Metabolites

18 pages, 673 KiB

Open AccessArticle

Transcriptome Profile Reveals Genetic and Metabolic Mechanisms Related to Essential Fatty Acid Content of Intramuscular Longissimus thoracis in Nellore Cattle

by Gustavo Pimenta Schettini, Elisa Peripolli, Pâmela Almeida Alexandre, Wellington Bizarria dos Santos, Angélica Simone Cravo Pereira, Lúcia Galvão de Albuquerque, Fernando Baldi and Rogério Abdallah Curi

Metabolites 2022, 12(5), 471; https://doi.org/10.3390/metabo12050471 - 23 May 2022

Cited by 3 | Viewed by 3110

Abstract

Beef is a source of essential fatty acids (EFA), linoleic (LA) and alpha-linolenic (ALA) acids, which protect against inflammatory and cardiovascular diseases in humans. However, the intramuscular EFA profile in cattle is a complex and polygenic trait. Thus, this study aimed to identify [...] Read more.

Beef is a source of essential fatty acids (EFA), linoleic (LA) and alpha-linolenic (ALA) acids, which protect against inflammatory and cardiovascular diseases in humans. However, the intramuscular EFA profile in cattle is a complex and polygenic trait. Thus, this study aimed to identify potential regulatory genes of the essential fatty acid profile in Longissimus thoracis of Nellore cattle finished in feedlot. Forty-four young bulls clustered in four groups of fifteen animals with extreme values for each FA were evaluated through differentially expressed genes (DEG) analysis and two co-expression methodologies (WGCNA and PCIT). We highlight the ECHS1, IVD, ASB5, and ERLIN1 genes and the TF NFIA, indicated in both FA. Moreover, we associate the NFYA, NFYB, PPARG, FASN, and FADS2 genes with LA, and the RORA and ELOVL5 genes with ALA. Furthermore, the functional enrichment analysis points out several terms related to FA metabolism. These findings contribute to our understanding of the genetic mechanisms underlying the beef EFA profile in Nellore cattle finished in feedlot. Full article

(This article belongs to the Special Issue Insights into Increasing Meat Production Using Omics Technologies)

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12 pages, 444 KiB

Open AccessArticle

Volatile Organic Compounds Frequently Identified after Hyperbaric Hyperoxic Exposure: The VAPOR Library

by Feiko J. M. de Jong, Paul Brinkman, Thijs T. Wingelaar, Pieter-Jan A. M. van Ooij and Rob A. van Hulst

Metabolites 2022, 12(5), 470; https://doi.org/10.3390/metabo12050470 - 23 May 2022

Cited by 9 | Viewed by 2480

Abstract

Diving or hyperbaric oxygen therapy with increased partial pressures of oxygen (pO₂) can have adverse effects such as central nervous system oxygen toxicity or pulmonary oxygen toxicity (POT). Prevention of POT has been a topic of interest for several decades. One [...] Read more.

Diving or hyperbaric oxygen therapy with increased partial pressures of oxygen (pO₂) can have adverse effects such as central nervous system oxygen toxicity or pulmonary oxygen toxicity (POT). Prevention of POT has been a topic of interest for several decades. One of the most promising techniques to determine early signs of POT is the analysis of volatile organic compounds (VOCs) in exhaled breath. We reanalyzed the data of five studies to compose a library of potential exhaled markers for the early detection of POT. GC-MS data from five hyperbaric hyperoxic studies were collected. Wilcoxon signed-rank tests were used to compare baseline- and postexposure measurements; all ion fragments that significantly varied were compared by similarity using the National Institute of Standards and Technology (NIST) library. All identified molecules were cross-referenced with open-source databases and other scientific publications on VOCs to exclude compounds that occurred as a result of contamination, and to identify the compounds most likely to occur due to hyperbaric hyperoxic exposure. After identification and removal of contaminants, 29 compounds were included in the library. This library of hyperbaric hyperoxic-related VOCs can help to advance the development of an early noninvasive marker of POT. It enables validation by others who use more targeted MS-related techniques, instead of full-scale GC-MS, for their exhaled VOC research. Full article

(This article belongs to the Special Issue Mass Spectral Libraries and Databases for Metabolomics)

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13 pages, 1896 KiB

Open AccessArticle

Increased Ammonium Toxicity in Response to Exogenous Glutamine in Metastatic Breast Cancer Cells

by Violet A. Kiesel, Madeline P. Sheeley, Shawn S. Donkin, Michael K. Wendt, Stephen D. Hursting and Dorothy Teegarden

Metabolites 2022, 12(5), 469; https://doi.org/10.3390/metabo12050469 - 23 May 2022

Viewed by 2379

Abstract

Several cancers, including breast cancers, show dependence on glutamine metabolism. The purpose of the present study was to determine the mechanistic basis and impact of differential glutamine metabolism in nonmetastatic and metastatic murine mammary cancer cells. Universally labeled ¹³C₅-glutamine metabolic [...] Read more.

Several cancers, including breast cancers, show dependence on glutamine metabolism. The purpose of the present study was to determine the mechanistic basis and impact of differential glutamine metabolism in nonmetastatic and metastatic murine mammary cancer cells. Universally labeled ¹³C₅-glutamine metabolic tracing, qRT-PCR, measures of reductive–oxidative balance, and exogenous ammonium chloride treatment were used to assess glutamine reprogramming. Results show that 4 mM media concentration of glutamine, compared with 2 mM, reduced viability only in metastatic cells, and that this decrease in viability was accompanied by increased incorporation of glutamine-derived carbon into the tricarboxylic acid (TCA) cycle. While increased glutamine metabolism in metastatic cells occurred in tandem with a decrease in the reduced/oxidized glutathione ratio, treatment with the antioxidant molecule N-acetylcysteine did not rescue cell viability. However, the viability of metastatic cells was more sensitive to ammonium chloride treatment compared with nonmetastatic cells, suggesting a role of metabolic reprogramming in averting nitrogen cytotoxicity in nonmetastatic cells. Overall, these results demonstrate the ability of nonmetastatic cancer cells to reprogram glutamine metabolism and that this ability may be lost in metastatic cells. Full article

(This article belongs to the Special Issue Cancer Associated Changes in Metabolism)

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8 pages, 238 KiB

Open AccessProject Report

Obesity and Voiding Parameters in a Community-Based Population of Okinawa, Japan: Kumejima Digital Health Project (KDHP)

by Asuka Ashikari, Minoru Miyazato, Koshi Nakamura, Kiyoto Yamashiro, Takehiro Nakamura, Tsugumi Uema, Moriyuki Uehara, Hiroaki Masuzaki, Seiichi Saito, Shiro Maeda, Hajime Ishida and Masayuki Matsushita

Metabolites 2022, 12(5), 468; https://doi.org/10.3390/metabo12050468 - 23 May 2022

Viewed by 2467

Abstract

(1) Background: Evidence has accumulated regarding the etiology of lower urinary tract symptoms associated with obesity and metabolic syndrome. Therefore, the present study aimed to identify which subjectively and objectively measured voiding parameters were associated with obesity in a community-based population. (2) Methods: [...] Read more.

(1) Background: Evidence has accumulated regarding the etiology of lower urinary tract symptoms associated with obesity and metabolic syndrome. Therefore, the present study aimed to identify which subjectively and objectively measured voiding parameters were associated with obesity in a community-based population. (2) Methods: Voiding parameters on a self-administered questionnaire and a digital self-health monitoring system for urine excretion (s-HMSU) were compared between participants with and without obesity, defined as a body mass index ≥ 25 kg/m² (n = 30 and 29, respectively), from a community in Okinawa, Japan. Logistic regression analysis was employed to calculate the odds ratios of abnormalities in voiding parameters for the obese group, with the non-obese group serving as a reference. (3) Results: The obese group had odds ratios of 5.17 (95% confidence interval: 1.33–20.0) for shortened hours of undisturbed sleep (<302 min) by s-HMSU and 7.65 (1.88–31.1) for nighttime urinary frequency by a questionnaire after adjusting for age and sex. In addition, the obese group had an adjusted odds ratio of 2.27 (0.76–6.78) for decreased maximum bladder capacity (<212 mL) by s-HMSU. (4) Conclusion: the results of the present study suggest that nocturia and shortened hours of undisturbed sleep are signs of obesity. Full article

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

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10 pages, 1520 KiB

Open AccessArticle

Neonatal Hypoxic-Ischemic Brain Injury Alters Brain Acylcarnitine Levels in a Mouse Model

by Amanda M. Dave, Thiago C. Genaro-Mattos, Zeljka Korade and Eric S. Peeples

Metabolites 2022, 12(5), 467; https://doi.org/10.3390/metabo12050467 - 22 May 2022

Cited by 5 | Viewed by 2307

Abstract

Hypoxic-ischemic brain injury (HIBI) leads to depletion of ATP, mitochondrial dysfunction, and enhanced oxidant formation. Measurement of acylcarnitines may provide insight into mitochondrial dysfunction. Plasma acylcarnitine levels are altered in neonates after an HIBI, but individual acylcarnitine levels in the brain have not [...] Read more.

Hypoxic-ischemic brain injury (HIBI) leads to depletion of ATP, mitochondrial dysfunction, and enhanced oxidant formation. Measurement of acylcarnitines may provide insight into mitochondrial dysfunction. Plasma acylcarnitine levels are altered in neonates after an HIBI, but individual acylcarnitine levels in the brain have not been evaluated. Additionally, it is unknown if plasma acylcarnitines reflect brain acylcarnitine changes. In this study, postnatal day 9 CD1 mouse pups were randomized to HIBI induced by carotid artery ligation, followed by 30 min at 8% oxygen, or to sham surgery and normoxia, with subgroups for tissue collection at 30 min, 24 h, or 72 h after injury (12 animals/group). Plasma, liver, muscle, and brain (dissected into the cortex, cerebellum, and striatum/thalamus) tissues were collected for acylcarnitine analysis by LC-MS. At 30 min after HIBI, acylcarnitine levels were significantly increased, but the differences resolved by 24 h. Palmitoylcarnitine was increased in the cortex, muscle, and plasma, and stearoylcarnitine in the cortex, striatum/thalamus, and cerebellum. Other acylcarnitines were elevated only in the muscle and plasma. In conclusion, although plasma acylcarnitine results in this study mimic those seen previously in humans, our data suggest that the plasma acylcarnitine profile was more reflective of muscle changes than brain changes. Acylcarnitine metabolism may be a target for therapeutic intervention after neonatal HIBI, though the lack of change after 30 min suggests a limited therapeutic window. Full article

(This article belongs to the Topic Proteomics and Metabolomics in Biomedicine)

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17 pages, 10449 KiB

Open AccessArticle

Metabolomics Study Suggests the Mechanism of Different Types of Tieguanyin (Oolong) Tea in Alleviating Alzheimer’s Disease in APP/PS1 Transgenic Mice

by Youying Tu, Hyunuk Kang, Eunhye Kim, Jiangfan Yang, Puming He, Yuanyuan Wu, Bo Li, Xiaobo Liu and Junsheng Liu

Metabolites 2022, 12(5), 466; https://doi.org/10.3390/metabo12050466 - 22 May 2022

Cited by 3 | Viewed by 2625

Abstract

Previously, we found that three types of Tieguanyin tea (Tgy-Q, Tgy-N and Tgy-C) extracts could alleviate Alzheimer’s disease (AD) in a mouse model among which Tgy-C was more effective. In this study, APP/PS1 transgenic mice were used to investigate the metabolomic changes in [...] Read more.

Previously, we found that three types of Tieguanyin tea (Tgy-Q, Tgy-N and Tgy-C) extracts could alleviate Alzheimer’s disease (AD) in a mouse model among which Tgy-C was more effective. In this study, APP/PS1 transgenic mice were used to investigate the metabolomic changes in the feces of mice treated with Tieguanyin tea extracts. Results showed that the profile of fecal metabolites was obviously changed in AD mice. Metabolomics analysis found the effects of Tgy-C, especially its decreasing effect on the fecal metabolites in AD mice—132 of the 155 differential metabolites were decreased. KEGG enrichment revealed that differential metabolites could participate in functional pathways including protein digestion and absorption, biosynthesis of amino acids and ABC transporters. Further comparisons of the metabolites between groups showed that although Tgy-N and Tgy-Q exerted a decreasing effect on the fecal metabolites, Tgy-C was more effective. Moreover, correlation analysis found that the levels of the fecal metabolites were highly correlated with the contents of functional components in tea extracts. Finally, 16S rDNA sequencing presented that Tieguanyin extracts modified the gut microbiota by targeting diverse bacteria. In this study, we investigated the differences of three types of Tieguanyin tea extracts on the fecal metabolites as well as the bacterial community of the gut microbiota in AD mice. The identified differential metabolites and the changed intestinal bacteria might provide potential diagnostic biomarkers for the occurrence and progression of AD. Full article

(This article belongs to the Topic Microbiology Metabolomics)

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9 pages, 1534 KiB

Open AccessArticle

Lactate Neuroprotection against Transient Ischemic Brain Injury in Mice Appears Independent of HCAR1 Activation

by Lara Buscemi, Melanie Price, Julia Castillo-González, Jean-Yves Chatton and Lorenz Hirt

Metabolites 2022, 12(5), 465; https://doi.org/10.3390/metabo12050465 - 21 May 2022

Cited by 13 | Viewed by 2678

Abstract

Lactate can protect against damage caused by acute brain injuries both in rodents and in human patients. Besides its role as a metabolic support and alleged preferred neuronal fuel in stressful situations, an additional signaling mechanism mediated by the hydroxycarboxylic acid receptor 1 [...] Read more.

Lactate can protect against damage caused by acute brain injuries both in rodents and in human patients. Besides its role as a metabolic support and alleged preferred neuronal fuel in stressful situations, an additional signaling mechanism mediated by the hydroxycarboxylic acid receptor 1 (HCAR1) was proposed to account for lactate’s beneficial effects. However, the administration of HCAR1 agonists to mice subjected to middle cerebral artery occlusion (MCAO) at reperfusion did not appear to exert any relevant protective effect. To further evaluate the involvement of HCAR1 in the protection against ischemic damage, we looked at the effect of HCAR1 absence. We subjected wild-type and HCAR1 KO mice to transient MCAO followed by treatment with either vehicle or lactate. In the absence of HCAR1, the ischemic damage inflicted by MCAO was less pronounced, with smaller lesions and a better behavioral outcome than in wild-type mice. The lower susceptibility of HCAR1 KO mice to ischemic injury suggests that lactate-mediated protection is not achieved or enhanced by HCAR1 activation, but rather attributable to its metabolic effects or related to other signaling pathways. Additionally, in light of these results, we would disregard HCAR1 activation as an interesting therapeutic strategy for stroke patients. Full article

(This article belongs to the Special Issue Biochemical and Physiological Perspectives of Brain Energy Metabolism)

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24 pages, 5836 KiB

Open AccessArticle

Short Linear Motifs Orchestrate Functioning of Human Proteins during Embryonic Development, Redox Regulation, and Cancer

by Susanna S. Sologova, Sergey P. Zavadskiy, Innokenty M. Mokhosoev and Nurbubu T. Moldogazieva

Metabolites 2022, 12(5), 464; https://doi.org/10.3390/metabo12050464 - 21 May 2022

Cited by 5 | Viewed by 2884

Abstract

Short linear motifs (SLiMs) are evolutionarily conserved functional modules of proteins that represent amino acid stretches composed of 3 to 10 residues. The biological activities of two short peptide segments of human alpha-fetoprotein (AFP), a major embryo-specific and cancer-related protein, have been confirmed [...] Read more.

Short linear motifs (SLiMs) are evolutionarily conserved functional modules of proteins that represent amino acid stretches composed of 3 to 10 residues. The biological activities of two short peptide segments of human alpha-fetoprotein (AFP), a major embryo-specific and cancer-related protein, have been confirmed experimentally. This is a heptapeptide segment LDSYQCT in domain I designated as AFP_14–20 and a nonapeptide segment EMTPVNPGV in domain III designated as GIP-9. In our work, we searched the UniprotKB database for human proteins that contain SLiMs with sequence similarity to the both segments of human AFP and undertook gene ontology (GO)-based functional categorization of retrieved proteins. Gene set enrichment analysis included GO terms for biological process, molecular function, metabolic pathway, KEGG pathway, and protein–protein interaction (PPI) categories. We identified the SLiMs of interest in a variety of non-homologous proteins involved in multiple cellular processes underlying embryonic development, cancer progression, and, unexpectedly, the regulation of redox homeostasis. These included transcription factors, cell adhesion proteins, ubiquitin-activating and conjugating enzymes, cell signaling proteins, and oxidoreductase enzymes. They function by regulating cell proliferation and differentiation, cell cycle, DNA replication/repair/recombination, metabolism, immune/inflammatory response, and apoptosis. In addition to the retrieved genes, new interacting genes were identified. Our data support the hypothesis that conserved SLiMs are incorporated into non-homologous proteins to serve as functional blocks for their orchestrated functioning. Full article

(This article belongs to the Special Issue Metabolic Heterogeneity of Cancer Cells: Protein Turnover and Redox Signaling)

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12 pages, 3055 KiB

Open AccessArticle

Intestinal Absorption Study of a Granular Form of Ferric Pyrophosphate

by Marta Micheletto, Elisa Gaio, Erik Tedesco, Giovanni Di Maira, Etienne Mantovan, Michela Zanella, Paolo Pastore, Marco Roverso, Gabriella Favaro and Federico Benetti

Metabolites 2022, 12(5), 463; https://doi.org/10.3390/metabo12050463 - 21 May 2022

Cited by 3 | Viewed by 2893

Abstract

Iron deficiency is one of the most prevalent nutritional disorders worldwide. The standard treatment involves iron supplementation, but this task is challenging because of poor solubility and organoleptic issues. Moreover, the need to increase iron bioavailability represents a challenge for treating iron-related disorders. [...] Read more.

Iron deficiency is one of the most prevalent nutritional disorders worldwide. The standard treatment involves iron supplementation, but this task is challenging because of poor solubility and organoleptic issues. Moreover, the need to increase iron bioavailability represents a challenge for treating iron-related disorders. In this study, gastroresistance and iron intestinal absorption of an innovative granular formulation composed of ferric pyrophosphate, modified starch and phospholipids branded as Ferro Fosfosoma^® was investigated. Gastroresistant properties were studied using standard protocols, and a bioaccessible fraction was obtained by exposing a food supplement to in vitro digestion. This fraction was used for investigating iron absorption in Caco-2 and human follicle-associated intestinal epithelium (FAE) models. Ferro Fosfosoma^® showed an improved resistance to gastric digestion and higher intestinal absorption than ferric pyrophosphate salt used as a control in both models. In the FAE model, Ferro Fosfosoma^® induces larger iron absorption than in the Caco-2 monolayer, most likely due to the transcytosis ability of M cells. The larger iron absorption in the Ferro Fosfosoma^®-treated FAE model corresponds to higher ferritin level, proving physiological iron handling that was once delivered by granular formulation. Finally, the formulation did not induce any alterations in viability and barrier integrity. To conclude, Ferro Fosfosoma^® favors iron absorption and ferritin expression, while preserving any adverse effects. Full article

(This article belongs to the Special Issue Advances in Iron Metabolism and Anemia)

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22 pages, 1012 KiB

Open AccessReview

The Roles of Fatty Acids and Apolipoproteins in the Kidneys

by Xiaoyue Pan

Metabolites 2022, 12(5), 462; https://doi.org/10.3390/metabo12050462 - 20 May 2022

Cited by 7 | Viewed by 4381

Abstract

The kidneys are organs that require energy from the metabolism of fatty acids and glucose; several studies have shown that the kidneys are metabolically active tissues with an estimated energy requirement similar to that of the heart. The kidneys may regulate the normal [...] Read more.

The kidneys are organs that require energy from the metabolism of fatty acids and glucose; several studies have shown that the kidneys are metabolically active tissues with an estimated energy requirement similar to that of the heart. The kidneys may regulate the normal and pathological function of circulating lipids in the body, and their glomerular filtration barrier prevents large molecules or large lipoprotein particles from being filtered into pre-urine. Given the permeable nature of the kidneys, renal lipid metabolism plays an important role in affecting the rest of the body and the kidneys. Lipid metabolism in the kidneys is important because of the exchange of free fatty acids and apolipoproteins from the peripheral circulation. Apolipoproteins have important roles in the transport and metabolism of lipids within the glomeruli and renal tubules. Indeed, evidence indicates that apolipoproteins have multiple functions in regulating lipid import, transport, synthesis, storage, oxidation and export, and they are important for normal physiological function. Apolipoproteins are also risk factors for several renal diseases; for example, apolipoprotein L polymorphisms induce kidney diseases. Furthermore, renal apolipoprotein gene expression is substantially regulated under various physiological and disease conditions. This review is aimed at describing recent clinical and basic studies on the major roles and functions of apolipoproteins in the kidneys. Full article

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

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9 pages, 275 KiB

Open AccessReview

The Legend of ATP: From Origin of Life to Precision Medicine

by Xin-Yi Chu, Yuan-Yuan Xu, Xin-Yu Tong, Gang Wang and Hong-Yu Zhang

Metabolites 2022, 12(5), 461; https://doi.org/10.3390/metabo12050461 - 20 May 2022

Cited by 9 | Viewed by 2989

Abstract

Adenosine triphosphate (ATP) may be the most important biological small molecule. Since it was discovered in 1929, ATP has been regarded as life’s energy reservoir. However, this compound means more to life. Its legend starts at the dawn of life and lasts to [...] Read more.

Adenosine triphosphate (ATP) may be the most important biological small molecule. Since it was discovered in 1929, ATP has been regarded as life’s energy reservoir. However, this compound means more to life. Its legend starts at the dawn of life and lasts to this day. ATP must be the basic component of ancient ribozymes and may facilitate the origin of structured proteins. In the existing organisms, ATP continues to construct ribonucleic acid (RNA) and work as a protein cofactor. ATP also functions as a biological hydrotrope, which may keep macromolecules soluble in the primitive environment and can regulate phase separation in modern cells. These functions are involved in the pathogenesis of aging-related diseases and breast cancer, providing clues to discovering anti-aging agents and precision medicine tactics for breast cancer. Full article

(This article belongs to the Section Thematic Reviews)

18 pages, 1606 KiB

Open AccessHypothesis

The Lipid Energy Model: Reimagining Lipoprotein Function in the Context of Carbohydrate-Restricted Diets

by Nicholas G. Norwitz, Adrian Soto-Mota, Bob Kaplan, David S. Ludwig, Matthew Budoff, Anatol Kontush and David Feldman

Metabolites 2022, 12(5), 460; https://doi.org/10.3390/metabo12050460 - 20 May 2022

Cited by 18 | Viewed by 53728

Abstract

When lean people adopt carbohydrate-restricted diets (CRDs), they may develop a lipid profile consisting of elevated LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) with low triglycerides (TGs). The magnitude of this lipid profile correlates with BMI such that those with lower BMI exhibit larger increases [...] Read more.

When lean people adopt carbohydrate-restricted diets (CRDs), they may develop a lipid profile consisting of elevated LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) with low triglycerides (TGs). The magnitude of this lipid profile correlates with BMI such that those with lower BMI exhibit larger increases in both LDL-C and HDL-C. The inverse association between BMI and LDL-C and HDL-C change on CRD contributed to the discovery of a subset of individuals—termed Lean Mass Hyper-Responders (LMHR)—who, despite normal pre-diet LDL-C, as compared to non-LMHR (mean levels of 148 and 145 mg/dL, respectively), exhibited a pronounced hyperlipidemic response to a CRD, with mean LDL-C and HDL-C levels increasing to 320 and 99 mg/dL, respectively, in the context of mean TG of 47 mg/dL. In some LMHR, LDL-C levels may be in excess of 500 mg/dL, again, with relatively normal pre-diet LDL-C and absent of genetic findings indicative of familial hypercholesterolemia in those who have been tested. The Lipid Energy Model (LEM) attempts to explain this metabolic phenomenon by positing that, with carbohydrate restriction in lean persons, the increased dependence on fat as a metabolic substrate drives increased hepatic secretion and peripheral uptake of TG contained within very low-density lipoproteins (VLDL) by lipoprotein lipase, resulting in marked elevations of LDL-C and HDL-C, and low TG. Herein, we review the core features of the LEM. We review several existing lines of evidence supporting the model and suggest ways to test the model’s predictions. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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15 pages, 787 KiB

Open AccessReview

Glutamate Efflux across the Blood–Brain Barrier: New Perspectives on the Relationship between Depression and the Glutamatergic System

by Benjamin Fredrick Gruenbaum, Alexander Zlotnik, Amit Frenkel, Ilya Fleidervish and Matthew Boyko

Metabolites 2022, 12(5), 459; https://doi.org/10.3390/metabo12050459 - 20 May 2022

Cited by 19 | Viewed by 3318

Abstract

Depression is a significant cause of disability and affects millions worldwide; however, antidepressant therapies often fail or are inadequate. Current medications for treating major depressive disorder can take weeks or months to reach efficacy, have troubling side effects, and are limited in their [...] Read more.

Depression is a significant cause of disability and affects millions worldwide; however, antidepressant therapies often fail or are inadequate. Current medications for treating major depressive disorder can take weeks or months to reach efficacy, have troubling side effects, and are limited in their long-term capabilities. Recent studies have identified a new set of glutamate-based approaches, such as blood glutamate scavengers, which have the potential to provide alternatives to traditional antidepressants. In this review, we hypothesize as to the involvement of the glutamate system in the development of depression. We identify the mechanisms underlying glutamate dysregulation, offering new perspectives on the therapeutic modalities of depression with a focus on its relationship to blood–brain barrier (BBB) permeability. Ultimately, we conclude that in diseases with impaired BBB permeability, such as depression following stroke or traumatic brain injury, or in neurogenerative diseases, the glutamate system should be considered as a pathway to treatment. We propose that drugs such as blood glutamate scavengers should be further studied for treatment of these conditions. Full article

(This article belongs to the Special Issue Altered Metabolism in Depressive Disorders)

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9 pages, 521 KiB

Open AccessOpinion

Metabolomics in Bariatric and Metabolic Surgery Research and the Potential of Deep Learning in Bridging the Gap

by Athanasios G. Pantelis

Metabolites 2022, 12(5), 458; https://doi.org/10.3390/metabo12050458 - 19 May 2022

Cited by 8 | Viewed by 2304

Abstract

During the past several years, there has been a shift in terminology from bariatric surgery alone to bariatric and metabolic surgery (BMS). More than a change in name, this signifies a paradigm shift that incorporates the metabolic effects of operations performed for weight [...] Read more.

During the past several years, there has been a shift in terminology from bariatric surgery alone to bariatric and metabolic surgery (BMS). More than a change in name, this signifies a paradigm shift that incorporates the metabolic effects of operations performed for weight loss and the amelioration of related medical problems. Metabolomics is a relatively novel concept in the field of bariatrics, with some consistent changes in metabolite concentrations before and after weight loss. However, the abundance of metabolites is not easy to handle. This is where artificial intelligence, and more specifically deep learning, would aid in revealing hidden relationships and would help the clinician in the decision-making process of patient selection in an individualized way. Full article

(This article belongs to the Special Issue Deep Learning for Metabolomics)

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13 pages, 2537 KiB

Open AccessArticle

Oral Adelmidrol Administration Up-Regulates Palmitoylethanolamide Production in Mice Colon and Duodenum through a PPAR-γ Independent Action

by Alessandro Del Re, Irene Palenca, Luisa Seguella, Marcella Pesce, Chiara Corpetti, Luca Steardo, Sara Rurgo, Giovanni Sarnelli and Giuseppe Esposito

Metabolites 2022, 12(5), 457; https://doi.org/10.3390/metabo12050457 - 19 May 2022

Cited by 6 | Viewed by 2484

Abstract

Adelmidrol is a promising palmitoylethanolamide (PEA) analog which displayed up-and-coming anti-inflammatory properties in several inflammatory conditions. Recent studies demonstrated that Adelmidrol is an in vitro enhancer of PEA endogenous production, through the so called “entourage” effect. The present study investigated the ability of [...] Read more.

Adelmidrol is a promising palmitoylethanolamide (PEA) analog which displayed up-and-coming anti-inflammatory properties in several inflammatory conditions. Recent studies demonstrated that Adelmidrol is an in vitro enhancer of PEA endogenous production, through the so called “entourage” effect. The present study investigated the ability of Adelmidrol (1 and 10 mg/Kg per os) to increase the endogenous level of PEA in the duodenum and colon of mice after 21-day oral administration in the presence and absence of PPAR-γ inhibitor (1 mg/kg). The level of PEA was analyzed by HPLC-MS. The expression of PEA-related enzymatic machinery was evaluated by western blot and RT-PCR analysis. Our findings demonstrated that Adelmidrol significantly increased PEA levels in the duodenum and colon in a dose/time-dependent manner. We also revealed that Adelmidrol up regulated the enzymatic machinery responsible for PEA metabolism and catabolism. Interestingly, the use of the selective irreversible PPAR-γ antagonist did not affect either PEA intestinal levels or expression/transcription of PEA metabolic enzymes following Adelmidrol administration. The “entourage effect” with Adelmidrol as an enhancer of PEA was thus PPAR-γ-independent. The findings suggest that Adelmidrol can maximize a PEA therapeutic-based approach in several intestinal morbidities. Full article

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16 pages, 2970 KiB

Open AccessArticle

PET/MRI-Evaluated Activation of Brown Adipose Tissue via Cold Exposure Impacts Lipid Metabolism

by Katarzyna Miniewska, Katarzyna Maliszewska, Karolina Pietrowska, Joanna Godzień, Łukasz Łabieniec, Małgorzata Mojsak, Adam Krętowski and Michał Ciborowski

Metabolites 2022, 12(5), 456; https://doi.org/10.3390/metabo12050456 - 19 May 2022

Cited by 2 | Viewed by 2716

Abstract

Although brown adipose tissue (BAT) is considered to play a protective role against obesity and type 2 diabetes, the mechanisms of its activation and associations with clinical parameters are not well described. Male adults underwent a 2 h cold exposure (CE) to activate [...] Read more.

Although brown adipose tissue (BAT) is considered to play a protective role against obesity and type 2 diabetes, the mechanisms of its activation and associations with clinical parameters are not well described. Male adults underwent a 2 h cold exposure (CE) to activate BAT and, based on the results of PET/MRI performed after the CE, were divided into BAT(+) and BAT(−) groups. During the CE procedure, blood samples were collected and alterations in plasma metabolome in both groups were investigated using LC-MS. Additionally, associations between clinical factors and BAT were examined. Moreover, levels of glucose, insulin, leptin, TNF-α, FGF21, and FABP4 were assessed in serum samples. In the BAT(+) group, levels of LPC(17:0), LPE(20:4), LPE(22:4), LPE(22:6), DHA, linoleic acid, and oleic acid increased during CE, whereas levels of sphinganine-phosphate and sphingosine-1-phosphate decreased. Levels of LPE(O-18:0), 9-HpODE, and oleic acid were elevated, while the level of LPE(20:5) was reduced in BAT(+) compared to BAT(−) subjects. AUCs of LPC(18:2), LPC(O-18:2)/LPC(P-18:1), and SM(d32:2) negatively correlated with BAT. In the BAT(+) group, the concentration of FABP4 during and after CE was decreased compared to the basal level. No alterations were observed in the BAT(−) group. In conclusion, using untargeted metabolomics, we proved that the plasma metabolome is affected by cold-induced BAT activation. Full article

(This article belongs to the Special Issue Insulin Resistance, Adipose Tissue Metabolism and Type 2 Diabetes)

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15 pages, 1830 KiB

Open AccessArticle

Automated Cancer Diagnostics via Analysis of Optical and Chemical Images by Deep and Shallow Learning

by Olof Gerdur Isberg, Valentina Giunchiglia, James S. McKenzie, Zoltan Takats, Jon Gunnlaugur Jonasson, Sigridur Klara Bodvarsdottir, Margret Thorsteinsdottir and Yuchen Xiang

Metabolites 2022, 12(5), 455; https://doi.org/10.3390/metabo12050455 - 18 May 2022

Cited by 3 | Viewed by 3507

Abstract

Optical microscopy has long been the gold standard to analyse tissue samples for the diagnostics of various diseases, such as cancer. The current diagnostic workflow is time-consuming and labour-intensive, and manual annotation by a qualified pathologist is needed. With the ever-increasing number of [...] Read more.

Optical microscopy has long been the gold standard to analyse tissue samples for the diagnostics of various diseases, such as cancer. The current diagnostic workflow is time-consuming and labour-intensive, and manual annotation by a qualified pathologist is needed. With the ever-increasing number of tissue blocks and the complexity of molecular diagnostics, new approaches have been developed as complimentary or alternative solutions for the current workflow, such as digital pathology and mass spectrometry imaging (MSI). This study compares the performance of a digital pathology workflow using deep learning for tissue recognition and an MSI approach utilising shallow learning to annotate formalin-fixed and paraffin-embedded (FFPE) breast cancer tissue microarrays (TMAs). Results show that both deep learning algorithms based on conventional optical images and MSI-based shallow learning can provide automated diagnostics with F1-scores higher than 90%, with the latter intrinsically built on biochemical information that can be used for further analysis. Full article

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

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20 pages, 4113 KiB

Open AccessArticle

Sex-Specific Metabolic Effects of Dietary Folate Withdrawal in Wild-Type and Aldh1l1 Knockout Mice

by Jaspreet Sharma, Blake R. Rushing, Madeline S. Hall, Kristi L. Helke, Susan L. McRitchie, Natalia I. Krupenko, Susan J. Sumner and Sergey A. Krupenko

Metabolites 2022, 12(5), 454; https://doi.org/10.3390/metabo12050454 - 18 May 2022

Cited by 7 | Viewed by 2569

Abstract

ALDH1L1 (10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism, is highly expressed in the liver. It regulates the overall flux of folate-bound one-carbon groups by converting 10-formyltetrahydrofolate to tetrahydrofolate and CO₂ in a NADP⁺-dependent reaction. Our previous study revealed that Aldh1l1 [...] Read more.

ALDH1L1 (10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism, is highly expressed in the liver. It regulates the overall flux of folate-bound one-carbon groups by converting 10-formyltetrahydrofolate to tetrahydrofolate and CO₂ in a NADP⁺-dependent reaction. Our previous study revealed that Aldh1l1 knockout (KO) mice have an altered liver metabotype with metabolic symptoms of folate deficiency when fed a standard chow diet containing 2 ppm folic acid. Here we performed untargeted metabolomic analysis of liver and plasma of KO and wild-type (WT) male and female mice fed for 16 weeks either standard or folate-deficient diet. OPLS-DA, a supervised multivariate technique that was applied to 6595 and 10,678 features for the liver and plasma datasets, respectively, indicated that genotype and diet, alone or in combination, gave distinct metabolic profiles in both types of biospecimens. A more detailed analysis of affected metabolic pathways based on most confidently identified metabolites in the liver and plasma (OL1 and OL2a ontology level) indicated that the dietary folate restriction itself does not fully recapitulate the metabolic effect of the KO. Of note, dietary folate withdrawal enhanced the metabolic perturbations linked to the ALDH1L1 loss only for a subset of metabolites. Importantly, both the ALDH1L1 loss and dietary folate deficiency produced sex-specific metabolic effects. Full article

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14 pages, 1281 KiB

Open AccessArticle

A Comparison of Solvent-Based Extraction Methods to Assess the Central Carbon Metabolites in Mouse Bone and Muscle

by Daniela B. Dias, Raphaela Fritsche-Guenther, Friederike Gutmann, Georg N. Duda, Jennifer Kirwan and Patrina S. P. Poh

Metabolites 2022, 12(5), 453; https://doi.org/10.3390/metabo12050453 - 18 May 2022

Cited by 3 | Viewed by 2607

Abstract

The identification of endogenous metabolites has great potential for understanding the underlying tissue processes occurring in either a homeostatic or a diseased state. The application of gas chromatography-mass spectrometry (GC-MS)-based metabolomics on musculoskeletal tissue samples has gained traction. However, limited comparison studies exist [...] Read more.

The identification of endogenous metabolites has great potential for understanding the underlying tissue processes occurring in either a homeostatic or a diseased state. The application of gas chromatography-mass spectrometry (GC-MS)-based metabolomics on musculoskeletal tissue samples has gained traction. However, limited comparison studies exist evaluating the sensitivity, reproducibility, and robustness of the various existing extraction protocols for musculoskeletal tissues. Here, we evaluated polar metabolite extraction from bone and muscle of mouse origin. The extraction methods compared were (1) modified Bligh–Dyer (mBD), (2) low chloroform (CHCl₃)-modified Bligh–Dyer (mBD-low), and (3) modified Matyash (mMat). In particular, the central carbon metabolites (CCM) appear to be relevant for musculoskeletal regeneration, given their role in energy metabolism. However, the sensitivity, reproducibility, and robustness of these methods for detecting targeted polar CCM remains unknown. Overall, the extraction of metabolites using the mBD, mBD-low, and mMat methods appears sufficiently robust and reproducible for bone, with the mBD method slightly bettering the mBD-low and mMat methods. Furthermore, mBD, mBD-low, and mMat were sufficiently sensitive in detecting polar metabolites extracted from mouse muscle; however, they lacked repeatability. This study highlights the need for a re-thinking, towards a tissue-specific optimization of methods for metabolite extractions, ensuring sufficient sensitivity, repeatability, and robustness. Full article

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17 pages, 4160 KiB

Open AccessArticle

Ammonia Concentration in the Eluent Influences Fragmentation Pattern of Triacylglycerols in Mass Spectrometry Analysis

by Marta Velasco, David Balgoma and Olimpio Montero

Metabolites 2022, 12(5), 452; https://doi.org/10.3390/metabo12050452 - 18 May 2022

Viewed by 2373

Abstract

Correct assessment of the fatty acyl at the glycerol sn-2 position in triacylglycerol (TAG) analysis by liquid chromatography and mass spectrometry (LC-MS) is challenging. Ammonium hydroxide (NH₄OH) is the preferred choice for the solvent additive for the formation of the [...] Read more.

Correct assessment of the fatty acyl at the glycerol sn-2 position in triacylglycerol (TAG) analysis by liquid chromatography and mass spectrometry (LC-MS) is challenging. Ammonium hydroxide (NH₄OH) is the preferred choice for the solvent additive for the formation of the ammonium adduct ([M + NH₄]⁺). In this study, the influence of different NH₄OH concentrations in the eluents on TAG adduct formation and fragmentation under LC-MS analysis was assessed. Increasing NH₄OH concentrations delayed the chromatographic elution time according to a power function. The [M + NH₄]⁺ and [M + ACN + NH₄]⁺ adducts (where ACN means acetonitrile) were formed at all ammonium concentrations assayed. [M + ACN + NH₄]⁺ predominated above 18.26 mM [NH₄OH], and the intensity of [M + NH₄]⁺ dropped. TAG fragmentation for fatty acyl release in the MS^E was reduced with increasing [M + ACN + NH₄]⁺ adduct, which suggests that ACN stabilizes the adduct in a way that inhibits the rupture of the ester bonds in TAGs. A linear equation (H_sn-I = a × H_[M+NH4]+, where sn-I refers to the sn position of the glycerol (I = 1, 2, or 3) and H is the peak height) was deduced to quantify the dehydroxydiacylglycerol fragment intensity in relation to [M + NH₄]⁺ intensity in the full scan. This equation had a slope mean value of 0.369 ± 0.058 for the sn-1 and sn-3 positions, and of 0.188 ± 0.007 for the sn-2 position. Full article

(This article belongs to the Special Issue Advances in Lipidomics: Biomedicine, Nutrition and Methodology Volume 2)

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31 pages, 4541 KiB

Open AccessArticle

Untargeted Metabolomic Profiling and Antioxidant Capacities of Different Solvent Crude Extracts of Ephedra foeminea

by Ruba Al-Nemi, Arwa A. Makki, Khaled Sawalha, Dina Hajjar and Mariusz Jaremko

Metabolites 2022, 12(5), 451; https://doi.org/10.3390/metabo12050451 - 17 May 2022

Cited by 23 | Viewed by 4291

Abstract

Ephedra foeminea is a traditional medicinal plant used in the Eastern Mediterranean region. This study aims to investigate the chemical profiles of different solvent extracts of E. foeminea via an untargeted metabolomics approach, alongside determining their antioxidant capacities. E. foeminea samples collected from [...] Read more.

Ephedra foeminea is a traditional medicinal plant used in the Eastern Mediterranean region. This study aims to investigate the chemical profiles of different solvent extracts of E. foeminea via an untargeted metabolomics approach, alongside determining their antioxidant capacities. E. foeminea samples collected from Jordan were macerated in solvents of varying polarities; dichloromethane/methanol, methanol, ethanol, ethyl acetate, and acetone. The crude extracts were subjected to comprehensive chemical profiling and metabolomics study using Gas chromatography–Mass spectrometry (GC–MS), Liquid chromatography–Mass spectrometry (LC–MS), and Nuclear Magnetic Resonance (NMR). The obtained data were analyzed using Venn diagrams, Principle Component Analysis (PCA), and Metabolite Enrichment Set Analysis (MESA). ABTS assay was performed to measure the crude extracts’ antioxidant activity. MESA revealed the dominant chemical groups as amino acids, fatty acids, carboxylic acids, and carbohydrates. Results indicated that dichloromethane/methanol and methanolic extracts had the most distinct composition as well as the most unique compounds. The methanolic extract had the most potency (IC₅₀ 249.6 µg/mL) in the ABTS assay. However, no significant differences were found. In conclusion, solvents influenced the recovery of metabolites in E. foeminea and the antioxidant activity of the E. foeminea methanolic extract could be correlated to the abundant presence of diverse bioactive compounds. Full article

(This article belongs to the Section Plant Metabolism)

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15 pages, 2635 KiB

Open AccessArticle

An Update on Sphingolipidomics: Is Something Still Missing? Some Considerations on the Analysis of Complex Sphingolipids and Free-Sphingoid Bases in Plasma and Red Blood Cells

by Camillo Morano, Aida Zulueta, Anna Caretti, Gabriella Roda, Rita Paroni and Michele Dei Cas

Metabolites 2022, 12(5), 450; https://doi.org/10.3390/metabo12050450 - 17 May 2022

Cited by 9 | Viewed by 2285

Abstract

The main concerns in targeted “sphingolipidomics” are the extraction and proper handling of biological samples to avoid interferences and achieve a quantitative yield well representing all the sphingolipids in the matrix. Our work aimed to compare different pre-analytical procedures and to [...] Read more.

The main concerns in targeted “sphingolipidomics” are the extraction and proper handling of biological samples to avoid interferences and achieve a quantitative yield well representing all the sphingolipids in the matrix. Our work aimed to compare different pre-analytical procedures and to evaluate a derivatization step for sphingoid bases quantification, to avoid interferences and improve sensitivity. We tested four protocols for the extraction of sphingolipids from human plasma, at different temperatures and durations, and two derivatization procedures for the conversion of sphingoid bases into phenylthiourea derivatives. Different columns and LC-MS/MS chromatographic conditions were also tested. The protocol that worked better for sphingolipids analysis involved a single-phase extraction in methanol/chloroform mixture (2:1, v/v) for 1 h at 38 °C, followed by a 2 h alkaline methanolysis at 38 °C, for the suppression of phospholipids signals. The derivatization of sphingoid bases promotes the sensibility of non-phosphorylated species but we proved that it is not superior to a careful choice of the appropriate column and a full-length elution gradient. Our procedure was eventually validated by analyzing plasma and erythrocyte samples of 20 volunteers. While both extraction and methanolysis are pivotal steps, our final consideration is to analyze sphingolipids and sphingoid bases under different chromatographic conditions, minding the interferences. Full article

(This article belongs to the Special Issue Advances in Metabolic Profiling of Biological Samples)

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21 pages, 7303 KiB

Open AccessArticle

Proteobacteria and Firmicutes Secreted Factors Exert Distinct Effects on Pseudomonas aeruginosa Infection under Normoxia or Mild Hypoxia

by Anna Charalambous, Evangelos Grivogiannis, Irene Dieronitou, Christina Michael, Laurence Rahme and Yiorgos Apidianakis

Metabolites 2022, 12(5), 449; https://doi.org/10.3390/metabo12050449 - 17 May 2022

Cited by 7 | Viewed by 3316

Abstract

Microbiota may alter a pathogen’s virulence potential at polymicrobial infection sites. Here, we developed a multi-modal Drosophila assay, amenable to the assessment of human bacterial interactions using fly survival or midgut regeneration as a readout, under normoxia or mild hypoxia. Deploying a matrix [...] Read more.

Microbiota may alter a pathogen’s virulence potential at polymicrobial infection sites. Here, we developed a multi-modal Drosophila assay, amenable to the assessment of human bacterial interactions using fly survival or midgut regeneration as a readout, under normoxia or mild hypoxia. Deploying a matrix of 12 by 33 one-to-one Drosophila co-infections via feeding, we classified bacterial interactions as neutral, synergistic, or antagonistic, based on fly survival. Twenty six percent of these interactions were antagonistic, mainly occurring between Proteobacteria. Specifically, Pseudomonas aeruginosa infection was antagonized by various Klebsiella strains, Acinetobacter baumannii, and Escherichia coli. We validated these interactions in a second screen of 7 by 34 one-to-one Drosophila co-infections based on assessments of midgut regeneration, and in bacterial co-culture test tube assays, where antagonistic interactions depended on secreted factors produced upon high sugar availability. Moreover, Enterococci interacted synergistically with P. aeruginosa in flies and in test tubes, enhancing the virulence and pyocyanin production by P. aeruginosa. However, neither lactic acid bacteria nor their severely hypoxic culture supernatants provided a survival benefit upon P. aeruginosa infection of flies or mice, respectively. We propose that at normoxic or mildly hypoxic sites, Firmicutes may exacerbate, whereas Proteobacteria secreted factors may ameliorate, P. aeruginosa infections. Full article

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

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12 pages, 288 KiB

Open AccessArticle

The Occurrence of a Negative Energy Balance in Holstein-Friesian and Simmental Cows and Its Association with the Time of Resumption of Reproductive Activity

by Krzysztof Młynek, Ilona Strączek and Beata Głowińska

Metabolites 2022, 12(5), 448; https://doi.org/10.3390/metabo12050448 - 17 May 2022

Cited by 2 | Viewed by 2199

Abstract

Intensive lactation (lactogenesis) in cows is conducive to a negative energy balance (NEB), so the search for traits associated with the physiological capacity to cope with its consequences is a current area of research. This is especially important because NEB overlaps with the [...] Read more.

Intensive lactation (lactogenesis) in cows is conducive to a negative energy balance (NEB), so the search for traits associated with the physiological capacity to cope with its consequences is a current area of research. This is especially important because NEB overlaps with the resumption of the reproductive cycle, which determines the profitability of herds. This study analysed the relationship between NEB and the time of resumption of reproductive activity in cows with varying genetic potential (Simmental and Holstein-Friesian), fed a similar diet (TMR). The aim of the study was to analyse the dependencies between NEB markers and changes in progesterone levels between 25 and 31 days postpartum. A strong positive correlation was shown between daily milk production (DMP) and loss of body condition (LBCS; 0.772; p ≤ 0.05). These parameters were associated with the levels of NEB biomarkers. Higher values of NEB indicators (LBCS, C16:0, C18:1, NEFA, and BHBA) were usually noted during periods with higher DMP (II and III). The trends observed were confirmed by positive correlation coefficients (r), which ranged from 0.324 to 0.810 (p ≤ 0.05). The reverse trend was noted for glucose and leptin, which decreased as productivity increased, as confirmed by r values from −0.368 to −0.530 (p ≤ 0.05). In both breeds, the glucose and leptin levels decreased as DMP increased. Higher values for NEB indicators were shown to be negatively correlated with progesterone levels (r from −0.300 to −0.712; p ≤ 0.05), and a lower progesterone level was associated with a longer calving-to-first-service interval and calving-to-conception interval. The rate of postpartum triglyceride release depends on daily milk production, and therefore the adaptability of the liver should be considered an important element of mitigation of the consequences of NEB. This may have practical applications by extending productive life, which is often shortened due to deteriorating reproductive performance. Full article

(This article belongs to the Special Issue Mineral and Energy Metabolism of Mammals during Pregnancy)

13 pages, 5050 KiB

Open AccessArticle

Metabolomic Analysis of Plasma from Breast Cancer Patients Using Ultra-High-Performance Liquid Chromatography Coupled with Mass Spectrometry: An Untargeted Study

by Patricia A. Da Cunha, Diana Nitusca, Luisa Matos Do Canto, Rency S. Varghese, Habtom W. Ressom, Shawna Willey, Catalin Marian and Bassem R. Haddad

Metabolites 2022, 12(5), 447; https://doi.org/10.3390/metabo12050447 - 17 May 2022

Cited by 4 | Viewed by 2871

Abstract

Breast cancer (BC) is one of the leading causes of cancer mortality in women worldwide, and therefore, novel biomarkers for early disease detection are critically needed. We performed herein an untargeted plasma metabolomic profiling of 55 BC patients and 55 healthy controls (HC) [...] Read more.

Breast cancer (BC) is one of the leading causes of cancer mortality in women worldwide, and therefore, novel biomarkers for early disease detection are critically needed. We performed herein an untargeted plasma metabolomic profiling of 55 BC patients and 55 healthy controls (HC) using ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS). Pre-processed data revealed 2494 ions in total. Data matrices’ paired t-tests revealed 792 ions (both positive and negative) which presented statistically significant changes (FDR < 0.05) in intensity levels between cases versus controls. Metabolites identified with putative names via MetaboQuest using MS/MS and mass-based approaches included amino acid esters (i.e., N-stearoyl tryptophan, L-arginine ethyl ester), dipeptides (ile-ser, met-his), nitrogenous bases (i.e., uracil derivatives), lipid metabolism-derived molecules (caproleic acid), and exogenous compounds from plants, drugs, or dietary supplements. LASSO regression selected 16 metabolites after several variables (TNM Stage, Grade, smoking status, menopausal status, and race) were adjusted. A predictive conditional logistic regression model on the 16 LASSO selected ions provided a high diagnostic performance with an area-under-the-curve (AUC) value of 0.9729 (95% CI 0.96–0.98) on all 55 samples. This study proves that BC possesses a specific metabolic signature that could be exploited as a novel metabolomics-based approach for BC detection and characterization. Future studies of large-scale cohorts are needed to validate these findings. Full article

(This article belongs to the Special Issue Metabolomic Analysis of Plasma)

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16 pages, 3038 KiB

Open AccessArticle

Circulating Metabolites as Biomarkers of Disease in Patients with Mesial Temporal Lobe Epilepsy

by Alexandre B. Godoi, Amanda M. do Canto, Amanda Donatti, Douglas C. Rosa, Danielle C. F. Bruno, Marina K. Alvim, Clarissa L. Yasuda, Lucas G. Martins, Melissa Quintero, Ljubica Tasic, Fernando Cendes and Iscia Lopes-Cendes

Metabolites 2022, 12(5), 446; https://doi.org/10.3390/metabo12050446 - 17 May 2022

Cited by 3 | Viewed by 3557

Abstract

A major challenge in the clinical management of patients with mesial temporal lobe epilepsy (MTLE) is identifying those who do not respond to antiseizure medication (ASM), allowing for the timely pursuit of alternative treatments such as epilepsy surgery. Here, we investigated changes in [...] Read more.

A major challenge in the clinical management of patients with mesial temporal lobe epilepsy (MTLE) is identifying those who do not respond to antiseizure medication (ASM), allowing for the timely pursuit of alternative treatments such as epilepsy surgery. Here, we investigated changes in plasma metabolites as biomarkers of disease in patients with MTLE. Furthermore, we used the metabolomics data to gain insights into the mechanisms underlying MTLE and response to ASM. We performed an untargeted metabolomic method using magnetic resonance spectroscopy and multi- and univariate statistical analyses to compare data obtained from plasma samples of 28 patients with MTLE compared to 28 controls. The patients were further divided according to response to ASM for a supplementary and preliminary comparison: 20 patients were refractory to treatment, and eight were responsive to ASM. We only included patients using carbamazepine in combination with clobazam. We analyzed the group of patients and controls and found that the profiles of glucose (p = 0.01), saturated lipids (p = 0.0002), isoleucine (p = 0.0001), β-hydroxybutyrate (p = 0.0003), and proline (p = 0.02) were different in patients compared to controls (p < 0.05). In addition, we found some suggestive metabolites (without enough predictability) by multivariate analysis (VIP scores > 2), such as lipoproteins, lactate, glucose, unsaturated lipids, isoleucine, and proline, that might be relevant to the process of pharmacoresistance in the comparison between patients with refractory and responsive MTLE. The identified metabolites for the comparison between MTLE patients and controls were linked to different biological pathways related to cell-energy metabolism and pathways related to inflammatory processes and the modulation of neurotransmitter release and activity in MTLE. In conclusion, in addition to insights into the mechanisms underlying MTLE, our results suggest that plasma metabolites may be used as disease biomarkers. These findings warrant further studies exploring the clinical use of metabolites to assist in decision-making when treating patients with MTLE. Full article

(This article belongs to the Special Issue Omics Technologies in Evaluating New Insights into Molecular Aspects of Human Health)

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21 pages, 3083 KiB

Open AccessArticle

Effects of Acute and Chronic Resistance Exercise on the Skeletal Muscle Metabolome

by Sebastian Gehlert, Patrick Weinisch, Werner Römisch-Margl, Richard T. Jaspers, Anna Artati, Jerzy Adamski, Kenneth A. Dyar, Thorben Aussieker, Daniel Jacko, Wilhelm Bloch, Henning Wackerhage and Gabi Kastenmüller

Metabolites 2022, 12(5), 445; https://doi.org/10.3390/metabo12050445 - 16 May 2022

Cited by 11 | Viewed by 4931

Abstract

Resistance training promotes metabolic health and stimulates muscle hypertrophy, but the precise routes by which resistance exercise (RE) conveys these health benefits are largely unknown. Aim: To investigate how acute RE affects human skeletal muscle metabolism. Methods: We collected vastus lateralis biopsies from [...] Read more.

Resistance training promotes metabolic health and stimulates muscle hypertrophy, but the precise routes by which resistance exercise (RE) conveys these health benefits are largely unknown. Aim: To investigate how acute RE affects human skeletal muscle metabolism. Methods: We collected vastus lateralis biopsies from six healthy male untrained volunteers at rest, before the first of 13 RE training sessions, and 45 min after the first and last bouts of RE. Biopsies were analysed using untargeted mass spectrometry-based metabolomics. Results: We measured 617 metabolites covering a broad range of metabolic pathways. In the untrained state RE altered 33 metabolites, including increased 3-methylhistidine and N-lactoylvaline, suggesting increased protein breakdown, as well as metabolites linked to ATP (xanthosine) and NAD (N1-methyl-2-pyridone-5-carboxamide) metabolism; the bile acid chenodeoxycholate also increased in response to RE in muscle opposing previous findings in blood. Resistance training led to muscle hypertrophy, with slow type I and fast/intermediate type II muscle fibre diameter increasing by 10.7% and 10.4%, respectively. Comparison of post-exercise metabolite levels between trained and untrained state revealed alterations of 46 metabolites, including decreased N-acetylated ketogenic amino acids and increased beta-citrylglutamate which might support growth. Only five of the metabolites that changed after acute exercise in the untrained state were altered after chronic training, indicating that training induces multiple metabolic changes not directly related to the acute exercise response. Conclusion: The human skeletal muscle metabolome is sensitive towards acute RE in the trained and untrained states and reflects a broad range of adaptive processes in response to repeated stimulation. Full article

(This article belongs to the Section Integrative Metabolomics)

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29 pages, 8654 KiB

Open AccessArticle

Differential Metabolic Responses of Lettuce Grown in Soil, Substrate and Hydroponic Cultivation Systems under NH₄⁺/NO₃⁻ Application

by Muhammad Khalid Hameed, Wajid Umar, Ali Razzaq, Tariq Aziz, Muhammad Aamer Maqsood, Shiwei Wei, Qingliang Niu, Danfeng Huang and Liying Chang

Metabolites 2022, 12(5), 444; https://doi.org/10.3390/metabo12050444 - 16 May 2022

Cited by 14 | Viewed by 4000

Abstract

Nitrogen (N) is an essential element for plant growth and development. The application of a balanced and optimal amount of N is required for sustainable plant yield. For this, different N sources and forms are used, that including ammonium (NH₄⁺) [...] Read more.

Nitrogen (N) is an essential element for plant growth and development. The application of a balanced and optimal amount of N is required for sustainable plant yield. For this, different N sources and forms are used, that including ammonium (NH₄⁺) and nitrate (NO₃⁻). These are the main sources for N uptake by plants where NH₄⁺/NO₃⁻ ratios have a significant effect on the biomass, quality and metabolites composition of lettuce grown in soil, substrate and hydroponic cultivation systems. A limited supply of N resulted in the reduction in the biomass, quality and overall yield of lettuce. Additionally, different types of metabolites were produced with varying concentrations of N sources and can be used as metabolic markers to improve the N use efficiency. To investigate the differential metabolic activity, we planted lettuce with different NH₄⁺/NO₃⁻ ratios (100:0, 75:25, 50:50, 25:75 and 0:100%) and a control (no additional N applied) in soil, substrate and hydroponic cultivation systems. The results revealed that the 25% NH₄^+/75% NO₃⁻ ratio increased the relative chlorophyll contents as well as the biomass of lettuce in all cultivation systems. However, lettuce grown in the hydroponic cultivation system showed the best results. The concentration of essential amino acids including alanine, valine, leucine, lysine, proline and serine increased in soil and hydroponically grown lettuce treated with the 25% NH₄^+/75% NO₃⁻ ratio. The taste and quality-related compounds in lettuce showed maximum relative abundance with the 25% NH₄^+/75% NO₃⁻ ratio, except ascorbate (grown in soil) and lactupicrin (grown in substrate), which showed maximum relative abundance in the 50% NH₄^+/50% NO₃⁻ ratio and control treatments, respectively. Moreover, 1-O-caffeoylglucose, 1,3-dicaffeoylquinic acid, aesculetin and quercetin-3-galactoside were increased by the application of the 100% NH₄^+/0% NO₃⁻ ratio in soil-grown lettuce. The 25% NH₄^+/75% NO₃⁻ ratio was more suitable in the hydroponic cultivation system to obtain increased lettuce biomass. The metabolic profiling of lettuce showed different behaviors when applying different NH₄⁺/NO₃⁻ ratios. Therefore, the majority of the parameters were largely influenced by the 25% NH₄^+/75% NO₃⁻ ratio, which resulted in the hyper-accumulation of health-promoting compounds in lettuce. In conclusion, the optimal N applications improve the quality of lettuce grown in soil, substrate and hydroponic cultivation systems which ultimately boost the nutritional value of lettuce. Full article

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14 pages, 2429 KiB

Open AccessArticle

Attenuation of Olanzapine-Induced Endoplasmic Reticulum Stress Improves Insulin Secretion in Pancreatic Beta Cells

by Diana Grajales, Patricia Vázquez, Rosa Alén, Ana B. Hitos and Ángela M. Valverde

Metabolites 2022, 12(5), 443; https://doi.org/10.3390/metabo12050443 - 16 May 2022

Cited by 6 | Viewed by 2745

Abstract

Second-generation antipsychotics (SGAs), in particular, olanzapine and clozapine, have been associated with the development of type 2 diabetes mellitus (T2D) and metabolic syndrome in individuals with schizophrenia. In this context, beta cell dysfunction is a plausible mechanism by which SGAs cause T2D. Herein, [...] Read more.

Second-generation antipsychotics (SGAs), in particular, olanzapine and clozapine, have been associated with the development of type 2 diabetes mellitus (T2D) and metabolic syndrome in individuals with schizophrenia. In this context, beta cell dysfunction is a plausible mechanism by which SGAs cause T2D. Herein, we analyzed the direct effects of olanzapine, a commonly prescribed SGA with diabetogenic properties, on the INS-1 (821/13) beta cell line and isolated pancreatic islets. Treatment of INS-1 beta cells with non-toxic concentrations of olanzapine (3–6 μM) during 4 h activated endoplasmic reticulum (ER) stress-mediated signaling by increasing PERK/eIF2α phosphorylation, IRE-1 phosphorylation and XBP-1 splicing. Moreover, glucose-stimulated insulin secretion (GSIS) was inhibited when olanzapine was present for 16 h. The insulin secretory function of INS-1 cells was restored by inhibiting olanzapine-induced ER stress with tauroursodeoxycholic acid (TUDCA). Similar effects of olanzapine with or without TUDCA on ER-stress-mediated signaling and GSIS were found in pancreatic islets from female mice. Our results indicate that early activation of ER stress in pancreatic beta cells is a potential mechanism behind the alterations in glucose homeostasis induced by olanzapine. Full article

(This article belongs to the Special Issue Metabolism and Metabolite Markers in Type 2 Diabetes)

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12 pages, 2564 KiB

Open AccessArticle

Evaluation of Hypoglycemic and Antioxidant Activities of Soybean Meal Products Fermented by Lactobacillus plantarum FPS 2520 and Bacillus subtilis N1 in Rats Fed with High-Fat Diet

by Chung-Hsiung Huang, Chun-Lung Chen, Chen-Che Shieh, Shun-Hsien Chang and Guo-Jane Tsai

Metabolites 2022, 12(5), 442; https://doi.org/10.3390/metabo12050442 - 14 May 2022

Cited by 3 | Viewed by 2629

Abstract

The hypoglycemic and antioxidant activities of Lactobacillus plantarum FPS 2520 and/or Bacillus subtilis N1 fermented soybean meal (SBM) in rats fed a high-fat diet (HFD) were investigated by assessing plasma glucose levels, insulin resistance, and oxidative stress-induced organ damage. Supplementation with FPS 2520- [...] Read more.

The hypoglycemic and antioxidant activities of Lactobacillus plantarum FPS 2520 and/or Bacillus subtilis N1 fermented soybean meal (SBM) in rats fed a high-fat diet (HFD) were investigated by assessing plasma glucose levels, insulin resistance, and oxidative stress-induced organ damage. Supplementation with FPS 2520- and/or N1-fermented SBM (500 and 1000 mg/kg of body weight per day) to HFD-induced obese rats for 6 weeks significantly down-regulated the concentration of plasma glucose during the oral glucose tolerance test (OGTT), as well as the concentration of fasting plasma glucose, insulin, and the value of the homeostasis model assessment of insulin resistance (HOMA-IR). In addition, plasma and hepatic levels of malondialdehyde (MDA) were alleviated in rats fed fermented SBM, especially SBM fermented by mixed strains. Moreover, fermented SBM treatment reduced HFD-exacerbated increases in plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, and uric acid levels. Based on these results, we clearly demonstrate the effect of fermented SBM on improving insulin resistance and oxidation-induced organ damage. Therefore, it is suggested that fermented SBM has the potential to be developed as functional foods for the management of obesity-induced hyperglycemia and organ damage. Full article

(This article belongs to the Special Issue Functional Foods and Diabetes)

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