scholarly journals Paraquat Exposure Increases Oxidative Stress Within the Dorsal Striatum of Male Mice With a Genetic Deficiency in One-carbon Metabolism

2019 ◽  
Vol 169 (1) ◽  
pp. 25-33 ◽  
Author(s):  
Nafisa M Jadavji ◽  
Lauren K Murray ◽  
Joshua T Emmerson ◽  
Chris A Rudyk ◽  
Shawn Hayley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Carbon Metabolism ◽  
Methylenetetrahydrofolate Reductase ◽  
Memory Function ◽  
Dorsal Striatum ◽  
Cell Loss ◽  
Human Populations ◽  
Mthfr Polymorphism ◽  
One Carbon Metabolism ◽  
The Impact

Abstract Paraquat is an herbicide that is commonly used worldwide. Exposure to paraquat results in Parkinson’s disease (PD)-like symptoms including dopaminergic cell loss. Nutrition has also been linked in the pathogenesis of PD, such as reduced levels of folic acid, a B-vitamin, and component of one-carbon metabolism. Within one-carbon metabolism, methylenetetrahydrofolate reductase (MTHFR) catalyzes the irreversible conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. A polymorphism in MTHFR (677 C&→T) has been reported in 5%–15% of North American and European human populations. The MTHFR polymorphism is also prevalent in PD patients. The goal of this study was to investigate the impact of paraquat-induced PD-like pathology in the context of reduced levels of MTHFR. Three-month-old male Mthfr+/− mice, which model the MTHFR polymorphism observed in humans, were administered intraperitoneal injections of paraquat (10 mg/kg) or saline 6 times over 3 weeks. At the end of paraquat treatment, motor and memory function were assessed followed by collection of brain tissue for biochemical analysis. Mthfr+/– mice treated with paraquat showed impaired motor function. There was increased microglial activation within the substantia nigra (SN) of Mthfr+/− mice treated with paraquat. Additionally, all Mthfr+/− mice that were treated with paraquat showed increased oxidative stress within the dorsal striatum, but not the SN. The present results show that paraquat exposure increases PD-like pathology in mice deficient in one-carbon metabolism.

scholarly journals Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism

2020 ◽  
Vol 295 (47) ◽  
pp. 16037-16057 ◽  
Author(s):  
Muskan Bhatia ◽  
Jyotika Thakur ◽  
Shradha Suyal ◽  
Ruchika Oniel ◽  
Rahul Chakraborty ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Methylenetetrahydrofolate Reductase ◽  
Isotope Labeling ◽  
Redox Homeostasis ◽  
Regulatory Region ◽  
Regulatory Control ◽  
Growth Defect ◽  
Transsulfuration Pathway ◽  
One Carbon Metabolism ◽  
The Impact

Methylenetetrahydrofolate reductase (MTHFR) links the folate cycle to the methionine cycle in one-carbon metabolism. The enzyme is known to be allosterically inhibited by SAM for decades, but the importance of this regulatory control to one-carbon metabolism has never been adequately understood. To shed light on this issue, we exchanged selected amino acid residues in a highly conserved stretch within the regulatory region of yeast MTHFR to create a series of feedback-insensitive, deregulated mutants. These were exploited to investigate the impact of defective allosteric regulation on one-carbon metabolism. We observed a strong growth defect in the presence of methionine. Biochemical and metabolite analysis revealed that both the folate and methionine cycles were affected in these mutants, as was the transsulfuration pathway, leading also to a disruption in redox homeostasis. The major consequences, however, appeared to be in the depletion of nucleotides. 13C isotope labeling and metabolic studies revealed that the deregulated MTHFR cells undergo continuous transmethylation of homocysteine by methyltetrahydrofolate (CH3THF) to form methionine. This reaction also drives SAM formation and further depletes ATP reserves. SAM was then cycled back to methionine, leading to futile cycles of SAM synthesis and recycling and explaining the necessity for MTHFR to be regulated by SAM. The study has yielded valuable new insights into the regulation of one-carbon metabolism, and the mutants appear as powerful new tools to further dissect out the intersection of one-carbon metabolism with various pathways both in yeasts and in humans.

scholarly journals Interplay among the Variants of One Carbon Metabolism, Methylenetetrahydrofolate Reductase Polymorphisms and Lung Cancer

2021 ◽  
Author(s):  
Mandeep Kaur Sodhi ◽  
Varinder Saini ◽  
Vishal Sharma ◽  
Jasbinder Kaur ◽  
Jagdeep Kaur
Keyword(s):  
Lung Cancer ◽  
Dna Synthesis ◽  
Carbon Metabolism ◽  
Molecular Mechanisms ◽  
Methylenetetrahydrofolate Reductase ◽  
Serum Folate ◽  
Bronchial Biopsy ◽  
Mthfr Polymorphism ◽  
Mthfr Polymorphisms ◽  
One Carbon Metabolism

Introduction: Folates perform an integral task in DNA synthesis, methylationand repair. Methylenetetrahydrofolate Reductase (MTHFR) potrays a key part in the metabolism of folate and regulates the equilibrium between the various forms of folate for DNA synthesis and DNA methylation. MTHFR irrevocably transforms 5,10 methylenetetrahydrofolate to 5-methyltetrahydrofolate, the principal circulating folate and the carbon donor for remethylation processes. MTHFR is vastly polymorphic in the general population. Materials and Methods: It was a case-control study conducted during March 2010 to September 2011 in the Department of Pulmonary Medicine in collaboration with the Department of Biochemistry at Government Medical College and Hospital, Chandigarh, to see whether any association exists between the variants of one carbon metabolism, MTHFR polymorphisms (C677T and A1298C), and lung cancer. Twenty biopsy proven lung cancer patients and 20 age and sex matched cancer-free controls were selected. Results: The mean serum folate in cases was higher (12.84 ng/mL±7.527 ng/mL) as compared to controls (4.46 ng/mL±1.346 ng/mL), suggesting that high levels of serum folate are associated with lung cancer. There was no significant variance in the levels of vitamin B12 and plasma homocysteine between cases and controls. No MTHFR polymorphism C677T was seen in the blood and the bronchial biopsy samples of all cases as well as blood samples of all the controls. The MTHFR polymorphism A1298C was present in the blood as well as bronchial biopsy samples of cases as well as blood of controls. Thus, in the present study, there was no relation of this polymorphism with lung cancer. Conclusion: Polymorphisms in MTHFR may contribute to lung cancer. More research on the basis of cellular and molecular mechanisms of lung cancer is urgently needed to aid in understanding of pathogenesis of the disease.

Genetic Variation: Impact on Folate (and Choline) Bioefficacy

2010 ◽  
Vol 80 (45) ◽  
pp. 319-329 ◽  
Author(s):  
Allyson A. West ◽  
Marie A. Caudill
Keyword(s):  
Carbon Metabolism ◽  
Genetic Variants ◽  
Plasma Homocysteine ◽  
Water Soluble ◽  
Gene Interactions ◽  
Dietary Folate ◽  
Methyl Donors ◽  
Common Genetic Variants ◽  
One Carbon Metabolism ◽  
The Impact

Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.

scholarly journals Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, intakes of folate and related B vitamins and colorectal cancer: a case–control study in a population with relatively low folate intake

2008 ◽  
Vol 99 (2) ◽  
pp. 379-389 ◽  
Author(s):  
Linda Sharp ◽  
Julian Little ◽  
Nigel T. Brockton ◽  
Seonaidh C. Cotton ◽  
Lindsey F. Masson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Carbon Metabolism ◽  
Methylenetetrahydrofolate Reductase ◽  
Case Control Study ◽  
Case Control ◽  
B Vitamins ◽  
Folate Intake ◽  
Vitamin B ◽  
One Carbon Metabolism ◽  
Control Study

Folate is key in one-carbon metabolism, disruption of which can interfere with DNA synthesis, repair, and methylation. Efficient one-carbon metabolism requires other B vitamins and the optimal activity of enzymes including 5,10-methylenetetrahydrofolate reductase (MTHFR). We report a population-based case–control study of folate intake, related dietary factors andMTHFRpolymorphisms (C677T, A1298C) and colorectal cancer in a population with relatively high colorectal cancer incidence and relatively low folate intake. A total of 264 cases with histologically confirmed incident colorectal cancer and 408 controls participated. There was no clear trend in risk with reported intakes of total, or dietary, folate, riboflavin, vitamin B12or vitamin B6, nor were there interactions between folate intake and the other B vitamins or alcohol. For C677T, risk decreased with increasing variant alleles (multivariate OR for CTv.CC = 0·77 (95 % CI 0·52, 1·16); OR for TTv.CC = 0·62 (95 % CI 0·31, 1·24)), which, although not statistically significant, was consistent with previous studies. For A1298C, compared with AA subjects, CC subjects had modest, non-significant, reduced risk (multivariate OR = 0·81 (95 % CI 0·45, 1·49)). There were significant interactions between total folate and C677T (P = 0·029) and A1298C (P = 0·025), and total vitamin B6and both polymorphisms (C677T,P = 0·016; A1298C,P = 0·033), although the patterns observed differed from previous studies. Seen against the setting of low folate intake, the results suggest that the role of folate metabolism in colorectal cancer aetiology may be more complex than previously thought. Investigation of particular folate vitamers (for example, tetrahydrofolate, 5,10-methylenetetrahydrofolate) may help clarify carcinogenesis pathways.

scholarly journals Effects of oxidative stress on fatty acid‐ and one‐carbon‐metabolism in psychiatric and cardiovascular disease comorbidity

2014 ◽  
Vol 130 (3) ◽  
pp. 163-180 ◽  
Author(s):  
J. Assies ◽  
R. J. T. Mocking ◽  
A. Lok ◽  
H. G. Ruhé ◽  
F. Pouwer ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Disease ◽  
Fatty Acid ◽  
Carbon Metabolism ◽  
One Carbon Metabolism

scholarly journals Metabolomic Predictors of Non-alcoholic Steatohepatitis and Advanced Fibrosis in Children

2021 ◽  
Vol 12 ◽  
Author(s):  
Kattayoun Kordy ◽  
Fan Li ◽  
David J. Lee ◽  
Jason M. Kinchen ◽  
Michael H. Jew ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Mitochondrial Dysfunction ◽  
Carbon Metabolism ◽  
Fatty Liver Disease ◽  
Plasma Metabolites ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
One Carbon Metabolism

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in western countries both in children and adults. Metabolic dysregulation associated with gut microbial dysbiosis may influence disease progression from hepatic steatosis to inflammation and subsequent fibrosis. Using a multi-omics approach, we profiled the oral and fecal microbiome and plasma metabolites from 241 predominantly Latino children with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver (NAFL), and controls. Children with more severe liver pathology were dysbiotic and had increased gene content associated with lipopolysaccharide biosynthesis and lipid, amino acid and carbohydrate metabolism. These changes were driven by increases in Bacteroides and concomitant decreases of Akkermansia, Anaerococcus, Corynebacterium, and Finegoldia. Non-targeted mass spectrometry revealed perturbations in one-carbon metabolism, mitochondrial dysfunction, and increased oxidative stress in children with steatohepatitis and fibrosis. Random forests modeling of plasma metabolites was highly predictive of non-alcoholic steatohepatitis (NASH) (97% accuracy) and hepatic fibrosis, steatosis and lobular inflammation (93.8% accuracy), and can differentiate steatohepatitis from simple steatosis (90.0% accuracy). Multi-omics predictive models for disease and histology findings revealed perturbations in one-carbon metabolism, mitochondrial dysfunction, and increased oxidative stress in children with steatohepatitis and fibrosis. These results highlight the promise of non-invasive biomarkers for the growing epidemic of fatty liver disease.

scholarly journals Genetic Polymorphisms in Enzymes Involved in One-Carbon Metabolism and Anti-epileptic Drug Monotherapy on Homocysteine Metabolism in Patients With Epilepsy

2021 ◽  
Vol 12 ◽  
Author(s):  
Shaofang Zhu ◽  
Guanzhong Ni ◽  
Lisen Sui ◽  
Yiran Zhao ◽  
Xiaoxu Zhang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Carbon Metabolism ◽  
Methylenetetrahydrofolate Reductase ◽  
Folate Receptor ◽  
Linear Regression Analysis ◽  
Elevated Serum ◽  
Anti Epileptic Drug ◽  
Independent Risk Factors ◽  
One Carbon Metabolism ◽  
Patients With Epilepsy

Aims: To investigate the effects of single nucleotide polymorphisms (SNPs) in genes of one-carbon metabolism (OCM) related enzymes and anti-epileptic drug (AED) monotherapy on homocysteine (Hcy) metabolism in patients with epilepsy, and to further explore specific SNPs that may increase patients' susceptibility to the effects of AEDs on the Hcy imbalance.Method: This case-control study analyzed 279 patients with epilepsy, including patients receiving monotherapy with valproate (VPA) (n = 53), oxcarbazepine (OXC) (n = 71), lamotrigine (LTG) (n = 55), or levetiracetam (LEV) (n = 35) and patients who had not taken any AEDs (controls, n = 65) for at least 6 months. Serum levels of vitamin B12 (vit B12), folate (FA) and Hcy were measured, and 23 SNPs in 13 genes of OCM-related enzymes were genotyped in all patients.Results: Methylenetetrahydrofolate reductase (MTHFR) rs1801133 was associated with elevated serum Hcy levels in patients with epilepsy (P < 0.001), and patients presenting the TT genotype exhibited higher serum Hcy levels than patients with the CC (P < 0.001) or CT (P < 0.001) genotype. A subsequent multiple linear regression analysis showed that AED monotherapy with VPA (vs. control: P = 0.023) or OXC (vs. control: P = 0.041), and genotypes of MTHFR rs1801133 TT (vs. CC: P < 0.001; vs. CT: P < 0.001), transcobalamin 2 (TCN2) rs1801198 CC (vs. GC: P = 0.039) and folate receptor 1 (FOLR1) rs2071010 AA (vs. GA: P = 0.031) were independent risk factors for higher Hcy levels. In the subgroup analysis of patients taking OXC, we found that patients with genotypes of MTHFR rs1801133 TT (vs. CC: P = 0.001; vs. CT: P < 0.001) and TCN2 rs1801198 CC (vs. GC: P = 0.021; vs. GG: P = 0.018) exhibited higher serum Hcy levels.Conclusions: VPA, OXC, and genotypes of MTHFR rs1801133 TT, TCN2 rs1801198 CC, and FOLR1 rs2071010 AA are all independent risk factors for elevated Hcy levels in patients with epilepsy. Moreover, genotypes of MTHFR rs1801133 TT and TCN2 rs1801198 CC may increase patients' susceptibility to the effect of OXC on disrupting Hcy homeostasis.

scholarly journals B Vitamins and Cognitive Performance in Older Adults: Review

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
J. L. Reay ◽  
M. A. Smith ◽  
L. M. Riby
Keyword(s):  
Cognitive Function ◽  
Carbon Metabolism ◽  
Optimal Dose ◽  
Epidemiological Studies ◽  
B Vitamins ◽  
Therapeutic Window ◽  
Vitamin Therapy ◽  
One Carbon Metabolism ◽  
B Vitamin ◽  
The Impact

A copious amount of scientific scrutiny has been dedicated to documenting typical and atypical human ageing, with a substantial body of work focusing upon the impact of lifestyle choices. One such lifestyle choice is that of diet and, in particular, micronutrient ingestion. Epidemiological studies have reported positive associations between B vitamin status and cognitive function, including negative associations between biological markers (i.e., homocysteine) of dysregulated one-carbon metabolism and cognitive function. This has led to a surge of randomised control trials (RCTs) investigations into B vitamin therapy. However, results have continuingly failed to show beneficial behavioural effects. Despite this, results reliably show treatment-related increases in B vitamin level and decreases in homocysteine level—both of which have been identified as risk factors for atypical ageing. In this paper we argue that it would be premature to conclude that B vitamin therapy has no potential and that more research is needed to systematically investigate the optimal dose, the therapeutic “window,” and individual differences in therapy responders and nonresponders. We start with a brief look at one-carbon metabolism and then consider the evidence from epidemiological studies and RCTs in relation to three specific B vitamins: folic acid (B9), pyridoxine (B6), and cobamides (B12).

scholarly journals Evidence of a Role for One-Carbon Metabolism in Blood Pressure: Can B Vitamin Intervention Address the Genetic Risk of Hypertension Owing to a Common Folate Polymorphism?

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Helene McNulty ◽  
J J Strain ◽  
Catherine F Hughes ◽  
Kristina Pentieva ◽  
Mary Ward
Keyword(s):  
Blood Pressure ◽  
Carbon Metabolism ◽  
Genetic Risk ◽  
Methylenetetrahydrofolate Reductase ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Hypertension In Pregnancy ◽  
Increased Risk ◽  
One Carbon Metabolism ◽  
In Pregnancy

ABSTRACT Hypertension in adulthood is recognized as the leading risk factor contributing to mortality worldwide, primarily from cardiovascular disease, whereas hypertension in pregnancy leads to serious adverse fetal and maternal outcomes. This article explores the under-recognized role of one-carbon metabolism in blood pressure (BP) and the potential for folate-related B vitamins to protect against hypertension. Genome-wide association studies and clinical studies provide evidence linking the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with BP and increased risk of hypertension and hypertension in pregnancy. A novel role for riboflavin (the MTHFR cofactor) has recently emerged, however, with evidence from randomized trials that supplemental riboflavin can lower BP specifically in adults with the variant MTHFR 677TT genotype. Further studies are required to elucidate the biological mechanisms linking one-carbon metabolism with BP and explore the effect of riboflavin in modulating the genetic risk of hypertension in early and later life.

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