Search Results (86)

Methylation is a biochemical process involving the addition of methyl groups to proteins, lipids, and nucleic acids (both DNA and RNA). DNA methylation predominantly occurs on cytosine and adenine nucleobases, and the resulting products—most frequently 5-methylcytosine and N⁶-methyladenine epigenetic marks—can significantly influence gene activity at the affected genomic sites without modifying the DNA sequence called nucleotide order. Various environmental factors can alter the DNA methylation pattern. Among these, methyl donor micronutrients, such as specific amino acids, choline, and several B vitamins (including folate, pyridoxine, thiamine, riboflavin, niacin, and cobalamin), primarily regulate one-carbon metabolism. This molecular pathway stimulates glutathione synthesis and recycles intracellular methionine. Glutathione plays a pivotal role during oocyte activation by protecting against oxidative stress, whereas methionine is crucial for the production of S-adenosyl-L-methionine, which serves as the universal direct methyl donor for cellular methylation reactions. Because local DNA methylation patterns at genes regulating fertility can be inherited by progeny for multiple generations even in the absence of the original disrupting factors to which the parent was exposed, and DNA methylation levels at specific genomic sites highly correlate with age and can also be passed to offspring, nutrition can influence reproduction and life span in a transgenerational manner. Full article

Epigenetic modifications act as crucial regulators of gene activity and are influenced by both internal and external environmental factors, with diet being the most impactful external factor. On the other hand, cellular metabolism encompasses a complex network of biochemical reactions essential for maintaining cellular function, and it impacts every cellular process. Many metabolic cofactors are critical for the activity of chromatin-modifying enzymes, influencing methylation and the global acetylation status of the epigenome. For instance, dietary nutrients, particularly those involved in one-carbon metabolism (e.g., folate, vitamins B12 and B6, riboflavin, methionine, choline, and betaine), take part in the generation of S-adenosylmethionine (SAM), which represents the main methyl donor for DNA and histone methylation; α-ketoglutarate and ascorbic acid (vitamin C) act, respectively, as a co-substrate and cofactor for Ten-eleven Translocation (TET), which is responsible for DNA demethylation; and metabolites such as Acetyl-CoA directly impact histone acetylation, linking metabolism of the TCA cycle to epigenetic regulation. Further, bioactive compounds, such as polyphenols, modulate epigenetic patterns by affecting methylation processes or targeting epigenetic enzymes. Since diet and nutrition play a critical role in shaping epigenome functions and supporting human health, this review offers a comprehensive update on recent advancements in metabolism, epigenetics, and nutrition, providing insights into how nutrients contribute to metabolic balance, epigenome integrity maintenance and, consequently, disease prevention. Full article

Background/Objectives: We examined the association between dietary intake and blood concentrations of one-carbon metabolism (OCM)-related nutrients in the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: Blood concentrations and dietary intake of the vitamins riboflavin (B2), Pyridoxal 5′-phosphate (PLP and B6), folate (B9), B12, and methionine, concentrations of homocysteine, and dietary intake of betaine, choline, and cysteine were pooled from 16,267 participants in nine EPIC nested case–control studies. Correlation analyses between dietary intakes and blood concentrations were carried out. Principal component (PC) analysis identified latent factors in the two sets of measurements. Results: Pearson correlations between dietary intakes and blood concentrations ranged from 0.08 for methionine to 0.12 for vitamin B2, 0.15 for vitamin B12, 0.17 for vitamin B6, and 0.19 for folate. Individual dietary intakes showed higher correlations (ranging from −0.14 to 0.82) compared to individual blood concentrations (from −0.31 to 0.29). Correlations did not vary by smoking status, case–control status, or vitamin supplement use. The first PC of dietary intakes was mostly associated with methionine, vitamin B12, cysteine, and choline, while the first PC of blood concentrations was associated with folate and vitamin B6. Conclusions: Within this large European study, we found weak to moderate associations between dietary intakes and concentrations of OCM-related nutrients. Full article

Autism Spectrum Disorder (ASD) has been associated with disruptions in one-carbon metabolism and vitamin D pathways. Nutritional exposures—particularly vitamin D, vitamin B₁₂, and homocysteine—may influence neurodevelopmental outcomes. However, a comprehensive, lifespan-spanning synthesis of these modifiable nutritional biomarkers has not been conducted. This systematic review and stratified meta-analysis critically synthesized data on vitamin D, vitamin B₁₂, and homocysteine to elucidate their relationships with ASD risk and symptomatology. Our central question was: How do levels of vitamin D, vitamin B₁₂, and homocysteine—measured before and after birth—affect the risk, severity, and potential treatment outcomes for ASD? We conducted a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) compliant systematic review and stratified meta-analysis (2015–2025) of 35 studies (11 randomized controlled trials, 24 observational), examining prenatal, neonatal, and postnatal biomarker levels. Eligibility criteria were defined using the PICOS (Population, Intervention, Comparator, Outcome, and Study Design) framework to ensure scientific rigor and clinical relevance, including studies involving human participants aged 0–18 years with a formal Autism Spectrum Disorder (ASD) diagnosis or prenatal exposures potentially linked to later ASD onset, while excluding animal studies, adult-only ASD populations, and studies lacking ASD cohorts or biomarker data. The search strategy, developed according to PRISMA, and Cochrane best practices, encompassed five major databases (PubMed/MEDLINE, Cochrane Library, Google Scholar, ClinicalTrials.gov, and ProQuest) alongside manual searches of key references, grey literature, and clinical trial registries to ensure comprehensive retrieval of both published and unpublished studies. Study quality was assessed using version 2 of the Cochrane risk-of-bias tool for RCTs (RoB2) and the Newcastle–Ottawa Scale (NOS) for observational studies; certainty of evidence was graded via GRADE (Grading of Recommendations Assessment, Development and Evaluation). Random-effects meta-analyses were stratified by biomarker and study design. Heterogeneity, small-study effects, and publication bias were evaluated using Cochran’s Q, I², Egger’s test, and trim-and-fill. Prenatal vitamin D deficiency was associated with approximately two-fold increased odds of Autism Spectrum Disorder (ASD) in offspring (pooled OR ≈ 2.0; p < 0.05), while excessively elevated maternal B₁₂ concentrations, often co-occurring with folate excess, were similarly linked to increased ASD risk. Meta-analytic comparisons revealed significantly lower circulating vitamin D (SMD ≈ −1.0; p < 0.001) and B₁₂ levels (SMD ≈ −0.7; p < 0.001), alongside elevated homocysteine (SMD ≈ 0.7; p < 0.001), in children with ASD versus neurotypical controls. Early-life vitamin D/B₁₂ insufficiency and elevated homocysteine are important, modifiable correlates of ASD risk and severity. Adequate maternal and child nutritional status could have risk-reducing and symptom-mitigating effects, although causality remains to be confirmed. This evidence supports tailored nutritional interventions as a component of ASD risk reduction and management strategies, within the bounds of overall developmental healthcare. The article processing charges (APC) were supported by “Dunărea de Jos” University of Galati, Romania. No external funding was received for the execution of the research. The review was not prospectively registered in PROSPERO or any other systematic review registry. Full article

Background: Maternal nutrition during early gestation induces metabolic adaptations that support maternal health and fetal development. This study evaluated the effects of maternal one-carbon metabolite (OCM: methionine, choline, folate, and vitamin B₁₂) supplementation and restricted rates of maternal gain on the hepatic lipid profiles of dams and fetuses at day 63 of gestation. Methods: Thirty-one crossbred Angus heifers were inseminated and assigned to a 2 × 2 factorial design with two factors: maternal dietary intake (control [CON]; 0.60 kg/day average daily gain [ADG] vs. restricted [RES]; −0.23 kg/day ADG) and OCM supplementation (supplemented [+OCM] vs. not supplemented [−OCM]). The four resulting groups (CON − OCM, CON + OCM, RES − OCM, RES + OCM) were maintained for 63 days post-breeding. Maternal and fetal liver samples were collected, and lipidomic profiling was performed using ultra-performance liquid chromatography–tandem mass-spectrometry. Results: In maternal liver, 485 lipid metabolites were detected, with 243 differing significantly in maternal gain. RES heifers showed increased levels (p ≤ 0.05) of acylcarnitines, plasmalogens, lysoplasmalogens, glycosphingolipids, and sphingomyelins. Additionally, RES combined with OCM supplementation led to the accumulation of secondary bile acids and a depletion of monoacylglycerols (p ≤ 0.05) in maternal liver. In fetal liver, 487 lipid metabolites were detected, but treatment effects were minimal. Conclusions: Maternal rate of gain significantly influenced hepatic lipid metabolism in the maternal liver, while fetal liver lipid profiles remained relatively unaffected. These findings underscore the significant role of dietary intake/rate of gain compared with OCM supplementation in modulating hepatic lipid metabolism and highlight the maternal liver’s metabolic adaptations during early pregnancy. Full article

Dietary folic acid supplementation is well known for playing a crucial role in the closure of the neural tube. Individuals have continued to increase dietary intake of folic acid in counties with mandatory fortication laws in place. Some studies have demonstrated adverse health effects in individuals with high dietary intake of folic acid. Nutrition is a modifiable risk factor for ischemic stroke. Specifically, elevated levels of homocysteine, they can be reduced by increasing intake of vitamins, such as folic acid, a B-vitamin. Hypoxia, when levels of oxygen are reduced, is a major component of cardiovascular diseases. The aim of this review paper was to summarize how increased dietary intake of folic acid interaction with hypoxia to impact health outcomes. Our survey of the literature found that increased dietary intake of folic acid promotes inflammation, angiogenesis, and neurotoxicity. We also report negative actions of increased dietary intake of folic acid with vitamin B12 and genetic deficiencies in one-carbon metabolism. Increased dietary intake of folic acid also results in elevated levels of unmetabolized folic acid in the population, of which the impact on health risks has not yet been determined. Our review of the literature emphasizes that a more comprehensive understanding of the action between increased dietary intake of folic acid on disease outcomes could pave the way for improved public health guidelines. Furthermore, adequate knowledge of an individual’s one-carbon metabolism status can inform proactive management for patients at higher risk of experiencing negative health outcomes. Full article

Background: Individuals diagnosed with autism spectrum disorder (ASD) commonly experience sensory processing that differs from general-population norms, and the autistic lived experience of eating includes preferences for routine, and sensory processing difficulty related to scents, tastes, temperatures, and textures of food. Meanwhile, research indicates that nutrients involved in one-carbon metabolism (OCM) may be related to sensory processing. Methods: This study enrolled 33 school-aged children with autism to assess whether OCM nutrient intake is associated with sensory processing. Parents completed two parent-report assessments: the youth and adult food frequency questionnaire (YAFFQ), and a sensory processing tool, Sensory Profile 2 (SP2). Results: Participant data showed generally good nutritional profiles mirroring those of general-population U.S. children. A group-binarized linear regression model showed the following relationships (p < 0.05): vitamin B12 consumption had a negative association with the SP2 Oral and Sensor domain scores. Choline intake had a positive association with the SP2 Avoider domain score. Vitamin B1 showed a positive association with the SP2 Visual domain score. Conclusions: These results support the possible existence of a relationship between sensory symptoms and OCM nutrient consumption levels in school-aged children diagnosed with autism. Future research is needed to confirm and explore the potential for causality. Full article

Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort (“fatigue”) that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods. Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies. A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma. The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS. Full article

Neural tube defects (NTDs) are malformations of the central nervous system that represent the second most common cause of congenital morbidity and mortality, following cardiovascular abnormalities. Maternal nutrition, particularly folic acid, a B vitamin, is crucial in the etiology of NTDs. FA plays a key role in DNA methylation, synthesis, and repair, acting as a cofactor in one-carbon transfer reactions essential for neural tube development. Randomized trials have shown that FA supplementation during preconceptional and periconceptional periods reduces the incidence of NTDs by nearly 80%. Consequently, it is recommended that all women of reproductive age take 400 µg of FA daily. Many countries have introduced FA fortification of staple foods to prevent NTDs, addressing the high rate of unplanned pregnancies. These policies have increased FA intake and decreased NTD incidence. Although the precise mechanisms by which FA protects against NTDs remain unclear, compelling evidence supports its efficacy in preventing most NTDs, leading to national recommendations for FA supplementation in women. This review focuses on preconceptional and periconceptional FA supplementation in the female population of the Visegrad Group countries (Slovakia, Czech Republic, Poland, and Hungary). Our findings emphasize the need for a comprehensive approach to NTDs, including FA supplementation programs, tailored counseling, and effective national-level policies. Full article

Background/Objectives: Gastric cancer is one of the leading malignancies worldwide. B vitamins play important roles in DNA synthesis and methylation because they are considered co-enzymes in one-carbon metabolism. There is inconclusive evidence regarding the associations between dietary vitamins B₁, B₂, and B₆ with the risk of gastric cancer in different epidemiologic studies. We, therefore, investigated such associations in a hospital-based case-control study comprising 1182 incident cases of gastric cancer and 2995 controls in Vietnam. Methods: Dietary vitamins B₁, B₂, and B₆ were derived from a semi-quantitative validated food frequency questionnaire. An unconditional logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer in relation to dietary intake of vitamins B₁, B₂, and B₆. Results: Overall, dietary vitamins B₁ (OR_{per-SD increment} = 0.83; 95% CI: 0.78–0.89; P_trend < 0.001) and B₆ (OR_{per-SD increment} = 0.88; 95% CI: 0.81–0.94; P_trend < 0.001) were associated with a reduced risk of gastric cancer. Compared with the lowest quintile, the ORs (95% CIs) of gastric cancer for quintiles 2, 3, 4, and 5 of the vitamin B₁ intake were 0.64 (0.51–0.79), 0.54 (0.43–0.69), 0.57 (0.44–0.74), and 0.42 (0.31–0.55), respectively; for vitamin B₆ intake, quintiles 2, 3, 4, and 5 were 0.53 (0.42–0.66), 0.54 (0.42–0.70), 0.61 (0.46–0.81), and 0.46 (0.33–0.63), respectively. This inverse association was not different across sex, BMI, and smoking statuses. No association was found between dietary vitamin B₂ and gastric cancer risk. Conclusions: Dietary vitamins B₁ and B₆ were associated with a reduced risk of gastric cancer in the Vietnamese population. Future studies are warranted to replicate our findings, which also have great implications for gastric cancer prevention and control programs in low- and middle-income countries. Full article

Background: ALDH1L1 plays a crucial role in folate metabolism, regulating the flow of one-carbon groups through the conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO₂ in a NADP⁺-dependent reaction. The downregulation of ALDH1L1 promotes malignant tumor growth, and silencing of ALDH1L1 is commonly observed in many cancers. In a previous study, Aldh1l1 knockout (KO) mice were found to have an altered liver metabotype, including significant alterations in glycine and serine. Serine and glycine play crucial roles in pathways linked to cancer initiation and progression, including one-carbon metabolism. Objective/Methods: To further investigate the metabolic role of ALDH1L1, an untargeted metabolomic analysis was conducted on the liver and plasma of both KO and wild-type (WT) male and female mice. Since ALDH1L1 affects glycine- and serine-coupled metabolites and metabolic pathways, correlation analyses between liver glycine and serine with other liver or plasma metabolites were performed for both WT and KO mice. Significantly correlated metabolites were input into MetaboAnalyst 5.0 for pathway analysis to uncover metabolic pathways coupled with serine and glycine in the presence or absence of ALDH1L1 expression. Results: This analysis showed substantial alterations in pathways associated with glycine and serine following ALDH1L1 loss, including the amino acid metabolism, antioxidant pathways, fatty acid oxidation, and vitamin B5 metabolism. These results indicate the glycine- and serine-linked metabolic reprogramming following ALDH1L1 loss to support macromolecule biosynthesis and antioxidant defense. Additional research is required to further explore the correlation between specific alterations in these pathways and tumor growth, as well as to identify potential dietary interventions to mitigate the detrimental effects of ALDH1L1 loss. Full article

Background/Objectives: One-carbon metabolism is a critical pathway for epigenetic mechanisms. Circulating biomarkers of one-carbon metabolism have been associated with changes in nuclear DNA methylation levels in individuals affected by age-related diseases. More and more studies are showing that even mitochondrial DNA (mtDNA) could be methylated. In particular, methylation of the mitochondrial displacement (D-loop) region modulates the gene expression and replication of mtDNA and, when altered, can contribute to the development of human illnesses. However, no study until now has demonstrated an association between circulating biomarkers of one-carbon metabolism and D-loop methylation levels. Methods: In the study presented herein, we searched for associations between circulating one-carbon metabolism biomarkers, including folate, homocysteine, and vitamin B12, and the methylation levels of the D-loop region in DNA obtained from the peripheral blood of 94 elderly voluntary subjects. Results: We observed a positive correlation between D-loop methylation and vitamin B12 (r = 0.21; p = 0.03), while no significant correlation was observed with folate (r = 0.02; p = 0.80) or homocysteine levels (r = 0.02; p = 0.82). Moreover, D-loop methylation was increased in individuals with high vitamin B12 levels compared to those with normal vitamin B12 levels (p = 0.04). Conclusions: This is the first study suggesting an association between vitamin B12 circulating levels and mtDNA methylation in human subjects. Given the potential implications of altered one-carbon metabolism and mitochondrial epigenetics in human diseases, a deeper understanding of their interaction could inspire novel interventions with beneficial effects for human health. Full article

Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) metabolism playing a pivotal role. Folate, a B vitamin, is a key cofactor in this pathway, supporting DNA synthesis, methylation processes, and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability and preventing carcinogenesis. Additionally, in neurodevelopment, folate is essential for neural tube closure and central nervous system formation. Thus, dysregulation of folate metabolism can contribute to pathologies such as cancer, severe birth defects, and neurodegenerative diseases. Epidemiological evidence highlights folate’s impact on disease risk and its potential as a therapeutic target. In cancer, antifolate drugs that inhibit key enzymes of folate-dependent 1C metabolism and strategies targeting folate receptors are current therapeutic options. However, folate’s impact on cancer risk is complex, varying among cancer types and dietary contexts. In neurodegenerative conditions, including Alzheimer’s and Parkinson’s diseases, folate deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing to neuronal damage. Clinical trials of folic acid supplementation show mixed outcomes, underscoring the complexities of its neuroprotective effects. This review integrates current knowledge on folate metabolism in cancer and neurodegeneration, exploring molecular mechanisms, clinical implications, and therapeutic strategies, which can provide crucial information for advancing treatments. Full article

Background and objectives: Riboflavin in the form flavin mononucleotide (FMN) acts as a cofactor for the pyridoxine phosphate oxidase required to generate pyridoxal 5′-phosphate (PLP), the active form of vitamin B6 in tissues. Few human studies have investigated this metabolic interaction between riboflavin and vitamin B6. The primary objective of this study was to examine the response of plasma PLP to riboflavin supplementation in individuals with the MTHFR 677TT genotype. A secondary objective was to consider whether the dose of riboflavin (1.6 mg/d vs. 10 mg/d) affects the PLP response. Methods: Data from four randomised controlled trials (RCTs) of riboflavin supplementation previously conducted at this centre were accessed to identify 209 participants of 19–60 years meeting the inclusion criteria (≤60 years, MTHFR 677TT genotype, not taking a vitamin B6 supplement). In the original RCTs, participants were randomly assigned to receive a placebo (n = 85) or 1.6 mg/d of riboflavin (n = 87) for 16 weeks. In one trial only, a higher riboflavin dose, 10 mg/d (n = 37), was administered. Plasma PLP was measured via reversed phase HPLC with fluorescence detection. Riboflavin status was assessed using the functional assay, erythrocyte glutathione reductase activation coefficient (EGRac). Results: riboflavin supplementation resulted in a decrease (p < 0.001) in the mean EGRac values, from 1.34 (1.32, 1.37) to 1.21 (1.19, 1.22). Correspondingly, PLP increased (p = 0.027), an effect driven by those with a sub-optimal riboflavin status at baseline (EGRac > 1.26), whereby PLP increased by 5.2 nmol/L, from 44.9 (40.3, 49.4) to 50.1 (44.6, 55.6) nmol/L (p = 0.042), while with the optimal baseline riboflavin (EGRac ≤ 1.26), there was no significant PLP response to the intervention. Although 10 mg/d vs. 1.6 mg/d of riboflavin resulted in a greater EGRac response (p = 0.012), there was no significant effect of riboflavin dose on the PLP response. Discussion: These results provide randomised trial evidence that optimising riboflavin status leads to an increase in plasma PLP, confirming the metabolic dependency of vitamin B6 on FMN. The findings indicate that riboflavin intake may need to be considered when setting dietary recommendations for vitamin B6 in adults. Further work is needed to explore the impact of the common MTHFR C677T polymorphism of the interrelationship of these B vitamins. Full article

Carcinogenesis is closely related to the expression, maintenance, and stability of DNA. These processes are regulated by one-carbon metabolism (1CM), which involves several vitamins of the complex B (folate, B2, B6, and B12), whereas alcohol disrupts the cycle due to the inhibition of folate activity. The relationship between nutrients related to 1CM (all aforementioned vitamins and alcohol) in breast cancer has been reviewed. The interplay of genes related to 1CM was also analyzed. Single nucleotide polymorphisms located in those genes were selected by considering the minor allele frequency in the Caucasian population and the linkage disequilibrium. These genes were used to perform several in silico functional analyses (considering corrected p-values < 0.05 as statistically significant) using various tools (FUMA, ShinyGO, and REVIGO) and databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GeneOntology (GO). The results of this study showed that intake of 1CM-related B-complex vitamins is key to preventing breast cancer development and survival. Also, the genes involved in 1CM are overexpressed in mammary breast tissue and participate in a wide variety of biological phenomena related to cancer. Moreover, these genes are involved in alterations that give rise to several types of neoplasms, including breast cancer. Thus, this study supports the role of one-carbon metabolism B-complex vitamins and genes in breast cancer; the interaction between both should be addressed in future studies. Full article