Special Issue "Metabolomics in the Study of Disease"

A special issue of Metabolites (ISSN 2218-1989).

Deadline for manuscript submissions: closed (30 August 2019).

Special Issue Editor

Dr. James McCullagh
E-Mail Website
Guest Editor
University of Oxford, Oxford, UK
Interests: metabolomics; mass spectrometry; bioanalytical chemistry; method development; disease biomarkers; cancer metabolism; bioinformatics

Special Issue Information

Dear Colleagues,

Metabolomics can be used to investigate complex diseases that affect modern society including diabetes, dementia, heart disease, and cancer. Such diseases are often associated with, and characterised by, genetic mutations, but downstream metabolic consequences are not always well understood. Metabolomics has the potential to elucidate changes in cellular metabolism that may not be predictable from genetics but that present a cellular phenotype where therapeutic interventions can have selective and targeted effects. New metabolomics methods and applications, which help us gain insight into the complexities of the disease metabolome, are of particular relevence. In this Special Issue of Metabolites, we will demonstrate current developments and applications for diagnosis, understanding mechanisms, and finding new treatments for disease.

Dr. James McCullagh
Guest Editor

Manuscript Submission Information

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Keywords

  • Using metabolomics to elucidate cellular metabolism in disease.
  • Monitoring disease progression and treatment by metabolomics or multi-omics.
  • Prognostic and diagnostic metabolite markers of disease.
  • Elucidating metabolic pathways in disease states.
  • Understanding the metabolic effects of drugs and treatments.
  • New analytical methods for monitoring metabolism in disease.

Published Papers (6 papers)

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Research

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Open AccessArticle
Metabolomic Analysis Reveals Unique Biochemical Signatures Associated with Protection from Radiation Induced Lung Injury by Lack of cd47 Receptor Gene Expression
Metabolites 2019, 9(10), 218; https://doi.org/10.3390/metabo9100218 - 08 Oct 2019
Abstract
The goal of this study was to interrogate biochemical profiles manifested in mouse lung tissue originating from wild type (WT) and cd47 null mice with the aim of revealing the in vivo role of CD47 in the metabolic response to ionizing radiation, especially [...] Read more.
The goal of this study was to interrogate biochemical profiles manifested in mouse lung tissue originating from wild type (WT) and cd47 null mice with the aim of revealing the in vivo role of CD47 in the metabolic response to ionizing radiation, especially changes related to the known association of CD47 deficiency with increased tissue viability and survival. For this objective, we performed global metabolomic analysis in mouse lung tissue collected from (C57Bl/6 background) WT and cd47 null mice with and without exposure to 7.6 Gy whole body radiation. Principal component analysis and hierarchical clustering revealed a consistent separation between genotypes following radiation exposure. Random forest analysis also revealed a unique biochemical signature in WT and cd47 null mice following treatment. Our data show that cd47 null irradiated lung tissue activates a unique set of metabolic pathways that facilitate the handling of reactive oxygen species, lipid metabolism, nucleotide metabolism and nutrient metabolites which may be regulated by microbial processing. Given that cd47 has pleiotropic effects on responses to ionizing radiation, we not only propose this receptor as a therapeutic target but postulate that the biomarkers regulated in this study associated with radioprotection are potential mitigators of radiation-associated pathologies, including the onset of pulmonary disease. Full article
(This article belongs to the Special Issue Metabolomics in the Study of Disease)
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Open AccessArticle
Reactive Carbonyl Species as Potential Pro-Oxidant Factors Involved in Lichen Planus Pathogenesis
Metabolites 2019, 9(10), 213; https://doi.org/10.3390/metabo9100213 - 03 Oct 2019
Abstract
The constant generation of reactive carbonyl species (RCSs) by lipid peroxidation during aerobic metabolism denotes their involvement in cell homeostasis. Skin represents the largest organ of the body that is exposed to lipid peroxidation. Previous studies have suggested the involvement of oxidative stress [...] Read more.
The constant generation of reactive carbonyl species (RCSs) by lipid peroxidation during aerobic metabolism denotes their involvement in cell homeostasis. Skin represents the largest organ of the body that is exposed to lipid peroxidation. Previous studies have suggested the involvement of oxidative stress in the development of lichen planus (LP), a chronic inflammatory skin condition with a complex pathogenesis. The aim of our study is to investigate a panel of pro-oxidants (4-hydroxy-nonenal (4-HNE), thiobarbituric acid reactive substances (TBARS), and malondialdehyde (MDA)), the total antioxidant status (TAS), and thiol-disulfide homeostasis parameters (TDHP), including total thiol (TT), native thiol (NT), disulfides (DS), DS/NT ratio, DS/TT ratio, and NT/TT ratio. The comparative determinations of serum levels of 4-HNE, TBARS, and MDA in patients with LP (n = 31) and controls (n = 26) show significant differences between the two groups (4-HNE: 7.81 ± 1.96 µg/mL vs. 6.15 ± 1.17 µg/mL, p < 0.05, TBARS: 4.23 ± 0.59 µmol/L vs. 1.99 ± 0.23 µmol/L, p < 0.05, MDA: 32.3 ± 6.26 ng/mL vs. 21.26 ± 2.36 ng/mL). The serum levels of TAS are lower in LP patients compared to the control group (269.83 ± 42.63 µmol/L vs. 316.46 ± 28.76 µmol/L, p < 0.05). The serum levels of TDHP are altered in LP patients compared to controls (NT: 388.10 ± 11.32 µmol/L vs. 406.85 ± 9.32., TT: 430.23 ± 9.93 µmol/L vs. 445.88 ± 9.01 µmol/L, DS: 21.06 ± 1.76 µmol/L vs. 19.52 ± 0.77µmol/L). Furthermore, a negative association between pro-oxidants and TAS is identified (4-HNE – rho = −0.83, p < 0.01, TBARS – rho = −0.63, p < 0.01, and MDA – rho = −0.69, p < 0.01). Understanding the mechanisms by which bioactive aldehydes exert their biological effects on the skin could help define effective therapeutical strategies to counteract the cytotoxic effects of these reactive metabolic intermediates. Full article
(This article belongs to the Special Issue Metabolomics in the Study of Disease)
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Open AccessArticle
Feasibility of Localized Metabolomics in the Study of Pancreatic Islets and Diabetes
Metabolites 2019, 9(10), 207; https://doi.org/10.3390/metabo9100207 - 29 Sep 2019
Abstract
(1) Background: Disruption of insulin production by native or transplanted pancreatic islets caused by auto/allo-immunity leads to hyperglycemia, a serious health condition and important therapeutic challenge due to the lifelong need for exogeneous insulin administration. Early metabolic biomarkers can prompt timely interventions to [...] Read more.
(1) Background: Disruption of insulin production by native or transplanted pancreatic islets caused by auto/allo-immunity leads to hyperglycemia, a serious health condition and important therapeutic challenge due to the lifelong need for exogeneous insulin administration. Early metabolic biomarkers can prompt timely interventions to preserve islet function, but reliable biomarkers are currently lacking. We explored the feasibility of “localized metabolomics” where initial biomarker discovery is made in aqueous humor samples for further validation in the circulation. (2) Methods: We conducted non-targeted metabolomic studies in parallel aqueous humor and plasma samples from diabetic and nondiabetic mice. Metabolite levels and associated pathways were compared in both compartments as well as to an earlier longitudinal dataset in hyperglycemia-progressor versus non-progressor non-obese diabetic (NOD) mice. (3) Results: We confirmed that aqueous humor samples can be used to assess metabolite levels. About half of the identified metabolites had well-correlated levels in the aqueous humor and plasma. Several plasma metabolites were significantly different between diabetic and nondiabetic animals and between males and females, and many of them were correlated with the aqueous humor. (4) Conclusions: This study provides proof-of-concept evidence that aqueous humor samples enriched with islet-related metabolites and representative of the immediate islet microenvironment following intraocular islet transplant can be used to assess metabolic changes that could otherwise be overlooked in the general circulation. The findings support localized metabolomics, with and without intraocular islet transplant, to identify biomarkers associated with diabetes and islet allograft rejection. Full article
(This article belongs to the Special Issue Metabolomics in the Study of Disease)
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Open AccessArticle
Propolis Exerts an Anti-Inflammatory Effect on PMA-Differentiated THP-1 Cells via Inhibition of Purine Nucleoside Phosphorylase
Metabolites 2019, 9(4), 75; https://doi.org/10.3390/metabo9040075 - 16 Apr 2019
Cited by 1
Abstract
Previous research has shown that propolis has immunomodulatory activity. Propolis extracts from different geographic origins were assessed for their anti-inflammatory activities by investigating their ability to alter the production of tumour necrosis factor-α (TNF-α) and the cytokines interleukin-1β (IL-1β), IL-6 and IL-10 in [...] Read more.
Previous research has shown that propolis has immunomodulatory activity. Propolis extracts from different geographic origins were assessed for their anti-inflammatory activities by investigating their ability to alter the production of tumour necrosis factor-α (TNF-α) and the cytokines interleukin-1β (IL-1β), IL-6 and IL-10 in THP-1-derived macrophage cells co-stimulated with lipopolysaccharide (LPS). All the propolis extracts suppressed the TNF-α and IL-6 LPS-stimulated levels. Similar suppression effects were detected for IL-1β, but the release of this cytokine was synergised by propolis samples from Ghana and Indonesia when compared with LPS. Overall, the Cameroonian propolis extract (P-C) was the most active and this was evaluated for its effects on the metabolic profile of unstimulated macrophages or macrophages activated by LPS. The levels of 81 polar metabolites were identified by liquid chromatography (LC) coupled with mass spectrometry (MS) on a ZIC-pHILIC column. LPS altered the energy, amino acid and nucleotide metabolism in THP-1 cells, and interpretation of the metabolic pathways showed that P-C reversed some of the effects of LPS. Overall, the results showed that propolis extracts exert an anti-inflammatory effect by inhibition of pro-inflammatory cytokines and by metabolic reprogramming of LPS activity in macrophage cells, suggesting an immunomodulatory effect. Full article
(This article belongs to the Special Issue Metabolomics in the Study of Disease)
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Open AccessArticle
A Noninvasive Comparison Study between Human Gliomas with IDH1 and IDH2 Mutations by MR Spectroscopy
Metabolites 2019, 9(2), 35; https://doi.org/10.3390/metabo9020035 - 20 Feb 2019
Cited by 2
Abstract
The oncogenes that are expressed in gliomas reprogram particular pathways of glucose, amino acids, and fatty acid metabolism. Mutations in isocitrate dehydrogenase genes (IDH1/2) in diffuse gliomas are associated with abnormally high levels of 2-hydroxyglutarate (2-HG) levels. The aim of this study was [...] Read more.
The oncogenes that are expressed in gliomas reprogram particular pathways of glucose, amino acids, and fatty acid metabolism. Mutations in isocitrate dehydrogenase genes (IDH1/2) in diffuse gliomas are associated with abnormally high levels of 2-hydroxyglutarate (2-HG) levels. The aim of this study was to determine whether metabolic reprogramming associated with IDH mutant gliomas leads to additional 1H MRS-detectable differences between IDH1 and IDH2 mutations, and to identify metabolites correlated with 2-HG. A total of 21 glioma patients (age= 37 ± 11, 13 males) were recruited for magnetic resonance spectroscopy (MRS) using semi-localization by adiabatic selective refocusing pulse sequence at an ultra-high-field (7T). For 20 patients, the tumor mutation subtype was confirmed by immunohistochemistry and DNA sequencing. LCModel analysis was applied for metabolite quantification. A two-sample t-test was used for metabolite comparisons between IDH1 (n = 15) and IDH2 (n = 5) mutant gliomas. The Pearson correlation coefficients between 2-HG and associated metabolites were calculated. A Bonferroni correction was applied for multiple comparison. IDH2 mutant gliomas have a higher level of 2-HG/tCho (total choline=phosphocholine+glycerylphosphorylcholine) (2.48 ± 1.01vs.0.72 ± 0.38, Pc < 0.001) and myo-Inositol/tCho (2.70 ± 0.90 vs. 1.46 ± 0.51, Pc = 0.011) compared to IDH1 mutation gliomas. Associated metabolites, myo-Inositol and glucose+taurine were correlated with 2-HG levels. These results show the improved characterization of the metabolic pathways in IDH1 and IDH2 gliomas for precision medicine. Full article
(This article belongs to the Special Issue Metabolomics in the Study of Disease)
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Review

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Open AccessReview
Inborn Errors of Metabolism in the Era of Untargeted Metabolomics and Lipidomics
Metabolites 2019, 9(10), 242; https://doi.org/10.3390/metabo9100242 - 21 Oct 2019
Abstract
Inborn errors of metabolism (IEMs) are a group of inherited diseases with variable incidences. IEMs are caused by disrupting enzyme activities in specific metabolic pathways by genetic mutations, either directly or indirectly by cofactor deficiencies, causing altered levels of compounds associated with these [...] Read more.
Inborn errors of metabolism (IEMs) are a group of inherited diseases with variable incidences. IEMs are caused by disrupting enzyme activities in specific metabolic pathways by genetic mutations, either directly or indirectly by cofactor deficiencies, causing altered levels of compounds associated with these pathways. While IEMs may present with multiple overlapping symptoms and metabolites, early and accurate diagnosis of IEMs is critical for the long-term health of affected subjects. The prevalence of IEMs differs between countries, likely because different IEM classifications and IEM screening methods are used. Currently, newborn screening programs exclusively use targeted metabolic assays that focus on limited panels of compounds for selected IEM diseases. Such targeted approaches face the problem of false negative and false positive diagnoses that could be overcome if metabolic screening adopted analyses of a broader range of analytes. Hence, we here review the prospects of using untargeted metabolomics for IEM screening. Untargeted metabolomics and lipidomics do not rely on predefined target lists and can detect as many metabolites as possible in a sample, allowing to screen for many metabolic pathways simultaneously. Examples are given for nontargeted analyses of IEMs, and prospects and limitations of different metabolomics methods are discussed. We conclude that dedicated studies are needed to compare accuracy and robustness of targeted and untargeted methods with respect to widening the scope of IEM diagnostics. Full article
(This article belongs to the Special Issue Metabolomics in the Study of Disease)
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