Folate Nutrition Research Articles

Red blood cell folate level is associated with periodontitis in American adults: results from the NHANES 2009–2014

BackgroundRed blood cell (RBC) folate is an indicator of long-term folate nutrition. Whether there is an association between RBC folate and periodontitis is unclear. This study aimed to use the NHANES database to determine whether RBC folate is associated with moderate/severe periodontitis.MethodsA cross-sectional analysis of 10,151 participants in the NHANES database from 2009 to 2014 was performed. Multivariate logistic regression was used to analyze the independent relationship between RBC folate and moderate/severe periodontitis. The generalized additive model (GAM), restricted cubic splines (RCS), smooth curve fitting, and threshold effect analysis were used to explore the dose–response relationship and the potential nonlinear relationship between RBC folate and periodontitis. Finally, subgroup analysis and interaction tests were performed to determine the effect of covariates on the relationship between RBC folate and moderate/severe periodontitis.ResultsAfter adjusting for all confounders, there was a negative association between RBC folate concentration and moderate/severe periodontitis. The lowest fraction Q1 (< 360 ng/mL) of RBC folate concentration was used as the reference group, multivariable-adjusted ORs and 95% CIs of the second (360-463 ng/mL), third (464-569 ng/mL), fourth (570-732 ng/mL), and the highest quintile (> 733 ng/mL) categories were 0.88 (0.77, 1.01), 0.83 (0.72, 0.96), 0.77 (0.67, 0.90), 0.65 (0.56, 0.77) respectively. Additionally, a threshold nonlinear association was found between RBC folate (ng/mL) log2 transformation and moderate/severe periodontitis.ConclusionThis cross-sectional study revealed a negative relationship between RBC folate and moderate/severe periodontitis within a certain threshold range. Dentists and policymakers should pay closer attention to oral hygiene and health care for people with low or high RBC folate levels. Further causal and longitudinal research mechanisms are needed to validate our findings.

Protective effects of diversified diets for dietary folate adequacy and serum homocysteine in breastfeeding mothers amid historic drought.

The United Nations recommends that women consume ≥5 food groups, also known as the minimum dietary diversity score for women (MDD-W), for nutritional health. This is increasingly unattainable for populations in climate hot zones coping with food insecurity by prioritizing calories over dietary breadth. Breastfeeding mothers may be particularly vulnerable to adverse health impacts of low dietary diversity due to elevated nutritional requirements for lactation. We investigated how the protective effects of MDD-W for folate adequacy varies by MDD-W score and mother-infant life history characteristics. We conducted a secondary analysis of cross-sectional data from breastfeeding mothers (n = 228) in northern Kenya, surveyed during the 2006 Horn-of-Africa drought. Logistic regression models for adequate dietary folate (and vitamins B12 and B6) and normal homocysteine (folate-replete status) evaluated the effect of MDD-W alone and in interaction with infant/maternal characteristics. MDD-W (as ordinal or dichotomous variable) was positively associated with adequate folate (and vitamin B12). Having male infant was inversely associated with adequate dietary folate. MDD-W was generally unassociated with homocysteine. However, there was an interaction between MDD-W and sex of the infant. Namely, MDD-W ≥ 3 predicted increased probability of normal homocysteine among mothers with female infants but not male infants. Diets consisting of three or more food groups may protect adequate folate intake for many breastfeeding mothers. More research is needed to establish what level of dietary diversity would protect against hyperhomocysteinemia during breastfeeding and what factors promote or hinder the benefit of diversified diets on maternal folate nutrition.

Folate and vitamin B12 status and predicted neural tube defects risk among nonpregnant women of reproductive age from the Malawi National Micronutrient Survey, 2015-2016.

Maternal folate and vitamin B12 deficiency can lead to serious adverse pregnancy outcomes. There are no nationally representative estimates on folate and vitamin B12 status among women of reproductive age (WRA) in Malawi. We assessed folate and vitamin B12 status among nonpregnant WRA in Malawi and predicted the risk of folate-sensitive neural tube defects (NTDs) were they to become pregnant. Using data from the cross-sectional, nationally representative 2015-2016 Malawi Micronutrient Survey, we calculated the proportion of folate and vitamin B12 deficiency and insufficiency by demographic characteristics among 778 nonpregnant WRA (15-49 years). We predicted NTD prevalence using red blood cell (RBC) folate distributions and a published Bayesian model of the association between RBC folate and NTD risk. Analyses accounted for complex survey design. Among WRA, 8.5% (95% CI: 6.2, 11.6) and 13.3% (10.0, 17.4) had serum (<7 nmol/L) and RBC folate (<305 nmol/L) deficiency, respectively. The proportion of vitamin B12 deficiency (<148 pmol/L) and insufficiency (≤221 pmol/L) was 11.8% (8.6, 16.0) and 40.6% (34.1, 47.4), respectively. RBC folate insufficiency (<748 nmol/L, defined as the concentration associated with the threshold for elevated NTD risk: >8 cases per 10,000 births) was widespread: 81.4% (75.0, 86.4). The predicted NTD risk nationally was 24.7 cases per 10,000 live births. RBC folate insufficiency and higher predicted NTD risk were more common among WRA living in urban areas or with higher education. These findings highlight the importance of nutritional and NTD surveillance in Malawi and the opportunity for improving folate and vitamin B12 nutrition among Malawian WRA.

Update on the impact of voluntary folic acid fortification of corn masa flour on red blood cell folate concentrations-National Health and Nutrition Examination Survey, 2011-March 2020.

Folic acid is a micronutrient that is effective at preventing neural tube defects (NTDs). In 2016, the FDA authorized the voluntary fortification of corn masa flour (CMF) with folic acid to reduce disparities in NTDs among infants of women who do not regularly consume other fortified cereal grains, in particular Hispanic women of reproductive age (WRA). We analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to March 2020 assessing the impact of voluntary fortification of CMF on the folate status of Hispanic WRA. We analyzed folic acid usual intake and red blood cell (RBC) folate concentrations among non-pregnant, non-lactating Hispanic WRA, comparing pre-fortification (2011-2016) to post-fortification (2017-March 2020) data. RBC folate concentrations were used to create model-based estimation of NTD rates. The proportion of Hispanic WRA with folic acid usual intakes <400 μg/d did not change (2011-2016: 86.1% [95% Confidence Interval, CI: 83.7-88.5]; 2017-March 2020: 87.8% [95% CI: 84.8-90.7]; p = .38) nor did the proportion of Hispanic WRA with RBC folate below optimal concentrations (<748 nmol/L, 2011-2016: 16.0% [95% CI: 13.7-18.2]; 2017-March 2020: 18.1% [95% CI: 12.1-24.0]; p = 0.49). Model-based estimates of NTD rates suggest further improvements in the folate status of Hispanic WRA might prevent an additional 157 (95% Uncertainty Interval: 0, 288) NTDs/year. Voluntary fortification of CMF with folic acid has yet to have a significant impact on the folate status of WRA. Continued monitoring and further research into factors such as fortified product availability, community knowledge, and awareness of folic acid benefits would inform and improve future public health interventions.

Neurodevelopment with Low Nutritional Folate Increases Childhood Autism

Neurodevelopment with Low Nutritional Folate Increases Childhood Autism

Urinary Excretion of Deuterium-Labeled Folate and the Metabolite p-Aminobenzoylglutamate in Humans1–4

Stable isotopic methods were employed to determine the proportion of ingested folate excreted as the metabolite p-aminobenzoylglutamate (pABG, free and N-acetyl) in urine. Adult male subjects (n = 7) were maintained on a 4.54 mumol/d (2 mg/d) folate saturation regimen. After 7 d, subjects were given a mixed oral dose containing 0.67 mumol (300 micrograms) each of bideuterofolic acid (d2) and tetradeutero-folic acid (d4). Urine was collected for the following 48 h and analyzed for folate and pABG. The extent of deuterium labeling of urinary folate and pABG was determined by gas chromatography-mass spectrometry. Urinary total pABG excretion increased less than twofold as a result of the folate saturation, whereas urinary folate increased over 10-fold. Urinary d2 and d4 folates each contained 14-15% of the respective oral doses of labeled compounds, whereas urinary d2 and d4 pABG comprised only 0.98-1.15% of the labeled doses. Molar ratios (d2/d4) of excreted folate and pABG indicated that there was no in vivo isotopic discrimination between the labeled folates. Urinary pABG accounted for 5.1 +/- 0.6% of total ingested folate, whereas labeled pABG was about 6.7-7.6% of the excretion of labeled compounds (i.e., labeled folate + pABG). This study indicated that pABG is not a major excretory product during folate supplementation, but its relative importance may increase in conditions of reduced folate nutriture.

Folate Deficiency Is Spatially Dependent and Associated with Local Farming Systems among Women in Ethiopia

ABSTRACTBackgroundFolate is essential for the synthesis and integrity of DNA, normal cell formation, and body growth. Folate deficiency among women of reproductive age (WRA) increases the risk of poor birth outcomes including neural tube defect (NTD)-affected pregnancies. Folate status is largely dependent on dietary intakes.ObjectivesWe aimed to explore the spatial distribution of biomarkers of folate status and their association with farming systems among nonpregnant WRA in Ethiopia.MethodsSerum and RBC folate concentration data were derived from the Ethiopia National Micronutrient Survey of 2015. The spatial dependencies of folate concentration of WRA were investigated and its relation with the dominant local farming system was explored.ResultsThe median serum folate and RBC folate concentrations were 12.3 nmol/L and 567.3 nmol/L, respectively. The national prevalence of folate deficiency using homocysteine concentration as a metabolic indicator based on serum and RBC folate concentration was 11.6% and 5.7%, respectively. The majority of women (77.9%) had low RBC folate concentrations consistent with increased risk of NTD-affected pregnancies. Folate nutrition was spatially dependent at distances of ≤ 300 km. A marked variability in folate concentration was observed between farming systems: greater RBC folate concentration (median: 1036 nmol/L) was found among women from the Lake Tana fish-based system, whereas the lowest RBC folate concentration (median: 386.7 nmol/L) was observed in the highland sorghum chat mixed system.ConclusionsThe majority (78%) of WRA in Ethiopia had low folate status potentially increasing the risk of NTD-affected pregnancies. These findings may help national and subnational nutrition intervention strategies to target the most affected areas in the country.

Assessment of Baseline Nutritional Status, Vitamin B12, and Folate Levels in Patients with Acute Leukemia and Their Effect on Initial Treatment Outcome: A Prospective Observational Study

Abstract Introduction Poor nutrition is a common finding in patients with acute leukemia, affecting disease progression, treatment outcome, and survival. Overall nutritional status and micronutrients status evaluation may be an important step in management of acute leukemia. Objective The objective of this study was to investigate baseline nutritional status, vitamin B12, and folate levels in patients with acute leukemia at the time of admission before starting chemotherapy and their initial treatment outcome. Materials and Methods This was a prospective observational study. We assessed the pretreatment nutritional status of 73 patients by body mass index (BMI), serum vitamin B12 using a two-step chemiluminescent microparticle immunoassay, and serum folate using electrochemiluminescence by Cobas e411 analyzer before initiation of induction chemotherapy and evaluated for treatment response at the end of induction chemotherapy. Results Out of a total of 73 patients, 51 (69.8%) completed induction chemotherapy, 36 (49.3%) showed complete remission, and 15 (20.5%) were in incomplete remission. Of the remaining 22 (30.1%) patients, 11 (15.1%) died due to toxicity during therapy. The mean values of baseline BMI, serum vitamin B12, and folate was 20.46 kg/m2, 956.04, and 13.52 ng/mL, respectively. There was no significant association between vitamin B12 (p-value = 0.609) and folate (p-value = 0.404) deficiency and the response to treatment. Conclusion Baseline nutritional status, serum vitamin B12, and folate levels have no significant role in induction outcome in response to treatment, including mortality in patients with acute leukemia.

Folate content and retention in wheat grains and wheat-based foods: Effects of storage, processing, and cooking methods

Folates are essential micronutrients for human health. The aim of this study was to evaluate the effects of storage, processing and cooking methods on folate content and identify factors with great influence on folate retention in wheat grains and wheat-based foods. For this, the folate levels of wheat grains after 2–8 months of storage, wheat flours, noodles, fermented dough, steamed bun, and bread were sequentially analyzed. An average of 26% folate loss was observed after eight-month storage in wheat grains. The milling process, with an extraction rate of 70%, led to a severe (71%) folate loss. The folate retention rate in noodles was 78%. Fermentation by yeast production enabled a 1.5–4-fold enhancement of folate levels in steamed bun and bread. Boiling, steaming and baking led to a folate loss of 13%, 16%, and 11%, respectively. These results help to guide industrial/household preparation of wheat-based foods for folate nutrition.

Effect of folic acid supplementation during pregnancy on brain health of the child at 11 years: the FASSTT Offspring trial

AbstractPericonceptional folic acid (FA) has an established role in the prevention of neural tube defects (NTDs), leading to global recommendations for FA supplementation before and in early pregnancy. However, it is unclear whether there are any benefits for offspring brain health arising from continued maternal FA supplementation beyond the first trimester. The aim of this study was to investigate the role of maternal folate nutrition during pregnancy in relation to cognitive performance and brain function in the offspring at 11 years. The children of mothers who had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) were investigated, providing a unique opportunity to examine offspring brain health in relation to maternal folate (the FASSTT Offspring trial; n = 68). Cognitive performance was assessed using the Wechsler Intelligence Scale for Children, Fourth UK Edition (WISC-IV). The WISC-IV measures Full Scale IQ and specific domains of cognitive performance: Verbal Comprehension, Perceptual Reasoning, Working Memory and Processing Speed. Brain function was measured using magnetoencephalography (MEG) in a subset of the child participants (n = 33). The results showed no significant difference in Full Scale IQ between the children of mothers who had received folic acid versus placebo during pregnancy (P = 0.993). Processing Speed subtest scores were however significantly higher in the folic acid group compared with placebo (Symbol Search: P = 0.046 and Cancellation: P = 0.011). The application of MEG analysis showed that at rest, there were differences in brain functioning with significantly lower overall power at Broad band [1–48Hz] (P = 0.041) and a trend (not significant) towards lower power in all other frequency bands (Theta, Mu, Beta, Low Gamma and High Gamma) in children from the FA group compared with placebo. Results for the responses to the language task (congruent and incongruent sentences) in children from the FA group showed significantly lower power within the Theta band [4–8Hz] and significantly higher power within high frequency bands i.e. Beta [13–30 Hz] and High Gamma [49–70 Hz]. This suggested more efficient language processing abilities in these children compared to children of mothers in the placebo group. The findings provide scientific evidence that continuing FA supplementation beyond the periconceptional period that is protective against NTDs, may be beneficial for brain health in the offspring. Furthermore, this study demonstrates that MEG is a useful tool for objective assessment of functional brain activity in healthy children in response to nutrition intervention.

Maternal folate nutrition and offspring health: evidence and current controversies.

Periconceptional folic acid (FA) is known to have a protective effect in the prevention of neural tube defects (NTD), leading to global recommendations for FA supplementation before and in early pregnancy. Maternal folate throughout pregnancy may have other roles in offspring health, including neurodevelopment and cognitive performance in childhood. Folate is essential for C1 metabolism, a network of pathways involved in several biological processes including nucleotide synthesis, DNA repair and methylation reactions. The evidence reviewed here shows a conclusive role for offspring health of maternal folate nutrition in early pregnancy and probable benefits in later pregnancy. Folate-mediated epigenetic changes in genes related to brain development and function offer a plausible biological basis to link maternal folate with effects in offspring brain, albeit this research is in its infancy. Mandatory FA fortification of food has proven to be highly effective in decreasing NTD cases in populations where it has been implemented, but this policy is controversial owing to concerns related to potential adverse effects of over-exposure to FA. In the absence of population-wide fortification, and given the generally poor compliance with current FA recommendations, optimising folate status of mothers in very early pregnancy for protection against NTD remains challenging. Thus, current policy in the UK, Ireland and elsewhere in Europe for the prevention of NTD (based on periconceptional FA supplementation only), has proven to be largely ineffective. This review addresses the evidence and the controversies that surround this area, as well as identifying the challenges in translating policy into practice.

Folate Nutrition Status in Mothers of the Boston Birth Cohort, Sample of a US Urban Low-Income Population.

To examine maternal folic acid supplementation and plasma folate concentrations in the Boston Birth Cohort, a predominantly urban, low-income, minority population in Boston, Massachusetts. This report includes 7612 mothers with singleton live births (3829 Black, 2023 Hispanic, 865 White, and 895 others) enrolled in the Boston Birth Cohort at the Boston Medical Center, during 1999 to 2014. Folic acid supplementation during preconception and each trimester was obtained via interview questionnaire. In a subset (n = 2598), maternal plasma folate concentrations were measured in blood samples drawn within a few days of delivery. The percentage of mothers taking folic acid supplementation almost daily during preconception and the first, second, and third trimesters were 4.3%, 55.9%, 59.4%, and 58.0%, respectively. Most striking, we observed a wide range of maternal plasma folate concentrations, with approximately 11% insufficient (< 13.4 nmol/L) and 23% elevated (> 45.3 nmol/L). Findings indicate that fewer than 5% of mothers in the Boston Birth Cohort started folic acid supplements before pregnancy, and approximately one third of mothers had either too low or too high plasma folate levels, which may have important health consequences on both the mother and the child.

Folate Deficiency Facilitates Genomic Integration of Human Papillomavirus Type 16 DNA In Vivo in a Novel Mouse Model for Rapid Oncogenic Transformation of Human Keratinocytes

Epidemiologic and in vitro studies suggest independent linkages between poor folate and/or vitamin B-12 nutrition, genomic human papillomavirus (HPV) type 16 viral integration, and cancer. However, there is no direct evidence in vivo to support the causative role of poor folate nutrition in HPV16 integration into the cellular genome. We tested the hypothesis that folate deficiency enables the integration of HPV16 into the genome of HPV16-harboring keratinocytes, and could thereby influence earlier transformation of these cells to cancer in an animal model. HPV16-harboring human keratinocytes [(HPV16)BC-1-Ep/SL] were differentiated into 3-dimensional HPV16-organotypic rafts under either folate-replete or folate-deficient conditions in vitro. These were then subcutaneously implanted in severely immunocompromised female Beige Nude XID (Hsd: NIHS-LystbgFoxn1nuBtkxid) mice (4-6 wk old, 16-18 g) fed either a folate-replete diet (1200 nmol folate/kg diet) or a progressively folate-deficient diet (600 or 400 nmol folate/kg diet) for 2 mo prior to raft-implantation surgery, and indefinitely thereafter. The tumors that subsequently developed were characterized for onset, pattern of growth, morphology, HPV16 oncogene expression, and HPV16-genomic integration. All HPV16-organotypic rafts developed in either folate-replete or physiologic low-folate media in vitro and subsequently implanted in folate-replete mice eventually transformed into aggressive malignancies within weeks. When compared to HPV16-high folate-organotypic raft-derived tumors from mice fed either a 1200 or 600 nmol folate/kg diet, those raft-derived cancers that developed in mice fed a 400 nmol folate/kg diet expressed significantly more HPV16 E6 (1.8-fold more) and E7 (2.8-fold more) oncogenic proteins (P=0.001), and revealed significantly more HPV16-integration sites in genomic DNA (2-fold more), either directly into, or in the vicinity of, cellular genes (P<0.05). This unprecedented animal model for the consistent rapid transformation of differentiated (HPV16)BC-1-Ep/SL-derived organotypic raft-keratinocytes to cancer in Beige Nude XID mice confirms that dietary folate deficiency can profoundly influence and modulate events leading to HPV16-induced carcinogenesis, and facilitates genomic integration of HPV16 DNA in vivo.

Recent Developments in Folate Nutrition.

The term folate (vitamin B9) refers to a group of water-soluble compounds that are nutritionally essential for the support of optimal human health and development. Folates participate in numerous one-carbon transfer reactions, including the methylation of important biomolecules (lipids, amino acids, DNA). A deficiency of folate leads to pathological outcomes including anemia and impairments in reproductive health and fetal development. Due to the linkage of impaired folate status with an increased prevalence of neural tube defects (NTDs) in babies, several jurisdictions required the fortification of the food supply with folic acid, a synthetic and stable form of folate. Data from the postfortification era have provided strong evidence for the reduction of NTDs due to folic acid fortification. However, concern is now growing with respect to the amount of synthetic folic acid within the human food supply. Excess folic acid intake has been linked to a masking of vitamin B12 deficiency, and concerns regarding the promotion of folate-sensitive cancers, including colorectal cancer. New strategies to ensure the supply of optimal folate to at-risk populations may be needed, including the use of biofortification approaches, in order to address recent concerns.

The impact of nutritional vitamin B12, folate and hemoglobin deficiency on school performance of elementary school children

Deficiencies of nutrients such as vitamin B12, folic acid and iron are frequently associated with impairment of memory, concentration and learning ability. Deficiencies of these micronutrients are very rare in Western countries, whereas they are common in developing countries. This study was carried out to determine the impact of vitamin B12 deficiency, folic acid deficiency and/or anemia on the academic achievement of elementary school children from a low socio-economic population, i.e., impoverished Bedouin population living in southern Israel. Sixty-seven elementary school children, nine to eleven years of age, were randomly tested. Serum levels of vitamin B12, folic acid, and hemoglobin were measured using automated chemiluminescence systems. An individual questionnaire was filled out for each student, which included information on number of meat meals consumed per week, the number of people in the family and information about the father's employment status. Significant positive correlations were observed between number of meat meals consumed per week and low vitamin B12 levels and attainment of low marks in school, respectively. There was a negative correlation between the total number of family members and the attainment of low marks in school. No correlation between anemia or low folic acid levels and school performance was observed. Despite the small sample number, results indicated a high prevalence of vitamin B12 deficiency among these elementary school children, which could be linked to inadequate meat meal intake. This ultimately affected school performance of these children.

U.S. women of childbearing age who are at possible increased risk of a neural tube defect-affected pregnancy due to suboptimal red blood cell folate concentrations, National Health and Nutrition Examination Survey 2007 to 2012.

Red blood cell (RBC) folate concentrations are a potential biomarker of folate-sensitive neural tube defect (NTD) risk in the population. The purpose of this analysis was to describe women in the U.S. population with RBC folate concentrations below those associated with optimal NTD prevention. We used data from the 2007 to 2012 National Health and Nutrition Examination Survey (NHANES) to assess the RBC folate status of U.S. women of childbearing age relative to risk categories for NTD risk based on RBC folate concentrations. We defined suboptimal RBC folate concentrations as those associated with a prevalence of ≥9 NTDs per 10,000 live births. Among nonpregnant women age 12 to 49 years, 22.8% (95% Confidence Interval: 21.1, 24.6) had suboptimal RBC folate concentrations. Women had greater odds of having a suboptimal RBC folate concentration if they did not use dietary supplements containing folic acid; had mandatorily fortified enriched cereal grain products as their only source of folic acid; were non-Hispanic black or Hispanic; or were current smokers. Based on RBC folate concentrations, we would predict that the majority of U.S. women of reproductive age are not at increased risk for folate sensitive NTDs in the presence of mandatory folic acid fortification. Prevention policies and programs can be aimed at population subgroups identified as having higher predicted risk for folate-sensitive NTDs based on RBC folate concentrations.

Gene-Nutrient Interaction between Folate and Dihydrofolate Reductase in Risk for Adenomatous Polyp Occurrence: A Preliminary Report.

Folate and related gene variants are significant risk factors in the aetiology of colorectal cancer. Dihydrofolate reductase (DHFR) is critical in the metabolism of synthetic folic acid (pteroylmonoglutamatamic, PteGlu) to tetrahydrofolate following absorption. Therefore, the 19bp deletion variant of DHFR may lead to the alteration of folate-related colorectal disease susceptibility. This study examined the association between PteGlu and 19bp del-DHFR, and adenomatous polyp (AP) occurrence, an antecedent of colorectal cancer. A total of 199 subjects (162 controls and 37 AP cases) were analysed to determine dietary intake of total folate, natural methylfolate and synthetic PteGlu, level of erythrocyte folate and plasma homocysteine (tHcy), and genotype of 19bp del-DHFR. Dietary folate intake, erythrocyte folate, tHcy and 19bp del-DHFR variants did not independently predict the occurrence of AP. However, a gene-nutrient interaction was observed when subjects were stratified according to dietary folate intake. In subjects with a folate intake above the median value due to significant dietary PteGlu content, the presence of the 19bp-deletion allele decreased the risk for AP (OR=0.35, 95% CI: 0.13-0.97). However, such association was not evident in individuals with a folate intake below the median value. In conclusion, the finding suggests that folate nutrition and 19bp del-DHFR variation may interact to modify AP risk.

Nutritional B vitamin deficiency alters the expression of key proteins associated with vascular smooth muscle cell proliferation and migration in the aorta of atherosclerotic apolipoprotein E null mice.

Low B vitamin status is linked with human vascular disease. We employed a proteomic and biochemical approach to determine whether nutritional folate deficiency and/or hyperhomocysteinemia altered metabolic processes linked with atherosclerosis in ApoE null mice. Animals were fed either a control fat (C; 4% w/w lard) or a high-fat [HF; 21% w/w lard and cholesterol (0/15% w/w)] diet with different B vitamin compositions for 16weeks. Aorta tissue was prepared and global protein expression, B vitamin, homocysteine and lipoprotein status measured. Changes in the expression of aorta proteins were detected in response to multiple B vitamin deficiency combined with a high-fat diet (P<0.05) and were strongly linked with lipoprotein concentrations measured directly in the aorta adventitia (P<0.001). Pathway analysis revealed treatment effects in the aorta-related primarily to cytoskeletal organisation, smooth muscle cell adhesion and invasiveness (e.g., fibrinogen, moesin, transgelin, vimentin). Combined B vitamin deficiency induced striking quantitative changes in the expression of aorta proteins in atherosclerotic ApoE null mice. Deregulated expression of these proteins is associated with human atherosclerosis. Cellular pathways altered by B vitamin status included cytoskeletal organisation, cell differentiation and migration, oxidative stress and chronic inflammation. These findings provide new insight into the molecular mechanisms through which B vitamin deficiency may accelerate atherosclerosis.

Haematological implications of folate food fortification

Reports from some Western countries indicate that mandatory folate food fortification (FFF) has substantially reduced the prevalence of folate deficiency, leading to calls for folate testing following FFF to be limited to specific indications such as macrocytic anaemia. This is premature for low-income countries, where folate deficiency is predominantly the result of poor intake coupled with the increasing demand in pregnancy. There is also evidence that HIV infection is prejudicial to folate nutrition, and low-income HIV-infected women and their offspring could be among the most susceptible to folate deficiency. In assessing folate nutrition, the value of serum folate has been compromised by FFF, and both serum and red cell folate are necessary for optimal assessment of folate status. Although the limited data available suggest that large-scale masking of vitamin B12 deficiency by FFF has not occurred, it has been suggested that B12 be incorporated into folate-fortified foods. However, significant B12 deficiency is usually due to malabsorption, and physiological doses added to food would be of questionable value because they would not be absorbed. Extensive work, especially randomised clinical trials, must be done before dietary intervention with B12 on a national scale can be justified.

Interrelationships among genetic C677T polymorphism of 5,10‐methylenetetrahydrofolate reductase, biochemical folate status, and lymphocytic p53 oxidative damage in association with tumor malignancy and survivals of patients with hepatocellular carcinoma

Metabolic genotypes of 5,10-methylenetetrahydrofolate reductase (MTHFR) and folate status on oxidative DNA lesions in hepatocellular carcinoma (HCC) has not been elucidated. The aims of the study were to investigate the folate-polymorphic interactions on genetic oxidative damage in association with advanced HCC malignancy and prognosis. The study included 232 HCC patients with folate nutrition, MTHFR C677T polymorphic, p53 genetic and tumour pathological data collected and analyzed for their survivals after a 7.8-years following up. By adjustment for oxidative risk factors of HCC, the compound CT and TT genotypes in relative to the CC wild-type were associated with 83% reduced lymphocytic p53 oxidative lesions of HCC patients with RBC folate lower than 688ng/mL (OR: 0.17, 95%CI: 0.07-0.43). Such genetic protective effects by the CT/TT genotypes were 2-fold enhanced among those with high RBC folate (OR: 0.08, 95% CI: 0.03-0.21, P for interaction < 0.001). For those with non-folate-deficient status, the compound CT and TT vs. CC genotypes were associated with 80% reduced risks of advanced HCC stages (III&IV) (OR: 0.2, 95%CI: 0.08-0.56). Such protection was negated either by adjustment of lymphocytic p53 oxidative lesions or by 3-fold increased risks among those with high RBC status (OR: 0.6, 95%CI; 0.31-1.41, P for interaction = 0.009). Multivariate Cox proportional hazards analysis showed that the CT/TT genotypes vs. CC wild-type were the independent predictable factor for better survival outcome of HCC patients (HR: 0.48, CI = 0.30-0.79). For CC homozygote, the second vs. the bottom tertile levels of RBC status were associated with 2-fold increased mortality rate of HCC patients (HR: 2.05, CI = 1.0-4.1). Our data demonstrated that reduced MTHFR activities associated with the MTHFR T allele may interact with RBC folate as the risk modifiers of lymphocytic p53 oxidative lesions of HCC patients. The CT/TT genotypes correlated with lower risks of late-stage HCC and a favorable survival of HCC patients, depending on p53 oxidative lesions or RBC folate status.