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Cells
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Metabolomics in Physiology and Diseases
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Metabolomics in Physiology and Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (15 March 2020) | Viewed by 54773

Special Issue Editors

Prof. Dr. Ritva Tikkanen

E-Mail Website
Guest Editor
Institute of Biochemistry, Medical Faculty, Justus-Liebig University of Giessen, Friedrichstrasse 24, D-35392 Giessen, Germany
Interests: lysosomal storage disorders; vesicular trafficking; endosomal sorting; lysosome biogenesis; mitochondrial diseases; autoimmune disorders
Special Issues, Collections and Topics in MDPI journals
Dr. Nina S. Kurrle

E-Mail Website1 Website2
Guest Editor
Department of Hematology/Oncology, Goethe University Frankfurt, Frankfurt am Main, Germany
Interests: RedOx regulation; haematology; hypoxia; haematological cancers; cancer metabolomics

Special Issue Information

Dear Colleagues,

Metabolomics, i.e., the concise analysis of products of cellular metabolism, has emerged as an important way to analyze cellular functions under both physiological and pathogenic conditions. Metabolic analysis provides an overview of the functional physiological state of the cell and gives insights into malfunctions or alterations upon diseases. Thus, understanding the fine tuning of metabolism and the networks of molecules involved in this process will be a major task in the future.

In this Special Issue, we are interested in both exhaustive and specific reviews and original articles that address all aspects of this important topic. This Special Issue shall focus on various features of metabolomics, including metabolomics in cancer and other diseases, methodological issues and improvements, as well as characterization of metabolic processes in physiological processes. We hope that this intriguing topic will attract a large number of contributions from both basic and clinical scientists.

Prof. Dr. Ritva Tikkanen
Dr. Nina S. Kurrle
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metabolic analysis
  • mass spectrometry
  • cancer metabolome
  • differentiation and growth
  • signaling networks and metabolome
  • regulation of metabolome

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Published Papers (9 papers)

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Research

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15 pages, 3261 KiB  
Article
Metabolomic Profiling of Plasma and Erythrocytes in Sickle Mice Points to Altered Nociceptive Pathways
by Klétigui Casimir Dembélé, Thomas Mintz, Charlotte Veyrat-Durebex, Floris Chabrun, Stéphanie Chupin, Lydie Tessier, Gilles Simard, Daniel Henrion, Delphine Mirebeau-Prunier, Juan Manuel Chao de la Barca, Pierre-Louis Tharaux and Pascal Reynier
Cells 2020, 9(6), 1334; https://doi.org/10.3390/cells9061334 - 26 May 2020
Cited by 10 | Viewed by 3160
Abstract
Few data-driven metabolomic approaches have been reported in sickle cell disease (SCD) to date. We performed a metabo-lipidomic study on the plasma and red blood cells of a steady-state mouse model carrying the homozygous human hemoglobin SS, compared with AS and AA genotypes. [...] Read more.
Few data-driven metabolomic approaches have been reported in sickle cell disease (SCD) to date. We performed a metabo-lipidomic study on the plasma and red blood cells of a steady-state mouse model carrying the homozygous human hemoglobin SS, compared with AS and AA genotypes. Among the 188 metabolites analyzed by a targeted quantitative metabolomic approach, 153 and 129 metabolites were accurately measured in the plasma and red blood cells, respectively. Unsupervised PCAs (principal component analyses) gave good spontaneous discrimination between HbSS and controls, and supervised OPLS-DAs (orthogonal partial least squares-discriminant analyses) provided highly discriminant models. These models confirmed the well-known deregulation of nitric oxide synthesis in the HbSS genotype, involving arginine deficiency and increased levels of dimethylarginines, ornithine, and polyamines. Other discriminant metabolites were newly evidenced, such as hexoses, alpha-aminoadipate, serotonin, kynurenine, and amino acids, pointing to a glycolytic shift and to the alteration of metabolites known to be involved in nociceptive pathways. Sharp remodeling of lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins was evidenced in red blood cells. Our metabolomic study provides an overview of the metabolic remodeling induced by the sickle genotype in the plasma and red blood cells, revealing a biological fingerprint of altered nitric oxide, bioenergetics and nociceptive pathways. Full article
(This article belongs to the Special Issue Metabolomics in Physiology and Diseases)
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15 pages, 12126 KiB  
Article
Aspirin Mitigated Tumor Growth in Obese Mice Involving Metabolic Inhibition
by Jiaan-Der Wang, Wen-Ying Chen, Jian-Ri Li, Shih-Yi Lin, Ya-Yu Wang, Chih-Cheng Wu, Su-Lan Liao, Chiao-Chen Ko and Chun-Jung Chen
Cells 2020, 9(3), 569; https://doi.org/10.3390/cells9030569 - 28 Feb 2020
Cited by 8 | Viewed by 3409
Abstract
Obesity is associated with a wide range of chronic diseases, including cancer. It has been noted that the integration of metabolic mechanisms in obese patients may predispose them to suffer from cancer incidence and its progression. Thus, a better understanding of metabolic alterations [...] Read more.
Obesity is associated with a wide range of chronic diseases, including cancer. It has been noted that the integration of metabolic mechanisms in obese patients may predispose them to suffer from cancer incidence and its progression. Thus, a better understanding of metabolic alterations in obesity, along with the development of feasible therapeutic approaches for intervention, are theoretically relevant to the prevention and treatment of cancer malignancy. Using a syngeneic tumor model involving Lewis Lung Carcinoma (LLC) cells and C57BL/6 mice fed with a high fat diet, obesity was found to be associated with dysregulated glucose and glutamine metabolism, inflammation, along with platelet activation and the promotion of tumor growth. Tumor-bearing lowered glucose levels while moderately increasing inflammation, platelet activation, and glutamine levels. The antiplatelet drug aspirin, mitigated tumor growth in obese mice, paralleled by a decrease in systemic glucose, insulin, inflammation, platelet activation, glutamine and tumor expression of cell proliferation, aerobic glycolysis, glutaminolysis, platelets, and leukocyte molecules. The anti- and pro-cell proliferation, aerobic glycolysis, and glutaminolysis effects of aspirin and glutamine were further demonstrated in a LLC cell study. Although there remains limitations to our experiments, glucose and glutamine metabolism are proposed targets for the anticancer effects of aspirin. Full article
(This article belongs to the Special Issue Metabolomics in Physiology and Diseases)
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17 pages, 5566 KiB  
Article
Metabolomic Analysis of the Liver of a Dextran Sodium Sulfate-Induced Acute Colitis Mouse Model: Implications of the Gut–Liver Connection
by Sou Hyun Kim, Wonho Lee, Doyoung Kwon, Seunghyun Lee, Seung Won Son, Min-Soo Seo, Kil Soo Kim, Yun-Hee Lee, Suhkmann Kim and Young-Suk Jung
Cells 2020, 9(2), 341; https://doi.org/10.3390/cells9020341 - 1 Feb 2020
Cited by 23 | Viewed by 4647
Abstract
The incidence of ulcerative colitis (UC) is increasing worldwide, and it has become a growing problem in Asia. Previous research on UC has focused on serum, plasma, urine, gut tissues, and fecal metabolic profiling, but a comprehensive investigation into the correlation between the [...] Read more.
The incidence of ulcerative colitis (UC) is increasing worldwide, and it has become a growing problem in Asia. Previous research on UC has focused on serum, plasma, urine, gut tissues, and fecal metabolic profiling, but a comprehensive investigation into the correlation between the severity of colitis and changes in liver metabolism is still lacking. Since the liver and gut exchange nutrients and metabolites through a complex network, intestinal diseases can affect both the liver and other organs. In the present study, concentration-dependent dextran sodium sulfate (DSS)-induced ulcerative colitis was employed to examine changes in liver metabolism using a proton nuclear magnetic resonance spectroscopy (1H-NMR)-and ultra-performance liquid chromatography time of flight mass spectroscopy (UPLC-TOF MS)-based metabolomics study. Using the multivariate statistical analysis method orthogonal projections to latent structures discriminant analysis (OPLS-DA), changes in metabolites depending on the DSS dose could be clearly distinguished. Specifically, hepatic metabolites involved in one-carbon metabolism, carnitine-related metabolism, and nucleotide synthesis were found to be affected by intestinal inflammation, implying the existence of a metabolic connection between the gut and liver. We are currently investigating the significance of this metabolic condition in UC. Full article
(This article belongs to the Special Issue Metabolomics in Physiology and Diseases)
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22 pages, 4789 KiB  
Article
Systemic Metabolomic Profiling of Acute Myeloid Leukemia Patients before and During Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid, Valproic Acid, and Low-Dose Chemotherapy
by Ida Sofie Grønningsæter, Hanne Kristin Fredly, Bjørn Tore Gjertsen, Kimberley Joanne Hatfield and Øystein Bruserud
Cells 2019, 8(10), 1229; https://doi.org/10.3390/cells8101229 - 10 Oct 2019
Cited by 20 | Viewed by 3703
Abstract
Acute myeloid leukemia (AML) is an aggressive malignancy, and many elderly/unfit patients cannot receive intensive and potentially curative therapy. These patients receive low-toxicity disease-stabilizing treatment. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid can stabilize the disease [...] Read more.
Acute myeloid leukemia (AML) is an aggressive malignancy, and many elderly/unfit patients cannot receive intensive and potentially curative therapy. These patients receive low-toxicity disease-stabilizing treatment. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid can stabilize the disease for a subset of such patients. We performed untargeted serum metabolomic profiling for 44 AML patients receiving treatment based on ATRA and valproic acid combined with low-dose cytotoxic drugs (cytarabine, hydroxyurea, 6-mercaptopurin) which identified 886 metabolites. When comparing pretreatment samples from responders and non-responders, metabolites mainly belonging to amino acid and lipid (i.e., fatty acid) pathways were altered. Furthermore, patients with rapidly progressive disease showed an extensively altered lipid metabolism. Both ATRA and valproic acid monotherapy also altered the amino acid and lipid metabolite profiles; however, these changes were only highly significant for valproic acid treatment. Twenty-three metabolites were significantly altered by seven-day valproic acid treatment (p < 0.05, q < 0.05), where the majority of altered metabolites belonged to lipid (especially fatty acid metabolism) and amino acid pathways, including several carnitines. These metabolomic effects, and especially the effects on lipid metabolism, may be important for the antileukemic and epigenetic effects of this treatment. Full article
(This article belongs to the Special Issue Metabolomics in Physiology and Diseases)
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18 pages, 3138 KiB  
Article
Chronic Hypoxia Enhances β-Oxidation-Dependent Electron Transport via Electron Transferring Flavoproteins
by Dominik C. Fuhrmann, Catherine Olesch, Nina Kurrle, Frank Schnütgen, Sven Zukunft, Ingrid Fleming and Bernhard Brüne
Cells 2019, 8(2), 172; https://doi.org/10.3390/cells8020172 - 18 Feb 2019
Cited by 16 | Viewed by 5756
Abstract
Hypoxia poses a stress to cells and decreases mitochondrial respiration, in part by electron transport chain (ETC) complex reorganization. While metabolism under acute hypoxia is well characterized, alterations under chronic hypoxia largely remain unexplored. We followed oxygen consumption rates in THP-1 monocytes during [...] Read more.
Hypoxia poses a stress to cells and decreases mitochondrial respiration, in part by electron transport chain (ETC) complex reorganization. While metabolism under acute hypoxia is well characterized, alterations under chronic hypoxia largely remain unexplored. We followed oxygen consumption rates in THP-1 monocytes during acute (16 h) and chronic (72 h) hypoxia, compared to normoxia, to analyze the electron flows associated with glycolysis, glutamine, and fatty acid oxidation. Oxygen consumption under acute hypoxia predominantly demanded pyruvate, while under chronic hypoxia, fatty acid- and glutamine-oxidation dominated. Chronic hypoxia also elevated electron-transferring flavoproteins (ETF), and the knockdown of ETF–ubiquinone oxidoreductase lowered mitochondrial respiration under chronic hypoxia. Metabolomics revealed an increase in citrate under chronic hypoxia, which implied glutamine processing to α-ketoglutarate and citrate. Expression regulation of enzymes involved in this metabolic shunting corroborated this assumption. Moreover, the expression of acetyl-CoA carboxylase 1 increased, thus pointing to fatty acid synthesis under chronic hypoxia. Cells lacking complex I, which experienced a markedly impaired respiration under normoxia, also shifted their metabolism to fatty acid-dependent synthesis and usage. Taken together, we provide evidence that chronic hypoxia fuels the ETC via ETFs, increasing fatty acid production and consumption via the glutamine-citrate-fatty acid axis. Full article
(This article belongs to the Special Issue Metabolomics in Physiology and Diseases)
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Review

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26 pages, 1498 KiB  
Review
Succinic Semialdehyde Dehydrogenase Deficiency: An Update
by Miroslava Didiasova, Antje Banning, Heiko Brennenstuhl, Sabine Jung-Klawitter, Claudio Cinquemani, Thomas Opladen and Ritva Tikkanen
Cells 2020, 9(2), 477; https://doi.org/10.3390/cells9020477 - 19 Feb 2020
Cited by 30 | Viewed by 7696
Abstract
Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degrees of mental [...] Read more.
Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degrees of mental retardation, autism, ataxia, and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved curative therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials, and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs, and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between researchers and patients. Full article
(This article belongs to the Special Issue Metabolomics in Physiology and Diseases)
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29 pages, 1107 KiB  
Review
Hyperglycemia-Induced Aberrant Cell Proliferation; A Metabolic Challenge Mediated by Protein O-GlcNAc Modification
by Tamás Nagy, Viktória Fisi, Dorottya Frank, Emese Kátai, Zsófia Nagy and Attila Miseta
Cells 2019, 8(9), 999; https://doi.org/10.3390/cells8090999 - 28 Aug 2019
Cited by 35 | Viewed by 6772
Abstract
Chronic hyperglycemia has been associated with an increased prevalence of pathological conditions including cardiovascular disease, cancer, or various disorders of the immune system. In some cases, these associations may be traced back to a common underlying cause, but more often, hyperglycemia and the [...] Read more.
Chronic hyperglycemia has been associated with an increased prevalence of pathological conditions including cardiovascular disease, cancer, or various disorders of the immune system. In some cases, these associations may be traced back to a common underlying cause, but more often, hyperglycemia and the disturbance in metabolic balance directly facilitate pathological changes in the regular cellular functions. One such cellular function crucial for every living organism is cell cycle regulation/mitotic activity. Although metabolic challenges have long been recognized to influence cell proliferation, the direct impact of diabetes on cell cycle regulatory elements is a relatively uncharted territory. Among other “nutrient sensing” mechanisms, protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification emerged in recent years as a major contributor to the deleterious effects of hyperglycemia. An increasing amount of evidence suggest that O-GlcNAc may significantly influence the cell cycle and cellular proliferation. In our present review, we summarize the current data available on the direct impact of metabolic changes caused by hyperglycemia in pathological conditions associated with cell cycle disorders. We also review published experimental evidence supporting the hypothesis that O-GlcNAc modification may be one of the missing links between metabolic regulation and cellular proliferation. Full article
(This article belongs to the Special Issue Metabolomics in Physiology and Diseases)
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45 pages, 2458 KiB  
Review
Analysis of Catecholamines and Pterins in Inborn Errors of Monoamine Neurotransmitter Metabolism—From Past to Future
by Sabine Jung-Klawitter and Oya Kuseyri Hübschmann
Cells 2019, 8(8), 867; https://doi.org/10.3390/cells8080867 - 9 Aug 2019
Cited by 27 | Viewed by 7101
Abstract
Inborn errors of monoamine neurotransmitter biosynthesis and degradation belong to the rare inborn errors of metabolism. They are caused by monogenic variants in the genes encoding the proteins involved in (1) neurotransmitter biosynthesis (like tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC)), [...] Read more.
Inborn errors of monoamine neurotransmitter biosynthesis and degradation belong to the rare inborn errors of metabolism. They are caused by monogenic variants in the genes encoding the proteins involved in (1) neurotransmitter biosynthesis (like tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC)), (2) in tetrahydrobiopterin (BH4) cofactor biosynthesis (GTP cyclohydrolase 1 (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SPR)) and recycling (pterin-4a-carbinolamine dehydratase (PCD), dihydropteridine reductase (DHPR)), or (3) in co-chaperones (DNAJC12). Clinically, they present early during childhood with a lack of monoamine neurotransmitters, especially dopamine and its products norepinephrine and epinephrine. Classical symptoms include autonomous dysregulations, hypotonia, movement disorders, and developmental delay. Therapy is predominantly based on supplementation of missing cofactors or neurotransmitter precursors. However, diagnosis is difficult and is predominantly based on quantitative detection of neurotransmitters, cofactors, and precursors in cerebrospinal fluid (CSF), urine, and blood. This review aims at summarizing the diverse analytical tools routinely used for diagnosis to determine quantitatively the amounts of neurotransmitters and cofactors in the different types of samples used to identify patients suffering from these rare diseases. Full article
(This article belongs to the Special Issue Metabolomics in Physiology and Diseases)
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28 pages, 4164 KiB  
Review
Metabolic Plasticity of Acute Myeloid Leukemia
by Johanna Kreitz, Christine Schönfeld, Marcel Seibert, Verena Stolp, Islam Alshamleh, Thomas Oellerich, Björn Steffen, Harald Schwalbe, Frank Schnütgen, Nina Kurrle and Hubert Serve
Cells 2019, 8(8), 805; https://doi.org/10.3390/cells8080805 - 31 Jul 2019
Cited by 102 | Viewed by 11404
Abstract
Acute myeloid leukemia (AML) is one of the most common and life-threatening leukemias. A highly diverse and flexible metabolism contributes to the aggressiveness of the disease that is still difficult to treat. By using different sources of nutrients for energy and biomass supply, [...] Read more.
Acute myeloid leukemia (AML) is one of the most common and life-threatening leukemias. A highly diverse and flexible metabolism contributes to the aggressiveness of the disease that is still difficult to treat. By using different sources of nutrients for energy and biomass supply, AML cells gain metabolic plasticity and rapidly outcompete normal hematopoietic cells. This review aims to decipher the diverse metabolic strategies and the underlying oncogenic and environmental changes that sustain continuous growth, mediate redox homeostasis and induce drug resistance in AML. We revisit Warburg’s hypothesis and illustrate the role of glucose as a provider of cellular building blocks rather than as a supplier of the tricarboxylic acid (TCA) cycle for energy production. We discuss how the diversity of fuels for the TCA cycle, including glutamine and fatty acids, contributes to the metabolic plasticity of the disease and highlight the roles of amino acids and lipids in AML metabolism. Furthermore, we point out the potential of the different metabolic effectors to be used as novel therapeutic targets. Full article
(This article belongs to the Special Issue Metabolomics in Physiology and Diseases)
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