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The impact of zinc and folic acid supplementation on sperm DNA methylation: results from the folic acid and zinc supplementation randomized clinical trial (FAZST).
Jenkins, T, Aston, K, Carrell, D, DeVilbiss, E, Sjaarda, L, Perkins, N, Mills, JL, Chen, Z, Sparks, A, Clemons, T, et al
Fertility and sterility. 2022;(1):75-85
Abstract
OBJECTIVE To determine if 6-month folic acid (5 mg) and zinc (30 mg) supplementation impacts sperm DNA methylation patterns. DESIGN A multicenter, double-blind, block randomized, placebo-controlled trial titled "The Folic Acid and Zinc Supplementation Trial (FAZST)." SETTING Infertility care centers. PATIENT(S): Male partners (18 years and older) from heterosexual couples (female partners aged 18-45 years) seeking fertility treatment were recruited. INTERVENTION(S): Men were randomized 1:1 to receive folic acid (5 mg) and elemental zinc (30 mg) (n = 713) or a matching placebo (n = 757) daily for 6 months. MAIN OUTCOME MEASURE(S): Sperm DNA methylation was analyzed using the EPIC methylation array (Illumina) at 6 months. Differential sperm DNA methylation was assessed at multiple levels (regional, single cytosine phosphate guanine, etc.). We additionally assessed the impact of supplementation on epigenetic age. RESULT(S): No significant differences were identified between the treatment and placebo groups although some trends appeared to be present. To determine if these trends were noteworthy, we implemented various permutations and found that the patterns we identified were no more than would be expected by random chance. CONCLUSION(S): The data presented here strongly suggest that this supplementation regimen is not effective at altering sperm DNA methylation. These data comport well with previous findings from the FAZST study that found no impact of supplementation on basic semen analysis parameters or live birth. CLINICAL TRIAL REGISTRATION NUMBER ClinicalTrials.gov Identifier: NCT01857310.
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Positive effects of folic acid supplementation on cognitive aging are dependent on ω-3 fatty acid status: a post hoc analysis of the FACIT trial.
van Soest, APM, van de Rest, O, Witkamp, RF, de Groot, LCPGM
The American journal of clinical nutrition. 2021;(4):801-809
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BACKGROUND Although epidemiological studies suggest a protective role of B vitamins and omega-3 (ω-3) fatty acids in cognitive decline, findings from intervention studies are conflicting. Mechanistic studies suggest that the ω-3 (n-3) fatty acid status can modulate the effects of B vitamins on cognitive decline. OBJECTIVES We investigated the interaction between baseline ω-3 fatty acid statuses and folic acid treatment on cognitive decline in a placebo-controlled trial [FACIT (Folic Acid and Carotid Intima-media Thickness)]. METHODS This post hoc analysis included 791 older adults aged 50-70 y with plasma total homocysteine ≥13 µmol/L and ≤26 µmol/L and serum vitamin B12 ≥200 pmol/L. Participants received 800 µg folic acid or placebo daily for 3 y. Global cognitive functioning and domain-specific functioning (episodic memory, information processing speed, executive functioning) were assessed at baseline and after 3 y. The effect of the folic acid supplementation was analyzed according to tertiles of baseline ω-3 fatty acid concentrations using linear multiple regression. RESULTS The mean ± SD age of the study population was 60.2 ± 5.6 y, and the mean ± SD Mini-Mental State Examination score was 28.6 ± 1.5. The treatment effect of folic acid was significantly larger in participants in the low compared to high ω-3 fatty acid tertile for global cognition (difference in z-score: mean ± SE = 0.16 ± 0.059; P < 0.01). Regarding domain-specific functioning, similar results were observed for information processing speed (mean ± SE = 0.167 ± 0.068; P = 0.01). There were no overall interactions between folic acid treatment and ω-3 fatty acid tertiles for episodic memory (P = 0.14) and executive functioning (P = 0.21). CONCLUSIONS This post hoc analysis revealed that the efficacy of folic acid treatment on cognitive functioning is dependent on the ω-3 fatty acid status. Individuals with a lower ω-3 fatty acid status at baseline benefited from folic acid treatment, while individuals with a higher ω-3 fatty acid status did not. The results potentially explain the inconsistency in outcomes of B-vitamin supplementation trials and emphasize the importance of a personalized approach. This trial was registered at clinicaltrials.gov as NCT00110604.
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Effects of Folic Acid Supplementation on Inflammatory Markers: A Grade-Assessed Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials.
Asbaghi, O, Ashtary-Larky, D, Bagheri, R, Moosavian, SP, Nazarian, B, Afrisham, R, Kelishadi, MR, Wong, A, Dutheil, F, Suzuki, K, et al
Nutrients. 2021;(7)
Abstract
It has been theorized that folic acid supplementation improves inflammation. However, its proven effects on inflammatory markers are unclear as clinical studies on this topic have produced inconsistent results. To bridge this knowledge gap, this systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the effects of folic acid supplementation on serum concentrations of the inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Methods: To identify eligible RCTs, a systematic search up to April 2021 was completed in PubMed/Medline, Scopus, Web of Science, EMBASE, Cochrane databases, and Google Scholar using relevant keywords. A fix or random-effects model was utilized to estimate the weighted mean difference (WMD) and 95% confidence interval (95% CI). Results: Twelve RCTs were included in the present meta-analysis. The pooled analysis revealed that serum concentrations of CRP (WMD: -0.59 mg/L, 95% CI -0.85 to -0.33, p < 0.001) were significantly reduced following folic acid supplementation compared to placebo, but did not affect serum concentrations of IL-6 (WMD: -0.12, 95% CI -0.95 to 0.72 pg/mL, p = 0.780) or TNF-α (WMD: -0.18, 95% CI -0.86 to 0.49 pg/mL, p = 0.594). The dose-response analysis demonstrated a significant relationship between an elevated dosage of folic acid supplementation and lower CRP concentrations (p = 0.002). Conclusions: We found that folic acid supplementation may improve inflammation by attenuating serum concentrations of CRP but without significant effects on IL-6 and TNF-α. Future RCTs including a larger number of participants and more diverse populations are needed to confirm and expand our findings.
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Cobalamin and folate status in women during early pregnancy in Bhaktapur, Nepal.
Schwinger, C, Sharma, S, Chandyo, RK, Hysing, M, Kvestad, I, Ulak, M, Ranjitkar, S, Shrestha, M, Shrestha, LP, McCann, A, et al
Journal of nutritional science. 2021;:e57
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The demand for cobalamin (vitamin B12) and folate is increased during pregnancy, and deficiency during pregnancy may lead to complications and adverse outcomes. Yet, the status of these micronutrients is unknown in many populations. We assessed the concentration of cobalamin, folate and their functional biomarkers, total homocysteine (tHcy) and methylmalonic acid (MMA), in 561 pregnant women enrolled in a community-based randomised controlled trial in Bhaktapur, Nepal. Plasma concentrations of cobalamin, folate, tHcy and MMA were measured and a combined indicator of vitamin B12 status (3cB12) was calculated. We report mean or median concentrations and the prevalence of deficiency according to commonly used cut-offs, and assessed their association with indicators of socio-economic status, and maternal and dietary characteristics by linear regression. Among the women at gestational week less than 15, deficiencies of cobalamin and folate were seen in 24 and 1 %, respectively. Being a vegetarian was associated with lower plasma cobalamin, and a higher socio-economic status was associated with a better micronutrient status. We conclude that cobalamin deficiency defined by commonly used cut-offs was common in Nepalese women in early pregnancy. In contrast, folate deficiency was rare. As there is no consensus on cut-off points for vitamin B12 deficiency during pregnancy, future studies are needed to assess the potential functional consequences of these low values.
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Prenatal Vitamins and the Risk of Offspring Autism Spectrum Disorder: Systematic Review and Meta-Analysis.
Friel, C, Leyland, AH, Anderson, JJ, Havdahl, A, Borge, T, Shimonovich, M, Dundas, R
Nutrients. 2021;(8)
Abstract
Prenatal nutrition is associated with offspring autism spectrum disorder (herein referred to as autism), yet, it remains unknown if the association is causal. Triangulation may improve causal inference by integrating the results of conventional multivariate regression with several alternative approaches that have unrelated sources of bias. We systematically reviewed the literature on the relationship between prenatal multivitamin supplements and offspring autism, and evidence for the causal approaches applied. Six databases were searched up to 8 June 2020, by which time we had screened 1309 titles/abstracts, and retained 12 articles. Quality assessment was guided using Newcastle-Ottawa in individual studies, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) for the body of evidence. The effect estimates from multivariate regression were meta-analysed in a random effects model and causal approaches were narratively synthesised. The meta-analysis of prenatal multivitamin supplements involved 904,947 children (8159 cases), and in the overall analysis showed no robust association with offspring autism; however, a reduced risk was observed in the subgroup of high-quality observational studies (RR 0.77, 95% CI (0.62, 0.96), I2 = 62.4%), early pregnancy (RR 0.76, 95% CI (0.58; 0.99), I2 = 79.8%) and prospective studies (RR 0.69, 95% CI (0.48, 1.00), I2 = 95.9%). The quality of evidence was very low, and triangulation was of limited utility because alternative methods were used infrequently and often not robustly applied.
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Biology of Perseverative Negative Thinking: The Role of Timing and Folate Intake.
Eszlari, N, Bruncsics, B, Millinghoffer, A, Hullam, G, Petschner, P, Gonda, X, Breen, G, Antal, P, Bagdy, G, Deakin, JFW, et al
Nutrients. 2021;(12)
Abstract
Past-oriented rumination and future-oriented worry are two aspects of perseverative negative thinking related to the neuroticism endophenotype and associated with depression and anxiety. Our present aim was to investigate the genomic background of these two aspects of perseverative negative thinking within separate groups of individuals with suboptimal versus optimal folate intake. We conducted a genome-wide association study in the UK Biobank database (n = 72,621) on the "rumination" and "worry" items of the Eysenck Personality Inventory Neuroticism scale in these separate groups. Optimal folate intake was related to lower worry, but unrelated to rumination. In contrast, genetic associations for worry did not implicate specific biological processes, while past-oriented rumination had a more specific genetic background, emphasizing its endophenotypic nature. Furthermore, biological pathways leading to rumination appeared to differ according to folate intake: purinergic signaling and circadian regulator gene ARNTL emerged in the whole sample, blastocyst development, DNA replication, and C-C chemokines in the suboptimal folate group, and prostaglandin response and K+ channel subunit gene KCNH3 in the optimal folate group. Our results point to possible benefits of folate in anxiety disorders, and to the importance of simultaneously taking into account genetic and environmental factors to determine personalized intervention in polygenic and multifactorial disorders.
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Effects of Folic Acid and Vitamin B12 Supplementation on Cognitive Impairment and Inflammation in Patients with Alzheimer's Disease: A Randomized, Single-Blinded, Placebo-Controlled Trial.
Chen, H, Liu, S, Ge, B, Zhou, D, Li, M, Li, W, Ma, F, Liu, Z, Ji, Y, Huang, G
The journal of prevention of Alzheimer's disease. 2021;(3):249-256
Abstract
OBJECTIVES To evaluate the combined action of folic acid and vitamin B12 supplementation on cognitive performance and inflammation in patients with Alzheimer's disease (AD). DESIGN This was a randomized, single-blind, placebo-controlled trial. PARTICIPANTS Patients (n=120) diagnosed clinically as probable AD and in stable condition from Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases. MEASUREMENTS Individuals were randomly divided into the intervention group (n=60, folic acid 1.2 mg/d + vitamin B12 50 μg/d) and the placebo group (n=60). Cognitive performance, blood folate, vitamin B12, one carbon cycle metabolite, and inflammatory cytokine levels were measured at baseline and after 6 months. The data were analyzed using linear mixed models for repeated measures. RESULTS A total of 101 participants (51 in the intervention group and 50 in the placebo group) completed the trial. Folic acid plus vitamin B12 supplementation had a beneficial effect on the MoCA total scores (P=0.029), naming scores (P=0.013), orientation scores (P=0.004), and ADAS-Cog domain score of attention (P=0.008), as compared to those of the control subjects. Moreover, supplementation significantly increased plasma SAM (P<0.001) and SAM/SAH (P<0.001), and significantly decreased the levels of serum Hcy (P<0.001), plasma SAH (P<0.001), and serum TNFα (P<0.001) compared to in the control subjects. CONCLUSIONS Folic acid and vitamin B12 supplementation showed a positive therapeutic effect in AD patients who were not on a folic acid-fortified diet. The findings of this study help to delineate nutrient intervention as far as public health management for the prevention of dementia is concerned.
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Periconceptional Folate Supplementation in Women after Bariatric Surgery-A Narrative Review.
Vynckier, AK, Ceulemans, D, Vanheule, G, De Mulder, P, Van Den Driessche, M, Devlieger, R
Nutrients. 2021;(5)
Abstract
The prevalence of obesity is increasing globally, and along with it, there is a growing number of patients opting to undergo bariatric surgery to treat this condition. Whilst it has many advantages, bariatric surgery is known to induce micronutrient deficiency, with possible deleterious effects on overall health. This topic becomes even more relevant during pregnancy, where deficiencies can also affect the developing fetus, possibly being the cause of an increase in congenital anomalies. Most notably amongst these micronutrients is folate, or vitamin B9, which plays an essential role in development, gene expression and genomic stability. As insufficient levels of folate are associated with neural tube defects in the fetus, preventing and treating folate deficiencies during pregnancies after bariatric surgery is a relevant issue. Unfortunately, folate supplementation recommendations for bariatric patients who wish to become pregnant are not clear. In this narrative review, we discuss whether the recommendations for the general population are still valid for bariatric patients. Furthermore, we discuss the role of folate in the human body, folate status in both non-bariatric and bariatric patients, the various types of folate that are available for substitution and the risk associated with over-supplementation.
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The 5-formyl-tetrahydrofolate proteome links folates with C/N metabolism and reveals feedback regulation of folate biosynthesis.
Li, W, Liang, Q, Mishra, RC, Sanchez-Mu Oz, R, Wang, H, Chen, X, Van Der Straeten, D, Zhang, C, Xiao, Y
The Plant cell. 2021;(10):3367-3385
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Folates are indispensable for plant development, but their molecular mode of action remains elusive. We synthesized a probe, "5-F-THF-Dayne," comprising 5-formyl-tetrahydrofolate (THF) coupled to a photoaffinity tag. Exploiting this probe in an affinity proteomics study in Arabidopsis thaliana, we retrieved 51 hits. Thirty interactions were independently validated with in vitro expressed proteins to bind 5-F-THF with high or low affinity. Interestingly, the interactors reveal associations beyond one-carbon metabolism, covering also connections to nitrogen (N) metabolism, carbohydrate metabolism/photosynthesis, and proteostasis. Two of the interactions, one with the folate biosynthetic enzyme DIHYDROFOLATE REDUCTASE-THYMIDYLATE SYNTHASE 1 (AtDHFR-TS1) and another with N metabolism-associated glutamine synthetase 1;4 (AtGLN1;4), were further characterized. In silico and experimental analyses revealed G35/K36 and E330 as key residues for the binding of 5-F-THF in AtDHFR-TS1 and AtGLN1;4, respectively. Site-directed mutagenesis of AtGLN1;4 E330, which co-localizes with the ATP-binding pocket, abolished 5-F-THF binding as well as AtGLN1;4 activity. Furthermore, 5-F-THF was noted to competitively inhibit the activities of AtDHFR-TS1 and AtGLN1;4. In summary, we demonstrated a regulatory role for 5-F-THF in N metabolism, revealed 5-F-THF-mediated feedback regulation of folate biosynthesis, and identified a total of 14 previously unknown high-affinity binding cellular targets of 5-F-THF. Together, this sets a landmark toward understanding the role of folates in plant development.
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A pilot study of thiamin and folic acid in hemodialysis patients with cognitive impairment.
Lu, R, Fang, Y, Zhou, Y, Che, M, Shen, J, Liu, Q, Zhang, H, Pan, S, Lin, Y, Wang, Q, et al
Renal failure. 2021;(1):766-773
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OBJECTIVE This study aimed to explore the effectiveness of thiamin and folic acid supplementation on the improvement of the cognitive function in patients with maintenance hemodialysis. METHOD In the present study, we randomly assigned patients undergoing hemodialysis who had the Montreal Cognitive Assessment (MoCA) score lower than 26 to treatment group (n = 25, thiamin 90 mg/day combined with folic acid 30 mg/day) or control group (n = 25, nonintervention). All subjects were followed up for 96 weeks. The primary outcome was the improvement of the MoCA score. The secondary outcomes included homocysteine level, survival and safety. RESULTS Patients in treatment group had an increase of the MoCA score from 21.95 ± 3.81 at baseline to 25.68 ± 1.96 at week 96 (p < 0.001, primary outcome), as compared with the MoCA score from 20.69 ± 3.40 to 19.62 ± 3.58 in control group. Thiamin combined with folic acid treatment also resulted in lower level of serum homocysteine in treatment group compare with control group at week 96 (p < 0.05, secondary outcome). 3 patients and 9 patients died during follow-up period in treatment and control group respectively (p = 0.048). The proportion of adverse events in treatment group was significantly lower than that in control group. CONCLUSION Hemodialysis patients with cognitive impairment treated with thiamin and folic acid had a significant improvement in MoCA score.