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Serum Homocysteine, Pyridoxine, Folate, and Vitamin B12 Levels in Migraine: Systematic Review and Meta-Analysis.
Liampas, I, Siokas, V, Mentis, AA, Aloizou, AM, Dastamani, M, Tsouris, Z, Aslanidou, P, Brotis, A, Dardiotis, E
Headache. 2020;(8):1508-1534
Abstract
BACKGROUND Migraine, especially migraine with aura (MA), has been linked to increased risk for ischemic cerebrovascular disease. The possible role of elevated serum homocysteine (Hcy, a cause of thrombophilia) in migraine has been demonstrated by several studies. OBJECTIVE The present study aims to review and meta-analyze data from studies investigating the difference of serum Hcy and Hcy lowering vitamins between migraine patients and healthy controls (HC), as well as between patients with MA and migraine without aura (MO). METHODS Literature search involved MEDLINE, Embase, CENTRAL, Google Scholar, and trial registries. The Newcastle-Ottawa Scale was used to evaluate the quality of the retrieved studies. Standardized mean differences (SMDs) and 95% confidence intervals (95%CIs) were calculated. Funnel-plots were utilized for the evaluation of publication bias. RESULTS Overall, 29 (28 case-control and 1 cross-sectional) studies were retrieved. Meta-analysis was indicative of higher Hcy concentration in migraine patients vs HC overall [adults and children: 16 studies, I2 = 81%, SMD = 0.41, 95%CI = (0.20, 0.61)]. Hcy was consistently elevated in adults with migraine [adults: 12 studies, I2 = 76%, SMD = 0.35, 95%CI = (0.15, 0.54); children: 1 study, SMD = 0.37, 95%CI = (-0.05, 0.79)]. Subgroup analyses reproduced the results for both adults with MA [7 studies, I2 = 83%, SMD = 0.37, 95%CI = (0.03, 0.71)] and MO [5 studies, I2 = 84%, SMD = 0.46, 95%CI = (0.03, 0.89)]. Figures for serum folate were lower in the overall comparison of migraine patients with HC [adults and children: 11 studies, I2 = 87%, SMD = -0.36, 95%CI = (-0.68, -0.05); adults: 8 studies, I2 = 6%, SMD = -0.11, 95%CI = (-0.22, 0.01); children: 1 study, SMD = -0.71, 95%CI = (-1.14, -0.29); MA adults: 4 studies, I2 = 44%, SMD = -0.16, 95%CI = (-0.35, 0.04); MO adults: 4 studies, I2 = 47%, SMD = -0.17, 95%CI = (-0.44, 0.10)]. Serum vitamin B12 levels were not different between migraine patients and HC [adults and children: 11 studies, I2 = 88%, SMD = -0.24, 95%CI = (-0.57, 0.09); adults: 8 studies, I2 = 57%, SMD = -0.10, 95%CI = (-0.28, 0.08); children: 1 study, SMD = 0.29, 95%CI = (-0.13, 0.71); MA adults: 4 studies, I2 = 63%, SMD = -0.14, 95%CI = (-0.48, 0.20); MO adults: 4 studies, I2 = 59%, SMD = -0.15, 95%CI = (-0.45, 0.15)]. Serum Hcy was lower in MO than MA [adults and children: 10 studies, I2 = 39%, SMD = 0.30, 95%CI = (0.14, 0.46), adults: 6 studies, I2 = 29%, SMD = 0.21, 95%CI = (0.09, 0.36), children: 1 study, SMD = 0.51, 95%CI = (0.22, 0.80)]. Serum folate and vitamin B12 did not differ between MA and MO. CONCLUSIONS Our results suggest that there is a possible link between migraine, mainly MA, and elevated serum Hcy.
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2.
Vitamin B12, B6, or Folate and Cognitive Function in Community-Dwelling Older Adults: A Systematic Review and Meta-Analysis.
Zhang, C, Luo, J, Yuan, C, Ding, D
Journal of Alzheimer's disease : JAD. 2020;(2):781-794
Abstract
BACKGROUND Previous studies have indicated that B vitamin deficiencies are an essential cause of neurological pathology. There is a need to provide evidence of the benefit of B vitamins for the prevention of cognitive decline in community-dwelling older adults. OBJECTIVE To examine the association between intake and plasma levels of vitamins B12, B6, and folate and cognitive function in older populations through a systematic review and meta-analysis. METHODS Medline (PubMed), EMBASE, and Cochrane databases were used to search the literature though August 8, 2019. We included observational population-based studies evaluating the association between concentrations or intake levels of vitamins B6, B12, or folate and cognition in older adults aged ≥45 years. The quality of all studies was assessed by the modified Newcastle-Ottawa Scale. Odds ratios (ORs) and hazard ratios (HRs) were analyzed by the random-effects model. Sensitivity analyses were conducted by excluding the studies with significant heterogeneity. RESULTS Twenty-one observational studies with sample sizes ranging from 155-7030 were included in the meta-analysis. Higher levels of vitamin B12 (OR = 0.77, 95% CI = 0.61-0.97) and folate concentration (OR = 0.68, 95% CI = 0.51-0.90) were associated with better cognition in cross-sectional studies, but not in sensitivity analyses or prospective studies. High vitamin B6 concentrations showed no significant benefit on cognition and dementia risk. Prospective studies did not provide substantial evidence for the relationship. CONCLUSION The results from our meta-analysis suggest that vitamins B12, B6, and folate may not be modifiable risk factors for slowing cognitive decline among community-dwelling older individuals.
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3.
Serum Folate Levels and Lung Cancer Risk: A Meta- Epidemiological Study of Population-based Case-Control Studies.
Bae, JM
Asian Pacific journal of cancer prevention : APJCP. 2020;(6):1829-1833
Abstract
OBJECTIVE While it has been claimed that lung cancer occurs due to epigenetic mechanisms, four systematic reviews were reported to investigate the association between serum folate levels and lung cancer risk. Considering some methodological problems founded in the systematic review, a meta-epidemiological study was conducted. METHODS The selection criteria of this study were defined that a case-control study was conducted to determine the risk of lung cancer occurrence according to the concentration of serum folate and its results showed odds ratio and its 95% confidence interval. Additional paper was explored from cited lists of 4 papers selected by previous systematic reviews. Random effect model was applied if I-squared value was over 50%. RESULTS For 5 case-control studies selected, the summary odds ratios (and their 95% confidence intervals) were 0.82 (0.74-0.90) in men, 0.70 (0.62-0.79) in former smokers, and 0.86 (0.75-1.00) in non-smokers. CONCLUSION Higher foliate levels can decrease lung cancer risk in men and former smokers. Especially, the protective effect was highest in former smokers compared in non-smokers and current smokers. Based on these facts, folate fortification programs to reduce lung cancer risk would be focused on former smokers in men. And some epidemiological studies are needed to provide a hypothesis to explain the sex differences in the association between folate and lung cancer risk.
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Effectiveness of community-based folate-oriented tertiary interventions on incidence of fetus and birth defects: a protocol for a single-blind cluster randomized controlled trial.
Li, M, Zhang, Y, Chen, X, Wang, D, Ji, M, Jiang, Y, Dou, Y, Ma, X, Sheng, W, Yan, W, et al
BMC pregnancy and childbirth. 2020;(1):475
Abstract
BACKGROUND Birth defects are the main cause of fetal death, infant mortality and morbidity worldwide. However, the etiology of birth defects remains largely unknown. Maternal folate status during periconception plays an important role in organogenesis and folic acid supplement reduces the risk of neural tube defects, congenital heart diseases, and several other birth defects. This trial seeks to evaluate the effectiveness of folate-oriented tertiary interventions during periconception on the incidence of fetus and birth defects. METHODS This is a single-blind, two-arm cluster randomized controlled trial in Shanghai, China. Eligible women from 22 clusters are recruited at pre-pregnancy physical examinations clinical settings. Compared to the routine perinatal care group (control arm), folate-oriented tertiary interventions will be provided to the intervention arm. The core interventions consist of assessments of folate status and metabolism, folate intake guidance, and re-evaluation of folate status to ensure red blood cell folate level above 400 ng/ml (906 nmol/L) before pregnancy. Screening and consulting of fetus and birth defects, and treatments of birth defects during pregnancy and afterward will be provided to both arms. The primary outcome is a composite incidence of fetus defects, stillbirth, and neonatal birth defects identified from the confirmation of pregnancy to 28 days after birth. Secondary outcomes include maternal and offspring adverse complications and cost-effectiveness of folate-oriented tertiary interventions. This protocol adheres to the SPIRIT Checklist. DISCUSSION To achieve the recommended folate status before or during pregnancy is still a challenge worldwide. This community-based cluster-randomized controlled intervention trial will evaluate the effectiveness of a package of interventions aiming at achieving recommended maternal folate status covering pre- and during pregnancy in reducing fetus and birth defects. Our study has the potential to improve the community-based practice of reducing modifiable risk factors of disease and improving primary prevention of the defects in China. The procedures would formulate the policy on folic acid supplementation during periconception against birth defects in primary care settings. TRIAL REGISTRATION Clinical Trial Registry, NCT03725878 . Prospectively registered on 31 October 2018.
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Folic acid and vitamin B12 supplementation in subjects with type 2 diabetes mellitus: A multi-arm randomized controlled clinical trial.
Satapathy, S, Bandyopadhyay, D, Patro, BK, Khan, S, Naik, S
Complementary therapies in medicine. 2020;:102526
Abstract
OBJECTIVE This study was conducted to investigate and compare the effects of add-on folic acid and vitamin B12 supplementation on glycaemic control, insulin resistance and serum lipid profile in subjects with type 2 diabetes mellitus. STUDY DESIGN & INTERVENTION This study was a randomized, multi-arm, open-label clinical trial. 80 patients with type 2 diabetes and on stable oral antidiabetics were enrolled and 20 patients each were randomly allocated to one of the four groups - Group A: add-on Folic acid (5 mg/day); Group B: add-on Methylcobalamin (500 mcg/day); Group C: add-on Folic acid (5 mg/day) + Methylcobalamin (500 mcg/day) and Group D: Standard oral anti-diabetic drugs. The patients were followed up after 8 weeks. RESULTS HbA1c improved significantly in Groups B and C [median changes from baseline - 1.2 % (- 13 mmol/mol) and - 1.5 % (- 16 mmol/mol) respectively, p values 0.04 and 0.02 respectively] compared to Group D. Groups B and C also showed significant improvements in plasma insulin, insulin resistance and serum adiponectin compared to Group D. Serum homocysteine declined significantly in all three groups with add-on supplementation compared to standard treatment. No improvement in the lipid profile was noted in any of the groups. CONCLUSIONS Add-on supplementation with vitamin B12 improved glycaemic control and insulin resistance in patients with type 2 diabetes mellitus.
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Serum folate modified the association between low-density lipoprotein cholesterol and carotid intima-media thickness in Chinese hypertensive adults.
Ding, C, Bi, C, Lin, T, Hu, L, Huang, X, Liu, L, Liu, C, Song, Y, Tang, G, Wang, B, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2020;(12):2303-2311
Abstract
BACKGROUND AND AIMS While folate is known for its importance in cardiovascular health, it is unknown whether folate status can modify the association between low-density lipoprotein cholesterol (LDL-C) and carotid intima-media thickness (CIMT). We aimed to investigate this question in a Chinese hypertensive population, who are at high-risk of low folate and atherosclerosis. METHODS AND RESULTS This report included 14,970 hypertensive adults (mean age 64.5 years; 40.3% male) from the China Stroke Primary Prevention Trial (CSPPT) and analyzed the fasting serum LDL-C and folate, and CIMT data obtained at the last follow-up visit. LDL-C was calculated using the Friedewald equation. Serum folate levels were measured by chemiluminescent immunoassay. CIMT was measured by ultrasound. Non-parametric smoothing plots, multivariate linear regression analysis, subgroup analyses and interaction testing were performed to examine the LDL-C-CIMI relationship and effect modification by folate. Consistent with graphic plots, multivariate linear regression showed that LDL-C levels were independently and positively associated with CIMT (β = 7.69, 95%CI: 5.76-9.62). More importantly, the relationship between LDL-C and CIMT was significantly attenuated with increasing serum folate levels (1st tertile: β = 10.06, 95%CI: 6.67-13.46; 2nd tertile: β = 6.81, 95%CI: 3.55-10.07; 3rd tertile: β = 5.96, 95%CI: 2.55-9.36; P-interaction = 0.045). Subgroup analyses showed the association between LDL-C and CIMT across serum folate tertiles was robust among various strata (all P-interaction >0.05). CONCLUSIONS Among Chinese hypertensive adults, the serum folate levels could modify the association between LDL-C and CIMT. Our findings, if further confirmed, have important clinical implications.
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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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Supplemental Vitamins and Minerals for Cardiovascular Disease Prevention and Treatment.
Ingles, DP, Cruz Rodriguez, JB, Garcia, H
Current cardiology reports. 2020;(4):22
Abstract
PURPOSE OF REVIEW The objective of this study is to explore the current literature supporting the use oral multivitamins and multi/minerals (OMVMs) for cardiovascular diseases (CVD) treatment and prevention. RECENT FINDINGS Data on multivitamins, vitamin C and D, coenzyme Q, calcium, and selenium, has showed no consistent benefit for the prevention of CVD, myocardial infarction, or stroke, nor was there a benefit for all-cause mortality to support their routine supplementation. Folic acid alone and B vitamins with folic acid, B6 and B12, reduce stroke, whereas niacin and antioxidants are associated with an increased risk of all-cause mortality. Iron deficiency should be avoided and treated if found, but routine supplementation to those without deficiency is not evidence based. Despite the high supplement use by the general public, there is no evidence to support the routine supplementation of oral multivitamins and multi/minerals (OVMN) for CVD prevention or treatment.
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Effect of Vitamin B12 Levels on the Association Between Folic Acid Treatment and CKD Progression: A Post Hoc Analysis of a Folic Acid Interventional Trial.
Li, Y, Spence, JD, Wang, X, Huo, Y, Xu, X, Qin, X
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2020;(3):325-332
Abstract
RATIONALE & OBJECTIVE In populations with folic acid fortification or supplementation, the main nutritional determinant of total homocysteine levels is vitamin B12 (B12) status. We aimed to evaluate the modifying effect of B12 levels on the association between folic acid treatment and chronic kidney disease (CKD) progression. STUDY DESIGN A post hoc analysis of an interventional trial. SETTING & PARTICIPANTS This is a post hoc analysis of 1,374 hypertensive adults with mild to moderate CKD and B12 measurements at baseline from the kidney disease substudy of the China Stroke Primary Prevention Trial (CSPPT), conducted in 20 communities in Jiangsu province in China, a region with low folate consumption. INTERVENTIONS Assignments to a double-blinded daily treatment of enalapril, 10mg, and folic acid, 0.8mg; or enalapril, 10mg, alone. OUTCOMES The primary outcome was progression of CKD (defined as a decrease in estimated glomerular filtration rate [eGFR] ≥ 30% and to a level of<60mL/min/1.73m2 if baseline eGFR was≥60mL/min/1.73m2; or a decrease in eGFR≥50% if baseline eGFR was<60mL/min/1.73m2; or kidney failure). RESULTS Mean baseline eGFR in this study was 86.1±20.5 (SD) mL/min/1.73m2. Median treatment duration was 4.4 years. Among participants with higher baseline B12 levels (≥248pmol/L), compared to enalapril alone, enalapril-folic acid treatment was associated with an 83% reduction in the odds of the primary outcome (OR, 0.17; 95% CI, 0.07-0.40). However, among those with baseline B12 levels<248pmol/L (metabolic B12 deficiency), there was no significant group difference in the primary outcome (OR, 1.21; 95% CI, 0.51-2.85). The interaction between B12 level and folic acid treatment was significant (P = 0.001). LIMITATIONS The analysis is post hoc and event rate is low. CONCLUSIONS Folic acid treatment was associated with a greater reduction in the odds of CKD progression among patients with mild to moderate CKD and higher B12 levels. FUNDING Government funding (National Key Research and Development Program of China).
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Alterations in Sulfur Amino Acids as Biomarkers of Disease.
Stabler, SP
The Journal of nutrition. 2020;(Suppl 1):2532S-2537S
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Abstract
Homocysteine (Hcy) is methylated by methionine synthase to form methionine with methyl-cobalamin as a cofactor. The reaction demethylates 5-methyltetrahydrofolate to tetrahydrofolate, which is required for DNA and RNA synthesis. Deficiency of either of the cobalamin (Cbl) and/or folate cofactors results in elevated Hcy and megaloblastic anemia. Elevated Hcy is a sensitive biomarker of Cbl and/or folate status and more specific than serum vitamin assays. Elevated Hcy normalizes when the correct vitamin is given. Elevated Hcy is associated with alcohol use disorder and drugs that target folate or Cbl metabolism, and is a risk factor for thrombotic vascular disease. Elevated methionine and cystathionine are associated with liver disease. Elevated Hcy, cystathionine, and cysteine, but not methionine, are common in patients with chronic renal failure. Higher cysteine predicts obesity and future weight gain. Serum S-adenosylhomocysteine (AdoHcy) is elevated in Cbl deficiency and chronic renal failure. Drugs that require methylation for catabolism may deplete liver S-adenosylmethionine and raise AdoHcy and Hcy. Deficiency of Cbl or folate or perturbations of their metabolism cause major changes in sulfur amino acids.