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A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Advances in Metabolomics".

Deadline for manuscript submissions: closed (30 August 2019) | Viewed by 54763

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Prof. Dr. James McCullagh

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Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, 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

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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.

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Published Papers (10 papers)

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Research

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15 pages, 2577 KiB

Open AccessArticle

Blood Metabolites Associate with Prognosis in Endometrial Cancer

by Elin Strand, Ingvild L. Tangen, Kristine E. Fasmer, Havjin Jacob, Mari K. Halle, Erling A. Hoivik, Bert Delvoux, Jone Trovik, Ingfrid S. Haldorsen, Andrea Romano and Camilla Krakstad

Metabolites 2019, 9(12), 302; https://doi.org/10.3390/metabo9120302 - 14 Dec 2019

Cited by 13 | Viewed by 3595

Abstract

Endometrial cancer has a high prevalence among post-menopausal women in developed countries. We aimed to explore whether certain metabolic patterns could be related to the characteristics of aggressive disease and poorer survival among endometrial cancer patients in Western Norway. Patients with endometrial cancer with short survival (n = 20) were matched according to FIGO (International Federation of Gynecology and Obstetrics, 2009 criteria) stage, histology, and grade, with patients with long survival (n = 20). Plasma metabolites were measured on a multiplex system including 183 metabolites, which were subsequently determined using liquid chromatography-mass spectrometry. Partial least square discriminant analysis, together with hierarchical clustering, was used to identify patterns which distinguished short from long survival. A proposed signature of metabolites related to survival was suggested, and a multivariate receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.820–0.965 (p ≤ 0.001). Methionine sulfoxide seems to be particularly strongly associated with poor survival rates in these patients. In a subgroup with preoperative contrast-enhanced computed tomography data, selected metabolites correlated with the estimated abdominal fat distribution parameters. Metabolic signatures may predict prognosis and be promising supplements when evaluating phenotypes and exploring metabolic pathways related to the progression of endometrial cancer. In the future, this may serve as a useful tool in cancer management. Full article

(This article belongs to the Special Issue Metabolomics in the Study of Disease)

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13 pages, 1812 KiB

Open AccessArticle

ADGRL4/ELTD1 Silencing in Endothelial Cells Induces ACLY and SLC25A1 and Alters the Cellular Metabolic Profile

by David M. Favara, Christos E. Zois, Syed Haider, Elisabete Pires, Helen Sheldon, James McCullagh, Alison H. Banham and Adrian L. Harris

Metabolites 2019, 9(12), 287; https://doi.org/10.3390/metabo9120287 - 25 Nov 2019

Cited by 18 | Viewed by 5010

Abstract

Adhesion G Protein-Coupled Receptor L4 (ADGRL4/ELTD1) is an endothelial cell adhesion G protein-coupled receptor (aGPCR) which regulates physiological and tumour angiogenesis, providing an attractive target for anti-cancer therapeutics. To date, ADGRL4/ELTD1′s full role and mechanism of function within endothelial biology remains unknown, as do its ligand(s). In this study, ADGRL4/ELTD1 silencing, using two independent small interfering RNAs (siRNAs), was performed in human umbilical vein endothelial cells (HUVECS) followed by transcriptional profiling, target gene validation, and metabolomics using liquid chromatography-mass spectrometry in order to better characterise ADGRL4/ELTD1′s role in endothelial cell biology. We show that ADGRL4/ELTD1 silencing induced expression of the cytoplasmic metabolic regulator ATP Citrate Lyase (ACLY) and the mitochondria-to-cytoplasm citrate transporter Solute Carrier Family 25 Member 1 (SLC25A1) but had no apparent effect on pathways downstream of ACLY (fatty acid and cholesterol synthesis or acetylation). Silencing induced KIT expression and affected the Notch signalling pathway, upregulating Delta Like Canonical Notch Ligand 4 (DLL4) and suppressing Jagged Canonical Notch Ligand 1 (JAG1) and Hes Family BHLH Transcription Factor 2 (HES2). The effect of ADGRL4/ELTD1 silencing on the cellular metabolic profile was modest but several metabolites were significantly affected. Cis-aconitic acid, uridine diphosphate (UDP)-glucoronate, fructose 2,6-diphosphate, uridine 5-diphosphate, and aspartic acid were all elevated as a result of silencing and phosphocreatine, N-acetylglutamic acid, taurine, deoxyadenosine triphosphate, and cytidine monophosphate were depleted. Metabolic pathway analysis implicated ADGRL4/ELTD1 in pyrimidine, amino acid, and sugar metabolism. In summary, this study shows that ADGRL4/ELTD1 impacts core components of endothelial metabolism and regulates genes involved in endothelial differentiation/homeostasis and Notch signalling. Full article

(This article belongs to the Special Issue Metabolomics in the Study of Disease)

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17 pages, 2550 KiB

Open AccessArticle

Multi-Organ NMR Metabolomics to Assess In Vivo Overall Metabolic Impact of Cisplatin in Mice

by Tatiana J. Carneiro, Rita Araújo, Martin Vojtek, Salomé Gonçalves-Monteiro, Carmen Diniz, Ana L.M. Batista de Carvalho, Maria Paula M. Marques and Ana M. Gil

Metabolites 2019, 9(11), 279; https://doi.org/10.3390/metabo9110279 - 13 Nov 2019

Cited by 14 | Viewed by 4115

Abstract

This work describes, to our knowledge, the first NMR metabolomics analysis of mice kidney, liver, and breast tissue in response to cisplatin exposure, in search of early metabolic signatures of cisplatin biotoxicity. Balb/c mice were exposed to a single 3.5 mg/kg dose of cisplatin and then euthanized; organs (kidney, liver, breast tissue) were collected at 1, 12, and 48 h. Polar tissue extracts were analyzed by NMR spectroscopy, and the resulting spectra were studied by multivariate and univariate analyses. The results enabled the identification of the most significant deviant metabolite levels at each time point, and for each tissue type, and showed that the largest metabolic impact occurs for kidney, as early as 1 h post-injection. Kidney tissue showed a marked depletion in several amino acids, comprised in an overall 13-metabolites signature. The highest number of changes in all tissues was noted at 12 h, although many of those recovered to control levels at 48 h, with the exception of some persistently deviant tissue-specific metabolites, thus enabling the identification of relatively longer-term effects of cDDP. This work reports, for the first time, early (1–48 h) concomitant effects of cDDP in kidney, liver, and breast tissue metabolism, thus contributing to the understanding of multi-organ cDDP biotoxicity. Full article

(This article belongs to the Special Issue Metabolomics in the Study of Disease)

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12 pages, 2436 KiB

Open AccessCommunication

Historical Biobanks in Breast Cancer Metabolomics— Challenges and Opportunities

by Torfinn S. Madssen, Maria D. Cao, Arne V. Pladsen, Lars Ottestad, Kristine K. Sahlberg, Tone F. Bathen and Guro F. Giskeødegård

Metabolites 2019, 9(11), 278; https://doi.org/10.3390/metabo9110278 - 13 Nov 2019

Cited by 4 | Viewed by 2931

Abstract

Background: Metabolomic characterization of tumours can potentially improve prediction of cancer prognosis and treatment response. Here, we describe efforts to validate previous metabolomic findings using a historical cohort of breast cancer patients and discuss challenges with using older biobanks collected with non-standardized sampling procedures. Methods: In total, 100 primary breast cancer samples were analysed by high-resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS) and subsequently examined by histology. Metabolomic profiles were related to the presence of cancer tissue, hormone receptor status, T-stage, N-stage, and survival. RNA integrity number (RIN) and metabolomic profiles were compared with an ongoing breast cancer biobank. Results: The 100 samples had a median RIN of 4.3, while the ongoing biobank had a significantly higher median RIN of 6.3 (p = 5.86 × 10⁻⁷). A low RIN was associated with changes in choline-containing metabolites and creatine, and the samples in the older biobank showed metabolic differences previously associated with tissue degradation. The association between metabolomic profile and oestrogen receptor status was in accordance with previous findings, however, with a lower classification accuracy. Conclusions: Our findings highlight the importance of standardized biobanking procedures in breast cancer metabolomics studies. Full article

(This article belongs to the Special Issue Metabolomics in the Study of Disease)

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18 pages, 2388 KiB

Open AccessArticle

Metabolomic Analysis Reveals Unique Biochemical Signatures Associated with Protection from Radiation Induced Lung Injury by Lack of cd47 Receptor Gene Expression

by Elizabeth R. Stirling, Katherine L. Cook, David D. Roberts and David R. Soto-Pantoja

Metabolites 2019, 9(10), 218; https://doi.org/10.3390/metabo9100218 - 8 Oct 2019

Cited by 9 | Viewed by 3577

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 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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12 pages, 888 KiB

Open AccessArticle

Reactive Carbonyl Species as Potential Pro-Oxidant Factors Involved in Lichen Planus Pathogenesis

by Madalina Irina Mitran, Ilinca Nicolae, Mircea Tampa, Cristina Iulia Mitran, Constantin Caruntu, Maria Isabela Sarbu, Corina Daniela Ene, Clara Matei, Simona Roxana Georgescu and Mircea Ioan Popa

Metabolites 2019, 9(10), 213; https://doi.org/10.3390/metabo9100213 - 3 Oct 2019

Cited by 15 | Viewed by 3247

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 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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18 pages, 3494 KiB

Open AccessArticle

Feasibility of Localized Metabolomics in the Study of Pancreatic Islets and Diabetes

by Oscar Alcazar, Luis F. Hernandez, Ashley Tschiggfrie, Michael J. Muehlbauer, James R. Bain, Peter Buchwald and Midhat H. Abdulreda

Metabolites 2019, 9(10), 207; https://doi.org/10.3390/metabo9100207 - 29 Sep 2019

Cited by 9 | Viewed by 4801

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 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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21 pages, 1468 KiB

Open AccessArticle

Propolis Exerts an Anti-Inflammatory Effect on PMA-Differentiated THP-1 Cells via Inhibition of Purine Nucleoside Phosphorylase

by Abdulmalik M. Alqarni, Kanidta Niwasabutra, Muhamad Sahlan, Hugo Fearnley, James Fearnley, Valerie A. Ferro and David G. Watson

Metabolites 2019, 9(4), 75; https://doi.org/10.3390/metabo9040075 - 16 Apr 2019

Cited by 25 | Viewed by 5468

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 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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11 pages, 2644 KiB

Open AccessArticle

A Noninvasive Comparison Study between Human Gliomas with IDH1 and IDH2 Mutations by MR Spectroscopy

by Xin Shen, Natalie L. Voets, Sarah J. Larkin, Nick de Pennington, Puneet Plaha, Richard Stacey, James S. O. McCullagh, Christopher J. Schofield, Stuart Clare, Peter Jezzard, Tom Cadoux-Hudson, Olaf Ansorge and Uzay E. Emir

Metabolites 2019, 9(2), 35; https://doi.org/10.3390/metabo9020035 - 20 Feb 2019

Cited by 23 | Viewed by 6938

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 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, P_c < 0.001) and myo-Inositol/tCho (2.70 ± 0.90 vs. 1.46 ± 0.51, P_c = 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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26 pages, 2108 KiB

Open AccessReview

Inborn Errors of Metabolism in the Era of Untargeted Metabolomics and Lipidomics

by Israa T Ismail, Megan R Showalter and Oliver Fiehn

Metabolites 2019, 9(10), 242; https://doi.org/10.3390/metabo9100242 - 21 Oct 2019

Cited by 64 | Viewed by 14121

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 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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