Metabolites

13 pages, 3878 KiB

Open AccessArticle

A Core Metabolome Response of Maize Leaves Subjected to Long-Duration Abiotic Stresses

by Jaya Joshi, Ghulam Hasnain, Taylor Logue, Madeline Lynch, Shan Wu, Jiahn-Chou Guan, Saleh Alseekh, Alisdair R. Fernie, Andrew D. Hanson and Donald R. McCarty

Metabolites 2021, 11(11), 797; https://doi.org/10.3390/metabo11110797 - 22 Nov 2021

Cited by 18 | Viewed by 2690

Abstract

Abiotic stresses reduce crop growth and yield in part by disrupting metabolic homeostasis and triggering responses that change the metabolome. Experiments designed to understand the mechanisms underlying these metabolomic responses have usually not used agriculturally relevant stress regimes. We therefore subjected maize plants [...] Read more.

Abiotic stresses reduce crop growth and yield in part by disrupting metabolic homeostasis and triggering responses that change the metabolome. Experiments designed to understand the mechanisms underlying these metabolomic responses have usually not used agriculturally relevant stress regimes. We therefore subjected maize plants to drought, salt, or heat stresses that mimic field conditions and analyzed leaf responses at metabolome and transcriptome levels. Shared features of stress metabolomes included synthesis of raffinose, a compatible solute implicated in tolerance to dehydration. In addition, a marked accumulation of amino acids including proline, arginine, and γ-aminobutyrate combined with depletion of key glycolysis and tricarboxylic acid cycle intermediates indicated a shift in balance of carbon and nitrogen metabolism in stressed leaves. Involvement of the γ-aminobutyrate shunt in this process is consistent with its previously proposed role as a workaround for stress-induced thiamin-deficiency. Although convergent metabolome shifts were correlated with gene expression changes in affected pathways, patterns of differential gene regulation induced by the three stresses indicated distinct signaling mechanisms highlighting the plasticity of plant metabolic responses to abiotic stress. Full article

(This article belongs to the Special Issue Plant Metabolic Responses to Biotic and Abiotic Stresses)

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29 pages, 1210 KiB

Open AccessReview

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

by Noyonika Mukherjee, Li Lin, Christopher J. Contreras and Andrew T. Templin

Metabolites 2021, 11(11), 796; https://doi.org/10.3390/metabo11110796 - 22 Nov 2021

Cited by 22 | Viewed by 4468

Abstract

β-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote [...] Read more.

β-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote β-cell death in diabetes, with a focus on the primary literature. We first review discoveries of insulin insufficiency, β-cell loss, and β-cell death in human diabetes. We discuss findings in humans and mouse models of diabetes related to autoimmune-associated β-cell loss and the roles of autoreactive T cells, B cells, and the β cell itself in this process. We review discoveries of the molecular mechanisms that underlie β-cell death-inducing stimuli, including proinflammatory cytokines, islet amyloid formation, ER stress, oxidative stress, glucotoxicity, and lipotoxicity. Finally, we explore recent perspectives on β-cell death in diabetes, including: (1) the role of the β cell in its own demise, (2) methods and terminology for identifying diverse mechanisms of β-cell death, and (3) whether non-canonical forms of β-cell death, such as regulated necrosis, contribute to islet inflammation and β-cell loss in diabetes. We believe new perspectives on the mechanisms of β-cell death in diabetes will provide a better understanding of this pathological process and may lead to new therapeutic strategies to protect β cells in the setting of diabetes. Full article

(This article belongs to the Special Issue The Role of β Cells in Diabetes)

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12 pages, 294 KiB

Open AccessArticle

Thyroid Hormones, Peripheral White Blood Count, and Dose of Basal Insulin Are Associated with Changes in Nerve Conduction Studies in Adolescents with Type 1 Diabetes

by Marta Wysocka-Mincewicz, Marta Baszyńska-Wilk, Maria Mazur, Aleksandra Byczyńska and Monika Nowacka-Gotowiec

Metabolites 2021, 11(11), 795; https://doi.org/10.3390/metabo11110795 - 22 Nov 2021

Cited by 1 | Viewed by 2204

Abstract

Type 1 diabetes (T1D) in the child population is the third most common chronic disease. Diabetic peripheral neuropathy (DPN) is a very disabling and silently developing complication. This prospective, observational study enrolled 182 (93 girls) patients with T1D, aged 16.5–18 years. The aim [...] Read more.

Type 1 diabetes (T1D) in the child population is the third most common chronic disease. Diabetic peripheral neuropathy (DPN) is a very disabling and silently developing complication. This prospective, observational study enrolled 182 (93 girls) patients with T1D, aged 16.5–18 years. The aim of the study was to assess the correlation between factors of diabetes metabolic control, blood count, thyroid hormones, thyroid-stimulating hormone (TSH), level of cortisol, vitamin D3, metabolic factors, demographic data, and nerve conduction study (NCS) parameters. We revealed that in multivariate regression models for almost all NCS parameters, beside height and diabetes duration, significant factors were basal insulin dose per kilogram of weight (BID/kg), body mass index (BMI), and thyroid hormones. For conduction velocities of the motor nerves, mean HbA1c exists in models. In all models for all NCS parameters there exists at least one parameter of peripheral white blood cell counts (predominantly monocytes). There is a significant influence of thyroid hormones, peripheral blood white cells count, and BID per weight on parameters of NCS. It is essential to take care of the proper insulin dose per weight of patients and the adequate proportion of basal to prandial insulin. Full article

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

11 pages, 1892 KiB

Open AccessReview

Sodium-Glucose Cotransporter-2 Inhibitors Improve Cardiovascular Dysfunction in Type 2 Diabetic East Asians

by Muhammad Afzal, Fahad A. Al-Abbasi, Muhammad Shahid Nadeem, Sultan Alshehri, Mohammed M. Ghoneim, Syed Sarim Imam, Waleed Hassan Almalki and Imran Kazmi

Metabolites 2021, 11(11), 794; https://doi.org/10.3390/metabo11110794 - 21 Nov 2021

Viewed by 2065

Abstract

In East Asians, the incidence of type 2 DM (T2DM) has increased as a result of major alterations in life. Cardiovascular problems are more likely in those with T2DM. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are novel insulin-independent antihyperglycemic drugs that limit renal glucose reabsorption [...] Read more.

In East Asians, the incidence of type 2 DM (T2DM) has increased as a result of major alterations in life. Cardiovascular problems are more likely in those with T2DM. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are novel insulin-independent antihyperglycemic drugs that limit renal glucose reabsorption and thereby improve glycemic control. They are used alone or in combination with insulin and other antihyperglycemic medications to treat diabetes, and they are also helpful in protecting against the progression of complications. This review has evaluated the available evidence not only on the efficacy of SGLT2 inhibitors in T2DM, but also on their favourable cardiovascular events in East Asians. DM is an independent risk factor for cardiovascular diseases. As a result, in addition to glycemic control in diabetes management, the therapeutic goal in East Asian diabetic patients should be to improve adverse cardiovascular outcomes. Besides establishing antidiabetic effects, several studies have reported cardioprotective benefits of SGLT2 inhibitors via numerous pathways. SGLT2 inhibitors show promising antidiabetic drugs with potential cardiovascular advantages, given that a high number of diabetic patients in East Asia have co-existing cardiovascular disorders. Despite significant positive results in favour of SGLT2, more research is needed to determine how SGLT2 inhibitors exert these impressive cardiovascular effects. Full article

(This article belongs to the Special Issue New Insights from Type 2 Diabetes Treatments in Real Life, Focus on GLP-1RAs and SGLT2i)

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11 pages, 7293 KiB

Open AccessArticle

Analyzing the Metabolomic Profile of Yellowtail (Seriola quinquerdiata) by Capillary Electrophoresis–Time of Flight Mass Spectrometry to Determine Geographical Origin

by Jiyoung Shin, Junho Yang, Eunji Cha, Hyunsuk Kim, Yoonhyeung Lee, Soi Kim, Iseul Choi and Jiyoung Yang

Metabolites 2021, 11(11), 793; https://doi.org/10.3390/metabo11110793 - 20 Nov 2021

Cited by 7 | Viewed by 2008

Abstract

Country-of-origin violations have occurred in which some merchants have fraudulently sold cheap Japanese yellowtail (Seriola quinqueradiata) by presenting them as domestic Korean products. There are many methods for determining the origins of marine organisms, such as molecular genetic methods and isotope [...] Read more.

Country-of-origin violations have occurred in which some merchants have fraudulently sold cheap Japanese yellowtail (Seriola quinqueradiata) by presenting them as domestic Korean products. There are many methods for determining the origins of marine organisms, such as molecular genetic methods and isotope analysis. However, this study aimed to develop a method for determining the origins of aquatic products using metabolite analysis technology. Ten yellowtail each from Korea and Japan were analyzed by capillary electrophoresis–time of flight/mass spectrometry (CETOF/MS). Hierarchical cluster analysis (HCA) and principal component analysis (PCA) results showed highly differing aspects between the Korean and Japanese samples. In the tricarboxylic acid (TCA) cycle, citric, malic, oxaloglutaric, and fumaric acids exhibited significant differences between Korean and Japanese yellowtail. Sixteen of the twenty essential amino acids analyzed as metabolites also differed significantly. All amino acids were involved in protein digestion, absorption, and metabolism. All 16 amino acid contents were higher in Japanese yellowtail than in Korean yellowtail, except for glutamine. The fasting period was found to be the biggest factor contributing to the difference in amino acid contents, in addition to environmental factors (including feeding habits). These significant differences indicated that metabolomics could be used to determine geographical origin. Full article

(This article belongs to the Section Metabolomic Profiling Technology)

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16 pages, 1089 KiB

Open AccessReview

Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective

by Jacob King, Maya Patel and Sriram Chandrasekaran

Metabolites 2021, 11(11), 792; https://doi.org/10.3390/metabo11110792 - 20 Nov 2021

Cited by 28 | Viewed by 4136

Abstract

Histone deacetylases (HDACs) are epigenetic enzymes that play a central role in gene regulation and are sensitive to the metabolic state of the cell. The cross talk between metabolism and histone acetylation impacts numerous biological processes including development and immune function. HDAC inhibitors [...] Read more.

Histone deacetylases (HDACs) are epigenetic enzymes that play a central role in gene regulation and are sensitive to the metabolic state of the cell. The cross talk between metabolism and histone acetylation impacts numerous biological processes including development and immune function. HDAC inhibitors are being explored for treating cancers, viral infections, inflammation, neurodegenerative diseases, and metabolic disorders. However, how HDAC inhibitors impact cellular metabolism and how metabolism influences their potency is unclear. Discussed herein are recent applications and future potential of systems biology methods such as high throughput drug screens, cancer cell line profiling, single cell sequencing, proteomics, metabolomics, and computational modeling to uncover the interplay between metabolism, HDACs, and HDAC inhibitors. The synthesis of new systems technologies can ultimately help identify epigenomic and metabolic biomarkers for patient stratification and the design of effective therapeutics. Full article

(This article belongs to the Special Issue Metabolism Applications in Histone Deacetylase Inhibitors)

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20 pages, 1848 KiB

Open AccessArticle

Feature-Based Molecular Networking—An Exciting Tool to Spot Species of the Genus Cortinarius with Hidden Photosensitizers

by Fabian Hammerle, Luis Quirós-Guerrero, Adriano Rutz, Jean-Luc Wolfender, Harald Schöbel, Ursula Peintner and Bianka Siewert

Metabolites 2021, 11(11), 791; https://doi.org/10.3390/metabo11110791 - 19 Nov 2021

Cited by 3 | Viewed by 2518

Abstract

Fungi have developed a wide array of defense strategies to overcome mechanical injuries and pathogen infections. Recently, photoactivity has been discovered by showing that pigments isolated from Cortinarius uliginosus produce singlet oxygen under irradiation. To test if this phenomenon is limited to dermocyboid [...] Read more.

Fungi have developed a wide array of defense strategies to overcome mechanical injuries and pathogen infections. Recently, photoactivity has been discovered by showing that pigments isolated from Cortinarius uliginosus produce singlet oxygen under irradiation. To test if this phenomenon is limited to dermocyboid Cortinarii, six colourful Cortinarius species belonging to different classical subgenera (i.e., Dermocybe, Leprocybe, Myxacium, Phlegmacium, and Telamonia) were investigated. Fungal extracts were explored by the combination of in vitro photobiological methods, UHPLC coupled to high-resolution tandem mass spectrometry (UHPLC-HRMS²), feature-based molecular networking (FBMN), and metabolite dereplication techniques. The fungi C. rubrophyllus (Dermocybe) and C. xanthophyllus (Phlegmacium) exhibited promising photobiological activity in a low concentration range (1–7 µg/mL). Using UHPLC-HRMS²-based metabolomic tools, the underlying photoactive principle was investigated. Several monomeric and dimeric anthraquinones were annotated as compounds responsible for the photoactivity. Furthermore, the results showed that light-induced activity is not restricted to a single subgenus, but rather is a trait of Cortinarius species of different phylogenetic lineages and is linked to the presence of fungal anthraquinones. This study highlights the genus Cortinarius as a promising source for novel photopharmaceuticals. Additionally, we showed that putative dereplication of natural photosensitizers can be done by FBMN. Full article

(This article belongs to the Special Issue Application of Metabolomics in Characterization of Novel Bioactive Natural Products)

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11 pages, 1030 KiB

Open AccessArticle

Central and Peripheral Oxygen Distribution in Two Different Modes of Interval Training

by Korbinian Sebastian Hermann Ksoll, Alexander Mühlberger and Fabian Stöcker

Metabolites 2021, 11(11), 790; https://doi.org/10.3390/metabo11110790 - 18 Nov 2021

Cited by 2 | Viewed by 1947

Abstract

In high-intensity interval training the interval duration can be adjusted to optimize training results in oxygen uptake, cardiac output, and local oxygen supply. This study aimed to compare these variables in two interval trainings (long intervals HIIT3m: 3 min work, 3 min active [...] Read more.

In high-intensity interval training the interval duration can be adjusted to optimize training results in oxygen uptake, cardiac output, and local oxygen supply. This study aimed to compare these variables in two interval trainings (long intervals HIIT3m: 3 min work, 3 min active rest vs. short intervals HIIT30s: 30 s work, 30 s active rest) at the same overall work rate and training duration. 24 participants accomplished both protocols, (work: 80% power output at VO₂peak, relief: 85% power output at gas exchange threshold) in randomized order. Spirometry, impedance cardiography, and near-infrared spectroscopy were used to analyze the physiological stress of the cardiopulmonary system and muscle tissue. Although times above gas exchange threshold were shorter in HIIT3m (HIIT3m 1669.9 ± 310.9 s vs. HIIT30s 1769.5 ± 189.0 s, p = 0.034), both protocols evoked similar average fractional utilization of VO₂peak (HIIT3m 65.23 ± 4.68% VO₂peak vs. HIIT30s 64.39 ± 6.78% VO₂peak, p = 0.261). However, HIIT3m resulted in higher cardiovascular responses during the loaded phases (VO₂p < 0.001, cardiac output p < 0.001). Local hemodynamics were not different between both protocols. Average physiological responses were not different in both protocols owning to incomplete rests in HIIT30s and large response amplitudes in HIIT3m. Despite lower acute cardiovascular stress in HIIT30s, short submaximal intervals may also trigger microvascular and metabolic adaptions similar to HIIT3m. Therefore, the adaption of interval duration is an important tool to adjust the goals of interval training to the needs of the athlete or patient. Full article

(This article belongs to the Special Issue Hemorheology and Metabolism)

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11 pages, 3449 KiB

Open AccessArticle

High-Throughput Analysis from Complex Matrices: Acoustic Ejection Mass Spectrometry from Phase-Separated Fluid Samples

by Yuzhu Guo, Michael Forbush, Thomas R. Covey, Lucien Ghislain and Chang Liu

Metabolites 2021, 11(11), 789; https://doi.org/10.3390/metabo11110789 - 18 Nov 2021

Cited by 11 | Viewed by 2061

Abstract

Acoustic ejection mass spectrometry is a novel high-throughput analytical technology that delivers high reproducibility without carryover observed. It eliminates the chromatography step used to separate analytes from matrix components. Fully-automated liquid–liquid extraction is widely used for sample cleanup, especially in high-throughput applications. We [...] Read more.

Acoustic ejection mass spectrometry is a novel high-throughput analytical technology that delivers high reproducibility without carryover observed. It eliminates the chromatography step used to separate analytes from matrix components. Fully-automated liquid–liquid extraction is widely used for sample cleanup, especially in high-throughput applications. We introduce a workflow for direct AEMS analysis from phase-separated liquid samples and explore high-throughput analysis from complex matrices. We demonstrate the quantitative determination of fentanyl from urine using this two-phase AEMS approach, with a LOD lower than 1 ng/mL, quantitation precision of 15%, and accuracy better than ±10% over the range of evaluation (1–100 ng/mL). This workflow offers simplified sample preparation and higher analytical throughput for some bioanalytical applications, in comparison to an LC-MS based approach. Full article

(This article belongs to the Special Issue Advances in Ambient Ionization Techniques for Mass Spectrometry)

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23 pages, 2734 KiB

Open AccessArticle

Binary Simplification as an Effective Tool in Metabolomics Data Analysis

by Francisco Traquete, João Luz, Carlos Cordeiro, Marta Sousa Silva and António E. N. Ferreira

Metabolites 2021, 11(11), 788; https://doi.org/10.3390/metabo11110788 - 18 Nov 2021

Cited by 7 | Viewed by 2161

Abstract

Metabolomics aims to perform a comprehensive identification and quantification of the small molecules present in a biological system. Due to metabolite diversity in concentration, structure, and chemical characteristics, the use of high-resolution methodologies, such as mass spectrometry (MS) or nuclear magnetic resonance (NMR), [...] Read more.

Metabolomics aims to perform a comprehensive identification and quantification of the small molecules present in a biological system. Due to metabolite diversity in concentration, structure, and chemical characteristics, the use of high-resolution methodologies, such as mass spectrometry (MS) or nuclear magnetic resonance (NMR), is required. In metabolomics data analysis, suitable data pre-processing, and pre-treatment procedures are fundamental, with subsequent steps aiming at highlighting the significant biological variation between samples over background noise. Traditional data analysis focuses primarily on the comparison of the features’ intensity values. However, intensity data are highly variable between experimental batches, instruments, and pre-processing methods or parameters. The aim of this work was to develop a new pre-treatment method for MS-based metabolomics data, in the context of sample profiling and discrimination, considering only the occurrence of spectral features, encoding feature presence as 1 and absence as 0. This “Binary Simplification” encoding (BinSim) was used to transform several benchmark datasets before the application of clustering and classification methods. The performance of these methods after the BinSim pre-treatment was consistently as good as and often better than after different combinations of traditional, intensity-based, pre-treatments. Binary Simplification is, therefore, a viable pre-treatment procedure that effectively simplifies metabolomics data-analysis pipelines. Full article

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

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12 pages, 1414 KiB

Open AccessArticle

The Echocardiographic Parameters of Systolic Function Are Associated with Specific Metabolomic Fingerprints in Obstructive and Non-Obstructive Hypertrophic Cardiomyopathy

by Martino Deidda, Antonio Noto, Daniele Pasqualucci, Claudia Fattuoni, Luigi Barberini, Cristina Piras, Pier Paolo Bassareo, Maurizio Porcu, Giuseppe Mercuro and Christian Cadeddu Dessalvi

Metabolites 2021, 11(11), 787; https://doi.org/10.3390/metabo11110787 - 18 Nov 2021

Cited by 3 | Viewed by 1631

Abstract

The purpose of this study was to assess whether metabolomics, associated with echocardiography, was able to highlight pathophysiological differences between obstructive (OHCM) or non-obstructive (NOHCM) hypertrophic cardiomyopathy. Thirty-one HCM patients underwent standard and advanced echocardiography; a plasma sample was collected for metabolomic analysis. [...] Read more.

The purpose of this study was to assess whether metabolomics, associated with echocardiography, was able to highlight pathophysiological differences between obstructive (OHCM) or non-obstructive (NOHCM) hypertrophic cardiomyopathy. Thirty-one HCM patients underwent standard and advanced echocardiography; a plasma sample was collected for metabolomic analysis. Results. Patients with OHCM compared with subjects with NOHCM had higher values of 2DLVEF (66.5 ± 3.3% vs. 60.6 ± 1.8%, p < 0.01), S wave (7.6 ± 1.1 vs. 6.3 ± 0.7 cm/s, p < 0.01) and 3D global longitudinal strain (17.2 ± 4.2%, vs. 13.4 ± 1.3%, p < 0.05). A 2-group PLS-Discriminant Analysis was performed to verify whether the two HCM groups differed also based on the metabolic fingerprint. A clear clustering was shown (ANOVA p = 0.014). The most discriminating metabolites resulted as follows: in the NOHCM Group, there were higher levels of threitol, aminomalonic acid, and sucrose, while the OHCM Group presented higher levels of amino acids, in particular those branched chains, of intermediates of glycolysis (lactate) and the Krebs cycle (fumarate, succinate, citrate), of fatty acids (arachidonic acid, palmitoleic acid), of ketone bodies (2-OH-butyrate). Our data point out a different systolic function related to a specific metabolic activity in the two HCM phenotypic forms, with specific metabolites associated with better contractility in OHCM. Full article

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

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3 pages, 169 KiB

Open AccessEditorial

Islet Biology and Metabolism

by Belinda Yau and Melkam A. Kebede

Metabolites 2021, 11(11), 786; https://doi.org/10.3390/metabo11110786 - 18 Nov 2021

Viewed by 1529

Abstract

This Special Issue, Islet Biology and Metabolism, was intended as a collection of studies highlighting the importance of the pancreatic islet—in both form and function—to our growing understanding of metabolic physiology and disease [...] Full article

(This article belongs to the Special Issue Islet Biology and Metabolism)

17 pages, 2214 KiB

Open AccessReview

Synthetic Biology Advanced Natural Product Discovery

by Junyang Wang, Jens Nielsen and Zihe Liu

Metabolites 2021, 11(11), 785; https://doi.org/10.3390/metabo11110785 - 17 Nov 2021

Cited by 7 | Viewed by 3158

Abstract

A wide variety of bacteria, fungi and plants can produce bioactive secondary metabolites, which are often referred to as natural products. With the rapid development of DNA sequencing technology and bioinformatics, a large number of putative biosynthetic gene clusters have been reported. However, [...] Read more.

A wide variety of bacteria, fungi and plants can produce bioactive secondary metabolites, which are often referred to as natural products. With the rapid development of DNA sequencing technology and bioinformatics, a large number of putative biosynthetic gene clusters have been reported. However, only a limited number of natural products have been discovered, as most biosynthetic gene clusters are not expressed or are expressed at extremely low levels under conventional laboratory conditions. With the rapid development of synthetic biology, advanced genome mining and engineering strategies have been reported and they provide new opportunities for discovery of natural products. This review discusses advances in recent years that can accelerate the design, build, test, and learn (DBTL) cycle of natural product discovery, and prospects trends and key challenges for future research directions. Full article

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18 pages, 4404 KiB

Open AccessArticle

Preventing the Increase in Lysophosphatidic Acids: A New Therapeutic Target in Pulmonary Hypertension?

by Thomas Duflot, Ly Tu, Matthieu Leuillier, Hind Messaoudi, Déborah Groussard, Guillaume Feugray, Saïda Azhar, Raphaël Thuillet, Fabrice Bauer, Marc Humbert, Vincent Richard, Christophe Guignabert and Jérémy Bellien

Metabolites 2021, 11(11), 784; https://doi.org/10.3390/metabo11110784 - 17 Nov 2021

Cited by 2 | Viewed by 2076

Abstract

Cardiovascular diseases (CVD) are the leading cause of premature death and disability in humans that are closely related to lipid metabolism and signaling. This study aimed to assess whether circulating lysophospholipids (LPL), lysophosphatidic acids (LPA) and monoacylglycerols (MAG) may be considered as potential [...] Read more.

Cardiovascular diseases (CVD) are the leading cause of premature death and disability in humans that are closely related to lipid metabolism and signaling. This study aimed to assess whether circulating lysophospholipids (LPL), lysophosphatidic acids (LPA) and monoacylglycerols (MAG) may be considered as potential therapeutic targets in CVD. For this objective, plasma levels of 22 compounds (13 LPL, 6 LPA and 3 MAG) were monitored by liquid chromatography coupled with tandem mass spectrometry (HPLC/MS²) in different rat models of CVD, i.e., angiotensin-II-induced hypertension (HTN), ischemic chronic heart failure (CHF) and sugen/hypoxia(SuHx)-induced pulmonary hypertension (PH). On one hand, there were modest changes on the monitored compounds in HTN (LPA 16:0, 18:1 and 20:4, LPC 16:1) and CHF (LPA 16:0, LPC 18:1 and LPE 16:0 and 18:0) models compared to control rats but these changes were no longer significant after multiple testing corrections. On the other hand, PH was associated with important changes in plasma LPA with a significant increase in LPA 16:0, 18:1, 18:2, 20:4 and 22:6 species. A deleterious impact of LPA was confirmed on cultured human pulmonary smooth muscle cells (PA-SMCs) with an increase in their proliferation. Finally, plasma level of LPA(16:0) was positively associated with the increase in pulmonary artery systolic pressure in patients with cardiac dysfunction. This study demonstrates that circulating LPA may contribute to the pathophysiology of PH. Additional experiments are needed to assess whether the modulation of LPA signaling in PH may be of interest. Full article

(This article belongs to the Special Issue Targeted Analysis and Quantification of Metabolites and Lipids in Plants, Mammals or Bioorganisms Using Metabolomics)

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17 pages, 3795 KiB

Open AccessArticle

Impacts of Constitutive and Induced Benzoxazinoids Levels on Wheat Resistance to the Grain Aphid (Sitobion avenae)

by Zhanfeng Zhang, Hao Lan, Hehe Cao, Xiangshun Hu, Yongliang Fan, Yue Song, Lijuan Wu and Tong-Xian Liu

Metabolites 2021, 11(11), 783; https://doi.org/10.3390/metabo11110783 - 16 Nov 2021

Cited by 9 | Viewed by 2332

Abstract

Benzoxazinoids are important secondary metabolites in gramineae plants and have inhibitory and toxic effects against a wide range of herbivore pests. However, the relationship between benzoxazinoid level and plant resistance to aphids remains controversial. In this study, we investigated the relationship between benzoxazinoids [...] Read more.

Benzoxazinoids are important secondary metabolites in gramineae plants and have inhibitory and toxic effects against a wide range of herbivore pests. However, the relationship between benzoxazinoid level and plant resistance to aphids remains controversial. In this study, we investigated the relationship between benzoxazinoids composition and concentration in wheat leaves and the resistance to the grain aphid Sitobion avenae. Overall, six benzoxazinoids were detected and identified by mass spectrometry based metabolites profiling, including three lactams, two hydroxamic acids, and one methyl derivative. The constitutive levels of these benzoxazinoids were significantly different among the wheat varieties/lines. However, none of these benzoxazinoids exhibited considerable correlation with aphid resistance. S. avenae feeding elevated the level of 2-O-β-D-glucopyranosyloxy-4,7-dimethoxy-(2H)-1,4-benzoxazin-3(4H)-one (HDMBOA-Glc) and reduced the level of 2-O-β-D-glucopyranosyloxy-4-hydroxy-7-(2H)-methoxy-1,4-benzoxazin-3(4H)-one (DIMBOA-Glc) in some of the wheat varieties/lines. Moreover, aphid-induced level of DIMBOA-Glc was positively related with callose deposition, which was closely associated with aphid resistance. Wheat leaves infiltrated with DIMBOA-Glc caused a noticeable increase of callose deposition and the effect was in a dose dependent manner. This study suggests that the constitutive level of benzoxazinoids has limited impact on S. avenae. Aphid feeding can affect the balance of benzoxazinoids metabolism and the dynamic level of benzoxazinoids can act as a signal of callose deposition for S. avenae resistance. This study will extend our understanding of aphid–wheat interaction and provides new insights in aphid-resistance wheat breeding. Full article

(This article belongs to the Special Issue Plant Protection Meets Metabolomics)

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13 pages, 1099 KiB

Open AccessArticle

Healthy and Chronic Kidney Disease (CKD) Dogs Have Differences in Serum Metabolomics and Renal Diet May Have Slowed Disease Progression

by Marcio Antonio Brunetto, Bruna Ruberti, Doris Pereira Halfen, Douglas Segalla Caragelasco, Thiago Henrique Annibale Vendramini, Vivian Pedrinelli, Henrique Tobaro Macedo, Juliana Toloi Jeremias, Cristiana Fonseca Ferreira Pontieri, Fernanda Maria Marins Ocampos, Luis Alberto Colnago and Marcia Mery Kogika

Metabolites 2021, 11(11), 782; https://doi.org/10.3390/metabo11110782 - 16 Nov 2021

Cited by 3 | Viewed by 3057

Abstract

Chronic kidney disease (CKD) is highly prevalent in dogs, and metabolomics investigation has been recently introduced for a better understanding of the role of diet in CKD. This study aimed to compare the serum metabolomic profile of healthy dogs (CG) and dogs with [...] Read more.

Chronic kidney disease (CKD) is highly prevalent in dogs, and metabolomics investigation has been recently introduced for a better understanding of the role of diet in CKD. This study aimed to compare the serum metabolomic profile of healthy dogs (CG) and dogs with CKD (CKD-T0 and CKD-T6) to evaluate whether the diet would affect metabolites. Six dogs (5 females; 1 male; 7.47 ± 2.31 years old) with CKD stage 3 or 4 (IRIS) were included. CG consisted of 10 healthy female dogs (5.89 ± 2.57 years old) fed a maintenance diet. Serum metabolites were analyzed by ¹H nuclear magnetic resonance (¹H NMR) spectra. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were performed to assess differences in metabolomic profiles between groups and before (CKD-T0) and after renal diet (CKD-T6). Data analysis was performed on SIMCA-P software. Dogs with CKD showed an altered metabolic profile with increased urea, creatinine, creatine, citrate, and lipids. Lactate, branched-chain amino acids (BCAAs), and glutamine were decreased in the CKD group. However, after 6 months of diet, the metabolite profiles of CKD-T0 and CKD-T6 were similar. Metabolomics profile may be useful to evaluate and recognize metabolic dysfunction and progression of CKD, and the diet may have helped maintain and retard the progression of CKD. 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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18 pages, 3080 KiB

Open AccessReview

Review of Recent Advances in Lipid Analysis of Biological Samples via Ambient Ionization Mass Spectrometry

by Haiyan Lu, Hua Zhang, Shuling Xu and Lingjun Li

Metabolites 2021, 11(11), 781; https://doi.org/10.3390/metabo11110781 - 15 Nov 2021

Cited by 9 | Viewed by 3843

Abstract

The rapid and direct structural characterization of lipids proves to be critical for studying the functional roles of lipids in many biological processes. Among numerous analytical techniques, ambient ionization mass spectrometry (AIMS) allows for a direct molecular characterization of lipids from various complex [...] Read more.

The rapid and direct structural characterization of lipids proves to be critical for studying the functional roles of lipids in many biological processes. Among numerous analytical techniques, ambient ionization mass spectrometry (AIMS) allows for a direct molecular characterization of lipids from various complex biological samples with no/minimal sample pretreatment. Over the recent years, researchers have expanded the applications of the AIMS techniques to lipid structural elucidation via a combination with a series of derivatization strategies (e.g., the Paternò–Büchi (PB) reaction, ozone-induced dissociation (OzID), and epoxidation reaction), including carbon–carbon double bond (C=C) locations and sn-positions isomers. Herein, this review summarizes the reaction mechanisms of various derivatization strategies for C=C bond analysis, typical instrumental setup, and applications of AIMS in the structural elucidation of lipids from various biological samples (e.g., tissues, cells, and biofluids). In addition, future directions of AIMS for lipid structural elucidation are discussed. Full article

(This article belongs to the Special Issue Advances in Ambient Ionization Techniques for Mass Spectrometry)

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22 pages, 4452 KiB

Open AccessReview

Recent Advances of Ambient Mass Spectrometry Imaging and Its Applications in Lipid and Metabolite Analysis

by Keke Qi, Liutian Wu, Chengyuan Liu and Yang Pan

Metabolites 2021, 11(11), 780; https://doi.org/10.3390/metabo11110780 - 15 Nov 2021

Cited by 18 | Viewed by 2843

Abstract

Ambient mass spectrometry imaging (AMSI) has attracted much attention in recent years. As a kind of unlabeled molecular imaging technique, AMSI can enable in situ visualization of a large number of compounds in biological tissue sections in ambient conditions. In this review, the [...] Read more.

Ambient mass spectrometry imaging (AMSI) has attracted much attention in recent years. As a kind of unlabeled molecular imaging technique, AMSI can enable in situ visualization of a large number of compounds in biological tissue sections in ambient conditions. In this review, the developments of various AMSI techniques are discussed according to one-step and two-step ionization strategies. In addition, recent applications of AMSI for lipid and metabolite analysis (from 2016 to 2021) in disease diagnosis, animal model research, plant science, drug metabolism and toxicology research, etc., are summarized. Finally, further perspectives of AMSI in spatial resolution, sensitivity, quantitative ability, convenience and software development are proposed. Full article

(This article belongs to the Special Issue Advances in Ambient Ionization Techniques for Mass Spectrometry)

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20 pages, 3600 KiB

Open AccessArticle

The Effects of Consuming White Button Mushroom Agaricus bisporus on the Brain and Liver Metabolome Using a Targeted Metabolomic Analysis

by Gloria I. Solano-Aguilar, Sukla Lakshman, Saebyeol Jang, Richi Gupta, Aleksey Molokin, Steven G. Schroeder, Patrick M. Gillevet and Joseph F. Urban, Jr.

Metabolites 2021, 11(11), 779; https://doi.org/10.3390/metabo11110779 - 15 Nov 2021

Cited by 1 | Viewed by 2621

Abstract

A targeted metabolomic analysis was performed on tissues derived from pigs fed diets supplemented with white button mushrooms (WBM) to determine the effect on the liver and brain metabolome. Thirty-one pigs were fed a grower diet alone or supplemented with either three or [...] Read more.

A targeted metabolomic analysis was performed on tissues derived from pigs fed diets supplemented with white button mushrooms (WBM) to determine the effect on the liver and brain metabolome. Thirty-one pigs were fed a grower diet alone or supplemented with either three or six servings of freeze-dried WBM for six weeks. Tissue metabolomes were analyzed using targeted liquid chromatography-mass spectrometry (LC-MS) combined with chemical similarity enrichment analysis (ChemRICH) and correlated to WBM-induced changes in fecal microbiome composition. Results indicated that WBM can differentially modulate metabolites in liver, brain cortex and hippocampus of healthy pigs. Within the glycero-phospholipids, there was an increase in alkyl-acyl-phosphatidyl-cholines (PC-O 40:3) in the hippocampus of pigs fed six servings of WBM. A broader change in glycerophospholipids and sphingolipids was detected in the liver with a reduction in several lipid species in pigs fed both WBM diets but with an increase in amino acids known as precursors of neurotransmitters in the cortex of pigs fed six servings of WBM. Metabolomic changes were positively correlated with increased abundance of Cryomorphaceae, Lachnospiraceae, Flammeovirgaceae and Ruminococcaceae in the microbiome suggesting that WBM can also positively impact tissue metabolite composition. Full article

(This article belongs to the Section Nutrition and Metabolism)

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13 pages, 3722 KiB

Open AccessArticle

l-Theanine Protects Bladder Function by Suppressing Chronic Sympathetic Hyperactivity in Spontaneously Hypertensive Rat

by Kanako Matsuoka, Hidenori Akaihata, Junya Hata, Ryo Tanji, Ruriko Honda-Takinami, Akifumi Onagi, Seiji Hoshi, Tomoyuki Koguchi, Yuichi Sato, Masao Kataoka, Soichiro Ogawa and Yoshiyuki Kojima

Metabolites 2021, 11(11), 778; https://doi.org/10.3390/metabo11110778 - 14 Nov 2021

Cited by 3 | Viewed by 3065

Abstract

Chronic sympathetic hyperactivity is known to affect metabolism and cause various organ damage including bladder dysfunction. In this study, we evaluated whether l-theanine, a major amino acid found in green tea, ameliorates bladder dysfunction induced by chronic sympathetic hyperactivity as a dietary [...] Read more.

Chronic sympathetic hyperactivity is known to affect metabolism and cause various organ damage including bladder dysfunction. In this study, we evaluated whether l-theanine, a major amino acid found in green tea, ameliorates bladder dysfunction induced by chronic sympathetic hyperactivity as a dietary component for daily consumption. Spontaneously hypertensive rats (SHRs), as an animal model of bladder dysfunction, were divided into SHR–water and SHR–theanine groups. After 6 weeks of oral administration, the sympathetic nervous system, bladder function, and oxidative stress of bladder tissue were evaluated. The mean blood pressure, serum noradrenaline level, and media-to-lumen ratio of small arteries in the suburothelium were significantly lower in the SHR–theanine than in the SHR–water group. Micturition interval was significantly longer, and bladder capacity was significantly higher in the SHR–theanine than in the SHR–water group. Bladder strip contractility was also higher in the SHR–theanine than in the SHR–water group. Western blotting of bladder showed that expression of malondialdehyde was significantly lower in the SHR–theanine than in the SHR–water group. These results suggested that orally administered l-theanine may contribute at least partly to the prevention of bladder dysfunctions by inhibiting chronic sympathetic hyperactivity and protecting bladder contractility. Full article

(This article belongs to the Special Issue Urinary Metabolomic Profiling Analysis and Evaluation)

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18 pages, 2279 KiB

Open AccessArticle

BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells

by Prashant Karki, Shayne Sensenbach, Vahideh Angardi and Mehmet A. Orman

Metabolites 2021, 11(11), 777; https://doi.org/10.3390/metabo11110777 - 14 Nov 2021

Cited by 2 | Viewed by 2927

Abstract

Acquired drug tolerance has been a major challenge in cancer therapy. Recent evidence has revealed the existence of slow-cycling persister cells that survive drug treatments and give rise to multi-drug-tolerant mutants in cancer. Cells in this dynamic persister state can escape drug treatment [...] Read more.

Acquired drug tolerance has been a major challenge in cancer therapy. Recent evidence has revealed the existence of slow-cycling persister cells that survive drug treatments and give rise to multi-drug-tolerant mutants in cancer. Cells in this dynamic persister state can escape drug treatment by undergoing various epigenetic changes, which may result in a transient metabolic rewiring. In this study, with the use of untargeted metabolomics and phenotype microarrays, we characterize the metabolic profiles of melanoma persister cells mediated by treatment with vemurafenib, a BRAF inhibitor. Our findings demonstrate that metabolites associated with phospholipid synthesis, pyrimidine, and one-carbon metabolism and branched-chain amino acid metabolism are significantly altered in vemurafenib persister cells when compared to the bulk cancer population. Our data also show that vemurafenib persisters have higher lactic acid consumption rates than control cells, further validating the existence of a unique metabolic reprogramming in these drug-tolerant cells. Determining the metabolic mechanisms underlying persister cell survival and maintenance will facilitate the development of novel treatment strategies that target persisters and enhance cancer therapy. Full article

(This article belongs to the Section Cell Metabolism)

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13 pages, 1156 KiB

Open AccessArticle

Hematological, Micro-Rheological, and Metabolic Changes Modulated by Local Ischemic Pre- and Post-Conditioning in Rat Limb Ischemia-Reperfusion

by Csaba Korei, Balazs Szabo, Adam Varga, Barbara Barath, Adam Deak, Erzsebet Vanyolos, Zoltan Hargitai, Ilona Kovacs, Norbert Nemeth and Katalin Peto

Metabolites 2021, 11(11), 776; https://doi.org/10.3390/metabo11110776 - 13 Nov 2021

Cited by 2 | Viewed by 1773

Abstract

In trauma and orthopedic surgery, limb ischemia-reperfusion (I/R) remains a great challenge. The effect of preventive protocols, including surgical conditioning approaches, is still controversial. We aimed to examine the effects of local ischemic pre-conditioning (PreC) and post-conditioning (PostC) on limb I/R. Anesthetized rats [...] Read more.

In trauma and orthopedic surgery, limb ischemia-reperfusion (I/R) remains a great challenge. The effect of preventive protocols, including surgical conditioning approaches, is still controversial. We aimed to examine the effects of local ischemic pre-conditioning (PreC) and post-conditioning (PostC) on limb I/R. Anesthetized rats were randomized into sham-operated (control), I/R (120-min limb ischemia with tourniquet), PreC, or PostC groups (3 × 10-min tourniquet ischemia, 10-min reperfusion intervals). Blood samples were taken before and just after the ischemia, and on the first postoperative week for testing hematological, micro-rheological (erythrocyte deformability and aggregation), and metabolic parameters. Histological samples were also taken. Erythrocyte count, hemoglobin, and hematocrit values decreased, while after a temporary decrease, platelet count increased in I/R groups. Erythrocyte deformability impairment and aggregation enhancement were seen after ischemia, more obviously in the PreC group, and less in PostC. Blood pH decreased in all I/R groups. The elevation of creatinine and lactate concentration was the largest in PostC group. Histology did not reveal important differences. In conclusion, limb I/R caused micro-rheological impairment with hematological and metabolic changes. Ischemic pre- and post-conditioning had additive changes in various manners. Post-conditioning showed better micro-rheological effects. However, by these parameters it cannot be decided which protocol is better. Full article

(This article belongs to the Special Issue Hemorheology and Metabolism)

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18 pages, 1608 KiB

Open AccessArticle

2C-B-Fly-NBOMe Metabolites in Rat Urine, Human Liver Microsomes and C. elegans: Confirmation with Synthesized Analytical Standards

by Jitka Nykodemová, Anna Šuláková, Petr Palivec, Hedvika Češková, Silvie Rimpelová, Klára Šíchová, Tereza Leonhardt, Bronislav Jurásek, Kateřina Hájková, Tomáš Páleníček and Martin Kuchař

Metabolites 2021, 11(11), 775; https://doi.org/10.3390/metabo11110775 - 12 Nov 2021

Cited by 8 | Viewed by 2449

Abstract

Compounds from the N-benzylphenethylamine (NBPEA) class of novel psychoactive substances are being increasingly utilized in neurobiological and clinical research, as diagnostic tools, or for recreational purposes. To understand the pharmacology, safety, or potential toxicity of these substances, elucidating their metabolic fate is [...] Read more.

Compounds from the N-benzylphenethylamine (NBPEA) class of novel psychoactive substances are being increasingly utilized in neurobiological and clinical research, as diagnostic tools, or for recreational purposes. To understand the pharmacology, safety, or potential toxicity of these substances, elucidating their metabolic fate is therefore of the utmost interest. Several studies on NBPEA metabolism have emerged, but scarce information about substances with a tetrahydrobenzodifuran (“Fly”) moiety is available. Here, we investigated the metabolism of 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran-4-yl)-N-(2-methoxybenzyl)ethan-1-amine (2C-B-Fly-NBOMe) in three different systems: isolated human liver microsomes, Cunninghamella elegans mycelium, and in rats in vivo. Phase I and II metabolites of 2C-B-Fly-NBOMe were first detected in an untargeted screening and identified by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Several hypothesized metabolites were then synthesized as reference standards; knowledge of their fragmentation patterns was utilized for confirmation or tentative identification of isomers. Altogether, thirty-five phase I and nine phase II 2C-B-Fly-NBOMe metabolites were detected. Major detected metabolic pathways were mono- and poly-hydroxylation, O-demethylation, oxidative debromination, and to a lesser extent also N-demethoxybenzylation, followed by glucuronidation and/or N-acetylation. Differences were observed for the three used media. The highest number of metabolites and at highest concentration were found in human liver microsomes. In vivo metabolites detected from rat urine included two poly-hydroxylated metabolites found only in this media. Mycelium matrix contained several dehydrogenated, N-oxygenated, and dibrominated metabolites. Full article

(This article belongs to the Special Issue Toxicokinetics and Metabolism)

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11 pages, 306 KiB

Open AccessArticle

A Matched Case-Control Study of Noncholesterol Sterols and Fatty Acids in Chronic Hemodialysis Patients

by Marek Vecka, Magdalena Dušejovská, Barbora Staňková, Ivan Rychlík and Aleš Žák

Metabolites 2021, 11(11), 774; https://doi.org/10.3390/metabo11110774 - 12 Nov 2021

Cited by 2 | Viewed by 1733

Abstract

Dyslipidemia is common among patients on hemodialysis, but its etiology is not fully understood. Although changes in cholesterol homeostasis and fatty acid metabolism play an important role during dialysis, the interaction of these metabolic pathways has yet to be studied in sufficient detail. [...] Read more.

Dyslipidemia is common among patients on hemodialysis, but its etiology is not fully understood. Although changes in cholesterol homeostasis and fatty acid metabolism play an important role during dialysis, the interaction of these metabolic pathways has yet to be studied in sufficient detail. In this study, we enrolled 26 patients on maintenance hemodialysis treatment (high-volume hemodiafiltration, HV HDF) without statin therapy (17 men/9 women) and an age/gender-matched group of 26 individuals without signs of nephropathy. The HV-HDF group exhibited more frequent signs of cardiovascular disease, disturbed saccharide metabolism, and altered lipoprotein profiles, manifesting in lower HDL-C, and raised concentrations of IDL-C and apoB-48 (all p < 0.01). HV-HDF patients had higher levels of campesterol (p < 0.01) and β-sitosterol (p = 0.06), both surrogate markers of cholesterol absorption and unchanged lathosterol concentrations. Fatty acid (FA) profiles were changed mostly in cholesteryl esters, with a higher content of saturated and n-3 polyunsaturated fatty acids (PUFA) in the HV-HDF group. However, n-6 PUFA in cholesteryl esters were less abundant (p < 0.001) in the HV-HDF group. Hemodialysis during end-stage kidney disease induces changes associated with higher absorption of cholesterol and disturbed lipoprotein metabolism. Changes in fatty acid metabolism reflect the combined effect of renal insufficiency and its comorbidities, mostly insulin resistance. Full article

(This article belongs to the Special Issue Advances in Cholesterol and Lipid Metabolism)

18 pages, 5609 KiB

Open AccessArticle

Differentiation of Cystic Fibrosis-Related Pathogens by Volatile Organic Compound Analysis with Secondary Electrospray Ionization Mass Spectrometry

by Jérôme Kaeslin, Srdjan Micic, Ronja Weber, Simona Müller, Nathan Perkins, Christoph Berger, Renato Zenobi, Tobias Bruderer and Alexander Moeller

Metabolites 2021, 11(11), 773; https://doi.org/10.3390/metabo11110773 - 11 Nov 2021

Cited by 11 | Viewed by 2981

Abstract

Identifying and differentiating bacteria based on their emitted volatile organic compounds (VOCs) opens vast opportunities for rapid diagnostics. Secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS) is an ideal technique for VOC-biomarker discovery because of its speed, sensitivity towards polar molecules and compound characterization [...] Read more.

Identifying and differentiating bacteria based on their emitted volatile organic compounds (VOCs) opens vast opportunities for rapid diagnostics. Secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS) is an ideal technique for VOC-biomarker discovery because of its speed, sensitivity towards polar molecules and compound characterization possibilities. Here, an in vitro SESI-HRMS workflow to find biomarkers for cystic fibrosis (CF)-related pathogens P. aeruginosa, S. pneumoniae, S. aureus, H. influenzae, E. coli and S. maltophilia is described. From 180 headspace samples, the six pathogens are distinguishable in the first three principal components and predictive analysis with a support vector machine algorithm using leave-one-out cross-validation exhibited perfect accuracy scores for the differentiation between the groups. Additionally, 94 distinctive features were found by recursive feature elimination and further characterized by SESI-MS/MS, which yielded 33 putatively identified biomarkers. In conclusion, the six pathogens can be distinguished in vitro based on their VOC profiles as well as the herein reported putative biomarkers. In the future, these putative biomarkers might be helpful for pathogen detection in vivo based on breath samples from patients with CF. Full article

(This article belongs to the Section Metabolomic Profiling Technology)

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14 pages, 2166 KiB

Open AccessArticle

Coupling Mixed Mode Chromatography/ESI Negative MS Detection with Message-Passing Neural Network Modeling for Enhanced Metabolome Coverage and Structural Identification

by Gang Xing, Vishnu Sresht, Zhongyuan Sun, Yuji Shi and Michelle F. Clasquin

Metabolites 2021, 11(11), 772; https://doi.org/10.3390/metabo11110772 - 11 Nov 2021

Cited by 2 | Viewed by 2636

Abstract

A key unmet need in metabolomics continues to be the specific, selective, accurate detection of traditionally difficult to retain molecules including simple sugars, sugar phosphates, carboxylic acids, and related amino acids. Designed to retain the metabolites of central carbon metabolism, this Mixed Mode [...] Read more.

A key unmet need in metabolomics continues to be the specific, selective, accurate detection of traditionally difficult to retain molecules including simple sugars, sugar phosphates, carboxylic acids, and related amino acids. Designed to retain the metabolites of central carbon metabolism, this Mixed Mode (MM) chromatography applies varied pH, salt concentration and organic content to a positively charged quaternary amine polyvinyl alcohol stationary phase. This MM method is capable of separating glucose from fructose, and four hexose monophosphates a single chromatographic run. Coupled to a QExactive Orbitrap Mass Spectrometer with negative ESI, linearity, LLOD, %CV, and mass accuracy were assessed using 33 metabolite standards. The standards were linear on average >3 orders of magnitude (R² > 0.98 for 30/33) with LLOD < 1 pmole (26/33), median CV of 12% over two weeks, and median mass accuracy of 0.49 ppm. To assess the breadth of metabolome coverage and better define the structural elements dictating elution, we injected 607 unique metabolites and determined that 398 are well retained. We then split the dataset of 398 documented RTs into training and test sets and trained a message-passing neural network (MPNN) to predict RT from a featurized heavy atom connectivity graph. Unlike traditional QSAR methods that utilize hand-crafted descriptors or pre-defined structural keys, the MPNN aggregates atomic features across the molecular graph and learns to identify molecular subgraphs that are correlated with variations in RTs. For sugars, sugar phosphates, carboxylic acids, and isomers, the model achieves a predictive RT error of <2 min on 91%, 50%, 77%, and 72% of held-out compounds from these subsets, with overall root mean square errors of 0.11, 0.34, 0.18, and 0.53 min, respectively. The model was then applied to rank order metabolite IDs for molecular features altered by GLS2 knockout in mouse primary hepatocytes. Full article

(This article belongs to the Section Integrative Metabolomics)

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12 pages, 306 KiB

Open AccessArticle

Pattern of Adiponectin, Osteocalcin, Irisin, FGF-21, and MCP-1 According to the Body Size Phenotype: Could They Be Markers of Metabolic Health in Mexican-Mestizo Middle-Aged Women?

by Lourdes Balcázar-Hernandez, Lourdes Basurto, Leticia Manuel-Apolinar, Sara Vega-García, Norma Basurto-Acevedo, Carlos Martínez-Murillo and Rosalinda Sánchez-Arenas

Metabolites 2021, 11(11), 771; https://doi.org/10.3390/metabo11110771 - 11 Nov 2021

Viewed by 1934

Abstract

Variations in levels of some adipokines, myokines, osteokines, hepatokines and inflammatory cytokines contribute to abnormal glucose and lipid metabolism. The aim of this study was to determine the pattern of adiponectin, osteocalcin (OCN), irisin, FGF-21, and MCP-1 according to the body size phenotype [...] Read more.

Variations in levels of some adipokines, myokines, osteokines, hepatokines and inflammatory cytokines contribute to abnormal glucose and lipid metabolism. The aim of this study was to determine the pattern of adiponectin, osteocalcin (OCN), irisin, FGF-21, and MCP-1 according to the body size phenotype of middle-aged women, and their associations with BMI, visceral adipose tissue (VAT), and HOMA-IR. A cross-sectional study in 265 women aged from 40 to 65 years was performed. The biochemical characteristics were evaluated in metabolically healthy normal weight, metabolically unhealthy normal weight, metabolically healthy obese, and metabolically unhealthy obese women. There was an association of OCN with BMI (r = −0.107; p = 0.047); adiponectin with BMI (r = −0.217; p = 0.001), insulin (r = −0.415; p = 0.0001), HOMA-IR (r = −0.429; p = 0.0001), and VAT (r = −0.134; p = 0.025); irisin with BMI (r = 0.604; p = 0.001), insulin (r = 0.446; p = 0.0001), HOMA-IR (r = 0.452; p = 0.0001), and VAT (r = 0.645; p = 0.0001); FGF−21 with insulin (r = −0.337; p= 0.030) and HOMA-IR (r = −0.341; p = 0.03); and MCP-1 with BMI (r = 0.481; p = 0.0001), VAT (r = 0.497; p = 0.001), insulin (r = 0.298; p= 0.001), and HOMA-IR (r = 0.255; p = 0.004). A multivariate analysis showed that an elevation of OCN (OR 1.4 (_95%CI 1.06–1.81)) and a reduction of adiponectin (OR 0.9 (0.84–0.96)) were associated factors for a metabolic unhealthy phenotype in normal weight participants. Likewise, higher irisin (OR 1.007 (1.003–1.011)) and MCP-1 (1.044 (1.008–1.083)) were risk factors for a metabolic unhealthy phenotype in woman with obesity. OCN, adiponectin, irisin, FGF-21, and MCP-1 are associated with some metabolic parameters such as BMI, HOMA-IR, and VAT, and could be possible biomarkers of an unhealthy metabolic phenotype in middle-aged women. Full article

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

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13 pages, 987 KiB

Open AccessReview

Cardiovascular Safety of Anti-Sclerostin Therapy in Chronic Kidney Disease

by Daniel Cejka

Metabolites 2021, 11(11), 770; https://doi.org/10.3390/metabo11110770 - 10 Nov 2021

Cited by 4 | Viewed by 2538

Abstract

The significance of sclerostin for bone and cardiovascular health in patients with chronic kidney disease (CKD) is complex and incompletely understood. Experimental evidence suggests that anti-sclerostin therapy shows diminished efficacy on bone in the setting of CKD. Limited clinical evidence suggests that the [...] Read more.

The significance of sclerostin for bone and cardiovascular health in patients with chronic kidney disease (CKD) is complex and incompletely understood. Experimental evidence suggests that anti-sclerostin therapy shows diminished efficacy on bone in the setting of CKD. Limited clinical evidence suggests that the osteoanabolic and anti-resorptive activity is attenuated, but hypocalcemia is more prevalent in patients with advanced CKD (eGFR < 30 mL/min) treated with anti-sclerostin (romosozumab) therapy as compared to patients without kidney disease. Furthermore, sclerostin is prominently expressed in uremic arteries. Whether the inhibition of sclerostin has adverse effects on cardiovascular health in CKD is currently unknown. This review summarizes the current understanding of the physiology and pathophysiology of sclerostin in CKD, with a focus on the cardiovascular safety of anti-sclerostin therapy in patients with or without CKD. Full article

(This article belongs to the Special Issue Frontiers in Bone Metabolism and Disorder in Chronic Kidney Disease)

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18 pages, 3829 KiB

Open AccessArticle

Effect of Cadmium and Copper Exposure on Growth, Physio-Chemicals and Medicinal Properties of Cajanus cajan L. (Pigeon Pea)

by Khizar Hayat, Asif Khan, Farkhanda Bibi, Salahuddin, Waheed Murad, Yujie Fu, Gaber El-Saber Batiha, Mohammed Alqarni, Ajmal Khan and Ahmed Al-Harrasi

Metabolites 2021, 11(11), 769; https://doi.org/10.3390/metabo11110769 - 10 Nov 2021

Cited by 11 | Viewed by 2154

Abstract

Soil contamination with heavy metals is an emerging concern in the modern era, affecting all forms of life. Pigeon pea is a multi-use shrub with medicinal and nutritional values. On the basis of a randomized complete design, we investigated in the current project [...] Read more.

Soil contamination with heavy metals is an emerging concern in the modern era, affecting all forms of life. Pigeon pea is a multi-use shrub with medicinal and nutritional values. On the basis of a randomized complete design, we investigated in the current project the combined cadmium (Cd) and copper (Cu) effect on plant growth and physio-chemical/medicinal properties of pigeon pea. Three-week-old seedlings were grown in combined Cd and Cu amended soil with increasing metal concentrations (control, 20 + 30 mg/kg, 40 + 60 mg/kg, and 60 + 90 mg/kg) for three months. At high-dose metal cumulative stress (60 + 90 mg/kg), plant shoot and root growth in terms of plant height as well as fresh and dry weight were significantly inhibited in association with decreased photosynthetic attributes (chlorophyll a and b contents, net photosynthesis, transpiration rate, stomatal conductance, intercellular CO₂ concentrations) and diminished nutrient contents. Cd and Cu at high amounts inflicted oxidative stresses as assessed in elevated lipid peroxidation (MDA), hydrogen peroxide (H₂O₂), and electrolyte leakage contents. Antioxidant enzyme activities, namely, those of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and glutathione peroxidase (GPX), were enhanced, along with proline content with increasing metal quantity. Phenolics and flavonoids exhibited a diverse response regarding metal concentration, and their biosynthesis was significantly suppressed at high Cd and Cu cumulative stress. The reduction in secondary metabolites may account for declined medicinal properties of pigeon pea as appraised in reduced antibacterial, 2, 2-diphenyl-1-picrylhydrazyl (DPPH), and ferric-reducing antioxidant potential (FRAP) activities. Our results clearly demonstrate that the exposure of pigeon pea to Cd- and Cu-contaminated soil might affect consumers due to the presence of metals and the negligible efficacy of the herbal products. Full article

(This article belongs to the Section Environmental Metabolomics)

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16 pages, 1850 KiB

Open AccessArticle

Opposing Immune-Metabolic Signature in Visceral Versus Subcutaneous Adipose Tissue in Patients with Adenocarcinoma of the Oesophagus and the Oesophagogastric Junction

by Aisling B. Heeran, Jessica McCready, Margaret R. Dunne, Noel E. Donlon, Timothy S. Nugent, Anshul Bhardwaj, Kathleen A. J. Mitchelson, Amy M. Buckley, Narayanasamy Ravi, Helen M. Roche, John V. Reynolds, Niamh Lynam-Lennon and Jacintha O’Sullivan

Metabolites 2021, 11(11), 768; https://doi.org/10.3390/metabo11110768 - 10 Nov 2021

Cited by 3 | Viewed by 2182

Abstract

Oesophageal adenocarcinoma (OAC) is an exemplar model of obesity-associated cancer. Previous work in our group has demonstrated that overweight/obese OAC patients have better responses to neoadjuvant therapy, but the underlying mechanisms are unknown. Unravelling the immune–metabolic signatures of adipose tissue may provide insight [...] Read more.

Oesophageal adenocarcinoma (OAC) is an exemplar model of obesity-associated cancer. Previous work in our group has demonstrated that overweight/obese OAC patients have better responses to neoadjuvant therapy, but the underlying mechanisms are unknown. Unravelling the immune–metabolic signatures of adipose tissue may provide insight for this observation. We hypothesised that different metabolic pathways predominate in visceral (VAT) and subcutaneous adipose tissue (SAT) and inflammatory secretions will differ between the fat depots. Real-time ex vivo metabolic profiles of VAT and SAT from 12 OAC patients were analysed. These samples were screened for the secretion of 54 inflammatory mediators, and data were correlated with patient body composition. Oxidative phosphorylation (OXPHOS) was significantly higher in VAT when compared to SAT. OXPHOS was significantly higher in the SAT of patients receiving neoadjuvant treatment. VEGF-A, VEGF-C, P1GF, Flt-1, bFGF, IL-15, IL-16, IL-17A, CRP, SAA, ICAM-1, VCAM-1, IL-2, IL-13, IFN-γ, and MIP-1β secretions were significantly higher from VAT than SAT. Higher levels of bFGF, Eotaxin-3, and TNF-α were secreted from the VAT of obese patients, while higher levels of IL-23 and TARC were secreted from the SAT of obese patients. The angiogenic factors, bFGF and VEGF-C, correlated with visceral fat area. Levels of OXPHOS are higher in VAT than SAT. Angiogenic, vascular injury and inflammatory cytokines are elevated in VAT versus SAT, indicating that VAT may promote inflammation, linked to regulating treatment response. Full article

(This article belongs to the Special Issue Diet, Metabolites and Adipose Tissue Metabolism)

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