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1.
Brain on food: The neuroepigenetics of nutrition.
Vaziri, A, Dus, M
Neurochemistry international. 2021;:105099
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Abstract
Humans have known for millennia that nutrition has a profound influence on health and disease, but it is only recently that we have begun mapping the mechanisms via which the dietary environment impacts brain physiology and behavior. Here we review recent evidence on the effects of energy-dense and methionine diets on neural epigenetic marks, gene expression, and behavior in invertebrate and vertebrate model organisms. We also discuss limitations, open questions, and future directions in the emerging field of the neuroepigenetics of nutrition.
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Genetic, epigenetic and genomic mechanisms of methionine dependency of cancer and tumor-initiating cells: What could we learn from folate and methionine cycles.
Guéant, JL, Oussalah, A, Zgheib, R, Siblini, Y, Hsu, SB, Namour, F
Biochimie. 2020;:123-128
Abstract
Methionine-dependency is a common feature of cancer cells, which cannot proliferate without constant inputs of exogenous methionine even in the presence of its precursor, homocysteine. The endogenous synthesis of methionine is catalyzed by methionine synthase, which transfers the methyl group of 5-methyltetrahydrofolate (5-methylTHF) to homocysteine in the presence of vitamin B12 (cobalamin, cbl). Diverse mechanisms can produce it, including somatic mutations, aberrant DNA methylation (epimutations) and altered expression of genes. Around twenty somatic mutations have been reported as a cause of methionine dependency. Some of them are contributors but not sufficient on their own to cause methionine dependency. Epigenetic invalidation of MMACHC gene expression triggers methionine dependency of the MeWo-LC1 melanoma cancer cell line. This epimutation is generated by aberrant antisense transcription of the adjacent gene PRDX1. Methionine dependency involves the abnormal expression of 1-CM genes in cancer stem cells. It is related to an increased demand for methionine and SAM, which is not compensated by the increased production of formate by glycine decarboxylase pathway in lung cancer tumor spheres. Tumor spheres of glioblastoma U251 are methionine-dependent through disruption of folate metabolism. The rescue of the growth of glioblastoma stem cells by folate shows the considerable importance to evaluate the influence of supplements and dietary intake of folate on the risk of tumor development, in particular in countries subjected to mandatory food fortification in folic acid. Dietary methionine restriction or the use of methioninase represent promising anticancer therapeutic strategies that deserve to be explored in combination with chemotherapy.
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Oral Methioninase for Covid-19 Methionine-restriction Therapy.
Hoffman, RM, Han, Q
In vivo (Athens, Greece). 2020;(3 Suppl):1593-1596
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Abstract
The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virally-induced T-cell- and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.
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Catechol-O-methyltransferase gene Val158Met polymorphism and obsessive compulsive disorder susceptibility: a meta-analysis.
Kumar, P, Rai, V
Metabolic brain disease. 2020;(2):241-251
Abstract
Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that affects approximately 1-3% of the general population. It is characterized by disabling obsessions (intrusive unwanted thoughts) and/or compulsions (ritualized repetitive behaviors). Catechol-O-methyltransferase (COMT) enzyme has an important role in inactivation of dopamine and higher dopamine levels may be implicated in OCD, hence COMT gene is a suitable candidate for OCD. Several case-control studies have evaluated the role of COMT Val 158Met (rs4680;472G- > A) polymorphism as a risk factor for OCD but the results remained inconclusive, hence present meta-analysis was designed to find out correct assessment. All studies that investigated the association of COMT gene Val158Met polymorphism with OCD risk, were considered in the present meta-analysis. Statistical analysis was performed with the software program MetaAnalyst. In the current meta-analysis, 14 case-control studies with 1435 OCD cases and 2753 healthy controls were included. The results indicated significant association between COMT Val158Met polymorphism and OCD risk using allele contrast, homozygote and dominant models (ORA vs G = 1.14; 95% CI = 1.02-1.27; p = 0.01; ORAAvs.GG = 1.33; 95% CI = 1.09-1.62, p = 0.004; ORAA + AGvs.GG = 1.14; 95% CI = 1.0-1.32; p = 0.04). In subgroup analysis based on case gender, meta-analysis of male cases showed significant association using all five genetic models (ORAAvsGG = 1.99; 95%CI = 1.42-2.59; p = <0.001; ORAA + AGvs.GG = 1.59; 95% CI = 1.20-2.10; p = 0.001), but did not show any association between COMT Val 158Met polymorphism and OCD risk in females. In conclusion, results of present meta-analysis supports that the COMT Val158Met polymorphism is a risk factor for OCD especially for males.
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5.
Chemoselective Methionine Bioconjugation on a Polypeptide, Protein, and Proteome.
Zang, J, Chen, Y, Zhu, W, Lin, S
Biochemistry. 2020;(2):132-138
Abstract
Methionine is one of the most hydrophobic, redox-sensitive, and one of the only two sulfur-containing amino acids on protein. Because of these biochemical properties, the methionine residue plays a central role in a variety of biological processes, such as metal coordination, antioxidant stress, and aging. However, studies on the molecular functions of methionine are much less common than the other primary sulfur-containing amino acid, cysteine. The limited number of publications on methionine-related studies is partially due to the lack of tools for methionine modification. Methionine bioconjugation offers a new strategy to decipher the biological function of methionine and expands the toolbox for protein functionalization in the context of the application, such as synthesizing proteins with novel properties and producing new biomaterials. The purpose of this Perspective is to highlight the biochemical properties and functions of methionine, list recent progress in the development of methionine bioconjugation reagents, and briefly demonstrate the application of these reagents on polypeptides, proteins, and proteomes.
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6.
Vitamin B Supplementation and Nutritional Intake of Methyl Donors in Patients with Chronic Kidney Disease: A Critical Review of the Impact on Epigenetic Machinery.
Cappuccilli, M, Bergamini, C, Giacomelli, FA, Cianciolo, G, Donati, G, Conte, D, Natali, T, La Manna, G, Capelli, I
Nutrients. 2020;(5)
Abstract
Cardiovascular morbidity and mortality are several-fold higher in patients with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) than in the general population. Hyperhomocysteinemia has undoubtedly a central role in such a prominent cardiovascular burden. The levels of homocysteine are regulated by methyl donors (folate, methionine, choline, betaine), and cofactors (vitamin B6, vitamin B12,). Uremia-induced hyperhomocysteinemia has as its main targets DNA methyltransferases, and this leads to an altered epigenetic control of genes regulated through methylation. In renal patients, the epigenetic landscape is strictly correlated with the uremic phenotype and dependent on dietary intake of micronutrients, inflammation, gut microbiome, inflammatory status, oxidative stress, and lifestyle habits. All these factors are key contributors in methylome maintenance and in the modulation of gene transcription through DNA hypo- or hypermethylation in CKD. This is an overview of the epigenetic changes related to DNA methylation in patients with advanced CKD and ESRD. We explored the currently available data on the molecular dysregulations resulting from altered gene expression in uremia. Special attention was paid to the efficacy of B-vitamins supplementation and dietary intake of methyl donors on homocysteine lowering and cardiovascular protection.
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Medicines associated with folate-homocysteine-methionine pathway disruption.
Vidmar, M, Grželj, J, Mlinarič-Raščan, I, Geršak, K, Dolenc, MS
Archives of toxicology. 2019;(2):227-251
Abstract
Folate is vital for cell development and growth. It is involved in one-carbon transfer reactions essential for the synthesis of purines and pyrimidines. It also acts in conjunction with cobalamin (vitamin B12) as a fundamental cofactor in the remethylation cycle that converts homocysteine to methionine. A deficiency in folate or vitamin B12 can lead to elevated homocysteine level, which has been identified as an independent risk factor in several health-related conditions. Adequate folate levels are essential in women of childbearing age and in pregnant women, and folate deficiency is associated with several congenital malformations. Low folate levels can be caused by dietary deficiencies, a genetic predisposition or treatment with medicines that affect folate concentration. Women who are pregnant or of child-bearing age commonly use medicines, so it is important to identify the basic biochemical mechanisms by which medicines interfere with the folate-homocysteine-methionine pathway. This review focuses on prescription medicines associated with folate disruption. It also summarizes their undesirable/toxic effects. Recommendations regarding folate supplementation during medical therapy are also reviewed.
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Autism spectrum disorder (ASD) - biomarkers of oxidative stress and methylation and transsulfuration cycle.
Waligóra, A, Waligóra, S, Kozarska, M, Damasiewicz-Bodzek, A, Gorczyca, P, Tyrpień-Golder, K
Psychiatria polska. 2019;(4):771-788
Abstract
Autism spectrum disorder (ASD) affects people from all regions of the globe, regardless of nationality, living standards or social group. Currently, it is assumed that ASD pathogenesis is multifactorial because there is no one specific cause of the disorder. According to literature, ASD may result from genetic defects, metabolic disorders or exposure to environmental factors. There is a number of hypotheses that attempt to explain the intensity of emotional and behavioral symptoms or the increased sensory threshold that is characteristic of ASD. It is suggested that neurological changes may be due to oxidative stress occurring in early brain tissue development and reduced antioxidative barrier. Due to the abnormalities in the synthesis of neurotransmitters, often occurring in ASD, autism is investigated for disorders of vital biochemical processes of methylation and transsulfuration. Finding a biomarker for a disturbed oxidative-reduction equilibrium, methylation pathway pathology, or other reason could be an important diagnostic tool and the base for individual treatment for patients with varying degrees of severity. This work provides a review of the potential biological indicators for ASD taking into account the occurrence of oxidative stress and the methylation and transsulfuration cycles.
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The use of amino acid PET and conventional MRI for monitoring of brain tumor therapy.
Galldiks, N, Law, I, Pope, WB, Arbizu, J, Langen, KJ
NeuroImage. Clinical. 2017;:386-394
Abstract
Routine diagnostics and treatment monitoring of brain tumors is usually based on contrast-enhanced MRI. However, the capacity of conventional MRI to differentiate tumor tissue from posttherapeutic effects following neurosurgical resection, chemoradiation, alkylating chemotherapy, radiosurgery, and/or immunotherapy may be limited. Metabolic imaging using PET can provide relevant additional information on tumor metabolism, which allows for more accurate diagnostics especially in clinically equivocal situations. This review article focuses predominantly on the amino acid PET tracers 11C-methyl-l-methionine (MET), O-(2-[18F]fluoroethyl)-l-tyrosine (FET) and 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine (FDOPA) and summarizes investigations regarding monitoring of brain tumor therapy.
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The one-carbon metabolism pathway highlights therapeutic targets for gastrointestinal cancer (Review).
Konno, M, Asai, A, Kawamoto, K, Nishida, N, Satoh, T, Doki, Y, Mori, M, Ishii, H
International journal of oncology. 2017;(4):1057-1063
Abstract
After the initial use of anti-folates for treatment of malignancies, folate metabolism has emerged as a rational diagnostic and therapeutic target in gastrointestinal cancer. The one-carbon metabolic pathway, which comprises three critical reactions (i.e., folate and methionine cycles), underlies this effect in conjunction with the trans-sulfuration pathway. Understanding of the one-carbon metabolism pathway has served to unravel the link between the causes and effects of cancer phenotypes leading to several seminal discoveries such as that of diadenosine tri-phosphate hydrolase, microRNAs, 5-FU and, more recently, trifluridine. In the folate cycle, glycine and serine fuel the mitochondrial enzymes SHMT2, MTHFD2 and ALDH1L2, which play critical roles in the cancer survival and proliferation presumably through purine production. In the methionine cycle, S-adenocyl methionine serves hydrocarbons and polyamines that are critical for the epigenetic controls. The trans-sulfuration pathway is a critical component in the synthesis of glutathione, which is involved in the production of reactive oxygen species in cancer stem cells. Therefore, characterization of one-carbon metabolism is indispensable to the development of precision medicine in the context of cancer diagnostics and therapeutics. In the present study, we review the historical issues associated with one-carbon metabolism and highlight the recent advances in cancer research.