453 - 14 Jul 2021

Cited by 33 | Viewed by 3388

Abstract

A paucity of information currently exists on plasma bile acid (BA) profiles in patients with and without type 2 diabetes mellitus (T2DM). We assayed 14 plasma BA species in 224 patients with T2DM and in 102 nondiabetic individuals with metabolic syndrome. Plasma BA [...] Read more.

A paucity of information currently exists on plasma bile acid (BA) profiles in patients with and without type 2 diabetes mellitus (T2DM). We assayed 14 plasma BA species in 224 patients with T2DM and in 102 nondiabetic individuals with metabolic syndrome. Plasma BA levels were measured with ultra-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) technique. Multivariable linear regression analyses were undertaken to assess associations between measured plasma BA species and T2DM status after adjustment for confounding factors. The presence of T2DM was significantly associated with higher plasma concentrations of both primary BAs (adjusted-standardized β coefficient: 0.279, p = 0.005) and secondary BAs (standardized β coefficient: 0.508, p < 0.001) after adjustment for age, sex, adiposity measures, serum alanine aminotransferase and use of statins or metformin. More specifically, the presence of T2DM was significantly associated with higher levels of plasma taurochenodeoxycholic acid, taurodeoxycholic acid, glycochenodeoxycholic acid, hyodeoxycholic acid, glycodeoxycholic acid, glycolithocholic acid, deoxycholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycochenodeoxycholic acid and glycodeoxycholic acid (adjusted-standardized β coefficients ranging from 0.315 to 0.600; p < 0.01 or less), as well as with lower plasma levels of cholic acid (adjusted-standardized β coefficient: −0.250, p = 0.013) and taurocholic acid (adjusted-standardized β coefficient: −0.309, p = 0.001). This study shows that there are marked differences in plasma BA profiles between patients with and without T2DM. Further research will be needed to better understand how these differences in plasma BA profiles may interplay with the pathophysiology of T2DM. Full article

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

15 pages, 584 KiB

Open AccessFeature PaperArticle

An R-Package for the Deconvolution and Integration of 1D NMR Data: MetaboDecon1D

by Martina Häckl, Philipp Tauber, Frank Schweda, Helena U. Zacharias, Michael Altenbuchinger, Peter J. Oefner and Wolfram Gronwald

Metabolites 2021, 11(7), 452; https://doi.org/10.3390/metabo11070452 - 13 Jul 2021

Cited by 13 | Viewed by 4381

Abstract

NMR spectroscopy is a widely used method for the detection and quantification of metabolites in complex biological fluids. However, the large number of metabolites present in a biological sample such as urine or plasma leads to considerable signal overlap in one-dimensional NMR spectra, [...] Read more.

NMR spectroscopy is a widely used method for the detection and quantification of metabolites in complex biological fluids. However, the large number of metabolites present in a biological sample such as urine or plasma leads to considerable signal overlap in one-dimensional NMR spectra, which in turn hampers both signal identification and quantification. As a consequence, we have developed an easy to use R-package that allows the fully automated deconvolution of overlapping signals in the underlying Lorentzian line-shapes. We show that precise integral values are computed, which are required to obtain both relative and absolute quantitative information. The algorithm is independent of any knowledge of the corresponding metabolites, which also allows the quantitative description of features of yet unknown identity. Full article

(This article belongs to the Special Issue Metabolomics Approaches for the Understanding, Diagnosis and Monitoring of Chronic Kidney Diseases)

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2 pages, 151 KiB

Open AccessEditorial

Special Issue: Development and Application of Statistical Methods for Analyzing Metabolomics Data

by Jos Hageman and Jasper Engel

Metabolites 2021, 11(7), 451; https://doi.org/10.3390/metabo11070451 - 13 Jul 2021

Viewed by 2218

Abstract

In the last decade, the field of metabolomics has developed tremendously: it is now possible to routinely measure a wide range of metabolites for many specimens at reduced costs, opening the door to many exciting experiments [...] Full article

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

11 pages, 2838 KiB

Open AccessArticle

Diabetes-Independent Retinal Phenotypes in an Aldose Reductase Transgenic Mouse Model

by Jonathan Mark Petrash, Biehuoy Shieh, David A. Ammar, Michelle G. Pedler and David J. Orlicky

Metabolites 2021, 11(7), 450; https://doi.org/10.3390/metabo11070450 - 10 Jul 2021

Cited by 6 | Viewed by 2722

Abstract

Aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, has been implicated in the onset and development of the ocular complications of diabetes, including cataracts and retinopathy. Despite decades of research conducted to address possible mechanisms, questions still persist in [...] Read more.

Aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, has been implicated in the onset and development of the ocular complications of diabetes, including cataracts and retinopathy. Despite decades of research conducted to address possible mechanisms, questions still persist in understanding if or how AR contributes to imbalances leading to diabetic eye disease. To address these questions, we created a strain of transgenic mice engineered for the overexpression of human AR (AR-Tg). In the course of monitoring these animals for age-related retinal phenotypes, we observed signs of Müller cell gliosis characterized by strong immunostaining for glial fibrillary acidic protein. In addition, we observed increased staining for Iba1, consistent with an increase in the number of retinal microglia, a marker of retinal inflammation. Compared to age-matched nontransgenic controls, AR-Tg mice showed an age-dependent loss of Brn3a-positive retinal ganglion cells and an associated decrease in PERG amplitude. Both RGC-related phenotypes were rescued in animals treated with Sorbinil in drinking water. These results support the hypothesis that increased levels of AR may be a risk factor for structural and functional changes known to accompany retinopathy in humans. Full article

(This article belongs to the Special Issue Metabolic Regulation of Aldo-Keto Reductases)

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27 pages, 4344 KiB

Open AccessArticle

Early Postnatal Genistein Administration Affects Mice Metabolism and Reproduction in a Sexually Dimorphic Way

by Marilena Marraudino, Giovanna Ponti, Chantal Moussu, Alice Farinetti, Elisabetta Macchi, Paolo Accornero, Stefano Gotti, Paloma Collado, Matthieu Keller and Giancarlo Panzica

Metabolites 2021, 11(7), 449; https://doi.org/10.3390/metabo11070449 - 10 Jul 2021

Cited by 7 | Viewed by 3837

Abstract

The phytoestrogen genistein (GEN) may interfere with permanent morphological changes in the brain circuits sensitive to estrogen. Due to the frequent use of soy milk in the neonatal diet, we aimed to study the effects of early GEN exposure on some physiological and [...] Read more.

The phytoestrogen genistein (GEN) may interfere with permanent morphological changes in the brain circuits sensitive to estrogen. Due to the frequent use of soy milk in the neonatal diet, we aimed to study the effects of early GEN exposure on some physiological and reproductive parameters. Mice of both sexes from PND1 to PND8 were treated with GEN (50 mg/kg body weight, comparable to the exposure level in babies fed with soy-based formulas). When adult, we observed, in GEN-treated females, an advanced pubertal onset and an altered estrous cycle, and, in males, a decrease of testicle weight and fecal testosterone concentration. Furthermore, we observed an increase in body weight and altered plasma concentrations of metabolic hormones (leptin, ghrelin, triiodothyronine) limited to adult females. Exposure to GEN significantly altered kisspeptin and POMC immunoreactivity only in females and orexin immunoreactivity in both sexes. In conclusion, early postnatal exposure of mice to GEN determines long-term sex-specific organizational effects. It impairs the reproductive system and has an obesogenic effect only in females, which is probably due to the alterations of neuroendocrine circuits controlling metabolism; thus GEN, should be classified as a metabolism disrupting chemical. Full article

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

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12 pages, 1973 KiB

Open AccessArticle

Azoxymethane Alters the Plasma Metabolome to a Greater Extent in Mice Fed a High-Fat Diet Compared to an AIN-93 Diet

by Huawei Zeng, Shahid Umar, Zhenhua Liu and Michael R. Bukowski

Metabolites 2021, 11(7), 448; https://doi.org/10.3390/metabo11070448 - 9 Jul 2021

Cited by 1 | Viewed by 3198

Abstract

Consumption of a high-fat diet (HFD) links obesity to colon cancer in humans. Our data show that a HFD (45% energy fat versus 16% energy fat in an AIN-93 diet (AIN)) promotes azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation in a mouse [...] Read more.

Consumption of a high-fat diet (HFD) links obesity to colon cancer in humans. Our data show that a HFD (45% energy fat versus 16% energy fat in an AIN-93 diet (AIN)) promotes azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation in a mouse cancer model. However, the underlying metabolic basis remains to be determined. In the present study, we hypothesize that AOM treatment results in different plasma metabolomic responses in diet-induced obese mice. An untargeted metabolomic analysis was performed on the plasma samples by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We found that 53 of 144 identified metabolites were different between the 4 groups of mice (AIN, AIN + AOM, HFD, HFD + AOM), and sparse partial least-squares discriminant analysis showed a separation between the HFD and HFD + AOM groups but not the AIN and AIN + AOM groups. Moreover, the concentrations of dihydrocholesterol and cholesterol were inversely associated with AOM-induced colonic ACF formation. Functional pathway analyses indicated that diets and AOM-induced colonic ACF modulated five metabolic pathways. Collectively, in addition to differential plasma metabolomic responses, AOM treatment decreases dihydrocholesterol and cholesterol levels and alters the composition of plasma metabolome to a greater extent in mice fed a HFD compared to the AIN. Full article

(This article belongs to the Special Issue Colon Cancer Metabolism)

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16 pages, 1669 KiB

Open AccessReview

Hypoxia Performance Curve: Assess a Whole-Organism Metabolic Shift from a Maximum Aerobic Capacity towards a Glycolytic Capacity in Fish

by Yangfan Zhang, Bog E. So and Anthony P. Farrell

Metabolites 2021, 11(7), 447; https://doi.org/10.3390/metabo11070447 - 8 Jul 2021

Cited by 12 | Viewed by 3764

Abstract

The utility of measuring whole-animal performance to frame the metabolic response to environmental hypoxia is well established. Progressively reducing ambient oxygen (O₂) will initially limit maximum metabolic rate as a result of a hypoxemic state and ultimately lead to a time-limited, [...] Read more.

The utility of measuring whole-animal performance to frame the metabolic response to environmental hypoxia is well established. Progressively reducing ambient oxygen (O₂) will initially limit maximum metabolic rate as a result of a hypoxemic state and ultimately lead to a time-limited, tolerance state supported by substrate-level phosphorylation when the O₂ supply can no longer meet basic needs (standard metabolic rate, SMR). The metabolic consequences of declining ambient O₂ were conceptually framed for fishes initially by Fry’s hypoxic performance curve, which characterizes the hypoxemic state and its consequences to absolute aerobic scope (AAS), and Hochachka’s concept of scope for hypoxic survival, which characterizes time-limited life when SMR cannot be supported by O₂ supply. Yet, despite these two conceptual frameworks, the toolbox to assess whole-animal metabolic performance remains rather limited. Here, we briefly review the ongoing debate concerning the need to standardize the most commonly used assessments of respiratory performance in hypoxic fishes, namely critical O₂ (the ambient O₂ level below which maintenance metabolism cannot be sustained) and the incipient lethal O₂ (the ambient O₂ level at which a fish loses the ability to maintain upright equilibrium), and then we advance the idea that the most useful addition to the toolbox will be the limiting-O₂ concentration (LOC) performance curve. Using Fry & Hart’s (1948) hypoxia performance curve concept, an LOC curve was subsequently developed as an eco-physiological framework by Neil et al. and derived for a group of fish during a progressive hypoxia trial by Claireaux and Lagardère (1999). In the present review, we show how only minor modifications to available respirometry tools and techniques are needed to generate an LOC curve for individual fish. This individual approach to the LOC curve determination then increases its statistical robustness and importantly opens up the possibility of examining individual variability. Moreover, if peak aerobic performance at a given ambient O₂ level of each individual is expressed as a percentage of its AAS, the water dissolved O₂ that supports 50% of the individual’s AAS (DO_AAS-50) can be interpolated much like the P₅₀ for an O₂ hemoglobin dissociation curve (when hemoglobin is 50% saturated with O₂). Thus, critical O₂, incipient lethal O₂, DO_AAS-50 and P₅₀ and can be directly compared within and across species. While an LOC curve for individual fish represents a start to an ongoing need to seamlessly integrate aerobic to anaerobic capacity assessments in a single, multiplexed respirometry trial, we close with a comparative exploration of some of the known whole-organism anaerobic and aerobic capacity traits to examine for correlations among them and guide the next steps. Full article

(This article belongs to the Special Issue Metabolic Strategies in Hypoxia)

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11 pages, 1936 KiB

Open AccessArticle

Experience with the Urinary Tetrasaccharide Metabolite for Pompe Disease in the Diagnostic Laboratory

by Jennifer T. Saville and Maria Fuller

Metabolites 2021, 11(7), 446; https://doi.org/10.3390/metabo11070446 - 8 Jul 2021

Cited by 7 | Viewed by 2814

Abstract

Following clinical indications, the laboratory diagnosis of the inherited metabolic myopathy, Pompe disease (PD), typically begins with demonstrating a reduction in acid alpha-glucosidase (GAA), the enzyme required for lysosomal glycogen degradation. Although simple in concept, a major challenge is defining reference intervals, as [...] Read more.

Following clinical indications, the laboratory diagnosis of the inherited metabolic myopathy, Pompe disease (PD), typically begins with demonstrating a reduction in acid alpha-glucosidase (GAA), the enzyme required for lysosomal glycogen degradation. Although simple in concept, a major challenge is defining reference intervals, as even carriers can have reduced GAA, and pseudodeficiencies complicate interpretation. Here, we developed a mass spectrometric assay for quantification of a urinary glycogen metabolite (tetrasaccharide) and reported on its utility as a confirmatory test for PD in a diagnostic laboratory. Using two age-related reference intervals, eight returned tetrasaccharide concentrations above the calculated reference interval but did not have PD, highlighting non-specificity. However, retrospective analysis revealed elevated tetrasaccharide in seven infantile-onset (IOPD) cases and sixteen late-onset (LOPD) cases, and normal concentrations in one heterozygote. Prospective tetrasaccharide analysis in nine individuals with reduced GAA confirmed IOPD in one, LOPD in six and identified two heterozygotes. Using this metabolite as a biomarker of therapeutic response was not overly informative; although most patients showed an initial drop following therapy initiation, tetrasaccharide concentrations fluctuated considerably and remained above reference intervals in all patients. While useful as a confirmation of PD, its utility as a biomarker for monitoring treatment warrants further investigation. Full article

(This article belongs to the Special Issue Inherited Metabolic Disease)

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41 pages, 1774 KiB

Open AccessReview

Metabolomics-Guided Elucidation of Plant Abiotic Stress Responses in the 4IR Era: An Overview

by Morena M. Tinte, Kekeletso H. Chele, Justin J. J. van der Hooft and Fidele Tugizimana

Metabolites 2021, 11(7), 445; https://doi.org/10.3390/metabo11070445 - 8 Jul 2021

Cited by 12 | Viewed by 5776

Abstract

Plants are constantly challenged by changing environmental conditions that include abiotic stresses. These are limiting their development and productivity and are subsequently threatening our food security, especially when considering the pressure of the increasing global population. Thus, there is an urgent need for [...] Read more.

Plants are constantly challenged by changing environmental conditions that include abiotic stresses. These are limiting their development and productivity and are subsequently threatening our food security, especially when considering the pressure of the increasing global population. Thus, there is an urgent need for the next generation of crops with high productivity and resilience to climate change. The dawn of a new era characterized by the emergence of fourth industrial revolution (4IR) technologies has redefined the ideological boundaries of research and applications in plant sciences. Recent technological advances and machine learning (ML)-based computational tools and omics data analysis approaches are allowing scientists to derive comprehensive metabolic descriptions and models for the target plant species under specific conditions. Such accurate metabolic descriptions are imperatively essential for devising a roadmap for the next generation of crops that are resilient to environmental deterioration. By synthesizing the recent literature and collating data on metabolomics studies on plant responses to abiotic stresses, in the context of the 4IR era, we point out the opportunities and challenges offered by omics science, analytical intelligence, computational tools and big data analytics. Specifically, we highlight technological advancements in (plant) metabolomics workflows and the use of machine learning and computational tools to decipher the dynamics in the chemical space that define plant responses to abiotic stress conditions. Full article

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

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18 pages, 4175 KiB

Open AccessArticle

Dereplication, Annotation, and Characterization of 74 Potential Antimicrobial Metabolites from Penicillium Sclerotiorum Using t-SNE Molecular Networks

by Téo Hebra, Nicolas Elie, Salomé Poyer, Elsa Van Elslande, David Touboul and Véronique Eparvier

Metabolites 2021, 11(7), 444; https://doi.org/10.3390/metabo11070444 - 8 Jul 2021

Cited by 19 | Viewed by 4128

Abstract

Microorganisms associated with termites are an original resource for identifying new chemical scaffolds or active metabolites. A molecular network was generated from a collection of strain extracts analyzed by liquid chromatography coupled to tandem high-resolution mass spectrometry, a molecular network was generated, and [...] Read more.

Microorganisms associated with termites are an original resource for identifying new chemical scaffolds or active metabolites. A molecular network was generated from a collection of strain extracts analyzed by liquid chromatography coupled to tandem high-resolution mass spectrometry, a molecular network was generated, and activities against the human pathogens methicillin-resistant Staphylococcus aureus, Candida albicans and Trichophyton rubrum were mapped, leading to the selection of a single active extract of Penicillium sclerotiorum SNB-CN111. This fungal species is known to produce azaphilones, a colorful family of polyketides with a wide range of biological activities and economic interests in the food industry. By exploring the molecular network data, it was shown that the chemical diversity related to the P. sclerotiorum metabolome largely exceeded the data already reported in the literature. According to the described fragmentation pathways of protonated azaphilones, the annotation of 74 azaphilones was proposed, including 49 never isolated or synthesized thus far. Our hypothesis was validated by the isolation and characterization of eight azaphilones, among which three new azaphilones were chlorogeumasnol (63), peniazaphilone E (74) and 7-deacetylisochromophilone VI (80). Full article

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

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12 pages, 1996 KiB

Open AccessArticle

Identification of Indicators for Preterm Birth Using Retinoid Metabolites

by Young-Ah You, Soo-Yeon Hwang, Soo-Min Kim, Seojeong Park, Ga-In Lee, Sunwha Park, AbuZar Ansari, Jeongae Lee, Youngjoo Kwon and Young-Ju Kim

Metabolites 2021, 11(7), 443; https://doi.org/10.3390/metabo11070443 - 7 Jul 2021

Cited by 10 | Viewed by 3039

Abstract

Metabolites reflect the biochemical dynamics for the maintenance of pregnancy and parturition. UPLC-Q/TOF-MS and LC-MS/MS metabolomics were performed to identify and validate the plasma metabolomic signatures of preterm birth (PTB). We recruited pregnant women between 16 and 40 weeks 5 days gestational age [...] Read more.

Metabolites reflect the biochemical dynamics for the maintenance of pregnancy and parturition. UPLC-Q/TOF-MS and LC-MS/MS metabolomics were performed to identify and validate the plasma metabolomic signatures of preterm birth (PTB). We recruited pregnant women between 16 and 40 weeks 5 days gestational age at Ewha Womans Mokdong Hospital for a nested case-control study. In untargeted UPLC-Q/TOF-MS, score plots of partial least-squares discriminant analysis clearly separated the PTB group from the term birth (TB, n = 10; PTB, n = 11). Fifteen metabolites were significantly different between the two groups, as indicated by a variable importance in projection >1 and p < 0.05. Metabolic pathways involving retinol, linoleic acid, D-arginine, and D-ornithine were associated with PTB. Verification by LC-MS/MS focused on retinol metabolism (TB, n = 39; PTB, n = 20). Retinol levels were significantly reduced in PTB compared to TB, while retinal palmitate, all-trans-retinal, and 13-cis-retinoic acid (¹³cis-RA) significantly increased (p < 0.05). Retinol-binding protein levels were also elevated in PTB. Additionally, all-trans-retinal (AUC 0.808, 95% CI: 0.683–0.933) and ¹³cis-RA (AUC 0.826, 95% CI: 0.723–0.930) showed improved predictions for PTB-related retinol metabolites. This study suggests that retinoid metabolism improves the accuracy of PTB predictions and plays an important role in maintaining pregnancy and inducing early parturition. Full article

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

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17 pages, 2315 KiB

Open AccessArticle

Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

by Cristina Gómez, Fadi Jebbawi, Michael Weingartner, Junhua Wang, Simon Stücheli, Bruno Stieger, Bruno Gottstein, Guido Beldi, Britta Lundström-Stadelmann and Alex Odermatt

Metabolites 2021, 11(7), 442; https://doi.org/10.3390/metabo11070442 - 6 Jul 2021

Cited by 1 | Viewed by 3379

Abstract

Alveolar echinococcosis (AE) caused by Echinococcus multilocularis is a chronic, progressive liver disease widely distributed in the Northern Hemisphere. The main treatment options include surgical interventions and chemotherapy with benzimidazole albendazole (ABZ). To improve the current diagnosis and therapy of AE, further investigations [...] Read more.

Alveolar echinococcosis (AE) caused by Echinococcus multilocularis is a chronic, progressive liver disease widely distributed in the Northern Hemisphere. The main treatment options include surgical interventions and chemotherapy with benzimidazole albendazole (ABZ). To improve the current diagnosis and therapy of AE, further investigations into parasite–host interactions are needed. This study used liquid chromatography–tandem mass spectrometry (LC-MS/MS) to assess serum and liver tissue bile acid profiles in the i.p. chronic E. multilocularis-infected mouse model and evaluated the effects of the anthelmintic drug ABZ. Additionally, hepatic mRNA and protein expression of enzymes and transporters regulating bile acid concentrations were analyzed. AE significantly decreased unconjugated bile acids in serum and liver tissue. Taurine-conjugated bile salts were unchanged or increased in the serum and unchanged or decreased in the liver. Ratios of unconjugated to taurine-conjugated metabolites are proposed as useful serum markers of AE. The expression of the bile acid synthesis enzymes cytochrome P450 (CYP) 7A1 and aldo-keto reductase (AKR) 1D1 tended to decrease or were decreased in mice with AE, along with decreased expression of the bile acid transporters Na+/taurocholate cotransporting polypeptide (NTCP) and bile salt efflux pump (BSEP). Importantly, treatment with ABZ partially or completely reversed the effects induced by E. multilocularis infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy. Full article

(This article belongs to the Section Animal Metabolism)

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12 pages, 1516 KiB

Open AccessFeature PaperArticle

Hyperpolarized Dihydroxyacetone Is a Sensitive Probe of Hepatic Gluconeogenic State

by Mukundan Ragavan, Marc A. McLeod, Anthony G. Giacalone and Matthew E. Merritt

Metabolites 2021, 11(7), 441; https://doi.org/10.3390/metabo11070441 - 5 Jul 2021

Cited by 9 | Viewed by 2900

Abstract

Type II diabetes and pre-diabetes are widely prevalent among adults. Elevated serum glucose levels are commonly treated by targeting hepatic gluconeogenesis for downregulation. However, direct measurement of hepatic gluconeogenic capacity is accomplished only via tracer metabolism approaches that rely on multiple assumptions, and [...] Read more.

Type II diabetes and pre-diabetes are widely prevalent among adults. Elevated serum glucose levels are commonly treated by targeting hepatic gluconeogenesis for downregulation. However, direct measurement of hepatic gluconeogenic capacity is accomplished only via tracer metabolism approaches that rely on multiple assumptions, and are clinically intractable due to expense and time needed for the studies. We previously introduced hyperpolarized (HP) [2-¹³C]dihydroxyacetone (DHA) as a sensitive detector of gluconeogenic potential, and showed that feeding and fasting produced robust changes in the ratio of detected hexoses (6C) to trioses (3C) in the perfused liver. To confirm that this ratio is robust in the setting of treatment and hormonal control, we used ex vivo perfused mouse livers from BLKS mice (glucagon treated and metformin treated), and db/db mice. We confirm that the ratio of signal intensities of 6C to 3C in ¹³C nuclear magnetic resonance spectra post HP DHA administration is sensitive to hepatic gluconeogenic state. This method is directly applicable in vivo and can be implemented with existing technologies without the need for substantial modifications. Full article

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

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17 pages, 1177 KiB

Open AccessArticle

Metabolic Profiling of Plasma in Patients with Irritable Bowel Syndrome after a 4-Week Starch- and Sucrose-Reduced Diet

by Hans Stenlund, Clara Nilholm, Elin Chorell, Bodil Roth, Mauro D’Amato and Bodil Ohlsson

Metabolites 2021, 11(7), 440; https://doi.org/10.3390/metabo11070440 - 4 Jul 2021

Cited by 12 | Viewed by 3253

Abstract

A 4-week dietary intervention with a starch- and sucrose-restricted diet (SSRD) was conducted in patients with irritable bowel syndrome (IBS) to examine the metabolic profile in relation to nutrient intake and gastrointestinal symptoms. IBS patients were randomized to SSRD intervention (n = [...] Read more.

A 4-week dietary intervention with a starch- and sucrose-restricted diet (SSRD) was conducted in patients with irritable bowel syndrome (IBS) to examine the metabolic profile in relation to nutrient intake and gastrointestinal symptoms. IBS patients were randomized to SSRD intervention (n = 69) or control continuing with their ordinary food habits (n = 22). Food intake was registered and the questionnaires IBS-symptoms severity scale (IBS-SSS) and visual analog scale for IBS (VAS-IBS) were completed. Metabolomics untargeted analysis was performed by gas chromatography mass spectrometry (GC-MS) and liquid chromatography mass spectrometry (LC-MS) in positive and negative ionization modes. SSRD led to marked changes in circulating metabolite concentrations at the group level, most prominent for reduced starch intake and increased polyunsaturated fat, with small changes in the control group. On an individual level, the correlations were weak. The marked reduction in gastrointestinal symptoms did not correlate with the metabolic changes. SSRD was observed by clear metabolic effects mainly related to linoleic acid metabolism, fatty acid biosynthesis, and beta-oxidation. Full article

(This article belongs to the Section Nutrition and Metabolism)

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10 pages, 798 KiB

Open AccessArticle

Serum Metabolomic Analysis Suggests Impairment of Myocardial Energy Production in Takotsubo Syndrome

by Iván J. Nuñez-Gil, Mireia Andrés, Begoña Benito, Esther Bernardo, Oscar Vedia, Ignacio Ferreira-Gonzalez and Ignasi Barba

Metabolites 2021, 11(7), 439; https://doi.org/10.3390/metabo11070439 - 3 Jul 2021

Cited by 7 | Viewed by 2824

Abstract

Introduction: Takotsubo syndrome is a complex entity that, although it usually has a good prognosis, can be life threatening. While recent advances have improved the knowledge of takotsubo syndrome, many aspects of its etiology still remain uncertain. Metabolomics, a hypothesis generating approach, could [...] Read more.

Introduction: Takotsubo syndrome is a complex entity that, although it usually has a good prognosis, can be life threatening. While recent advances have improved the knowledge of takotsubo syndrome, many aspects of its etiology still remain uncertain. Metabolomics, a hypothesis generating approach, could provide novel pathophysiology information about this disease. Methods and Results: Serum samples were obtained from takotsubo (n = 19) and acute myocardial infarction patients (n = 8) at the cath lab and, in the case of takotsubo, again once the patient had recovered, 3 months after the main event. ¹H NMR spectra of the serum were acquired at 9.4T using a CPMG pulse sequence (32 ms effective delay). Supervised and unsupervised pattern recognition approaches where applied to the data. Pattern recognition was able to differentiate between takotsubo and acute myocardial infarction during the acute phase with 95% accuracy. Myocardial infarction patients showed an increase in lipid signals, a known risk factor for the disease while takotsubo patients showed a relative increase in acetate that could suggest a reduced turnover of the Krebs cycle. When comparing acute and recovered phases, we could detect an increase in alanine and creatine once patients recovered. Conclusions: Our results demonstrate that takotsubo syndrome is metabolically different than AMI, showing limited myocardial energy production capacity during the acute phase. We achieved high classification success against AMI; however, this study should be considered as a proof of concept regarding clinical application of metabolic profiling in takotsubo cardiomyopathy. Full article

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

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13 pages, 1732 KiB

Open AccessArticle

Metabolomic Approaches to Studying the Response to Drought Stress in Corn (Zea mays) Cobs

by Isabella Gaffney, Jonathan Brett Sallach, Julie Wilson, Edmund Bergström and Jane Thomas-Oates

Metabolites 2021, 11(7), 438; https://doi.org/10.3390/metabo11070438 - 3 Jul 2021

Cited by 9 | Viewed by 3916

Abstract

Metabolomics is a technique that allows for the evaluation of the entire extractable chemical profile of a plant, for example, using high-resolution mass spectrometry (HRMS) and can be used to evaluate plant stress responses, such as those due to drought. Metabolomic analysis is [...] Read more.

Metabolomics is a technique that allows for the evaluation of the entire extractable chemical profile of a plant, for example, using high-resolution mass spectrometry (HRMS) and can be used to evaluate plant stress responses, such as those due to drought. Metabolomic analysis is dependent upon the efficiency of the extraction protocol. Currently, there are two common extraction procedures widely used in metabolomic experiments, those that extract from plant tissue processed in liquid nitrogen or extraction from lyophilised plant tissues. Here, we evaluated the two using non-targeted metabolomics to show that lyophilisation can stabilise the maize (Zea mays) extractable metabolome, increasing throughput and efficiency of extraction as compared to the more traditional processing in liquid nitrogen. Then, we applied the lyophilisation approach to explore the effect of drought upon the maize metabolome in a non-targeted HRMS metabolomics approach. Metabolomics revealed differences in the mature maize metabolome having undergone three drought conditions imposed at two critical development stages (three-leaf stage and grain-fill stage); moreover, this difference was observed across two tissue types (kernel and inner cob/pith). It was shown that under ideal conditions, the biochemical make-up of the tissue types is different. However, under stress conditions, the stress response dominates the metabolic profile. Drought-related metabolites known from other plant systems have been identified and metabolomics has revealed potential novel drought-stress indicators in our maize system. Full article

(This article belongs to the Special Issue Metabolomics to Elucidate the Metabolic Mechanisms of Plant Responses to Variable Environmental Stresses)

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