BACKGROUND: Existing evidence on the relation between folate intake and biomarkers with mortality risk is controversial.
OBJECTIVE: Previous cohort studies were examined regarding folate intake and biomarkers in relation to risk of all-cause, cardiovascular disease- (CVD), and cancer-related mortality through a systematic review and meta-analysis.
METHODS: A systematic search was performed of the PubMed, Scopus, and ISI Web of Science databases up to July 2023.
METHODS: Prospective cohort studies examining the association of folate biomarkers (in serum, plasma, red blood cells) and intake with risk of all-cause, CVD-, and cancer-related mortality were considered. A random-effects model was applied to combine study-specific risk estimates. Dose-response relations were assessed by 1-stage weighted mixed-effects meta-analysis.
METHODS: A total of 25 cohorts with 423 304 participants, 36 558 all-cause, 12 662 CVD-, and 2426 cancer-related deaths were included. No significant association was observed between the highest levels of folate biomarkers and all-cause mortality risk (hazard ratio [HR], 0.91; 95% CI, 0.77-1.06; n = 17; I2 = 89.4%; P < .001), CVD-related mortality risk (HR, 0.97; 95% CI, 0.87-1.06; n = 11; I2 = 0.0%; P = .57), and cancer-related mortality risk (HR, 0.85; 95% CI, 0.69-1.05; n = 6; I2 = 57.8%; P = .04) compared with the lowest. Furthermore, each 10 nmol/L increase was marginally related to a 12% reduced all-cause mortality risk but not to CVD- and cancer-related mortality risk. A significant inverse association was found between highest intake of dietary folate and the lowest, and risk of all-cause (HR, 0.87; 95% CI, 0.78-0.96; n = 3; I2 = 63.6%; P = .06) and CVD (HR, 0.77; 95% CI, 0.57-0.93; n = 4; I2 = 80.2%; P = .002) mortality.
CONCLUSIONS: This meta-analysis revealed a significant inverse relation between dietary folate intake and risk of all-cause and CVD mortality. Such an association was not found in the case of folate biomarkers. Further prospective studies are warranted to confirm these findings.
BACKGROUND: PROSPERO registration no. CRD42023401700.

Folate is a water-soluble B vitamin involved in the synthesis of purines and pyrimidines and is one of the essential vitamins for human growth and reproduction. Folate deficiency due to low dietary intake, poor absorption of folate, and alterations in folate metabolism due to genetic defects or drug interactions significantly increases the risk of diseases such as neural tube defects, cardiovascular disease, cancer, and cognitive dysfunction. Recent studies have shown that folate deficiency can cause hyperhomocysteinemia, which increases the risk of hypertension and cardiovascular disease, and that high homocysteine levels are an independent risk factor for liver fibrosis and cirrhosis. In addition, folate deficiency results in increased secretion of pro-inflammatory factors and impaired lipid metabolism in the liver, leading to lipid accumulation in hepatocytes and fibrosis. There is substantial evidence that folate deficiency contributes to the development and progression of a variety of liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), viral hepatitis, hepatic fibrosis, and liver cancer. Here we review key studies on the role of folate in the pathophysiology of liver diseases, summarize the current status of studies on folate in the treatment of liver diseases, and speculate that folate may be a potential therapeutic target for liver diseases.

Mitochondrial one-carbon metabolism provides carbon units to several pathways, including nucleic acid synthesis, mitochondrial metabolism, amino acid metabolism, and methylation reactions. Late-onset Alzheimer\'s disease is the most common age-related neurodegenerative disease, characterised by impaired energy metabolism, and is potentially linked to mitochondrial bioenergetics. Here, we discuss the intersection between the molecular pathways linked to both mitochondrial one-carbon metabolism and Alzheimer\'s disease. We propose that enhancing one-carbon metabolism could promote the metabolic processes that help brain cells cope with Alzheimer\'s disease-related injuries. We also highlight potential therapeutic avenues to leverage one-carbon metabolism to delay Alzheimer\'s disease pathology.

BACKGROUND: On May 29, 2023, the 76th World Health Assembly (WHA) unanimously adopted the resolution entitled, \"Accelerating efforts for preventing micronutrient deficiencies and their consequences, including spina bifida and other neural tube defects, through safe and effective food fortification.\" The Society for Birth Defects Research and Prevention published their resolution in 2015 supporting mandatory fortification of staple foods with folic acid and recommendations aiming to achieve global total prevention of folate-sensitive spina bifida and anencephaly, setting a goal to achieve by the year 2024. The WHA resolution provides another global push for the cause, with recommendations to member nations for food fortification to be achieved by the year 2030.
METHODS: This short communication documents the steps, from inception up to the passage, of the 76th WHA resolution on food fortification, with a narrative on the nature of strategic advocacy efforts by multiple governmental and nongovernmental organizations.
RESULTS: WHA resolutions can take many years to be introduced and passed by the assembly; however, this is a case study of the swiftness of the process enabled by powerful global partnership.
CONCLUSIONS: The documentation of this process serves as an example for developing and processing future WHA resolutions aiming to improve global maternal and child health.

BACKGROUND: Low folate intake and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have been suggested to increase the risk of Alzheimer\'s disease (AD). However, the synergistic effects and their impact on brain structure and perfusion remain unclear.
METHODS: This study explored the effects of dietary and genetic deficiencies in folate metabolism on the volume of the hippocampal subregions, cerebral perfusion, and cognitive decline in 71 cognitively unimpaired (CU) individuals and 102 patients with mild cognitive impairment (MCI) due to AD or AD. All participants underwent magnetic resonance imaging, laboratory examinations, and neuropsychological assessments. The hippocampal subfields were segmented using Freesurfer, and arterial spin labeling was used to measure the cerebral blood flow.
RESULTS: We found a significant group-by-MTHFR interaction effect on folate. Patients with AD and the 677 T allele showed hypoperfusion in the left precuneus compared to patients without this mutation, which mediated the relationship between low folate level and cognitive decline in patients carrying the 677 T allele. Moreover, a synergistic effect was observed for the combination of decreased folate concentrations and the presence of the MTHFR 677 T allele on the atrophy of specific hippocampal subregions in patients with AD.
CONCLUSIONS: In addition to offering insights into the neuronal mechanism underlying gene-dependent folate-induced cognitive impairment in AD, these findings may have clinical significance for the allocation of auxiliary folate supplementation therapy in patients with AD with low folate levels and carrying the MTHFR 677 T allele and may eventually promote the selection of early individualized AD drug therapy.

Background: Attention deficit hyperactivity disorder (ADHD) is a common childhood neurodevelopmental disorder that begins before age 12. Given the role of B group vitamins in cell metabolism, synthesis of nucleotides, and neurotransmitters, the present study systematically investigated the plasma levels of vitamins B9 and B12 in children with ADHD. Methods: We searched electronic databases including Web of Science, MEDLINE, EMBASE, Scopus, Iran MEDEX, Cochran database, and SID from conception to June 2023. Full-text case-control or cross-sectional studies were included in this study. Participants in the case group were children with ADHD aged 6-12 years. Review Manager Software (RevMan 5.4) was used for statistical analyses. Standardized mean differences (SMD) with 95% CIs were used to determine the differences between the two groups. Results: Six studies were included in the present meta-analysis. They included 982 children, of whom, 204 were girls and 744 were boys. The mean age of the children was 8.86±2.03 years. The level of vitamin B9 was significantly different between children with and without ADHD [SMD -0.80, 95% CI (-1.55, -0.04)]. Vitamin B12 was significantly lower in children with ADHD [SMD -0.29, 95% CI (-0.42, -0.16)]. However, due to high heterogeneity (I2 = 93%), sensitivity analysis was used, I2 fell to 21%, and significant difference was observed between the two groups [SMD -0.19, 95% CI (-0.34, -0.04)]. Conclusion: The results of this systematic review showed that the level of vitamins B9 and B12 in children with ADHD was significantly lower than that in healthy children.

The prevalence of anaemia in India remains high in children, especially those in rural areas, and in women of childbearing age, and its impairment of neurological development can have serious lifelong effects. It is concerning that the most recent official data (2019-21) indicate an increased prevalence compared with 2015-16. There is also considerable variability in childhood anaemia between Indian states with socioeconomic factors, such as wealth and education contributing to the risk of anaemia among adolescent women and their children. Dietary iron deficiency is often regarded as the main contributor to anaemia but increasing evidence accumulated from the authors\' ongoing literature database coupled with recent literature research suggests that it has a multifactorial aetiology, some of which is not related to nutrition. This narrative review focused on these multifactorial issues, notably the contribution of vitamin B12/folate deficiency, which also has a high prevalence in India. It was also noted that the dietary intake of bioavailable iron remains an important contributor for reducing anaemia, and the role of millets as an improved iron source compared to traditional staple cereals is briefly discussed. The overall conclusion is that anaemia has a multifactorial aetiology requiring multifactorial assessment that must include assessment of vitamin B12 status.

BACKGROUND: Gestational weight gain below or above the Institute of Medicine recommendations has been associated with adverse perinatal and neonatal outcomes. Very few studies have evaluated the association between serum and red blood cell folate concentrations and gestational weight gain in adolescents. Additionally, zinc deficiency during pregnancy has been associated with impaired immunity, prolonged labor, preterm and post-term birth, intrauterine growth restriction, low birth weight, and pregnancy-induced hypertension.
OBJECTIVE: The purpose of our study is to evaluate the association between serum concentrations of zinc, serum folate, and red blood cell folate, with the increase in gestational weight and the weight and length of the newborn in a group of adolescent mothers from Mexico City.
RESULTS: In our study, 406 adolescent-neonate dyads participated. The adolescents\' median age was 15.8 years old. The predominant socioeconomic level was middle-low (57.8%), single (57%), 89.9% were engaged in home activities, and 41.3% completed secondary education. Excessive gestational weight gain was observed in 36.7% of cases, while insufficient gestational weight gain was noted in 38.4%. Small for gestational age infants were observed in 20.9% of the sample. Low serum folate (OR 2.1, 95% CI 1.3-3.3), decreased red blood cell folate (OR 1.6, 95% CI 1.0-2.6), and reduced serum zinc concentrations (OR 3.3, 95% CI 2.1-5.2) were associated with insufficient gestational weight gain. Decreased serum zinc levels (OR 1.2, 95% CI 1.2-3.4) were linked to an increased probability of delivering a baby who is small for their gestational age.
CONCLUSIONS: Low serum folate, red blood cell folate, and serum zinc concentrations were associated with gestational weight gain and having a small gestational age baby. Both excessive and insufficient gestational weight gain, as well as having a small gestational age baby, are frequent among adolescent mothers.

Tetrahydrofolate is a cofactor involved in C1 metabolism including biosynthesis pathways for adenine and serine. In the classical tetrahydrofolate biosynthesis pathway, the steps removing three phosphate groups from the precursor 7,8-dihydroneopterin triphosphate (DHNTP) remain unclear in many bacteria. DHNTP pyrophosphohydrolase hydrolyzes pyrophosphate from DHNTP and produces 7,8-dihydroneopterin monophosphate. Although two structurally distinct DHNTP pyrophosphohydrolases have been identified in the intestinal bacteria Lactococcus lactis and Escherichia coli, the distribution of their homologs is limited. Here, we aimed to identify a third DHNTP pyrophosphohydrolase gene in the intestinal lactic acid bacterium Limosilactobacillus reuteri. In a gene operon including genes involved in dihydrofolate biosynthesis, we focused on the lreu_1276 gene, annotated as Ham1 family protein or XTP/dITP diphosphohydrolase, as a candidate encoding DHNTP pyrophosphohydrolase. The Lreu_1276 recombinant protein was prepared using E. coli and purified. Biochemical analyses of the reaction product revealed that the Lreu_1276 protein displays significant pyrophosphohydrolase activity toward DHNTP. The optimal reaction temperature and pH were 35°C and around 7, respectively. Substrate specificity was relatively strict among 17 tested compounds. Although previously characterized DHNTP pyrophosphohydrolases prefer Mg2+, the Lreu_1276 protein exhibited maximum activity in the presence of Mn2+, with a specific activity of 28.2 ± 2.0 µmol min-1 mg-1 in the presence of 1 mM Mn2+. The three DHNTP pyrophosphohydrolases do not share structural similarity to one another, and the distribution of their homologs does not overlap, implying that the Lreu_1276 protein represents a third structurally novel DHNTP pyrophosphohydrolase in bacteria.
OBJECTIVE: The identification of a structurally novel DHNTP pyrophosphohydrolase in L. reuteri provides valuable information in understanding tetrahydrofolate biosynthesis in bacteria that possess lreu_1276 homologs. Interestingly, however, even with the identification of a third family of DHNTP pyrophosphohydrolases, there are still a number of bacteria that do not harbor homologs for any of the three genes while possessing other genes involved in the biosynthesis of the pterin ring structure. This suggests the presence of an unrecognized DHNTP pyrophosphohydrolase gene in bacteria. As humans do not harbor DHNTP pyrophosphohydrolase, the high structural diversity of enzymes responsible for a reaction in tetrahydrofolate biosynthesis may provide an advantage in designing inhibitors targeting a specific group of bacteria in the intestinal microbiota.

Folate is an essential component of many metabolic processes, and folate deficiency is known to cause various disorders. Folate and folic acid, a synthetic and chemically stable form of folate, enriched diet are typically used to overcome this deficiency. Folic acid and folate however, are susceptible to harsh environment and folates enrichment using nanoparticles is an intensively studied strategy in food industry. This review highlights the current methods and types of matrices utilized to develop folic acid/folate carrying nanoparticles. The folic acid/folate loaded nanoparticles prevent cargo degradation during gut absorption and under harsh food processing conditions including, high temperatures, UV light, and autoclaving. The data demonstrates that nanofortifcation of folates using proteins and biopolymers effectively enhances the bioavailability of the cargo. The encapsulation of folic acid in biopolymers by emulsion, spray drying and ionic gelation represent simplistic methods that can be easily scaled up with applications in food industry.