Metabolism and Diseases

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 23873

Special Issue Editors

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
Interests: cancer metabolism; metabolic pathways; apoptosis; nucleotide metabolism; cellular metabolism
CRCI2NA (Centre de Recherche en Cancérologie et immunologie Intégré- Nantes, Angers), INSERM (Institut National en santé et de la Recherche Medicale), CNRS (Centre National de la Recherche Scientifique), Université de Nantes, 44007 Nantes, France
Interests: tumor metabolism; glioblastoma; microenvironment; cancer stem cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The proper control of metabolism is required for essentially every basic biological process. From recent work, it is becoming more evident that many human diseases involve abnormal metabolic states. Altered metabolism at the cellular level contributes to several serious diseases including Alzheimer's disease, obesity, diabetes, and cancer. This awareness leads us to understand the molecular mechanisms that underlie metabolism and its associated pathology. This Special Issue focuses on investigating the connection between metabolic perturbation and diseases, characterizing metabolic disorders, understanding how they compromise tissue function, identifying metabolites that can be potentially used as biomarkers, and designing therapies to restore normal metabolism and improve health.

Dr. Jiyeon Kim
Dr. Claire Pecqueur
Guest Editors

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Keywords

  • alzheimer's disease
  • obesity
  • diabetes
  • cancer
  • metabolism
  • pathology
  • metabolites

Published Papers (6 papers)

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Research

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13 pages, 4032 KiB  
Article
Metabolites Alterations and Liver Injury in Hepatic Encephalopathy Models Evaluated by Use of 7T-MRI
Metabolites 2022, 12(5), 396; https://doi.org/10.3390/metabo12050396 - 27 Apr 2022
Cited by 1 | Viewed by 1317
Abstract
This study is to observe a thioacetamide (TAA) administered Hepatic encephalopathy (HE) model rats at three and ten days after TAA administration using liver MRI and brain MR Spectroscopy (MRS) by use of 7T-MRI. Forty-two Wistar rats (control group, n = 14) were [...] Read more.
This study is to observe a thioacetamide (TAA) administered Hepatic encephalopathy (HE) model rats at three and ten days after TAA administration using liver MRI and brain MR Spectroscopy (MRS) by use of 7T-MRI. Forty-two Wistar rats (control group, n = 14) were intraperitoneally administered at 300 mg/kg (low-dose group, n = 14) or 400 mg/kg (high-dose group, n = 14) doses of TAA for induced of HE. At three days after TAA administration, glutamine (Gln) measured by MRS in high-dose and low-dose TAA groups showed significant increases in comparison to those of the control group (p < 0.05). Other metabolites measured by MRS showed no significant changes. Liver T and T2 relaxation times significantly increased three days after TAA injection compared to pre-injection. There was a correlation between Gln levels in the brain and the relaxation time of the liver. Furthermore, Gln levels and relaxation time changed depending on the TAA dose. The Gln concentration in the brain increased with the deterioration of liver function, as inferred from the prolonged relaxation time of the liver. The prolonged relaxation time of the liver corresponded with the level of Gln in the brain. Gln concentration for the alterations of brain metabolites and T relaxation time for the assessment of liver damage are useful markers for inter-organ association analysis in the HE model. Full article
(This article belongs to the Special Issue Metabolism and Diseases)
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21 pages, 2611 KiB  
Article
Metabolomic Abnormalities in Serum from Untreated and Treated Dogs with Hyper- and Hypoadrenocorticism
Metabolites 2022, 12(4), 339; https://doi.org/10.3390/metabo12040339 - 09 Apr 2022
Cited by 2 | Viewed by 2313
Abstract
The adrenal glands play a major role in metabolic processes, and both excess and insufficient serum cortisol concentrations can lead to serious metabolic consequences. Hyper- and hypoadrenocorticism represent a diagnostic and therapeutic challenge. Serum samples from dogs with untreated hyperadrenocorticism (n = [...] Read more.
The adrenal glands play a major role in metabolic processes, and both excess and insufficient serum cortisol concentrations can lead to serious metabolic consequences. Hyper- and hypoadrenocorticism represent a diagnostic and therapeutic challenge. Serum samples from dogs with untreated hyperadrenocorticism (n = 27), hyperadrenocorticism undergoing treatment (n = 28), as well as with untreated (n = 35) and treated hypoadrenocorticism (n = 23) were analyzed and compared to apparently healthy dogs (n = 40). A validated targeted proton nuclear magnetic resonance (1H NMR) platform was used to quantify 123 parameters. Principal component analysis separated the untreated endocrinopathies. The serum samples of dogs with untreated endocrinopathies showed various metabolic abnormalities with often contrasting results particularly in serum concentrations of fatty acids, and high- and low-density lipoproteins and their constituents, which were predominantly increased in hyperadrenocorticism and decreased in hypoadrenocorticism, while amino acid concentrations changed in various directions. Many observed serum metabolic abnormalities tended to normalize with medical treatment, but normalization was incomplete when compared to levels in apparently healthy dogs. Application of machine learning models based on the metabolomics data showed good classification, with misclassifications primarily observed in treated groups. Characterization of metabolic changes enhances our understanding of these endocrinopathies. Further assessment of the recognized incomplete reversal of metabolic alterations during medical treatment may improve disease management. Full article
(This article belongs to the Special Issue Metabolism and Diseases)
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15 pages, 1682 KiB  
Article
Metformin Decreases 2-HG Production through the MYC-PHGDH Pathway in Suppressing Breast Cancer Cell Proliferation
Metabolites 2021, 11(8), 480; https://doi.org/10.3390/metabo11080480 - 26 Jul 2021
Cited by 5 | Viewed by 3852
Abstract
The biguanide drug metformin has been widely used for the treatment of type 2 diabetes, and there is evidence supporting the anticancer effect of metformin despite some controversy. Here, we report the growth inhibitory activity of metformin in the breast cancer (MCF-7) cells, [...] Read more.
The biguanide drug metformin has been widely used for the treatment of type 2 diabetes, and there is evidence supporting the anticancer effect of metformin despite some controversy. Here, we report the growth inhibitory activity of metformin in the breast cancer (MCF-7) cells, both in vitro and in vivo, and the associated metabolic changes. In particular, a decrease in a well-known oncometabolite 2-hydroxyglutarate (2-HG) was discovered by a metabolomics approach. The decrease in 2-HG by metformin was accompanied by the reduction in histone methylation, consistent with the known tumorigenic mechanism of 2-HG. The relevance of 2-HG inhibition in breast cancer was also supported by a higher level of 2-HG in human breast cancer tissues. Genetic knockdown of PHGDH identified the PHGDH pathway as the producer of 2-HG in the MCF-7 cells that do not carry isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) mutations, the conventional producer of 2-HG. We also showed that metformin’s inhibitory effect on the PHGDH-2HG axis may occur through the regulation of the AMPK-MYC pathway. Overall, our results provide an explanation for the coherent pathway from complex I inhibition to epigenetic changes for metformin’s anticancer effect. Full article
(This article belongs to the Special Issue Metabolism and Diseases)
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Review

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22 pages, 2043 KiB  
Review
Toxic Metabolites and Inborn Errors of Amino Acid Metabolism: What One Informs about the Other
Metabolites 2022, 12(6), 527; https://doi.org/10.3390/metabo12060527 - 08 Jun 2022
Cited by 9 | Viewed by 3828
Abstract
In inborn errors of metabolism, such as amino acid breakdown disorders, loss of function mutations in metabolic enzymes within the catabolism pathway lead to an accumulation of the catabolic intermediate that is the substrate of the mutated enzyme. In patients of such disorders, [...] Read more.
In inborn errors of metabolism, such as amino acid breakdown disorders, loss of function mutations in metabolic enzymes within the catabolism pathway lead to an accumulation of the catabolic intermediate that is the substrate of the mutated enzyme. In patients of such disorders, dietarily restricting the amino acid(s) to prevent the formation of these catabolic intermediates has a therapeutic or even entirely preventative effect. This demonstrates that the pathology is due to a toxic accumulation of enzyme substrates rather than the loss of downstream products. Here, we provide an overview of amino acid metabolic disorders from the perspective of the ‘toxic metabolites’ themselves, including their mechanism of toxicity and whether they are involved in the pathology of other disease contexts as well. In the research literature, there is often evidence that such metabolites play a contributing role in multiple other nonhereditary (and more common) disease conditions, and these studies can provide important mechanistic insights into understanding the metabolite-induced pathology of the inborn disorder. Furthermore, therapeutic strategies developed for the inborn disorder may be applicable to these nonhereditary disease conditions, as they involve the same toxic metabolite. We provide an in-depth illustration of this cross-informing concept in two metabolic disorders, methylmalonic acidemia and hyperammonemia, where the pathological metabolites methylmalonic acid and ammonia are implicated in other disease contexts, such as aging, neurodegeneration, and cancer, and thus there are opportunities to apply mechanistic or therapeutic insights from one disease context towards the other. Additionally, we expand our scope to other metabolic disorders, such as homocystinuria and nonketotic hyperglycinemia, to propose how these concepts can be applied broadly across different inborn errors of metabolism and various nonhereditary disease conditions. Full article
(This article belongs to the Special Issue Metabolism and Diseases)
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23 pages, 1755 KiB  
Review
Fructose and Mannose in Inborn Errors of Metabolism and Cancer
Metabolites 2021, 11(8), 479; https://doi.org/10.3390/metabo11080479 - 25 Jul 2021
Cited by 12 | Viewed by 6800
Abstract
History suggests that tasteful properties of sugar have been domesticated as far back as 8000 BCE. With origins in New Guinea, the cultivation of sugar quickly spread over centuries of conquest and trade. The product, which quickly integrated into common foods and onto [...] Read more.
History suggests that tasteful properties of sugar have been domesticated as far back as 8000 BCE. With origins in New Guinea, the cultivation of sugar quickly spread over centuries of conquest and trade. The product, which quickly integrated into common foods and onto kitchen tables, is sucrose, which is made up of glucose and fructose dimers. While sugar is commonly associated with flavor, there is a myriad of biochemical properties that explain how sugars as biological molecules function in physiological contexts. Substantial research and reviews have been done on the role of glucose in disease. This review aims to describe the role of its isomers, fructose and mannose, in the context of inborn errors of metabolism and other metabolic diseases, such as cancer. While structurally similar, fructose and mannose give rise to very differing biochemical properties and understanding these differences will guide the development of more effective therapies for metabolic disease. We will discuss pathophysiology linked to perturbations in fructose and mannose metabolism, diagnostic tools, and treatment options of the diseases. Full article
(This article belongs to the Special Issue Metabolism and Diseases)
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13 pages, 834 KiB  
Review
Asparagine: A Metabolite to Be Targeted in Cancers
Metabolites 2021, 11(6), 402; https://doi.org/10.3390/metabo11060402 - 19 Jun 2021
Cited by 46 | Viewed by 4523
Abstract
Amino acids play central roles in cancer progression beyond their function as building blocks for protein synthesis. Thus, targeting amino acid acquisition and utilization has been proved to be therapeutically beneficial in various pre-clinical models. In this regard, depletion of circulating asparagine, a [...] Read more.
Amino acids play central roles in cancer progression beyond their function as building blocks for protein synthesis. Thus, targeting amino acid acquisition and utilization has been proved to be therapeutically beneficial in various pre-clinical models. In this regard, depletion of circulating asparagine, a nonessential amino acid, by L-asparaginase has been used in treating pediatric acute lymphoblastic leukemia (ALL) for decades. Of interest, unlike most solid tumor cells, ALL cells lack the ability to synthesize their own asparagine de novo effectively. However, only until recently, growing evidence suggests that solid tumor cells strive to acquire adequate amounts of asparagine to support tumor progression. This process is subjected to the regulation at various levels, including oncogenic signal, tumor-niche interaction, intratumor heterogeneity and dietary accessibility. We will review the literature on L-asparaginase-based therapy as well as recent understanding of asparagine metabolism in solid tumor progression, with the hope of shedding light into a broader cancer therapeutic strategy by perturbing its acquisition and utilization. Full article
(This article belongs to the Special Issue Metabolism and Diseases)
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