Metabolites

21 pages, 4472 KiB

Open AccessArticle

Lipidomic Signatures of Changes in Adiposity: A Large Prospective Study of 5849 Adults from the Australian Diabetes, Obesity and Lifestyle Study

by Habtamu B. Beyene, Gavriel Olshansky, Corey Giles, Kevin Huynh, Michelle Cinel, Natalie A. Mellett, Adam Alexander T. Smith, Jonathan E. Shaw, Dianna J. Magliano and Peter J. Meikle

Metabolites 2021, 11(9), 646; https://doi.org/10.3390/metabo11090646 - 21 Sep 2021

Cited by 14 | Viewed by 3254

Abstract

Lipid metabolism is tightly linked to adiposity. Comprehensive lipidomic profiling offers new insights into the dysregulation of lipid metabolism in relation to weight gain. Here, we investigated the relationship of the human plasma lipidome and changes in waist circumference (WC) and body mass [...] Read more.

Lipid metabolism is tightly linked to adiposity. Comprehensive lipidomic profiling offers new insights into the dysregulation of lipid metabolism in relation to weight gain. Here, we investigated the relationship of the human plasma lipidome and changes in waist circumference (WC) and body mass index (BMI). Adults (2653 men and 3196 women), 25–95 years old who attended the baseline survey of the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) and the 5-year follow-up were enrolled. A targeted lipidomic approach was used to quantify 706 distinct molecular lipid species in the plasma samples. Multiple linear regression models were used to examine the relationship between the baseline lipidomic profile and changes in WC and BMI. Metabolic scores for change in WC were generated using a ridge regression model. Alkyl-diacylglycerol such as TG(O-50:2) [NL-18:1] displayed the strongest association with change in WC (β-coefficient = 0.125 cm increment per SD increment in baseline lipid level, p = 2.78 × 10⁻¹¹. Many lipid species containing linoleate (18:2) fatty acids were negatively associated with both WC and BMI gain. Compared to traditional models, multivariate models containing lipid species identify individuals at a greater risk of gaining WC: top quintile relative to bottom quintile (odds ratio, 95% CI = 5.4, 3.8–6.6 for women and 2.3, 1.7–3.0 for men). Our findings define metabolic profiles that characterize individuals at risk of weight gain or WC increase and provide important insight into the biological role of lipids in obesity. Full article

(This article belongs to the Section Lipid Metabolism)

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15 pages, 1711 KiB

Open AccessArticle

Metabolomics Signature of Plasma Renin Activity and Linkage with Blood Pressure Response to Beta Blockers and Thiazide Diuretics in Hypertensive European American Patients

by Mai Mehanna, Caitrin W. McDonough, Steven M. Smith, Yan Gong, John G. Gums, Arlene B. Chapman, Julie A. Johnson, Lauren McIntyre and Rhonda M. Cooper-DeHoff

Metabolites 2021, 11(9), 645; https://doi.org/10.3390/metabo11090645 - 21 Sep 2021

Cited by 9 | Viewed by 3235

Abstract

Plasma renin activity (PRA) is a predictive biomarker of blood pressure (BP) response to antihypertensives in European–American hypertensive patients. We aimed to identify the metabolic signatures of baseline PRA and the linkages with BP response to β-blockers and thiazides. Using data from the [...] Read more.

Plasma renin activity (PRA) is a predictive biomarker of blood pressure (BP) response to antihypertensives in European–American hypertensive patients. We aimed to identify the metabolic signatures of baseline PRA and the linkages with BP response to β-blockers and thiazides. Using data from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) trial, multivariable linear regression adjusting for age, sex and baseline systolic-BP (SBP) was performed on European–American individuals treated with metoprolol (n = 198) and chlorthalidone (n = 181), to test associations between 856 metabolites and baseline PRA. Metabolites with a false discovery rate (FDR) < 0.05 or p < 0.01 were tested for replication in 463 European–American individuals treated with atenolol or hydrochlorothiazide. Replicated metabolites were then tested for validation based on the directionality of association with BP response. Sixty-three metabolites were associated with baseline PRA, of which nine, including six lipids, were replicated. Of those replicated, two metabolites associated with higher baseline PRA were validated: caprate was associated with greater metoprolol SBP response (β = −1.7 ± 0.6, p = 0.006) and sphingosine-1-phosphate was associated with reduced hydrochlorothiazide SBP response (β = 7.6 ± 2.8, p = 0.007). These metabolites are clustered with metabolites involved in sphingolipid, phospholipid, and purine metabolic pathways. The identified metabolic signatures provide insights into the mechanisms underlying BP response. Full article

(This article belongs to the Special Issue Biomarkers and Human Blood Metabolites)

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20 pages, 2247 KiB

Open AccessEditor’s ChoiceArticle

An Extensive Metabolomics Workflow to Discover Cardiotoxin-Induced Molecular Perturbations in Microtissues

by Tara J. Bowen, Andrew R. Hall, Gavin R. Lloyd, Ralf J. M. Weber, Amanda Wilson, Amy Pointon and Mark R. Viant

Metabolites 2021, 11(9), 644; https://doi.org/10.3390/metabo11090644 - 21 Sep 2021

Cited by 3 | Viewed by 3108

Abstract

Discovering modes of action and predictive biomarkers of drug-induced structural cardiotoxicity offers the potential to improve cardiac safety assessment of lead compounds and enhance preclinical to clinical translation during drug development. Cardiac microtissues are a promising, physiologically relevant, in vitro model, each composed [...] Read more.

Discovering modes of action and predictive biomarkers of drug-induced structural cardiotoxicity offers the potential to improve cardiac safety assessment of lead compounds and enhance preclinical to clinical translation during drug development. Cardiac microtissues are a promising, physiologically relevant, in vitro model, each composed of ca. 500 cells. While untargeted metabolomics is capable of generating hypotheses on toxicological modes of action and discovering metabolic biomarkers, applying this technology to low-biomass microtissues in suspension is experimentally challenging. Thus, we first evaluated a filtration-based approach for harvesting microtissues and assessed the sensitivity and reproducibility of nanoelectrospray direct infusion mass spectrometry (nESI-DIMS) measurements of intracellular extracts, revealing samples consisting of 28 pooled microtissues, harvested by filtration, are suitable for profiling the intracellular metabolome and lipidome. Subsequently, an extensive workflow combining nESI-DIMS untargeted metabolomics and lipidomics of intracellular extracts with ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) analysis of spent culture medium, to profile the metabolic footprint and quantify drug exposure concentrations, was implemented. Using the synthetic drug and model cardiotoxin sunitinib, time-resolved metabolic and lipid perturbations in cardiac microtissues were investigated, providing valuable data for generating hypotheses on toxicological modes of action and identifying putative biomarkers such as disruption of purine metabolism and perturbation of polyunsaturated fatty acid levels. Full article

(This article belongs to the Special Issue Toxicometabolomics)

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16 pages, 1004 KiB

Open AccessArticle

Postmortem Metabolomics: Strategies to Assess Time-Dependent Postmortem Changes of Diazepam, Nordiazepam, Morphine, Codeine, Mirtazapine and Citalopram

by Lana Brockbals, Yannick Wartmann, Dylan Mantinieks, Linda L. Glowacki, Dimitri Gerostamoulos, Thomas Kraemer and Andrea E. Steuer

Metabolites 2021, 11(9), 643; https://doi.org/10.3390/metabo11090643 - 20 Sep 2021

Cited by 12 | Viewed by 3502

Abstract

Postmortem redistribution (PMR) can result in artificial drug concentration changes following death and complicate forensic case interpretation. Currently, no accurate methods for PMR prediction exist. Hence, alternative strategies were developed investigating the time-dependent postmortem behavior of diazepam, nordiazepam, morphine, codeine, mirtazapine and citalopram. [...] Read more.

Postmortem redistribution (PMR) can result in artificial drug concentration changes following death and complicate forensic case interpretation. Currently, no accurate methods for PMR prediction exist. Hence, alternative strategies were developed investigating the time-dependent postmortem behavior of diazepam, nordiazepam, morphine, codeine, mirtazapine and citalopram. For 477 authentic postmortem cases, femoral blood samples were collected at two postmortem time-points. All samples were quantified for drugs of abuse (targeted; liquid chromatography-tandem mass spectrometry LC-MS/MS) and characterized for small endogenous molecules (untargeted; gas chromatography-high resolution MS (GC-HRMS). Trends for significant time-dependent concentration decreases (diazepam (n = 137), nordiazepam (n = 126)), increases (mirtazapine (n = 55), citalopram (n = 50)) or minimal median postmortem changes (morphine (n = 122), codeine (n = 92)) could be observed. Robust mathematical mixed effect models were created for the generalized postmortem behavior of diazepam and nordiazepam, which could be used to back-calculate drug concentrations towards a time-point closer to the estimated time of death (caution: inter-individual variability). Significant correlations between time-dependent concentration changes of morphine, mirtazapine and citalopram with individual endogenous molecules could be determined; no correlation was deemed strong enough for successful a posteriori estimation on the occurrence of PMR for specific cases. The current dataset did successfully lead to a significant knowledge gain in further understanding the time-dependent postmortem behavior of the studied drugs (of abuse). Full article

(This article belongs to the Special Issue Metabolomics in Forensic Sciences)

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13 pages, 4368 KiB

Open AccessArticle

Preliminary Observations on Skeletal Muscle Adaptation and Plasticity in Homer 2^-/- Mice

by Paola Lorenzon, Sandra Furlan, Barbara Ravara, Alessandra Bosutti, Gabriele Massaria, Annalisa Bernareggi, Marina Sciancalepore, Gabor Trautmann, Katharina Block, Dieter Blottner, Paul F. Worley, Sandra Zampieri, Michele Salanova and Pompeo Volpe

Metabolites 2021, 11(9), 642; https://doi.org/10.3390/metabo11090642 - 19 Sep 2021

Cited by 4 | Viewed by 3055

Abstract

Homer represents a diversified family of scaffold and transduction proteins made up of several isoforms. Here, we present preliminary observations on skeletal muscle adaptation and plasticity in a transgenic model of Homer 2^-/- mouse using a multifaceted approach entailing morphometry, quantitative RT-PCR [...] Read more.

Homer represents a diversified family of scaffold and transduction proteins made up of several isoforms. Here, we present preliminary observations on skeletal muscle adaptation and plasticity in a transgenic model of Homer 2^-/- mouse using a multifaceted approach entailing morphometry, quantitative RT-PCR (Reverse Transcription PCR), confocal immunofluorescence, and electrophysiology. Morphometry shows that Soleus muscle (SOL), at variance with Extensor digitorum longus muscle (EDL) and Flexor digitorum brevis muscle (FDB), displays sizable reduction of fibre cross-sectional area compared to the WT counterparts. In SOL of Homer 2^-/- mice, quantitative RT-PCR indicated the upregulation of Atrogin-1 and Muscle ring finger protein 1 (MuRF1) genes, and confocal immunofluorescence showed the decrease of neuromuscular junction (NMJ) Homer content. Electrophysiological measurements of isolated FDB fibres from Homer 2^-/- mice detected the exclusive presence of the adult ε-nAChR isoform excluding denervation. As for NMJ morphology, data were not conclusive, and further work is needed to ascertain whether the null Homer 2 phenotype induces any endplate remodelling. Within the context of adaptation and plasticity, the present data show that Homer 2 is a co-regulator of the normotrophic status in a muscle specific fashion. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy and Metabolic Adaptation)

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32 pages, 3833 KiB

Open AccessReview

Glutathione Metabolism in Plants under Stress: Beyond Reactive Oxygen Species Detoxification

by Sonia Dorion, Jasmine C. Ouellet and Jean Rivoal

Metabolites 2021, 11(9), 641; https://doi.org/10.3390/metabo11090641 - 19 Sep 2021

Cited by 109 | Viewed by 9440

Abstract

Glutathione is an essential metabolite for plant life best known for its role in the control of reactive oxygen species (ROS). Glutathione is also involved in the detoxification of methylglyoxal (MG) which, much like ROS, is produced at low levels by aerobic metabolism [...] Read more.

Glutathione is an essential metabolite for plant life best known for its role in the control of reactive oxygen species (ROS). Glutathione is also involved in the detoxification of methylglyoxal (MG) which, much like ROS, is produced at low levels by aerobic metabolism under normal conditions. While several physiological processes depend on ROS and MG, a variety of stresses can dramatically increase their concentration leading to potentially deleterious effects. In this review, we examine the structure and the stress regulation of the pathways involved in glutathione synthesis and degradation. We provide a synthesis of the current knowledge on the glutathione-dependent glyoxalase pathway responsible for MG detoxification. We present recent developments on the organization of the glyoxalase pathway in which alternative splicing generate a number of isoforms targeted to various subcellular compartments. Stress regulation of enzymes involved in MG detoxification occurs at multiple levels. A growing number of studies show that oxidative stress promotes the covalent modification of proteins by glutathione. This post-translational modification is called S-glutathionylation. It affects the function of several target proteins and is relevant to stress adaptation. We address this regulatory function in an analysis of the enzymes and pathways targeted by S-glutathionylation. Full article

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

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13 pages, 1669 KiB

Open AccessArticle

Combined LXR and RXR Agonist Therapy Increases ABCA1 Protein Expression and Enhances ApoAI-Mediated Cholesterol Efflux in Cultured Endothelial Cells

by Kun Huang, Hanjoong Jo, Jing Echesabal-Chen and Alexis Stamatikos

Metabolites 2021, 11(9), 640; https://doi.org/10.3390/metabo11090640 - 18 Sep 2021

Cited by 15 | Viewed by 3795

Abstract

Endothelial ABCA1 expression protects against atherosclerosis and this atheroprotective effect is partially attributed to enhancing apoAI-mediated cholesterol efflux. ABCA1 is a target gene for LXR and RXR; therefore, treating endothelial cells with LXR and/or RXR agonists may increase ABCA1 expression. We tested whether [...] Read more.

Endothelial ABCA1 expression protects against atherosclerosis and this atheroprotective effect is partially attributed to enhancing apoAI-mediated cholesterol efflux. ABCA1 is a target gene for LXR and RXR; therefore, treating endothelial cells with LXR and/or RXR agonists may increase ABCA1 expression. We tested whether treating cultured immortalized mouse aortic endothelial cells (iMAEC) with the endogenous LXR agonist 22(R)-hydroxycholesterol, synthetic LXR agonist GW3965, endogenous RXR agonist 9-cis-retinoic acid, or synthetic RXR agonist SR11237 increases ABCA1 protein expression. We observed a significant increase in ABCA1 protein expression in iMAEC treated with either GW3965 or SR11237 alone, but no significant increase in ABCA1 protein was observed in iMAEC treated with either 22(R)-hydroxycholesterol or 9-cis-retionic acid alone. However, we observed significant increases in both ABCA1 protein expression and apoAI-mediated cholesterol efflux when iMAEC were treated with a combination of either 22(R)-hydroxycholesterol and 9-cis-retinoic acid or GW3965 and SR11237. Furthermore, treating iMAEC with either 22(R)-hydroxycholesterol and 9-cis-retinoic acid or GW3965 and SR11237 did not trigger an inflammatory response, based on VCAM-1, ICAM-1, CCL2, and IL-6 mRNA expression. Based on our findings, delivering LXR and RXR agonists precisely to endothelial cells may be a promising atheroprotective approach. Full article

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

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13 pages, 2312 KiB

Open AccessArticle

Efficacy and Safety of Insulin Degludec/Insulin Aspart Compared with a Conventional Premixed Insulin or Basal Insulin: A Meta-Analysis

by Shinje Moon, Hye-Soo Chung, Yoon-Jung Kim, Jae-Myung Yu, Woo-Ju Jeong, Jiwon Park and Chang-Myung Oh

Metabolites 2021, 11(9), 639; https://doi.org/10.3390/metabo11090639 - 18 Sep 2021

Cited by 4 | Viewed by 3395

Abstract

Insulin degludec/insulin aspart (IDegAsp) is a novel co-formulation of 70% insulin degludec and 30% insulin aspart. The present meta-analysis was conducted to assess the efficacy and safety of IDegAsp compared with a conventional premixed insulin or basal insulin. We extracted data from citation [...] Read more.

Insulin degludec/insulin aspart (IDegAsp) is a novel co-formulation of 70% insulin degludec and 30% insulin aspart. The present meta-analysis was conducted to assess the efficacy and safety of IDegAsp compared with a conventional premixed insulin or basal insulin. We extracted data from citation databases, including PubMed, EMBASE, and the Cochrane Library, since inception to 2021. We calculated the mean differences for hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), self-measured mean glucose, and postprandial glucose (PPG) and odds ratios for confirmed hypoglycemia events. Compared with twice-daily conventional premixed insulin, twice-daily IDegAsp showed a similar effect on changes in HbA1c, but it significantly reduced FPG and self-measured mean glucose levels. Furthermore, compared to once-daily basal insulin, once-daily IDegAsp had a similar effect on changes in HbA1c, but it significantly reduced self-measured mean glucose and PPG levels. The risk of overall confirmed hypoglycemia was similar between treatments; however, the risk of nocturnal hypoglycemia events was significantly lower with IDegAsp than with conventional premixed insulin and basal insulin. Thus, IDegAsp was more effective than conventional premixed insulin and basal insulin at reducing blood glucose with fewer nocturnal hypoglycemia events. Full article

(This article belongs to the Special Issue Insulin: A Life-Saving Hormone and Key Regulator of Metabolism)

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22 pages, 1830 KiB

Open AccessArticle

Metabolite Ratios as Quality Indicators for Pre-Analytical Variation in Serum and EDTA Plasma

by Sven Heiling, Nadine Knutti, Franziska Scherr, Jörg Geiger, Juliane Weikert, Michael Rose, Roland Jahns, Uta Ceglarek, André Scherag and Michael Kiehntopf

Metabolites 2021, 11(9), 638; https://doi.org/10.3390/metabo11090638 - 18 Sep 2021

Cited by 6 | Viewed by 3467

Abstract

In clinical diagnostics and research, blood samples are one of the most frequently used materials. Nevertheless, exploring the chemical composition of human plasma and serum is challenging due to the highly dynamic influence of pre-analytical variation. A prominent example is the variability in [...] Read more.

In clinical diagnostics and research, blood samples are one of the most frequently used materials. Nevertheless, exploring the chemical composition of human plasma and serum is challenging due to the highly dynamic influence of pre-analytical variation. A prominent example is the variability in pre-centrifugation delay (time-to-centrifugation; TTC). Quality indicators (QI) reflecting sample TTC are of utmost importance in assessing sample history and resulting sample quality, which is essential for accurate diagnostics and conclusive, reproducible research. In the present study, we subjected human blood to varying TTCs at room temperature prior to processing for plasma or serum preparation. Potential sample QIs were identified by Ultra high pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) based metabolite profiling in samples from healthy volunteers (n = 10). Selected QIs were validated by a targeted MS/MS approach in two independent sets of samples from patients (n = 40 and n = 70). In serum, the hypoxanthine/guanosine (HG) and hypoxanthine/inosine (HI) ratios demonstrated high diagnostic performance (Sensitivity/Specificity > 80%) for the discrimination of samples with a TTC > 1 h. We identified several eicosanoids, such as 12-HETE, 15-(S)-HETE, 8-(S)-HETE, 12-oxo-HETE, (±)13-HODE and 12-(S)-HEPE as QIs for a pre-centrifugation delay > 2 h. 12-HETE, 12-oxo-HETE, 8-(S)-HETE, and 12-(S)-HEPE, and the HI- and HG-ratios could be validated in patient samples. Full article

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

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21 pages, 2327 KiB

Open AccessArticle

Perturbation-Based Modeling Unveils the Autophagic Modulation of Chemosensitivity and Immunogenicity in Breast Cancer Cells

by Isaac Quiros-Fernandez, Lucía Figueroa-Protti, Jorge L. Arias-Arias, Norman Brenes-Cordero, Francisco Siles, Javier Mora and Rodrigo Antonio Mora-Rodríguez

Metabolites 2021, 11(9), 637; https://doi.org/10.3390/metabo11090637 - 18 Sep 2021

Cited by 1 | Viewed by 3844

Abstract

In the absence of new therapeutic strategies, chemotherapeutic drugs are the most widely used strategy against metastatic breast cancer, in spite of eliciting multiple adverse effects and having low responses with an average 5-year patient survival rate. Among the new therapeutic targets that [...] Read more.

In the absence of new therapeutic strategies, chemotherapeutic drugs are the most widely used strategy against metastatic breast cancer, in spite of eliciting multiple adverse effects and having low responses with an average 5-year patient survival rate. Among the new therapeutic targets that are currently in clinical trials, here, we addressed the association between the regulation of the metabolic process of autophagy and the exposure of damage-associated molecular patterns associated (DAMPs) to immunogenic cell death (ICD), which has not been previously studied. After validating an mCHR-GFP tandem LC3 sensor capacity to report dynamic changes of the autophagic metabolic flux in response to external stimuli and demonstrating that both basal autophagy levels and response to diverse autophagy regulators fluctuate among different cell lines, we explored the interaction between autophagy modulators and chemotherapeutic agents in regards of cytotoxicity and ICD using three different breast cancer cell lines. Since these interactions are very complex and variable throughout different cell lines, we designed a perturbation-based model in which we propose specific modes of action of chemotherapeutic agents on the autophagic flux and the corresponding strategies of modulation to enhance the response to chemotherapy. Our results point towards a promising therapeutic potential of the metabolic regulation of autophagy to overcome chemotherapy resistance by eliciting ICD. Full article

(This article belongs to the Special Issue Computational Biology for Metabolic Modelling)

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13 pages, 794 KiB

Open AccessReview

The Mitochondrial Prohibitin (PHB) Complex in C. elegans Metabolism and Ageing Regulation

by Artur B. Lourenço and Marta Artal-Sanz

Metabolites 2021, 11(9), 636; https://doi.org/10.3390/metabo11090636 - 17 Sep 2021

Cited by 9 | Viewed by 3699

Abstract

The mitochondrial prohibitin (PHB) complex, composed of PHB-1 and PHB-2, is an evolutionarily conserved context-dependent modulator of longevity. This extremely intriguing phenotype has been linked to alterations in mitochondrial function and lipid metabolism. The true biochemical function of the mitochondrial PHB complex remains [...] Read more.

The mitochondrial prohibitin (PHB) complex, composed of PHB-1 and PHB-2, is an evolutionarily conserved context-dependent modulator of longevity. This extremely intriguing phenotype has been linked to alterations in mitochondrial function and lipid metabolism. The true biochemical function of the mitochondrial PHB complex remains elusive, but it has been shown to affect membrane lipid composition. Recent work, using large-scale biochemical approaches, has highlighted a broad effect of PHB on the C. elegans metabolic network. Collectively, the biochemical data support the notion that PHB modulates, at least partially, worm longevity through the moderation of fat utilisation and energy production via the mitochondrial respiratory chain. Herein, we review, in a systematic manner, recent biochemical insights into the impact of PHB on the C. elegans metabolome. Full article

(This article belongs to the Special Issue Caenorhabditis elegans Applied to Metabolism Research)

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24 pages, 14847 KiB

Open AccessReview

Mass Spectrometry-Based Zebrafish Toxicometabolomics: A Review of Analytical and Data Quality Challenges

by Katyeny Manuela da Silva, Elias Iturrospe, Chloe Bars, Dries Knapen, Steven Van Cruchten, Adrian Covaci and Alexander L. N. van Nuijs

Metabolites 2021, 11(9), 635; https://doi.org/10.3390/metabo11090635 - 17 Sep 2021

Cited by 15 | Viewed by 4939

Abstract

Metabolomics has achieved great progress over the last 20 years, and it is currently considered a mature research field. As a result, the number of applications in toxicology, biomarker, and drug discovery has also increased. Toxicometabolomics has emerged as a powerful strategy to [...] Read more.

Metabolomics has achieved great progress over the last 20 years, and it is currently considered a mature research field. As a result, the number of applications in toxicology, biomarker, and drug discovery has also increased. Toxicometabolomics has emerged as a powerful strategy to provide complementary information to study molecular-level toxic effects, which can be combined with a wide range of toxicological assessments and models. The zebrafish model has gained importance in recent decades as a bridging tool between in vitro assays and mammalian in vivo studies in the field of toxicology. Furthermore, as this vertebrate model is a low-cost system and features highly conserved metabolic pathways found in humans and mammalian models, it is a promising tool for toxicometabolomics. This short review aims to introduce zebrafish researchers interested in understanding the effects of chemical exposure using metabolomics to the challenges and possibilities of the field, with a special focus on toxicometabolomics-based mass spectrometry. The overall goal is to provide insights into analytical strategies to generate and identify high-quality metabolomic experiments focusing on quality management systems (QMS) and the importance of data reporting and sharing. Full article

(This article belongs to the Special Issue Zebrafish: A Model for the Study of Human Metabolism Diseases)

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14 pages, 1487 KiB

Open AccessArticle

Age-Dependent Decrease in Hepatic Geranylgeranoic Acid Content in C3H/HeN Mice and Its Oral Supplementation Prevents Spontaneous Hepatoma

by Yuki Tabata, Masahide Omori and Yoshihiro Shidoji

Metabolites 2021, 11(9), 634; https://doi.org/10.3390/metabo11090634 - 17 Sep 2021

Cited by 8 | Viewed by 2871

Abstract

Geranylgeranoic acid (GGA) has been developed as a preventive agent against second primary hepatoma. Recently, GGA was reported to induce cell death in human hepatoma cells via TLR4-mediated pyroptosis. We have reported that GGA is enzymatically biosynthesized from mevalonic acid in human hepatoma-derived [...] Read more.

Geranylgeranoic acid (GGA) has been developed as a preventive agent against second primary hepatoma. Recently, GGA was reported to induce cell death in human hepatoma cells via TLR4-mediated pyroptosis. We have reported that GGA is enzymatically biosynthesized from mevalonic acid in human hepatoma-derived cells and that endogenous GGA is found in most organs of rats. In addition, we found that upregulation of endogenous GGA levels by zaragozic acid A (ZAA) induced cell death in human hepatoma-derived cells. Therefore, we investigated the age-related changes in hepatic GGA and the possibility of suppressing hepatocarcinogenesis by GGA supplementation using male C3H/HeN mice that spontaneously develop hepatoma. We measured endogenous GGA and mRNA of monoamine oxidase (BMAOB), a key enzyme of GGA biosynthesis, in the liver of male C3H/HeN mice aged 6–93 weeks. We also tried suppressing spontaneous hepatocarcinogenesis by a single administration of GGA to C3H/HeN mice. Hepatic GGA content and Maob mRNA expression level age-dependently decreased in male C3H/HeN mice; some of which produced spontaneous hepatoma in 2 years. A single oral administration of GGA at 11 months of age significantly prevented hepatoma in terms of the number and weight of tumors per mouse at 24 months. Oral supplementation with GGA or geranylgeraniol significantly increased endogenous hepatic GGA contents dose-dependently; and ZAA dramatically upregulated hepatic GGA. In this study; we found an age-dependent decrease in hepatic endogenous GGA in male C3H/HeN mice and efficient prevention of spontaneous hepatoma by a single administration of GGA at 11 months of age. Full article

(This article belongs to the Section Lipid Metabolism)

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18 pages, 3025 KiB

Open AccessArticle

A Targeted Serum Metabolomics GC-MS Approach Identifies Predictive Blood Biomarkers for Retained Placenta in Holstein Dairy Cows

by Guanshi Zhang, Dawid Tobolski, Grzegorz Zwierzchowski, Rupasri Mandal, David S. Wishart and Burim N. Ametaj

Metabolites 2021, 11(9), 633; https://doi.org/10.3390/metabo11090633 - 17 Sep 2021

Cited by 9 | Viewed by 3447

Abstract

The retained placenta is a common pathology of dairy cows. It is associated with a significant drop in the dry matter intake, milk yield, and increased susceptibility of dairy cows to metritis, mastitis, and displaced abomasum. The objective of this study was to [...] Read more.

The retained placenta is a common pathology of dairy cows. It is associated with a significant drop in the dry matter intake, milk yield, and increased susceptibility of dairy cows to metritis, mastitis, and displaced abomasum. The objective of this study was to identify metabolic alterations that precede and are associated with the disease occurrence. Blood samples were collected from 100 dairy cows at −8 and −4 weeks prior to parturition and on the day of retained placenta, and only 16 healthy cows and 6 cows affected by retained placenta were selected to measure serum polar metabolites by a targeted gas chromatography–mass spectroscopy (GC-MS) metabolomics approach. A total of 27 metabolites were identified and quantified in the serum. There were 10, 18, and 17 metabolites identified as being significantly altered during the three time periods studied. However, only nine metabolites were identified as being shared among the three time periods including five amino acids (Asp, Glu, Ser, Thr, and Tyr), one sugar (myo-inositol), phosphoric acid, and urea. The identified metabolites can be used as predictive biomarkers for the risk of retained placenta in dairy cows and might help explain the metabolic processes that occur prior to the incidence of the disease and throw light on the pathomechanisms of the disease. Full article

(This article belongs to the Special Issue Multi-Omics Methods in Dairy Research)

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15 pages, 1470 KiB

Open AccessArticle

A Randomized Controlled Dietary Intervention Improved the Serum Lipid Signature towards a Less Atherogenic Profile in Patients with Rheumatoid Arthritis

by Helen M. Lindqvist, Linnea Bärebring, Inger Gjertsson, Antti Jylhä, Reijo Laaksonen, Anna Winkvist and Mika Hilvo

Metabolites 2021, 11(9), 632; https://doi.org/10.3390/metabo11090632 - 17 Sep 2021

Cited by 6 | Viewed by 2620

Abstract

Diet is a major modifiable risk factor for cardiovascular disease (CVD). One explanation for this is its effect on specific lipids. However, knowledge on how the lipidome is affected is limited. We aimed to investigate if diet can change the new ceramide- and [...] Read more.

Diet is a major modifiable risk factor for cardiovascular disease (CVD). One explanation for this is its effect on specific lipids. However, knowledge on how the lipidome is affected is limited. We aimed to investigate if diet can change the new ceramide- and phospholipid-based CVD risk score CERT2 and the serum lipidome towards a more favorable CVD signature. In a crossover trial (ADIRA), 50 patients with rheumatoid arthritis (RA) had 10 weeks of a Mediterranean-style diet intervention or a Western-style control diet and then switched diets after a 4-month wash-out-period. Five hundred and thirty-eight individual lipids were measured in serum by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Lipid risk scores were analyzed by Wilcoxon signed-rank test or mixed model and lipidomic data with multivariate statistical methods. In the main analysis, including the 46 participants completing ≥1 diet period, there was no significant difference in CERT2 after the intervention compared with the control, although several CERT2 components were changed within periods. In addition, triacylglycerols, cholesteryl esters, phosphatidylcholines, alkylphosphatidylcholines and alkenylphosphatidylcholines had a healthier composition after the intervention compared to after the control diet. This trial indicates that certain dietary changes can improve the serum lipid signature towards a less atherogenic profile in patients with RA. Full article

(This article belongs to the Section Lipid Metabolism)

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18 pages, 3133 KiB

Open AccessFeature PaperArticle

A New Pipeline for the Normalization and Pooling of Metabolomics Data

by Vivian Viallon, Mathilde His, Sabina Rinaldi, Marie Breeur, Audrey Gicquiau, Bertrand Hemon, Kim Overvad, Anne Tjønneland, Agnetha Linn Rostgaard-Hansen, Joseph A. Rothwell, Lucie Lecuyer, Gianluca Severi, Rudolf Kaaks, Theron Johnson, Matthias B. Schulze, Domenico Palli, Claudia Agnoli, Salvatore Panico, Rosario Tumino, Fulvio Ricceri, W. M. Monique Verschuren, Peter Engelfriet, Charlotte Onland-Moret, Roel Vermeulen, Therese Haugdahl Nøst, Ilona Urbarova, Raul Zamora-Ros, Miguel Rodriguez-Barranco, Pilar Amiano, José Maria Huerta, Eva Ardanaz, Olle Melander, Filip Ottoson, Linda Vidman, Matilda Rentoft, Julie A. Schmidt, Ruth C. Travis, Elisabete Weiderpass, Mattias Johansson, Laure Dossus, Mazda Jenab, Marc J. Gunter, Justo Lorenzo Bermejo, Dominique Scherer, Reza M. Salek, Pekka Keski-Rahkonen and Pietro Ferrari Show full author list Hide full author list

Metabolites 2021, 11(9), 631; https://doi.org/10.3390/metabo11090631 - 17 Sep 2021

Cited by 14 | Viewed by 6855

Abstract

Pooling metabolomics data across studies is often desirable to increase the statistical power of the analysis. However, this can raise methodological challenges as several preanalytical and analytical factors could introduce differences in measured concentrations and variability between datasets. Specifically, different studies may use [...] Read more.

Pooling metabolomics data across studies is often desirable to increase the statistical power of the analysis. However, this can raise methodological challenges as several preanalytical and analytical factors could introduce differences in measured concentrations and variability between datasets. Specifically, different studies may use variable sample types (e.g., serum versus plasma) collected, treated, and stored according to different protocols, and assayed in different laboratories using different instruments. To address these issues, a new pipeline was developed to normalize and pool metabolomics data through a set of sequential steps: (i) exclusions of the least informative observations and metabolites and removal of outliers; imputation of missing data; (ii) identification of the main sources of variability through principal component partial R-square (PC-PR2) analysis; (iii) application of linear mixed models to remove unwanted variability, including samples’ originating study and batch, and preserve biological variations while accounting for potential differences in the residual variances across studies. This pipeline was applied to targeted metabolomics data acquired using Biocrates AbsoluteIDQ kits in eight case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Comprehensive examination of metabolomics measurements indicated that the pipeline improved the comparability of data across the studies. Our pipeline can be adapted to normalize other molecular data, including biomarkers as well as proteomics data, and could be used for pooling molecular datasets, for example in international consortia, to limit biases introduced by inter-study variability. This versatility of the pipeline makes our work of potential interest to molecular epidemiologists. Full article

(This article belongs to the Special Issue Metabolomics Meets Epidemiology)

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25 pages, 572 KiB

Open AccessSystematic Review

Metabolomic Profiling in Lung Cancer: A Systematic Review

by Daniela Madama, Rosana Martins, Ana S. Pires, Maria F. Botelho, Marco G. Alves, Ana M. Abrantes and Carlos R. Cordeiro

Metabolites 2021, 11(9), 630; https://doi.org/10.3390/metabo11090630 - 17 Sep 2021

Cited by 20 | Viewed by 4253

Abstract

Lung cancer continues to be a significant burden worldwide and remains the leading cause of cancer-associated mortality. Two considerable challenges posed by this disease are the diagnosis of 61% of patients in advanced stages and the reduced five-year survival rate of around 4%. [...] Read more.

Lung cancer continues to be a significant burden worldwide and remains the leading cause of cancer-associated mortality. Two considerable challenges posed by this disease are the diagnosis of 61% of patients in advanced stages and the reduced five-year survival rate of around 4%. Noninvasively collected samples are gaining significant interest as new areas of knowledge are being sought and opened up. Metabolomics is one of these growing areas. In recent years, the use of metabolomics as a resource for the study of lung cancer has been growing. We conducted a systematic review of the literature from the past 10 years in order to identify some metabolites associated with lung cancer. More than 150 metabolites have been associated with lung cancer-altered metabolism. These were detected in different biological samples by different metabolomic analytical platforms. Some of the published results have been consistent, showing the presence/alteration of specific metabolites. However, there is a clear variability due to lack of a full clinical characterization of patients or standardized patients selection. In addition, few published studies have focused on the added value of the metabolomic profile as a means of predicting treatment response for lung cancer. This review reinforces the need for consistent and systematized studies, which will help make it possible to identify metabolic biomarkers and metabolic pathways responsible for the mechanisms that promote tumor progression, relapse and eventually resistance to therapy. Full article

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

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20 pages, 7092 KiB

Open AccessArticle

Bioassay-Guided Isolation of Broad-Spectrum Fungicidal Active Compound from Artemisia ordosica

by Gaijuan Tang, Shuyu Yang, Wenqiong Hu, Jingyi Jiang, He Yan, Juntao Feng, Chao Zhang and Yonghong Wang

Metabolites 2021, 11(9), 629; https://doi.org/10.3390/metabo11090629 - 17 Sep 2021

Cited by 4 | Viewed by 2869

Abstract

To avoid the widespread resistance of commercial fungicides, new broad-spectrum botanical fungicides need to be developed. In previous bioactive screening assays, extracts of Artemisia ordosica Krasch. (A. ordosica) had highly antifungal activities, but the responsible phytochemicals were unidentified. In this study, [...] Read more.

To avoid the widespread resistance of commercial fungicides, new broad-spectrum botanical fungicides need to be developed. In previous bioactive screening assays, extracts of Artemisia ordosica Krasch. (A. ordosica) had highly antifungal activities, but the responsible phytochemicals were unidentified. In this study, active compounds of A. ordosica extracts were identified using a bioassay-guided method, and antifungal assays were performed in vitro and in vivo. The bioactive compounds were dissolved in petroleum ether, and the best antifungal fraction contained four compounds: trans-dehydromatricaria ester (TDDE), 7, 4-demetylnringenin, capillarin, and stearic acid. Among them, TDDE exhibited the highest antifungal activity against six pathogenic fungi and five bacteria. It exhibited significant fungicidal activity against Thanatephorus cucumeris and Botrytis cinerea with EC₅₀ values of 0.464 μg/mL and 1.4 μg/mL, respectively. The living tissue bioassay results showed that the relative protection effects (RPE) of TDDE on tomato leaves, tomato fruit, and strawberry leaves infected with B. cinerea reached 76.78%, 86.2%, and 80.89%, respectively. In pot experiments, the RPE on tomato and strawberry plants infected with B. cinerea reached 84.11% and 96.37%, respectively. Morphological and physiological examination showed that TDDE had significant inhibitory effects on mycelial growth, including increased top offshoot, contorted hyphal tips, and extravasated cytochylema. Meanwhile, bactericidal activities of TDDE were significantly higher than kanamycin and streptomycin in five bacteria, and the plant tissue experiments further demonstrated that it had an 88.31% RPE on walnut leaves infected with Xanthomonas campestris pv. jugiandis, 72.18% RPE on potato infected with Erwinia carotovora subsp. carotovora, and 82.50% RPE on kiwifruit branches infected with Pseudomonas syringae pv. actinidiae. The active compounds isolated from A. ordosica in this study show great potential value for developing broad-spectrum fungicides, and also provide an important way to identify and isolate new bioactive products from medicinal plants. Full article

(This article belongs to the Section Plant Metabolism)

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14 pages, 13707 KiB

Open AccessArticle

A Distinctive Human Metabolomics Alteration Associated with Osteopenic and Osteoporotic Patients

by Shereen M. Aleidi, Eman A. Alnehmi, Mohammed Alshaker, Afshan Masood, Hicham Benabdelkamel, Mysoon M. Al-Ansari and Anas M. Abdel Rahman

Metabolites 2021, 11(9), 628; https://doi.org/10.3390/metabo11090628 - 16 Sep 2021

Cited by 29 | Viewed by 4125

Abstract

Osteoporosis is a common progressive metabolic bone disease resulting in decreased bone mineral density (BMD) and a subsequent increase in fracture risk. The known bone markers are not sensitive and specific enough to reflect the balance in the bone metabolism. Finding a metabolomics-based [...] Read more.

Osteoporosis is a common progressive metabolic bone disease resulting in decreased bone mineral density (BMD) and a subsequent increase in fracture risk. The known bone markers are not sensitive and specific enough to reflect the balance in the bone metabolism. Finding a metabolomics-based biomarker specific for bone desorption or lack of bone formation is crucial for predicting bone health earlier. This study aimed to investigate patients’ metabolomic profiles with low BMD (LBMD), including those with osteopenia (ON) and osteoporosis (OP), compared to healthy controls. An untargeted mass spectrometry (MS)-based metabolomics approach was used to analyze serum samples. Results showed a clear separation between patients with LBMD and control (Q² = 0.986, R² = 0.994), reflecting a significant difference in the dynamic of metabolic processes between the study groups. A total of 116 putatively identified metabolites were significantly associated with LBMD. Ninety-four metabolites were dysregulated, with 52 up- and 42 downregulated in patients with LBMD compared to controls. Histidine metabolism, aminoacyl-tRNA biosynthesis, glyoxylate, dicarboxylate metabolism, and biosynthesis of unsaturated fatty acids were the most common metabolic pathways dysregulated in LBMD. Furthermore, 35 metabolites were significantly dysregulated between ON and OP groups, with 11 up- and 24 downregulated in ON compared to OP. Among the upregulated metabolites were 3-carboxy-4-methyl-5-propyl-2-2furanopropionic acid (CMPF) and carnitine derivatives (i.e., 3-hydroxy-11-octadecenoylcarnitine, and l-acetylcarnitine), whereas phosphatidylcholine (PC), sphingomyelin (SM), and palmitic acid (PA) were among the downregulated metabolites in ON compared to OP. This study would add a layer to understanding the possible metabolic alterations associated with ON and OP. Additionally, this identified metabolic panel would help develop a prediction model for bone health and OP progression. Full article

(This article belongs to the Special Issue Metabolic Profiles in Diseases: From Diagnosis to Characterization and Clinical Management)

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22 pages, 5573 KiB

Open AccessArticle

Comparative Untargeted Metabolomic Profiling of Induced Mitochondrial Fusion in Pancreatic Cancer

by Nicholas D. Nguyen, Meifang Yu, Vinit Y. Reddy, Ariana C. Acevedo-Diaz, Enzo C. Mesarick, Joseph Abi Jaoude, Min Yuan, John M. Asara and Cullen M. Taniguchi

Metabolites 2021, 11(9), 627; https://doi.org/10.3390/metabo11090627 - 15 Sep 2021

Cited by 3 | Viewed by 3324

Abstract

Mitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp1). Mfn2 induces the fusion of nearby mitochondria, while Drp1 mediates mitochondrial fission. We previously found that the genetic or pharmacological [...] Read more.

Mitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp1). Mfn2 induces the fusion of nearby mitochondria, while Drp1 mediates mitochondrial fission. We previously found that the genetic or pharmacological activation of mitochondrial fusion was tumor suppressive against pancreatic ductal adenocarcinoma (PDAC) in several model systems. The mechanisms of how these different inducers of mitochondrial fusion reduce pancreatic cancer growth are still unknown. Here, we characterized and compared the metabolic reprogramming of these three independent methods of inducing mitochondrial fusion in KPC cells: overexpression of Mfn2, genetic editing of Drp1, or treatment with leflunomide. We identified significantly altered metabolites via robust, orthogonal statistical analyses and found that mitochondrial fusion consistently produces alterations in the metabolism of amino acids. Our unbiased methodology revealed that metabolic perturbations were similar across all these methods of inducing mitochondrial fusion, proposing a common pathway for metabolic targeting with other drugs. Full article

(This article belongs to the Special Issue MS-Based Drug Metabolism in Cancer Research)

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20 pages, 3300 KiB

Open AccessArticle

Metabolic Reprogramming of Mammary Epithelial Cells during TGF-β-Induced Epithelial-to-Mesenchymal Transition

by Wan Hua, Sarantos Kostidis, Oleg Mayboroda, Martin Giera, Marten Hornsveld and Peter ten Dijke

Metabolites 2021, 11(9), 626; https://doi.org/10.3390/metabo11090626 - 15 Sep 2021

Cited by 11 | Viewed by 3232

Abstract

The cytokine transforming growth factor-β (TGF-β) can induce normal breast epithelial cells to take on a mesenchymal phenotype, termed epithelial-to-mesenchymal transition (EMT). While the transcriptional and proteomic changes during TGF-β-induced EMT have been described, the metabolic rewiring that occurs in epithelial cells undergoing [...] Read more.

The cytokine transforming growth factor-β (TGF-β) can induce normal breast epithelial cells to take on a mesenchymal phenotype, termed epithelial-to-mesenchymal transition (EMT). While the transcriptional and proteomic changes during TGF-β-induced EMT have been described, the metabolic rewiring that occurs in epithelial cells undergoing EMT is not well understood. Here, we quantitively analyzed the TGF-β-induced metabolic reprogramming during EMT of non-transformed NMuMG mouse mammary gland epithelial cells using nuclear magnetic resonance (NMR) spectroscopy. We found that TGF-β elevates glycolytic and tricarboxylic acid (TCA)-cycle activity and increases glutaminolysis. Additionally, TGF-β affects the hexosamine pathway, arginine-proline metabolism, the cellular redox state, and strongly affects choline metabolism during EMT. TGF-β was found to induce phosphocholine production. A kinase inhibitor RSM-93A that inhibits choline kinase α (CHKα) mitigated TGF-β-induced changes associated with EMT, i.e., increased filamentous (F)-actin stress fiber formation and N-Cadherin mesenchymal marker expression. Full article

(This article belongs to the Section Cell Metabolism)

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12 pages, 4376 KiB

Open AccessFeature PaperArticle

Lipid Profile and Hepatic Fat Content Measured by ¹H MR Spectroscopy in Patients before and after Liver Transplantation

by Martin Burian, Milan Hajek, Petr Sedivy, Irena Mikova, Pavel Trunecka and Monika Dezortova

Metabolites 2021, 11(9), 625; https://doi.org/10.3390/metabo11090625 - 15 Sep 2021

Cited by 3 | Viewed by 2421

Abstract

Increased hepatic fat content (HFC) is a hallmark of non-alcoholic fatty liver (NAFL) disease, a common condition in liver transplant recipients. Proton MR spectroscopy (¹H MRS) and MR imaging-based proton density fat fraction as the only diagnosis modality enable precise non-invasive [...] Read more.

Increased hepatic fat content (HFC) is a hallmark of non-alcoholic fatty liver (NAFL) disease, a common condition in liver transplant recipients. Proton MR spectroscopy (¹H MRS) and MR imaging-based proton density fat fraction as the only diagnosis modality enable precise non-invasive measurement of HFC and, also, fatty acid profiles in vivo. Using ¹H MRS at 3T, we examined 47 liver transplantation candidates and 101 liver graft recipients. A point-resolved spectroscopy sequence was used to calculate the steatosis grade along with the saturated, unsaturated and polyunsaturated fractions of fatty acids in the liver. The steatosis grade measured by MRS was compared with the histological steatosis grade. HFC, represented by fat fraction values, is adept at distinguishing non-alcoholic steatohepatitis (NASH), NAFL and non-steatotic liver transplant patients. Relative hepatic lipid saturation increases while unsaturation decreases in response to increased HFC. Additionally, relative hepatic lipid saturation increases while unsaturation and polyunsaturation both decrease in liver recipients with histologically proven post-transplant NASH or NAFL compared to non-steatotic patients. HFC, measured by in vivo ¹H MRS, correlated well with histological results. ¹H MRS is a simple and fast method for in vivo analysis of HFC and its composition. It provides non-invasive support for NAFL and NASH diagnoses. Full article

(This article belongs to the Special Issue The Application of Imaging Technology in Studying Liver Metabolism)

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13 pages, 3174 KiB

Open AccessArticle

Matrix-Free High-Resolution Atmospheric-Pressure SALDI Mass Spectrometry Imaging of Biological Samples Using Nanostructured DIUTHAME Membranes

by Max A. Müller, Dhaka R. Bhandari and Bernhard Spengler

Metabolites 2021, 11(9), 624; https://doi.org/10.3390/metabo11090624 - 15 Sep 2021

Cited by 7 | Viewed by 3589

Abstract

Applications of mass spectrometry imaging (MSI), especially matrix-assisted laser desorption/ionization (MALDI) in the life sciences are becoming increasingly focused on single cell analysis. With the latest instrumental developments, pixel sizes in the micrometer range can be obtained, leading to challenges in matrix application, [...] Read more.

Applications of mass spectrometry imaging (MSI), especially matrix-assisted laser desorption/ionization (MALDI) in the life sciences are becoming increasingly focused on single cell analysis. With the latest instrumental developments, pixel sizes in the micrometer range can be obtained, leading to challenges in matrix application, where imperfections or inhomogeneities in the matrix layer can lead to misinterpretation of MS images. Thereby, the application of premanufactured, homogeneous ionization-assisting devices is a promising approach. Tissue sections were investigated using a matrix-free imaging technique (Desorption Ionization Using Through-Hole Alumina Membrane, DIUTHAME) based on premanufactured nanostructured membranes to be deposited on top of a tissue section, in comparison to the spray-coating of an organic matrix in a MALDI MSI approach. Atmospheric pressure MALDI MSI ion sources were coupled to orbital trapping mass spectrometers. MS signals obtained by the different ionization techniques were annotated using accurate-mass-based database research. Compared to MALDI MSI, DIUTHAME MS images captivated with higher signal homogeneities, higher contrast and reduced background signals, while signal intensities were reduced by about one order of magnitude, independent of analyte class. DIUTHAME membranes, being applicable only on tissue sections thicker than 50 µm, were successfully used for mammal, insect and plant tissue with a high lateral resolution down to 5 µm. Full article

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

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17 pages, 4201 KiB

Open AccessArticle

Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology

by Xiaoguang Liu, Kaluvu Balaraman, Ciarán C. Lynch, Michaeline Hebron, Christian Wolf and Charbel Moussa

Metabolites 2021, 11(9), 622; https://doi.org/10.3390/metabo11090622 - 15 Sep 2021

Cited by 14 | Viewed by 5329

Abstract

Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer’s disease (AD) and Parkinson’s disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration. We synthesized novel [...] Read more.

Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer’s disease (AD) and Parkinson’s disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration. We synthesized novel analogues of spautin-1 which is a non-specific USP13 inhibitor but unable to penetrate the brain. Our synthesized small molecule compounds are able to enter the brain, more potently inhibit USP13, and significantly reduce alpha-synuclein levels in vivo and in vitro. USP13 inhibition in transgenic mutant alpha-synuclein (A53T) mice increased the ubiquitination of alpha-synuclein and reduced its protein levels. The data suggest that novel USP13 inhibitors improve neurodegenerative pathology via antagonism of de-ubiquitination, thus alleviating neurotoxic protein burden in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Brain Metabolomics: New Perspective on Neurodegenerative Disorders)

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17 pages, 2298 KiB

Open AccessArticle

Correlation between Pre-Ovulatory Follicle Diameter and Follicular Fluid Metabolome Profiles in Lactating Beef Cows

by Casey C. Read, Lannett Edwards, Neal Schrick, Justin D. Rhinehart, Rebecca R. Payton, Shawn R. Campagna, Hector F. Castro, Jessica L. Klabnik, Emma J. Horn and Sarah E. Moorey

Metabolites 2021, 11(9), 623; https://doi.org/10.3390/metabo11090623 - 14 Sep 2021

Cited by 16 | Viewed by 5842

Abstract

Induced ovulation of small pre-ovulatory follicles reduced pregnancy rates, embryo survival, day seven embryo quality, and successful embryo cleavage in beef cows undergoing fixed-time artificial insemination. RNA-sequencing of oocytes and associated cumulus cells collected from pre-ovulatory follicles 23 h after gonadotropin-releasing hormone (GnRH) [...] Read more.

Induced ovulation of small pre-ovulatory follicles reduced pregnancy rates, embryo survival, day seven embryo quality, and successful embryo cleavage in beef cows undergoing fixed-time artificial insemination. RNA-sequencing of oocytes and associated cumulus cells collected from pre-ovulatory follicles 23 h after gonadotropin-releasing hormone (GnRH) administration to induce the pre-ovulatory gonadotropin surge suggested reduced capacity for glucose metabolism in cumulus cells of follicles ≤11.7 mm. We hypothesized that the follicular fluid metabolome influences metabolic capacity of the cumulus-oocyte complex and contributes to reduced embryo cleavage and quality grade observed following induced ovulation of small follicles. Therefore, we performed a study to determine the correlation between pre-ovulatory follicle diameter and follicular fluid metabolome profiles in lactating beef cows (Angus, n = 130). We synchronized the development of a pre-ovulatory follicle and collected the follicular contents approximately 20 h after GnRH administration. We then performed ultra-high performance liquid chromatography—high resolution mass spectrometry (UHPLC-HRMS) metabolomic studies on 43 follicular fluid samples and identified 38 metabolites within pre-ovulatory follicles of increasing size. We detected 18 metabolites with a significant, positive correlation to follicle diameter. Individual and pathway enrichment analysis of significantly correlated metabolites suggest that altered glucose and amino acid metabolism likely contribute to reduced developmental competence of oocytes when small pre-ovulatory follicles undergo induced ovulation. Full article

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

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26 pages, 1540 KiB

Open AccessReview

Lipid Metabolite Biomarkers in Cardiovascular Disease: Discovery and Biomechanism Translation from Human Studies

by Peter McGranaghan, Jennifer A. Kirwan, Mariel A. Garcia-Rivera, Burkert Pieske, Frank Edelmann, Florian Blaschke, Sandeep Appunni, Anshul Saxena, Muni Rubens, Emir Veledar and Tobias Daniel Trippel

Metabolites 2021, 11(9), 621; https://doi.org/10.3390/metabo11090621 - 14 Sep 2021

Cited by 31 | Viewed by 7001

Abstract

Lipids represent a valuable target for metabolomic studies since altered lipid metabolism is known to drive the pathological changes in cardiovascular disease (CVD). Metabolomic technologies give us the ability to measure thousands of metabolites providing us with a metabolic fingerprint of individual patients. [...] Read more.

Lipids represent a valuable target for metabolomic studies since altered lipid metabolism is known to drive the pathological changes in cardiovascular disease (CVD). Metabolomic technologies give us the ability to measure thousands of metabolites providing us with a metabolic fingerprint of individual patients. Metabolomic studies in humans have supported previous findings into the pathomechanisms of CVD, namely atherosclerosis, apoptosis, inflammation, oxidative stress, and insulin resistance. The most widely studied classes of lipid metabolite biomarkers in CVD are phospholipids, sphingolipids/ceramides, glycolipids, cholesterol esters, fatty acids, and acylcarnitines. Technological advancements have enabled novel strategies to discover individual biomarkers or panels that may aid in the diagnosis and prognosis of CVD, with sphingolipids/ceramides as the most promising class of biomarkers thus far. In this review, application of metabolomic profiling for biomarker discovery to aid in the diagnosis and prognosis of CVD as well as metabolic abnormalities in CVD will be discussed with particular emphasis on lipid metabolites. Full article

(This article belongs to the Special Issue Insights into the Bioenergetics and Metabolism in Normal and Failing Heart)

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12 pages, 2347 KiB

Open AccessArticle

KLF15 Regulates Oxidative Stress Response in Cardiomyocytes through NAD⁺

by Le Li, Weiyi Xu and Lilei Zhang

Metabolites 2021, 11(9), 620; https://doi.org/10.3390/metabo11090620 - 13 Sep 2021

Cited by 7 | Viewed by 2804

Abstract

KLF15 has recently emerged as a central regulator of metabolism. Although its connection to oxidative stress has been suspected, there has not been any study to date that directly demonstrates the molecular link. In this study, we sought to determine the role of [...] Read more.

KLF15 has recently emerged as a central regulator of metabolism. Although its connection to oxidative stress has been suspected, there has not been any study to date that directly demonstrates the molecular link. In this study, we sought to determine the role of KLF15 in cardiac oxidative stress. We found that KLF15 deficiency in the heart is associated with increased oxidative stress. Acute deficiency of KLF15 in neonatal rat ventricular myocytes (NRVMs) leads to the defective clearance of reactive oxygen species (ROS) and an exaggerated cell death following a variety of oxidative stresses. Mechanistically, we found that KLF15 deficiency leads to reduced amounts of the rate-limiting NAD⁺ salvage enzyme NAMPT and to NAD⁺ deficiency. The resultant SIRT3-dependent hyperacetylation and the inactivation of mitochondrial antioxidants can be rescued by MnSOD mimetics or NAD⁺ precursors. Collectively, these findings suggest that KLF15 regulates cardiac ROS clearance through the regulation of NAD⁺ levels. Our findings establish KLF15 as a central coordinator of cardiac metabolism and ROS clearance. Full article

(This article belongs to the Special Issue Insights into the Bioenergetics and Metabolism in Normal and Failing Heart)

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16 pages, 2979 KiB

Open AccessArticle

Metabolomic Analysis Reveals Changes in Plasma Metabolites in Response to Acute Cold Stress and Their Relationships to Metabolic Health in Cold-Acclimatized Humans

by Zuzana Kovaničová, Miloslav Karhánek, Tímea Kurdiová, Miroslav Baláž, Christian Wolfrum, Barbara Ukropcová and Jozef Ukropec

Metabolites 2021, 11(9), 619; https://doi.org/10.3390/metabo11090619 - 12 Sep 2021

Cited by 8 | Viewed by 3381

Abstract

Cold exposure results in activation of metabolic processes required for fueling thermogenesis, potentially promoting improved metabolic health. However, the metabolic complexity underlying this process is not completely understood. We aimed to analyze changes in plasma metabolites related to acute cold exposure and their [...] Read more.

Cold exposure results in activation of metabolic processes required for fueling thermogenesis, potentially promoting improved metabolic health. However, the metabolic complexity underlying this process is not completely understood. We aimed to analyze changes in plasma metabolites related to acute cold exposure and their relationship to cold-acclimatization level and metabolic health in cold-acclimatized humans. Blood samples were obtained before and acutely after 10–15 min of ice-water swimming (<5 °C) from 14 ice-water swimmers. Using mass spectrometry, 973 plasma metabolites were measured. Ice-water swimming induced acute changes in 70 metabolites. Pathways related to amino acid metabolism were the most cold-affected and cold-induced changes in several amino acids correlated with cold-acclimatization level and/or metabolic health markers, including atherogenic lipid profile or insulin resistance. Metabolites correlating with cold-acclimatization level were enriched in the linoleic/α-linolenic acid metabolic pathway. N-lactoyl-tryptophan correlated with both cold-acclimatization level and cold-induced changes in thyroid and parathyroid hormones. Acute cold stress in cold-acclimatized humans induces changes in plasma metabolome that involve amino acids metabolism, while the linoleic and α-linolenic acid metabolism pathway seems to be affected by regular cold exposure. Metabolites related to metabolic health, thermogenic hormonal regulators and acclimatization level might represent prospective molecular factors important in metabolic adaptations to regular cold exposure. Full article

(This article belongs to the Section Integrative Metabolomics)

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22 pages, 1209 KiB

Open AccessReview

Liver Impairment—The Potential Application of Volatile Organic Compounds in Hepatology

by Georgios Stavropoulos, Kim van Munster, Giuseppe Ferrandino, Marius Sauca, Cyriel Ponsioen, Frederik-Jan van Schooten and Agnieszka Smolinska

Metabolites 2021, 11(9), 618; https://doi.org/10.3390/metabo11090618 - 11 Sep 2021

Cited by 22 | Viewed by 3986

Abstract

Liver diseases are currently diagnosed through liver biopsy. Its invasiveness, costs, and relatively low diagnostic accuracy require new techniques to be sought. Analysis of volatile organic compounds (VOCs) in human bio-matrices has received a lot of attention. It is known that a musty [...] Read more.

Liver diseases are currently diagnosed through liver biopsy. Its invasiveness, costs, and relatively low diagnostic accuracy require new techniques to be sought. Analysis of volatile organic compounds (VOCs) in human bio-matrices has received a lot of attention. It is known that a musty odour characterises liver impairment, resulting in the elucidation of volatile chemicals in the breath and other body fluids such as urine and stool, which may serve as biomarkers of a disease. Aims: This study aims to review all the studies found in the literature regarding VOCs in liver diseases, and to summarise all the identified compounds that could be used as diagnostic or prognostic biomarkers. The literature search was conducted on ScienceDirect and PubMed, and each eligible publication was qualitatively assessed by two independent evaluators using the SANRA critical appraisal tool. Results: In the search, 58 publications were found, and 28 were kept for inclusion: 23 were about VOCs in the breath, one in the bile, three in urine, and one in faeces. Each publication was graded from zero to ten. A graphical summary of the metabolic pathways showcasing the known liver disease-related VOCs and suggestions on how VOC analysis on liver impairment could be applied in clinical practice are given. Full article

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

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24 pages, 1456 KiB

Open AccessReview

Adipose Tissue and Biological Factors. Possible Link between Lymphatic System Dysfunction and Obesity

by Klaudia Antoniak, Rita Hansdorfer-Korzon, Małgorzata Mrugacz and Katarzyna Zorena

Metabolites 2021, 11(9), 617; https://doi.org/10.3390/metabo11090617 - 11 Sep 2021

Cited by 11 | Viewed by 5939

Abstract

The World Health Organization (WHO) has recognised obesity as one of the top ten threats to human health. Obesity is not only a state of abnormally increased adipose tissue in the body, but also of an increased release of biologically active metabolites. Moreover, [...] Read more.

The World Health Organization (WHO) has recognised obesity as one of the top ten threats to human health. Obesity is not only a state of abnormally increased adipose tissue in the body, but also of an increased release of biologically active metabolites. Moreover, obesity predisposes the development of metabolic syndrome and increases the incidence of type 2 diabetes (T2DM), increases the risk of developing insulin resistance, atherosclerosis, ischemic heart disease, polycystic ovary syndrome, hypertension and cancer. The lymphatic system is a one-directional network of thin-walled capillaries and larger vessels covered by a continuous layer of endothelial cells that provides a unidirectional conduit to return filtered arterial and tissue metabolites towards the venous circulation. Recent studies have shown that obesity can markedly impair lymphatic function. Conversely, dysfunction in the lymphatic system may also be involved in the pathogenesis of obesity. This review highlights the important findings regarding obesity related to lymphatic system dysfunction, including clinical implications and experimental studies. Moreover, we present the role of biological factors in the pathophysiology of the lymphatic system and we propose the possibility of a therapy supporting the function of the lymphatic system in the course of obesity. Full article

(This article belongs to the Special Issue Metabolic Health and Weight II)

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