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Methyl Nutrients and One-Carbon Metabolism in Chronic Diseases

A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Nutrigenetics and Nutrigenomics".

Deadline for manuscript submissions: closed (5 March 2024) | Viewed by 2175

Special Issue Editor


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Guest Editor
1. Department of Nutritional Sciences, The Pennsylvania State University, State College, PA 16802, USA
2. Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal
Interests: homocysteine; one-carbon metabolism; endothelial dysfunction; atherosclerosis; inborn errors of methionine metabolism; methylation; nutrition
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

One-carbon metabolism provides one of the most common structural units of organic compounds, the methyl group, and includes the methionine and folate cycles, which are mechanistically co-dependent. Methyl group homeostasis ensures its correct utilization to carry out methylation reactions. S-adenosylmethionine (SAM) is the methyl donor in these reactions involved in multiple cellular functions such as epigenetic control of gene expression, redox defense, or the synthesis of creatinine, polyamine, and phospholipids. Besides methionine and folate, other nutrients that are substrates or cofactors in one-carbon metabolism include other B vitamins (B2, B6, and B12), betaine, and choline. Thus, one-carbon metabolism relies on dietary constituents to drive and coordinate the generation of methyl groups for myriad biological outcomes. Notably, changes in SAM-dependent methylation reactions have been linked to chronic diseases, such as vascular disease, dementia, cancer, and nonalcoholic fatty liver disease. More recently, attention has turned to the effects of paternal diet on epigenetic programming of offspring development and disease risk.

Authors are invited to submit research, reviews, and hypothesis-driven articles that address topics related to the relationship between nutrients and one-carbon metabolism with an emphasis on susceptibility to chronic diseases.

Dr. Rita Castro
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Nutrients 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 2900 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

  • homocysteine
  • B vitamins
  • epigenetics
  • lipid metabolism
  • methylation
  • hypertension
  • vascular disease
  • dementia
  • cancer
  • nonalcoholic fatty liver disease

Published Papers (2 papers)

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17 pages, 2216 KiB  
Article
Diet-Induced Severe Hyperhomocysteinemia Promotes Atherosclerosis Progression and Dysregulates the Plasma Metabolome in Apolipoprotein-E-Deficient Mice
by Stephen G. Andrews, Anthony M. Koehle, Devendra Paudel, Thomas Neuberger, A. Catharine Ross, Vishal Singh, Teodoro Bottiglieri and Rita Castro
Nutrients 2024, 16(3), 330; https://doi.org/10.3390/nu16030330 - 23 Jan 2024
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Abstract
Atherosclerosis and resulting cardiovascular disease are the leading causes of death in the US. Hyperhomocysteinemia (HHcy), or the accumulation of the intermediate amino acid homocysteine, is an independent risk factor for atherosclerosis, but the intricate biological processes mediating this effect remain elusive. Several [...] Read more.
Atherosclerosis and resulting cardiovascular disease are the leading causes of death in the US. Hyperhomocysteinemia (HHcy), or the accumulation of the intermediate amino acid homocysteine, is an independent risk factor for atherosclerosis, but the intricate biological processes mediating this effect remain elusive. Several factors regulate homocysteine levels, including the activity of several enzymes and adequate levels of their coenzymes, including pyridoxal phosphate (vitamin B6), folate (vitamin B9), and methylcobalamin (vitamin B12). To better understand the biological influence of HHcy on the development and progression of atherosclerosis, apolipoprotein-E-deficient (apoE−/− mice), a model for human atherosclerosis, were fed a hyperhomocysteinemic diet (low in methyl donors and B vitamins) (HHD) or a control diet (CD). After eight weeks, the plasma, aorta, and liver were collected to quantify methylation metabolites, while plasma was also used for a broad targeted metabolomic analysis. Aortic plaque burden in the brachiocephalic artery (BCA) was quantified via 14T magnetic resonance imaging (MRI). A severe accumulation of plasma and hepatic homocysteine and an increased BCA plaque burden were observed, thus confirming the atherogenic effect of the HHD. Moreover, a decreased methylation capacity in the plasma and aorta, indirectly assessed by the ratio of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH) was detected in HHD mice together with a 172-fold increase in aortic cystathionine levels, indicating increased flux through the transsulfuration pathway. Betaine and its metabolic precursor, choline, were significantly decreased in the livers of HHD mice versus CD mice. Widespread changes in the plasma metabolome of HHD mice versus CD animals were detected, including alterations in acylcarnitines, amino acids, bile acids, ceramides, sphingomyelins, triacylglycerol levels, and several indicators of dysfunctional lipid metabolism. This study confirms the relevance of severe HHcy in the progression of vascular plaque and suggests novel metabolic pathways implicated in the pathophysiology of atherosclerosis. Full article
(This article belongs to the Special Issue Methyl Nutrients and One-Carbon Metabolism in Chronic Diseases)
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11 pages, 1451 KiB  
Brief Report
Rescue of Methionine Dependence by Cobalamin in a Human Colorectal Cancer Cell Line
by Sarita Garg and Isabelle R. Miousse
Nutrients 2024, 16(7), 997; https://doi.org/10.3390/nu16070997 - 28 Mar 2024
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Abstract
Methionine dependence is a characteristic of most cancer cells where they are unable to proliferate when the essential amino acid methionine is replaced with its precursor homocysteine in the growing media. Normal cells, on the other hand, thrive under these conditions and are [...] Read more.
Methionine dependence is a characteristic of most cancer cells where they are unable to proliferate when the essential amino acid methionine is replaced with its precursor homocysteine in the growing media. Normal cells, on the other hand, thrive under these conditions and are referred to as methionine-independent. The reaction that adds a methyl group from 5-methyltetrahydrofolate to homocysteine to regenerate methionine is catalyzed by the enzyme methionine synthase with the cofactor cobalamin (vitamin B12). However, decades of research have shown that methionine dependence in cancer is not due to a defect in the activity of methionine synthase. Cobalamin metabolism has been tied to the dependent phenotype in rare cell lines. We have identified a human colorectal cancer cell line in which the cells regain the ability to proliferation in methionine-free, L-homocystine-supplemented media when cyanocobalamin is supplemented at a level of 1 µg/mL. In human SW48 cells, methionine replacement with L-homocystine does not induce any measurable increase in apoptosis or reactive oxygen species production in this cell line. Rather, proliferation is halted, then restored in the presence of cyanocobalamin. Our data show that supplementation with cyanocobalamin prevents the activation of the integrated stress response (ISR) in methionine-deprived media in this cell line. The ISR-associated cell cycle arrest, characteristic of methionine-dependence in cancer, is also prevented, leading to the continuation of proliferation in methionine-deprived SW48 cells with cobalamin. Our results highlight differences between cancer cell lines in the response to cobalamin supplementation in the context of methionine dependence. Full article
(This article belongs to the Special Issue Methyl Nutrients and One-Carbon Metabolism in Chronic Diseases)
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