Folate Bioavailability Research Articles

High Bioavailability of Spinach Folate Evaluated by Functional Biomarkers in a Folate Depletion-Repletion Mouse Model.

The bioavailability of natural folates is 50% lower than that of synthetic folic acid (FA); however, it remains unclear whether this value is universally applicable to all foods. Therefore, the present study investigated the bioavailability of folate from spinach using multiple biomarkers in a folate depletion-repletion mouse model. Mice were fed a folate-deficient diet for 4 wk and subsequently divided into three groups: folate-deficient, FA, and spinach folate. The folate repletion group received either FA or spinach folate at 2 mg/kg diet for 9 d. On the 7th day of repletion, half of each group underwent low-dose total body X-ray irradiation to induce chromosomal damage in bone marrow. Folate bioavailability biomarkers included measurements of folate levels in plasma, liver, and bone marrow along with an analysis of plasma homocysteine levels and chromosome damage, both of which are functional biomarkers of body folate. The consumption of a folate-deficient diet led to decreased tissue folate levels, increased plasma homocysteine levels, and chromosomal damage. Repletion with spinach folate restored folate levels in plasma, liver, and bone marrow to 69, 13, and 68%, respectively, of FA levels. Additionally, spinach folate repletion reduced plasma homocysteine levels and chromosome damage to 83% and 93-117%, respectively, of FA levels. Collectively, the present results demonstrated that the bioavailability of spinach folate exceeded 83% of FA, particularly when assessed using functional biomarkers.

Assessing a Fermented Whey Beverage Biofortified with Folate as a Potential Folate Source for Humans.

Folate, a vital water-soluble vitamin (B9), requires specific attention as its recommended daily intake frequently is not reached in countries without mandatory fortification. In this regard, biofortification with microorganisms like Bifidobacterium and Streptococcus offers a compelling approach for enhancing food with natural folates. A randomized, nonblinded, and monocentric human pilot study is conducted to assess the bioavailability of a folate-biofortified fermented whey beverage, comprising 3 intervention days and a controlled replenishment phase before and during the assay. Folate plasma concentration (5-CH3-H4folate) is determined using a stable isotope dilution assay and LC-MS/MS detection. Biokinetic parameters (cmax and tmax) are determined, and areas under the curve (AUC) normalized to the basal folate plasma concentration are calculated. An average bioavailability of 17.1% in relation to the 5-CH3-H4folate supplement, ranging from 0% to 39.8%, is obtained. These results reiterate the significance of additional research into folate bioavailability in general and dairy products. Further investigations are warranted into folate-binding proteins (FBP) and other potential limiting factors within the food and individual factors. In summary, biofortification via fermentation emerges as a promising avenue for enhancing the natural folate content in dairy and other food products.

In vivo determination of the bioavailability of folic acid through the utilization of the PBPK model in conjunction with UPLC

This paper employed a physiologically based pharmacokinetic model (PBPK) to investigate the transformations of folic acid and its metabolites in vivo. Additionally, an ultra-performance liquid chromatography (UPLC) method was developed to accurately measure the body's retention rate and conversion rate of folic acid, tetrahydrofolate, and 5-methyltetrahydrofolate. Furthermore, the bioavailability of folic acid in the body was assessed by combining this method with an evaluation technique for animal models. The study found that the gastric metabolism time was 2 h, while the small intestinal metabolism duration was 4 h. The maximum conversion rate was observed in plasma and liver after 6 h, and in the brain after 8 h. This serves as a framework for creating a model to assess the bioavailability of folic acid in living organisms, to enhance the safety and efficacy of folic acid intake.

Evaluation of In Vivo Folic Acid Bioavailability in Different Mouse Strains Using Enzymatic Digestion Combined with Ultra Performance Liquid Chromatography.

By analyzing the folic acid content of various mouse strains through the use of in vivo studies, this study sought to determine whether folic acid bioavailability varies between hosts. In order to examine the stability of folic acid in the gastrointestinal tract, the rate at which it enters the blood, its retention in the organs, and its entry into the brain, folic acid was gavaged for 10 days into male and female mice of the following four strains: C57BL/6, BALB/c, ICR, and Kunming. Folic acid was extracted from eight groups of mice via solid phase extraction and triple enzyme extraction; the folic acid was subsequently quantified by ultraperformance liquid chromatography. In contrast to the other groups, female C57BL/6 mice exhibited substantially greater bioavailability as well as variations in organ retention and blood entry rates, as indicated by the experimental findings. This finding indicated that using female C57BL/6 mice to evaluate the bioavailability of folic acid is more effective.

Safety of monosodium salt of l-5-methyltetrahydrofolic acid as a novel food pursuant to Regulation (EU) 2015/2283 and the bioavailability of folate from this source in the context of Directive 2002/46/EC, Regulation (EU) No 609/2013 and Regulation (EC) No 1925/2006.

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on monosodium salt of l-5-methyltetrahydrofolic acid (5-MTHF) as a novel food (NF) pursuant to Regulation (EU) 2015/2283 and to address the bioavailability of folate from this source in the context of Directive 2002/46/EC, Regulation (EU) No 609/2013 and Regulation (EC) No 1925/2006. The NF is produced by chemical synthesis and consists of at least 95% (w/w) of 5-MTHF and 4%-5% (w/w) of sodium. It is proposed to be used as a partial or complete substitute to folic acid and other sources of added folate in a number of food categories. The production process, composition, specifications and stability of the NF do not raise safety concerns. When used as an ingredient in different food matrices, proper processing/storage conditions need to be considered to preserve the stability of the NF. Regarding bioavailability, the Panel considers that the NF readily dissociates into Na and l-methylfolate ions, which subsequently are absorbed and enter the circulation. Thus, the bioavailability of 5-MTHF from the NF is comparable to that of other currently authorised salts of 5-MTHF. The Panel considers that the consumption of the NF is not nutritionally disadvantageous as long as the combined intake of the NF and the other supplemental forms of folate under their authorised conditions of use is below the ULs established for the different age groups of the general population. The Panel concludes that the NF is safe under the proposed conditions of use. The Panel also concludes that the NF is a source from which folate is bioavailable.

The evolution of folate supplementation - from one size for all to personalized, precision, poly-paths.

Folate is a crucial nutrient that supports physiological functions. Low folate levels is a risk factor for several diseases, including cardiovascular diseases and neural tube defects. The most used folate supplement is folic acid, a synthetic oxidative form, and folic acid grain fortification is a success story of public health. However, the metabolic conversion of folic acid to bioactive tetrahydrofolate requires several enzymes and cofactors. Therefore, these factors influence its bioavailability and efficacy. In contrast, 5-methyltetrahydrofolate is used directly and participates in one-carbon metabolism, and the use of 5-methyltetrahydrofolate as an alternative folate supplement has increased. The metabolism of 5-methyltetrahydrofolate is primarily dependent on the transmembrane transporter, reduced folate carrier (RFC), and the RFC gene SLC19A1 variant is a functional polymorphism that affects folate status indexes. Recent studies demonstrated that the expression of RFC and cystathionine β-synthase, another enzyme required for homocysteine clearance, increases significantly by supplementation with calcitriol (vitamin D3), suggesting that calcitriol intake promotes the bioavailability of folate and has synergistic effects in homocysteine clearance. The advancements in biomedical and cohort studies and clinical trials have enhanced our understanding of the critical roles of folate and the regulation of one-carbon metabolism. We anticipate that the field of folate supplementation is poised to evolve from one size for all to personalized, precision, poly-paths (3Ps), which is a critical measure to meet individual needs, maximize health benefits, and minimize side effects.

Folic Acid and Its Role in Oral Health: A Narrative Review

Vitamins, exogenous organic compounds that play a vital role in metabolic reactions, and fundamental powerful antioxidants with a crucial role in the genetic transcription process, are considered essential nutritional factors. Folic acid (FA), also known as folate, or Vitamin B9, plays an indispensable role in various intracellular reactions, being the main pawn, with a strong impact on medical and dental science. The aim of this paper mainly focuses on presenting the latest and most advanced aspects related to the following topics: (1) the resonance that FA, and more specifically FA deficiency, has at the level of the oral cavity; (2) the elements involved in the molecular landscape, which reflect the interaction and the possible mechanisms of action, through which FA influences oral health; and (3) the particular processes by which FA deficiency causes certain clinical conditions. Moreover, we aim to draw the attention and trigger the curiosity of health professionals on the need to know the specific host–environment interactions, particularly the linkage between individual genotype and phenotypic variability, which in the future could represent the basis of novel and effective treatment methods. From this perspective, we begin by providing an overview of the general radar echo of the human body induced by FA deficiency, before focusing on the genetic strategic substrate and biochemical processes involved in the molecular mechanisms through which FA acts at the cellular level. Finally, we reflect on the resulting conclusions: (1) the complex interrelationships between different types of cytokines (CKs) and abnormal folate metabolism are involved in the occurrence of neural tube defects (NTDs) and orofacial clefts (OFCs); (2) increased oxidative stress, endothelial dysfunction, and genomic instability, induced by folate deficiency, have a major impact on periodontal health; and (3) glutamate carboxypeptidase II, GCP2 1561C>T allelic variant, constitutes the main pawn, which specifically influences the bioavailability of natural folates and FA, as the main actors, with essential roles in oral health.

Folate supplementation as a strategy to reduce Neural Tube Defects

Folic acid is a vitamin known to prevent neural tube defects, megaloblastic anaemia, cardiovascular morbidity and mortality, etc. The main natural sources of folate are plant and vegetables e.g. green leafy vegetables, broccoli, asparagus, citrus fruits (orange, strawberry), beans, nuts, cauliflowers, beets, corn etc. and meat products like liver. The primary function of folate is its contribution in the synthesis and repair of the DNA. The bioavailability of food folate is approximately 50%. The bioavailability of folic acid taken with meal compared to with water on empty stomach is 85% and 100% respectively.(1) Hence, it is easier to achieve the recommended daily allowances with fortified food as compared to natural food due to higher stability and bioavailability of synthetic folate when compared to natural food.(2)

Women Taking a Folic Acid Supplement in Countries with Mandatory Food Fortification Programs May Be Exceeding the Upper Tolerable Limit of Folic Acid: A Systematic Review.

Background: In preconception and pregnancy, women are encouraged to take folic acid-based supplements over and above food intake. The upper tolerable limit of folic acid is 1000 mcg per day; however, this level was determined to avoid masking a vitamin B12 deficiency and not based on folic acid bioavailability and metabolism. This review’s aim is to assess the total all-source intake of folate in women of childbearing age and in pregnancy in high-income countries with folate food fortification programs. Methods: A systematic search was conducted in five databases to find studies published since 1998 that reported folate and folic acid intake in countries with a mandatory fortification policy. Results: Women of childbearing age do not receive sufficient folate intake from food sources alone even when consuming fortified food products; however, almost all women taking a folic acid-based supplement exceed the upper tolerable limit of folic acid intake. Conclusions: Folic acid supplement recommendations and the upper tolerable limit of 1000 mcg set by policy makers warrant careful review in light of potential adverse effects of exceeding the upper tolerable limit on folic acid absorption and metabolism, and subsequent impacts on women’s health during their childbearing years.

Role of fermented goat milk as a nutritional product to improve anemia.

Goat milk, like cow milk, needs some modifications to be used as the sole source of nutrition during early infancy. For goat milk to be more like human milk and more nutritionally complete, sugar, vitamins and minerals need to be added to it and for reduction of renal solute load, it needs to be diluted. To prevent megaloblastic anemia in infants fed exclusively on goat milk, folic acid should be supplied either by adding it to goat milk or by an oral folic acid supplement. In fortification of milk products, thermal processing, fermentation, and species differences in milk folate bioavailability are three additional factors that should be considered besides absolute difference in folate concentration between goat and human milk. Whether different feeding regimes (e.g., iron and folate content of diets) influence milk folate content needs to be elucidated by more research. Our findings showed that fermented goat milk during anemia recovery can be improve antioxidant status, protection from oxidative damage to biomolecules, protective effects on testis, improve Fe and skeletal muscle homeostasis as well as improve cardiovascular health. PRACTICAL APPLICATIONS: To be used as part of a postweaning nutritionally well-balanced diet, fermented goat milk is most likely an excellent source of nutrition for the human.

Effects of Simulated Weightlessness on Metabolizing Enzymes and Pharmacokinetics of Folic Acid in SD Rats.

Folic acid (FA) affect human physiology and drug metabolism. Up to now, the effect of microgravity on the pharmacokinetics of FA remains unclear. The pharmacokinetics of FA in Sprague-Dawley (SD) rats are laying a foundation for safe medicine administration of astronauts. Proteins expression of such FA metabolic enzymes as Methyltetrahydrofolate reductase (MTHFR), Cystathionine beta synthase (CBS) and Methionine synthase (MS) in a variety of organs was analyzed with Western-Blot, and mRNA expression was detected by RT-PCR. The plasma concentration-time profile of FA in normal or tail-suspended SD rats was acquired by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after oral administration of FA. Area under curve (AUC) and Cmax of FA in SD rats decreased significantly with extending period of tail-suspension. In terms of expressed level of metabolic enzymes over four suspension terms, as well as the level of the corresponding mRNAs, the following regularities were found: an obvious sharp decline of MTHFR tissue in kidney, a time-dependent increase of CBS in liver tissue and duodenum tissues, the resemblance of MS fluctuation to that of CBS in tested tissues. A four-week simulated microgravity of SD rats exhibits an unequivocal diminish of bioavailability of FA, and simulated microgravity shows a varying effect on the expression of FA-metabolizing enzyme in a variety of tissues.

Absorption of Folic Acid from Different Delivery Forms: A Randomized, Crossover Study

Abstract Objectives Folate, or folic acid, is a water-soluble B vitamin that plays a role in single carbon transfer reactions, which are involved in the synthesis and metabolism of nucleotides and amino acids. It has been established that adequate folic acid intake helps decrease the prevalence of neural tube defects during conception and early pregnancy. The objective of this study was to assess the bioavailability of folic acid from Prenatal Multi Gummies and Folic Acid tablets in women of childbearing age. Methods Eleven healthy, adult, premenopausal women of childbearing age (18–44 years) were recruited for a single-blind, randomized, crossover study. Each participant was randomly assigned to receive a single dose (2 gummies or 2 tablets) of Prenatal Multi Gummies or Folic Acid tablets (containing ∼800 µg folic acid) and then crossed over to receive the other study product after a wash-out period of ∼7 days. The study product was consumed along with a low folic acid breakfast meal. Blood samples were collected for the analysis of serum folate at t = −0.5, 1, 2, 4, 6 and 8 hours where t = 0 is the time of study product consumption. Results The mean serum folate total area under the curve (AUC0–8 hours) was 239.67 ± 24.50 h × ng/mL for the Prenatal Multi Gummies and 255.23 ± 30.17 h × ng/mL for the Folic Acid tablets. For both study products, the dose-adjusted net incremental AUC was significantly greater than 0 h × ng/mL (P ≤ 0.001). The maximum serum folate concentration (Cmax) was 47.69 ± 5.65 ng/mL for the Prenatal Multi Gummies and 52.45 ± 5.86 ng/mL for the Folic Acid tablets, and the median time to maximum serum concentration (Tmax) was 1.00 h for each product (interquartile limits for both included 1.00 to 1.08 hours). Conclusions In conclusion, folic acid contained in the Prenatal Multi Gummies and Folic Acid tablets was absorbed from both the Prenatal Multi Gummies and the Folic Acid tablets. Funding Sources This study was funded by Pharmavite LLC.

Food matrix structure (from Biscuit to Custard) has an impact on folate bioavailability in healthy volunteers.

We examined the impact of matrix food structure on post-prandial folate bioavailability (and other macronutrients) in human volunteers using a randomized, controlled, crossover experimental design. Twelve healthy male volunteers (22.6 ± 0.4years old) were offered four food models (differing in matrix structure: Custard, Pudding, Sponge cake and Biscuit) to which 1mg of folic acid was added, according to a randomized, controlled, crossover experimental design. Plasma folates, glucose, insulin, alpha amino nitrogen and triglycerides were measured over the post-prandial period (from T0 to T480min). Food matrix structure was capable of altering folate plasma availability. The highest folate availability was observed for pudding and to a lesser extent Sponge cake whereas the lowest was for the two matrices presenting extreme rheological properties: Custard (liquid) (P < 0.05 total AUC) and to a lesser extent Biscuit (hard solid) (P < 0.05, AUC 180min). The analysis of plasma kinetics of appearance of other nutrients/metabolites helps to understand/explain the lower bioavailability of folates in Custard and Biscuit. A least overall efficient bio-accessibility of all macronutrients and folic acid is observed in the gut lumen for Biscuit (delayed/incomplete destructuration of biscuit along the digestive tract). On the contrary, the lower folic acid absorption observed with custard does not fit with the rapid plasma appearance of other nutrients and should require further investigation.

The MTHFR 677C>T polymorphism is associated with unmetabolized folic acid in breast milk in a cohort of Canadian women

Maternal nutrition and genetics are determinants of breast-milk nutrient composition and, as such, are determinants of the nutritional exposure of breastfed infants. The aim of this study was to determine whether common maternal single nucleotide polymorphisms (SNPs) in folate-dependent enzymes are associated with breast-milk folate content in a cohort of mothers enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) study. The MIREC study is a Canadian prospective pregnancy cohort study that recruited 2001 participants between 2008 and 2011. Five folate-related SNPs-MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTHFR 1793G>A (rs2274976), MTR 2756A>G (rs1805087), and MTRR 66A>G (rs1801394)-were genotyped. Breast milk was sampled ∼1 mo postpartum, and tetrahydrofolate (THF), 5-methyl-THF, 5-formyl-THF, 5,10-methenyl-THF, and unmetabolized folic acid (UMFA) were measured using liquid chromatography-tandem mass spectrometry in a subset of participants (n=551). Associations were assessed using Wald's test. Associations were considered significant if P≤0.01 (Bonferroni correction for multiple testing). None of the SNPs were associated with total breast-milk folate. However, the MTHFR 677C>T SNP was associated with breast-milk UMFA (R2=0.01; unadjusted P=0.004), explaining a small portion of total variance; this association remained significant when adjusted for other covariates, including supplemental folic acid consumption. The MTHFR 1793G>A and MTRR 66A>G SNPs tended to be associated with 5-methyl-THF (R2=0.008, P=0.04) and reduced folates (THF+5-methyl-THF+5-formyl-THF+5,10-methenyl-THF; R2=0.01, P=0.02), respectively. We found that total breast-milk folate content was not associated with any of the folate-related SNPs examined. The association between the MTHFR 677C>T SNP and breast-milk UMFA, albeit modest, highlights the need to better understand the determinants of breast-milk folate and the impact they might have on milk folate bioavailability.

Addressing optimal folate and related B-vitamin status through the lifecycle: health impacts and challenges.

The functional effects of folate within C1 metabolism involve interrelationships with vitamin B12, vitamin B6 and riboflavin, and related gene-nutrient interactions. These B vitamins have important roles throughout life, from pregnancy, through childhood, to middle and older age. Achieving optimal nutritional status for preventing folate-related disease is challenging, however, primarily as a result of the poor stability and incomplete bioavailability of folate from natural food sources when compared with the synthetic vitamin form, folic acid. Thus, in European countries, measures to prevent neural tube defects (NTD) have been largely ineffective because of the generally poor compliance of women with folic acid supplementation as recommended before and in early pregnancy. In contrast, countries worldwide with mandatory folic acid fortification policies have experienced marked reductions in NTD. Low vitamin B12 status is associated with increased risk of cognitive dysfunction, CVD and osteoporosis. Achieving optimal B12 status can be problematic for older people, however, primarily owing to food-bound B12 malabsorption which leads to sub-clinical deficiency even with high dietary B12 intakes. Optimising B-vitamin intake may be particularly important for sub-populations with impaired folate metabolism owing to genetic characteristics, most notably the 677C→T variant in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR). This common folate polymorphism is linked with several adverse health outcomes, including stroke, however, recent evidence has identified its novel interaction with riboflavin (the MTHFR cofactor) in relation to blood pressure and risk of developing hypertension. This review addresses why and how the optimal status of folate-related B vitamins should be achieved through the lifecycle.

Iron and Folic Acid Bioavailability from a Multivitamin Tablet Following a Single Dose and After 28 Days of Supplementation (P24-010-19)

ObjectivesTo determine the bioavailability of folic acid and iron from a multivitamin tablet formulation following a single dose and 28 days of supplementation. MethodsThe tablet formulation included iron (ferrous fumarate, 18 mg) and folic acid (400 mcg) plus 21 additional nutrients; Cmax and Tmax were determined. For the single dose study, subjects (n = 35, 45–76 y, 49% Female/51% Male) ate standardized food the previous day, then fasted (10 h) prior to the intervention. The study tablet was consumed without food 15 min following baseline blood collection. Blood was drawn at 1, 2, 4, 8, and 10 h post-ingestion of the study tablet. For the 28-day supplementation study, subjects (n = 16, 18–65 y, 81% Female/19% Male) consumed 1 tablet/day; fasting blood iron and folic acid levels were determined every 7 days. Subjects ate standardized meals the day prior to blood draws. In both studies, differences compared to baseline were determined using paired t-tests for normally distributed data. In the 28-day supplementation study, differences compared to baseline for non-normally distributed data were determined using a Wilcoxon Signed Ranks test. ResultsIn the single dose study, iron concentration significantly increased (P < 0.05) compared to baseline at 1, 2, and 4 h with a Cmax of 130.24 ± 8.079 mcg/dL and Tmax at 160.0 ± 0.284 min. Folic acid concentration significantly increased (P < 0.05) compared to baseline at 1, 2, and 4 h with a Cmax of 23.32 ± 0.295 ng/mL and Tmax at 60.0 ± 0.254 min. In the 28-day study, blood iron concentrations significantly increased (P < 0.05) compared to baseline at days 21 and 28. Additionally, folic acid concentrations significantly increased (P < 0.05) compared to baseline at days 14, 21, and 28. ConclusionsA multivitamin tablet increased blood iron and folic acid levels when delivered as a single dose or daily for 28 consecutive days. These results demonstrate that folic acid and iron are readily absorbed and bioavailable from this multivitamin tablet formulation. Funding SourcesThis study was funded by Pharmavite LLC.

In vitro bioaccessibility of added folic acid in commercially available baby foods formulated with milk and milk products.

Milk contains a certain amount of folate binding proteins. The binding capacity varies in acidic conditions and affects the bioavailability of folic acid. Folic acid is commonly added into baby foods to ensure adequate intake of infants. The aim of this study was to determine the bioaccessibility of added folic acid in baby foods formulated with milk and milk products under different gastric pH values by an in vitro digestive system. The bioaccessibility of folic acid ranged between 56-71 and 35-49% in infant formula samples, between 59-78 and 31-67% in cereal-based baby foods, and between 42-67 and 38-57% in follow-on baby milk at gastric pH 1.5 and pH 4, respectively. Our results demonstrate that the bioaccesibility of folic acid that is added to baby food is affected by gastric pH. Therefore, it was observed that the bioaccesibility of folic acid was lower in the higher gastric pH.

Localization and modeling of reaction and diffusion to explain folate behavior during soaking of cowpea

A first modeling approach was used to understand the behavior of folate in cowpea seeds during soaking at different temperatures (30 °C, 60 °C and 95 °C). Folic acid, 10-formylfolic acid, 5-methyltetrahydrofolate, and 5-formyltetrahydrofolate were quantified in both the seeds and the soaking water during the process. A 2D-axisymmetric seed soaking simulator was then built considering these 4 folate vitamers to simultaneously describe diffusion, oxidation and interconversion of the single vitamers. The model adjustments revealed the predominance of folate diffusion at 60 °C and 95 °C (apparent diffusivity 2–3 × 10−11 m2 s−1) whereas at 30 °C enzymatic interconversions of all vitamers into 5-methyltetrahydrofolate were observed (reaction rate of 8.0 × 10−5 s−1 for 5-formyltetrahydrofolate). The results of this study allow us to recommend a preliminary soaking step to retain folate in seeds and to improve the bioavailability of folates for human nutrition.

A Study of the Role of Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism in Children With Attention Deficit Hyperactivity Disorder Khaled Ismail Abd El-Shakoor1, Tarek Mostafa Kamal2, Eman Ahmed Zaky3, Howida Hossny ElGebaly4. 1: Pediatric Specialist, Ministry of Health, Medical student at Medical Studies Department, Faculty of Postgraduate Childhood Studies, Ain Shams University, Egypt. 2: Consultant of Human Genetics, Faculty of Medicine

A BSTRACT Background: ADHD is a neuro-behavioral disorder that is typically manifested during childhood and often persists into adulthood, it is a complex disorder influenced by many genes, genetic and environmental risk factors co-occurring in a non-random fashion. The MTHFR gene C677T polymorphism affects both nucleotide synthesis and DNA methylation, and is associated with reduced folate bioavailability and folate metabolites. Objectives: To assess the relationship between Methylenetetrahydrofolate Reductase (MTHFR) gene polymorphisms (C667T) allele and Attention Deficit Hyperactivity Disorder (ADHD) in a sample of Egyptian children. Methodology: Out of 402 reviewed patients regularly attending the Psychiatric clinic, Faculty of Postgraduate Studies for Childhood - Ain Shams University, Cairo, Egypt. According to criteria of inclusion and exclusion a sample of 30 ADHD children were enrolled in this study. The patients were selected by simple random sample during the period from January to August, 2015 with age ranged from 6- to 12-year old. A matching number of 30 healthy children with normal developmental and psychiatric evaluation, of comparable age and sex, were randomly recruited as a study control. MTHFR gene polymorphism (C677T) allele was investigated in the selected sample. Results: There was heterozygous advantage (Heterosis) regarding C677T allele genotype, a statistically significant association was found in control group compared to ADHD cases (p=0.0159). The ADHD group revealed statistically significant family history of medical illness (10%) and psychiatric illness (8.33%) (p=0.0248) compared to control group. Conclusions: The study found no association between ADHD phenotype and the MTHFR C677T gene polymorphism in Egyptian children with attention deficit hyperactivity disorder. There was positive link between ADHD and family history of medical and psychiatric illness. Keywords: MTHFR gene, C677T allele, genotype, phenotype, attention deficit hyperactivity disorder (ADHD). دراسه تأثير تعدد الأشکال الجينية للميثيلين تتراهيدروفولات المختزل في الأطفال ذوي اضطراب نقص الانتباه و فرط النشاط مستخلص: الخلفية العلمية: اضطراب فرط الحرکة ونقص الانتباه هو اضطراب سلوکي عصبي يظهر عادة أثناء الطفولة وغالبا ما يستمر إلى مرحلة البلوغ ، وهو اضطراب معقد يتأثر بالعديد من الجينات وکذلک عوامل الخطر الجينية والبيئية و التي غالبا تحدث بطريقة غير عشوائية. يؤثر تعدد أشکال الجين ميثيلين تيتراهيدروفولات للأليل C677T على تخليق کل من النوکليوتيدات ومثيلته من الحمض النووي و کذلک يرتبط بتقلص الحيوية في حمض الفوليک ومستقلبات الفولات. الأهداف: کان الغرض من هذه الدراسه هو تقييم العلاقة بين تعدد الأشکال الجيني (MTHFR) للميثيلين تيتراهيدروفولات (MTHFR) (C667T) و اضطراب فرط الحرکه وتشتت الانتباه (ADHD) في عينة من الأطفال المصريين. المنهجيه: تم فحص 402 من المرضى الذين کانوا يحضرون بانتظام عيادة الأمراض النفسية ، کلية الدراسات العليا للطفولة - جامعة عين شمس ، القاهرة ، مصر ، وفقا لمعايير الإدراج والاستبعاد قد تم تسجيل عينة من 30 طفلا من المصابين بحالات اضطراب فرط الحرکه و تشتت الانتباه في هذه الدراسة. تم اختيار المرضى بعينة عشوائية بسيطة خلال الفترة من يناير إلى أغسطس 2015 وکانت تتراوح اعمارهم بين 6 و 12 عاما. تم تسجيل عدد مماثل من 30 طفل بصحة جيدة و قد تم تقييم النمو الطبيعي والنفسي لديهم وهم في نفس العمر والجنس مقارنه بالحالات کمجموعه تحکم . تم الفحص و الأختبار للتحقق من تعدد أشکال الجين ميثيلين تيتراهيدروفولات للأليل C677T في العينة المحددة و عينه التحکم. النتائج: کانت هناک ميزة متغايرة (Heterosis) بخصوص النمط الوراثي للأليل C677T ، حيث قد وجد ارتباط ذو دلالة إحصائية في مجموعة التحکم مقارنة بحالات اضطراب فرط الحرکه و تشتت الانتباه ((P = 0.0159. کشفت مجموعة حالات فرط الحرکه و تشتت الانتباه عن تاريخ عائلي ذو دلالة إحصائية للأمراض الطبيه بنسبه 10% و کذلک الأمراض النفسية بنسبه 8.33 % (P = 0.0248) مقارنة مع مجموعة التحکم. الاستنتاجات: أظهرت الدراسة أنه لا يوجد ارتباط بين تعدد الأشکال الجيني للميثيلين تيتراهيدروفولات للأليل حالات فرط الحرکه و تشتت الانتباه في الاطفال المصريين محل الدراسه. وC677T الکلمات الدالة: اضطراب فرط الحرکة وتشتت الانتباه، النمط الظاهري، النمط الجيني، الجين ميثيلين تيتراهيدروفولات، الأليل

A “Ship-in-a-Bottle” strategy to create folic acid nanoclusters inside the nanocages of γ-cyclodextrin metal-organic frameworks

Assembled between γ-cyclodextrins (CD) and potassium ions, γ-cyclodextrin metal-organic frameworks (CD-MOF) create spatially extended and ordered cage-like structures. Herein, it was demonstrated that folic acid (FA), a model molecule, could be densely packed inside CD-MOF reaching 2:1 FA:CD molar ratio. This “Ship-in-a-Bottle” strategy leads to a 1450 fold increase of the apparent solubility of FA. Moreover, the bioavailability of FA inside CD-MOF in rats was enhanced by a factor of 1.48 as compared to free FA. The unique mechanism of FA incorporation in the CD-MOF 3D network was also explored, which was different from the conventional CD inclusion complexation. Taylor dispersion investigations indicated that FA was incorporated on the basis of a two-component model, which was further supported by a set of complementary methods, including SEM, XRPD, BET, SR-FTIR, SAXS and molecular simulation. The hypothesized mechanism suggested that: i) tiny FA nanoclusters formed inside the hydrophilic cavities and onto the surface of CD-MOF and ii) FA was included inside dual-CD units in CD-MOF. In a nutshell, this dual incorporation mechanism is an original approach to dramatically increase the drug apparent solubility and bioavailability, and could be a promising strategy for other poorly soluble drugs.