Detection, isolation, and characterization of a novel impurity from several folic acid products / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Folic acid belongs to the group of water-soluble B vitamins and naturally exists in multiple forms in a wide variety of foods such as legumes, vegetables, liver, and milk (Iyer and Tomar, 2009; Lyon et al., 2020). It is involved in many biochemical reactions critical for cell division, such as purine and pyrimidine biosynthesis, DNA/RNA biosynthesis, and amino acid metabolism (Iyer and Tomar, 2009). Mammals cannot synthesize folic acid and thus they must acquire it from food. Although folic acid is ubiquitous in foods, folic acid deficiency still often occurs due to various causes such as unhealthy diet (Hildebrand et al., 2021; Iimura et al., 2022), disease-related malabsorption (Arcot and Shrestha, 2005), medication-related depletion (Arcot and Shrestha, 2005), or vitamin B12 deficiency (Fishman et al., 2000). Folic acid deficiency has been associated with several health problems, such as anemia (Carmel, 2005; Bailey and Caudill, 2012), cancer (Duthie, 1999), cardiovascular diseases (Wald et al., 2002), neural tube defects in newborns (van der Put et al., 2001), neuropsychiatric dysfunction (Shea et al., 2002), depression (Falade et al., 2021), inflammatory diseases (Suzuki and Kunisawa, 2015; Jones et al., 2019), and eye diseases (Sijilmassi, 2019). To prevent folic acid deficiency, its daily intake (400 μg/d) has been recommended for adults in the European Union, and its increased intake (600 μg/d) is advised for women before and during pregnancy (FAO/WHO, 2002; IOM, 2004). The New Zealand government mandated the fortification of non-organic wheat flour with folic acid in July 2021, and the UK government mandated the fortification of non-wholemeal wheat flour with folic acid in September 2021 (Haggarty, 2021).

Relevancia del metabolismo del folato en el contexto de enfermedades neurodegenerativas / Relevance of folate metabolism in neurodegenerative disorders

Introducción: Varias enfermedades neurodegenerativas están asociadas a alteraciones en el metabolismo del folato, lo que tiene sustanciales implicaciones fisiopatológicas, clínicas y terapéuticas potenciales. Objetivo: Reflejar la relevancia del metabolismo del folato para enfermedades neurodegenerativas, destacando su significación fisiopatológica y clínica, y sus implicaciones terapéuticas. Material y métodos: Se consultaron las bases de datos especializadas en busca de artículos publicados hasta marzo de 2020. Se emplearon descriptores específicos y operadores booleanos. Se empleó la estrategia de búsqueda avanzada para la selección de los artículos, teniendo en cuenta la calidad metodológica o validez de los estudios. Desarrollo: Fueron identificadas evidencias de asociación entre alteraciones del metabolismo del folato y enfermedades neurodegenerativas. Se han identificado variantes en genes que codifican enzimas involucradas en el metabolismo del folato, y modificaciones en patrones de metilación de ADN, asociadas al riesgo o a la gravedad clínica de las enfermedades de Alzheimer, Parkinson, Huntington, Temblor Esencial y Ataxia Espinocerebelosa tipo 2. Fueron encontradas asociaciones entre enfermedades neurodegenerativas y alteraciones en los niveles de metabolitos del folato, y la frecuencia de micronúcleos. Se han realizado varios estudios observacionales o experimentales que indican que la suplementación con ácido fólico y vitaminas B6 y B12, tiene utilidad terapéutica potencial en el contexto de enfermedades neurodegenerativas. Conclusiones: El metabolismo del folato es de relevancia fisiopatológica, clínica y terapéutica para enfermedades neurodegenerativas. El uso de estrategias dirigidas a restaurar los niveles normales de folatos o de co-factores enzimáticos involucrados en el metabolismo del folato, o a reducir la acumulación de homocisteína, tiene potenciales aplicaciones terapéuticas en el contexto de estas enfermedades(AU)

Introduction: Several neurodegenerative disorders are associated with alterations in folate metabolism, having essential physiopathological, clinical and therapeutic implications. Objective: To assess the relevance of folate metabolism in neurodegenerative disorders, highlighting its physiopathological, clinical and therapeutic significance. Material and Methods: Specialized biomedical databases were searched for studies published up to March 2020. Descriptors and Boolean operators were used. Advanced search strategy was used for the selection of articles, taking into account the methodological quality and validity of the studies. Results: Strong evidence of the association between folate metabolism and neurodegenerative disorders were identified. Enzyme-coding genes involved in folate metabolism and epigenetic DNA modifications associated with increased risk or disease severity in Alzheimer´s, Parkinson´s, and Huntington´s diseases, Essential Tremor, and Spinocerebellar ataxia type 2 were also identified. Associations between neurodegenerative disorders and altered levels of folate metabolites and the frequency of micronuclei were found. A number of observational and experimental studies have demonstrated that the supplementation with folic acid and vitamin B6 and B12 has therapeutic potential in the context of neurodegenerative disorders. Conclusions: Folate metabolism is of physiopathological, clinical and therapeutic relevance for neurodegenerative disorders. The use of strategies to normalize folate levels or enzyme cofactors involved in folate metabolism or to reduce homocysteine levels has potential therapeutic applications for these disorders(AU)

Can the genetic polymorphisms of the folate metabolism have an influence in the polycystic ovary syndrome?

ABSTRACT Objective To investigate the association of the genetic variants of the folate metabolism genes (MTHFR C677T; MTHFR A1298C; MTR A2756G; MTRR A66G and RFC-1 A80G) with the development of polycystic ovary syndrome (PCOS). Subjects and methods This study included 203 women (99 women with PCOS and 104 controls). The genotyping was performed by PCR-RFLP. Chi-squared test and multiple logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the SNPstat program. The results were presented in odds ratio (OR) and confidence interval of 95% (CI-95%), with a significance level of 5% (p ≤ 0.05). Results The genotypic distribution of the RFC-1 A80G polymorphism showed significant difference between the two groups, showing that the heterozygous genotype (AG genotype) was most frequent in controls. The polymorphic homozygous (GG genotype) of MTRR A66G polymorphism were most frequent in controls. The T-C haplotype MTHFR C677T and A1298C polymorphisms were more frequent in the control group (OR = 0.19; CI 95% — 0.04 to 0.93 e p = 0.042). The multivariate analysis evidenced that family history of PCOS was more frequent in the PCOS group (OR = 3.29; CI 95% — 1.48 to 7.31; p = 0.003). Conclusion In our casuistry, the polymorphic homozygous of MTRR A66G polymorphism gene and heterozygous of RFC-1 A80G polymorphism gene, the haplotype T-C C677T and A1298C polymorphisms of MTHFR gene, can be associated with protective factors for the disease.

Folic acid and diseases - supplement it or not? / Ácido fólico e doenças - suplementá-lo ou não?

SUMMARY Introduction: folic acid is a water soluble vitamin, which is synthetically-produced and found in fortified foods and supplements. Folate is found naturally in plants, such as the dark green leafy vegetables. Folate is not synthesizedde novo by humans, therefore the daily requirements are met from the dietary intake of folic acid supplements or food rich in this vitamin. Folate deficiency could lead to numerous common health problems. Hyperhomocysteinemia and the possibility of malignancy developments are the long term consequences of this deficit albeit contradictory findings on these claims. Methods: the articles included in this review focused on recent updated evidence-based reports and meta-analyses on the associations of the serum folate/folic acid and the various diseases found globally. Results: the benefit of folic acid supplementation in the pre-conception period for the prevention of neural tube defects (NTDs) was well established and it was suggested that counseling sessions should be given to women with previous pregnancies affected by NTDs. However, supplementation of folic acid and its medicinal effects in the treatment of other diseases were contradictory and unclear. Conclusion: more detailed investigations into the health benefits of folic acid are needed before it could be recommended for supplementation, treatment or prevention of some of the diseases discussed in this review.

RESUMO Introdução: ácido fólico é uma vitamina solúvel em água produzida sinteticamente e encontrada em alimentos e suplementos enriquecidos. O folato é encontrado naturalmente em plantas, como vegetais folhosos verde-escuros. O folato não é sintetizado de novo por seres humanos; portanto, as necessidades diárias são satisfeitas a partir da ingestão de suplementos de ácido fólico ou alimentos ricos nessa vitamina. A deficiência de folato pode levar a inúmeros problemas de saúde comuns. Hiper-homocisteinemia e a possibilidade de desenvolver malignidades são as consequências a longo prazo desse déficit, ainda que os resultados sejam contraditórios sobre essas afirmações. Métodos: os artigos incluídos nesta revisão tratam de relatórios recentes atualizados com base em provas e metanálises sobre a associação entre o folato/ácido fólico e várias doenças encontradas globalmente. Resultados: o benefício da suplementação de ácido fólico no período de pré-concepção para a prevenção de defeitos do tubo neural (DTN) foi bem estabelecido e foi sugerido que sessões de aconselhamento devem ser providas às mulheres com gravidezes anteriores afetadas por DTN. No entanto, os benefícios da suplementação de ácido fólico e os efeitos medicinais no tratamento de outras doenças são contraditórios e pouco claros. Conclusão: investigações mais detalhadas sobre os benefícios do ácido fólico são necessárias antes que a suplementação seja recomendada para tratamento ou prevenção de algumas das doenças discutidas nesta revisão.

Genetic Variants in Folate and Cobalamin Metabolism-Related Genes in Nonsyndromic Cleft Lip and/or Palate

The aim of this study was to evaluate the association of the polymorphisms in TCN2 (rs1801198) gene and in MTRR (rs1801394) gene with nonsyndromic cleft lip and/or palate (NSCL/P) in a Brazilian population. Genomic DNA was extracted from buccal cells. The polymorphisms in TCN2 (rs1801198) and MTRR (rs1801394) genes were genotyped by carrying out real-time PCR and Taqman assay. Chi-square test was used to determine the association between genotype and allele frequencies with NSCL/P and NSCL/P subgroups (cleft lip only, cleft lip and palate, and cleft palate only). Eight hundred and sixty seven unrelated individuals (401 cases with NSCL/P and 466 individuals without cleft) were evaluated. Genotype distributions of TCN2 and MTRR polymorphisms were in Hardy-Weinberg equilibrium. The TCN2 polymorphic genotype GG was identified in 16.7% of the NSCL/P group and in 14.1% of the non-cleft group (p>0.05). Similarly, the frequency of MTRR genotype (GG) was similar in NSCL/P group (15.5%) and control group (17.8%) (p>0.05). Multivariate analysis showed an association between MTRR and the subgroup that the mother smoked during pregnancy (p=0.039). Our findings did not demonstrate an association between TCN2 polymorphisms and NSCL/P, however suggests an association between MTRR and NSCL/P etiology.

Resumo O objetivo desse estudo foi avaliar a associação entre os polimorfismos no gene TCN2 (rs1801198) e no gene MTRR (rs1801394) com fissura de lábio e/ou palato não sindrômica (NSFL/P) em uma população brasileira. DNA genômico foi extraído de células bucais. Os polimorfismos nos genes TCN2 (rs1801198) e MTRR (rs1801394) foram genotipados através do PCR em tempo real pelo método Taqman. O teste do qui-quadrado foi utilizado para determinar a associação entre a frequência alélica e genotípica e NSFL/P e nos subtipos (fissura de lábio, fissura de lábio com palato e fissura de palato). Oitocentos e sessenta e sete indivíduos não aparentados (401 casos com NSFL/P e 466 indivíduos sem fissura) foram avaliados. A distribuição dos genótipos dos polimorfismos de TCN2 e MTRR estavam em equilíbrio de Hardy-Weinberg. O genótipo polimórfico GG do gene TCN2 foi identificado em 16,7% do grupo com NSFL/P e em 14,1% do grupo sem fissura (p>0,05). Da mesma forma, a freqüência do genótipo GG do gene MTRR foi bastante semelhante entre o grupo com NSFL/P (15,5%) e o grupo controle (17,8%). A análise multivariada mostrou associação entre o gene MTRR e o subgrupo que apresentou tabagismo materno durante a gestação (p=0,039). Nossos resultados mostraram que não há associação entre os polimorfismos nos genes TCN2 e NSFL/P, entretanto sugerem uma associação entre MTRR e a etiologia de NSFL/P.

Consumo dietético, variantes genéticas e relação com níveis sanguíneos de folato, ácido fólico não metabolizado e homocisteína após a fortificação mandatória de ácido fólico: estudo de base populacional - ISA - Capital / Dietary intake and genetic variants of folate and its relation to folate, unmetabolized folic acid and homocysteine blood concentrations after mandoty folic acid fortification population based study ISA-Capital

Em diversos países, inclusive no Brasil, a fortificação de alimentos com ácido fólico (AF) foi adotada como política pública de prevenção e combate à deficiência nutricional da vitamina, motivados principalmente pela redução da incidência dos defeitos do tubo neural. No período pós-fortificação observa-se tanto a evolução positiva do consumo e nível sérico da vitamina quanto a diminuição da concentração plasmática de homocisteína, e ainda, o aumento do ácido fólico não metabolizado na maioria desses países. Não se conhece ainda os efeitos biológicos do AFNM, no entanto, considera-se que o AFNM pode ser um fator relevante nas questões de segurança associadas com alto consumo de AF. Objetivo: Avaliar o consumo dietético e nível de folato, homocisteína e ácido fólico não metabolizado após a fortificação mandatória de alimentos com ácido fólico, e a interação com os polimorfismos envolvidos no metabolismo do folato e homocisteína. Metodologia: Os dados foram oriundos do estudo transversal de base populacional ISA Capital 2008 conduzido em uma amostra representativa de residentes do município de São Paulo, de ambos os sexos, e com idade acima de 14 anos. Coletou-se recordatórios alimentares de 24 horas e amostra de sangue em jejum de 12 horas para análises bioquímicas e moleculares. As análises estatísticas foram realizadas no programa STATA®, versão 13.0, com nível de significância de 5 por cento . Resultados: O estudo foi conduzido em 750 indivíduos, sendo 53,1 por cento mulheres e média de idade 40,7 (IC95 por cento 38,8-42,5) anos. A média de consumo e nível de folato foi de 375,8 (IC95 por cento 363,0-388,6) mcg/dia e 13 (IC95 por cento 12,0-13,9) ng/ml, respectivamente...

Food fortification is an important strategy in public health policy for controlling micronutrient malnutrition, and a major contributory factor in the eradication of micronutrients deficiencies. Motivated by the reduction in the occurrence of neural tube defects, countries worldwide, including Brazil, adopted food fortification with folic acid (FA). Folic acid fortification has increased dietary intakes of folic acid and folate status, but it is also associated with the presence of circulating FA. Although the metabolism and biological effects of circulating of folic acid are not well known, it may be a contributing factor in safety concerns associated with high oral doses of folic acid. Objective: To assess the folate intake and status, homocysteine and circulating FA after mandatory fortification with folic acid, and interaction with polymorphisms involved in 1-carbon metabolism. Material and Methods: Data were from 750 individuals aged > 14 years old who participated of a cross-sectional population-based survey in Sao Paulo City-Brazil. Fasting blood samples and information about food intake based on two measures of 24 hour food recall were collected. All analyses were carried out using STATA (version 13.0) and p-value <.05 was considered to be statistically significant in all tests. Results: Results were from 750 individuals...

Folatos y vitamina B12 en la salud humana / Folate, vitamin B12 and human health

During the past decade the role of folate and vitamin B12 in human nutrition have been under constant re-examination. Basic knowledge on the metabolism and interactions between these essential nutrients has expanded and multiple complexities have been unraveled. These micronutrients have shared functions and intertwined metabolic pathways that define the size of the "methyl donor" pool utilized in multiple metabolic pathways; these include DNA methylation and synthesis of nucleic acids. In Chile, folate deficiency is virtually nonexistent, while vitamin B12 deficiency affects approximately 8.5-51% depending on the cut-off value used to define deficiency. Folate is found naturally mainly in vegetables or added as folic acid to staple foods. Vitamin B12 in its natural form is present only in foods of animal origin, which is why deficit is more common among strict vegetarians and populations with a low intake of animal foods. Poorfolate status in vulnerable women of childbearing age increases the risk of neural tube birth defects, so the critical time for the contribution of folic acid is several months before conception since neural tube closure occurs during the first weeks of life. The absorption of vitamin B12 from food is lower in older adults, who are considered to have higher risk of gastric mucosa atrophy, altered production of intrinsic factor and acid secretion. Deficiency of these vitamins is associated with hematological disorders. Vitamin B12 deficiency can also induce clinical and sub-clinical neurological and of other disorders. The purpose of this review is to provide an update on recent advances in the basic and applied knowledge of these vitamins relative to human health.

Câncer de cabeça e pescoço: polimorfismos genéticos e metabolismo do folato / Head and neck cancer: genetic polymorphisms and folate metabolism

Evidências epidemiológicas sugerem que variantes genéticas que codificam enzimas envolvidas no metabolismo do folato podem modular o risco de câncer de cabeça e pescoço por alterar a metilação, síntese de DNA e estabilidade genômica. OBJETIVOS: Realizar uma revisão bibliográfica sobre polimorfismos genéticos envolvidos no metabolismo do folato e o risco de câncer de cabeça e pescoço. METODOLOGIA: Realizou-se uma busca eletrônica na base de dados Medline, selecionando estudos em câncer de cabeça do pescoço e polimorfismos envolvidos no metabolismo do folato. RESULTADOS: A associação do polimorfismo MTHFR C677T no risco dessa neoplasia foi avaliada em nove estudos e três deles mostraram associação com essa doença. Os polimorfismos MTR A2756G e MTRR A66G e RFC1 A80G também foram associados com aumento de risco para o câncer de cabeça e pescoço. O polimorfismo MTHFD1 G1958A não mostra associação com o risco dessa doença e os resultados da avaliação do polimorfismo MTHFR A1298C nesse tipo de neoplasia são contraditórios. Outros polimorfismos envolvidos no metabolismo do folato ainda não foram estudados nesse tipo de neoplasia. CONCLUSÃO: Concluímos que polimorfismos envolvidos no metabolismo do folato podem modular o risco desse tipo de tumor, no entanto, esses resultados precisam ser comprovados em diferentes populações.

Epidemiological evidence suggests that genetic variants encoding enzymes involved in folate metabolism may modulate HNSCC risk by altering DNA methylation synthesis and genomic estability. AIM: A review of the literature on genetic polymorphisms involved in folate metabolism and risk of head and neck cancer was carried out. METHODOLOGY: An electronic search was made on the Medline database to select papers on head and neck cancer and polymorphisms involved in folate metabolism. RESULTS: The association between MTHFR C677T polymorphism and the risk of this tumor type was evaluated in nine studies; there was an association with this disease in three papers. The MTR A2756G and MTRR A66G and RFC1 A80G polymorphisms were also associated with increased risk for HNSCC. MTHFD1 G1958A polymorphism was not associated with increased risk of this disease; the evaluation results of the MTHFR A1298C polymorphism in this neoplasm were contradictory. Other polymorphisms involved in folate metabolism were not studied for this neoplasm. CONCLUSION: We conclude that polymorphisms involved in folate metabolism may modulate the risk of head and neck cancer, however, these results need to be demonstrated in different populations.

Profiling single nucleotide polymorphisms (SNPs) across intracellular folate metabolic pathway in healthy Indians.

Background & objectives: Many pharmacologically-relevant polymorphisms show variability among different populations. Though limited, data from Caucasian subjects have reported several single nucleotide polymorphism (SNPs) in folate biosynthetic pathway. These SNPs may be subjected to racial and ethnic differences. We carried out a study to determine the allelic frequencies of these SNPs in an Indian ethnic population. Methods: Whole blood samples were withdrawn from 144 unrelated healthy subjects from west India. DNA was extracted and genotyping was performed using PCR-RFLP and Real-time Taqman allelic discrimination for 12 polymorphisms in 9 genes of folate-methotrexate (MTX) metabolism. Results: Allele frequencies were obtained for MTHFR 677T (10%) and 1298 C (30%), TS 3UTR 0bp (46%), MDR1 3435T and 1236T (62%), RFC1 80A (57%), GGH 401T (61%), MS 2756G (34%), ATIC 347G (52%) and SHMT1 1420T (80%) in healthy subjects (frequency of underlined SNPs were different from published study data of European and African populations). Interpretation & conclusions: The current study describes the distribution of folate biosynthetic pathway SNPs in healthy Indians and validates the previous finding of differences due to race and ethnicity. Our results pave way to study the pharmacogenomics of MTX in the Indian population.

Consumo de fumonisinas y daños a la salud humana / Fumonisin intake and human health

Las fumonisinas son una familia de micotoxinas que contaminan al maíz, alteran el metabolismo de los esfingolípidos y del folato, se asocian con defectos del tubo neural y están catalogadas por la Agencia Internacional de Investigación en Cáncer (IARC por sus siglas en inglés) como posibles carcinógenos humanos. Debido a que en México los derivados de maíz constituyen una parte importante de la dieta y existe alta prevalencia de población genéticamente susceptible a la deficiencia de folato, en este ensayo se presentan las evidencias mundiales y nacionales de la exposición a fumonisinas y la relevancia que para México representa la evaluación de esta exposición.

Fumonisins are mycotoxins that contaminate maize, disrupt the folate and sphingolipid metabolism, are associated with neural tube defects, and are considered by the International Agency for Research on Cancer (IARC) as possible human carcinogens. Since maize-based foods are significant components of the Mexican diet and there is a high prevalence of genetic susceptibility for folate deficiency among Mexicans, this essay presents international and national evidence of fumonisin exposure and the relevance that such exposure represents for Mexico.

Folate content and retention in selected raw and processed foods / Contenido de folatos y retención en determinados alimentos crudos y procesados

Adequate intake of folate reduced the risk of abnormalities in early embryonic brain development such as the risk of malformations of the embryonic brain/spinal cord, collectively referred to as neural tube defects (NTDs). Folate is extremely sensitive to destruction by heat, oxidation and UV light. The purpose of this study was to evaluate the use of different extraction procedures and enzymatic treatment to determine folate concentrations in variety of foods using a microbiological assay (MA) with Lactobacillus rhamnosus as the test organism. This study also aimed to evaluate the retention of folate in foods after using different cooking processes. Nine of the most commonly consumed foods in Argentina and that contain folate were analyzed: broccoli, spinach, potato, lentil, soy (raw and boiled); hen whole egg and yolks (raw, boiled and fried); beef liver (raw and cooked); strawberry (raw) and white bread. For this study, rat plasma (RP) and human plasma (HP) conjugases together with acetate and phosphate buffers were tested. In extraction step for all analyses, RP conjugase was selected since it was easily available in our laboratory and small quantities were required. The acetate buffer was chosen since better growth and more reproducible results were obtained in the different conditions assayed. The results allowed the foods to be grouped into a) rich sources of folate: hen eggs, yolks, spinach, soybean (raw) and strawberry (100 and 350mg/100g fresh weight (FW); b) good sources of folate: broccoli (raw), soybean (boiled), lentils (raw) and potato (56 to 83mg/100g FW) and c) moderate sources of folate: broccoli, lentils (boiled), white breads, onions and beef liver (15 to 30mg/100g FW). The folate retention was in the range 14-99% according to both type of food and method of processing. Contents and losses of folate vary widely according to type of food and cooking method.

La ingesta adecuada de folatos reduce el riesgo de las anormalidades en el desarrollo temprano del cerebro embrionario, tales como el riego de malformaciones en el cerebro/médula espinal, conocidas en conjunto como defectos del tubo neural (NTDs). Los folatos son extremadamente sensibles al tratamiento con calor, la oxidación y la luz UV. El objetivo de este trabajo fue evaluar el uso de diferentes procedimientos de extracción y de tratamientos enzimáticos para determinar el contenido de folato en distintos alimentos empleando un método microbiológico que utiliza el microorganismo Lactobacillus rhamnosus. En este trabajo se evaluó también la retención de folatos en alimentos sometidos a diferentes procesos de cocción. Se analizaron 9 de los alimentos que contienen folatos y más comúnmente consumidos en Argentina: brócoli, espinaca, papa, lente ja, soja (crudos y cocidos): huevo entero de gallina y yema (crudo, hervido y frito). Bife de hígado vacuno (crudo y cocido); frutillas (crudas) y pan: blanco. Se probó para este estudio conjugasas de plasma de rata (PR) y de plasma humano (PH) conjuntamente con buffers fosfato y acetato. En la extracción para todos los análisis se escogió la conjugasa de PR por ser accesible para nuestro laboratorio y por que se utiliza en pequeñas cantidades. El buffer acetato fue elegido debido a que se obtuvo resultados más reproducibles y un mejor crecimiento en las diferentes condiciones ensayadas. Los resultados permitieron agrupar los alimentos en: a) fuente rica de folatos: huevo y su yema, espinaca, soja (cruda) y frutilla (100 a 350mg/100g peso fresco); b) fuente buena de folatos: brócoli (crudo), soja (hervidas), lentejas (cruda) y papa (cruda y hervida) (56 a 83mg/100g peso fresco) y c) fuente moderada de folatos: brócoli y lentejas (hervidos), bife de hígado, pan blanco y cebollas (15 a 30mg/100g peso fresco). La retención de folato estuvo en el rango de 14-99% de acuerdo al tipo de alimento y el método de procesado. El contenido de folato y sus perdidas fueron muy variables dependiendo del alimento y del método de cocción empleados.

19-base pair deletion polymorphism of the dihydrofolate reductase (DHFR) gene: maternal risk of Down syndrome and folate metabolism / Polimorfismo de deleção de 19 pares de bases do gene dihidrofolato redutase (DHFR): risco materno para síndrome de Down e metabolismo do folato

CONTEXT AND OBJECTIVE: Polymorphisms in genes involved in folate metabolism may modulate the maternal risk of Down syndrome (DS). This study evaluated the influence of a 19-base pair (bp) deletion polymorphism in intron-1 of the dihydrofolate reductase (DHFR) gene on the maternal risk of DS, and investigated the association between this polymorphism and variations in the concentrations of serum folate and plasma homocysteine (Hcy) and plasma methylmalonic acid (MMA). DESIGN AND SETTING: Analytical cross-sectional study carried out at Faculdade de Medicina de São José do Rio Preto (Famerp). METHODS: 105 mothers of individuals with free trisomy of chromosome 21, and 184 control mothers were evaluated. Molecular analysis on the polymorphism was performed using the polymerase chain reaction (PCR) through differences in the sizes of fragments. Folate was quantified by means of chemiluminescence, and Hcy and MMA by means of liquid chromatography and sequential mass spectrometry. RESULTS: There was no difference between the groups in relation to allele and genotype frequencies (P = 0.44; P = 0.69, respectively). The folate, Hcy and MMA concentrations did not differ significantly between the groups, in relation to genotypes (P > 0.05). CONCLUSIONS: The 19-bp deletion polymorphism of DHFR gene was not a maternal risk factor for DS and was not related to variations in the concentrations of serum folate and plasma Hcy and MMA in the study population.

CONTEXTO E OBJETIVO: Polimorfismos em genes do metabolismo do folato podem modular o risco materno para síndrome de Down (SD). Este estudo avaliou a influência do polimorfismo de deleção de 19 pares de base (pb) no íntron 1 do gene dihidrofolato redutase (DHFR) no risco materno para SD e investigou a associação entre esse polimorfismo e variações nas concentrações de folato sérico, homocisteína (Hcy) e ácido metilmalônico (MMA) plasmáticos. TIPO DE ESTUDO E LOCAL: Estudo transversal analítico realizado na Faculdade de Medicina de São José do Rio Preto (Famerp). MÉTODOS: 105 mães de indivíduos com trissomia livre do cromossomo 21 e 184 mães controles foram avaliadas. A análise molecular do polimorfismo foi realizada pela reação em cadeia da polimerase (PCR) por diferença de tamanho dos fragmentos. O folato foi quantificado por quimioluminescência, e Hcy e MMA foram determinados por cromatografia líquida/espectrometria de massas sequencial. RESULTADOS: Não houve diferença entre os grupos em relação às frequências alélica e genotípica (P = 0,44; P = 0,69, respectivamente). As concentrações de folato, Hcy e MMA não mostraram diferença significativa entre os genótipos, entre grupos (P > 0,05). CONCLUSÕES: O polimorfismo de deleção de 19 pb do gene DHFR não é um fator de risco materno para SD e não está relacionado com variações nas concentrações de folato sérico, Hcy e MMA plasmáticos na população estudada.

Progress on relationship between omega-3 polyunsaturated fatty acids and violent-aggressive behavior / 法医学杂志

The relationship between omega-3 polyunsaturated fatty acids (PUFAs) and violent-aggressive behavior has been payed attention since 1980s. Their correlation was explored by many epidemiological investigations, and the effect of PUFAs on prevention or reduction of violent-aggressive behavior in different groups were also affirmed by some intervention studies. This article summarized the previous studies and reviewed the history of epidemiological or intervention studies on PUFAs and its relationship with violent-aggressive behavior. It also presented the possible influencing factors in these studies and possible mechanisms.

Ácido fólico na prevenção de gravidez acometida por morbidade fetal: aspectos atuais / Folic acid in prevention of pregnancy affected by fetal morbidity: actual aspects

Os estudos em países desenvolvidos sugerem uma tendência à redução da incidência e gravidade dos defeitos abertos do tubo neural (DATN), após a adoção de programas de fortificação de grãos e farináceos. No Brasil, a mesma tendência foi observada, porém não com a mesma intensidade, decorrente da diversidade dos hábitos alimentares regionais, inferindo que apenas a adoção do programa de fortificação não seja suficiente para haver redução significativa dos DATN. O papel do ácido fólico na prevenção de malformações do tubo neural está bem definido. A prevenção de cardiopatias, malformações faciais e cromossomopatias ainda permanece incerta, sendo necessários estudos para avaliar a ação do micronutriente na profilaxia de outras morbidades fetais. Constatou-se aumento do conhecimento de pacientes e profissionais de saúde envolvidos na assistência pré-natal sobre o papel do ácido fólico e, em particular, no seu uso periconcepcional especialmente em países desenvolvidos. Assim, apesar dos programas de fortificação implantados em alguns países desenvolvidos terem sido eficientes em reduzir de forma significativa a incidência dos DFTN, no Brasil, precisam-se considerar as variações regionais e promover melhor a suplementação farmacológica do ácido fólico periconcepcional

Studies in developed countries have suggested a tendency of reduction in incidence and severity of neural tube defects (NTD), after the adoption of folic acid food fortification programs. In Brazil, the same trend was observed; however not with the same intensity. This finding seems to be associated with the great diversity of the Brazilian regional alimentary habits, leading some researchers to infer that only foods fortification programs are not enough to reach a significant reduction of NTD incidence. The knowledge of folic acid prevention of NTD malformations is well-established by consistent publications. It is not completely clear the folate role in preventing congenital cardiopathies, facial malformations and cromossomic disorders. An increase in patients and physicians' knowledge about folic acid role in the prevention of NTD malformations was noticed. Its periconceptional use has increased more significantly especially in developed countries. Although food fortification programs in some developed countries have been efficient in reducing significantly the incidence and severity of NTD malformations, in Brazil, the program must consider regional variations and improve folate promotion for medical supplementation in periconceptional folic acid

Sacarose como veículo de suplementação dietética de ácido fólico em camundongos prenhes / Saccharose as a vehicle for the supplementation of folic acid in pregnant mice

INTRODUÇÃO: A ingestão adequada de folato é essencial durante a embriogênese, e sua deficiência está associada à ocorrência de defeitos no fechamento do tubo neural. OBJETIVO: Determinar se a sacarose é um bom veículo para a suplementação de folato em camundongos. MATERIAL E MÉTODOS: Quarenta camundongos Swiss fêmeas foram divididos nos grupos: C: ração comercial + água ad libitum; DS: ração balanceada isenta de folato + folato adicionado à sacarose diluída na água por 14 dias; D/DS: ração balanceada isenta de folato + água com sacarose sem folato por 14 dias seguida de ração balanceada isenta de folato + folato adicionado à sacarose diluída na água por mais 14 dias; D: ração balanceada isenta de folato + água com sacarose sem folato por 14 dias. Os animais de todos os grupos experimentais receberam ração balanceada isenta de folato + folato adicionado à sacarose diluída na água durante os três dias do acasalamento e nos 15 dias restantes até o sacrifício. RESULTADOS: Os animais dos grupos D e D/DS apresentaram alopecia, palidez ocular e adinamia enquanto consumiam água com sacarose sem folato, sinais que foram revertidos quando receberam folato adicionado à sacarose diluída na água. Não houve diferença entre os grupos em relação a prenhez, implantes, fetos vivos, reabsorção, morte fetal tardia, nível sérico de folato e contagem de hemácias ao final do experimento, não tendo sido observadas anomalias congênitas em nenhum dos grupos. CONCLUSÃO: A sacarose é um meio adequado para a suplementação de folato na dieta.

Adequate folate intake is essential during embryogenesis and its deficiency is associated with neural tube defects. OBJECTIVE: To investigate if saccharose is a good vehicle for the supplementation of folate in mice. MATERIAL AND METHODS: 40 Swiss female mice were allocated into the following groups: C (commercial mouse food + ad libitum water); DS (folate-free balanced diet + saccharose with folate diluted in water for 14 days); D/DS (folate-free balanced diet + folate-free saccharose diluted in water for 14 days, followed by folate-free balanced diet + saccharose with folate diluted in water for 14 days); D (folate-free balanced diet + folate-free saccharose diluted in water for 14 days). Mice from all experimental groups received folate-free balanced diet + saccharose with folate diluted in water during their three-day mating period and thereafter 15 days until animals were put down. RESULTS: Mice from groups D and D/DS showed alopecia, pale eyes and adynamia while on folate-free saccharose water regimen. These symptoms disappeared after the introduction of saccharose with folate diluted in water. No statistical difference was noted among groups as to pregnancy, number of implants, live fetuses, reabsorption, late fetal death, serum folate levels and red blood cells count and no congenital abnormalities were identified in any groups by the end of the experiment. CONCLUSION: Saccharose is a suitable vehicle for the dietary supplementation of folate.

Methylenetetrahydrofolate reductase [MTHFR] genotype association with the risk of chronic myelogenous leukemia

The metabolism of folate is essential in DNA synthesis, and polymorphisms of genes involved in this metabolism have been implicated in many types of cancer. One such gene is the Methylenetetrahydrofolate Reductase [MTHFR] gene, which encodes an enzyme that converts folate to a methyl donor used for DNA methylation. In this report, we studied the association between the different genotypes of the two most common MTHFR polymophisms, C677T and A1298C, and the risk of Chronic Myelogenous Leukemia [CML]. For this purpose, 149 of previously diagnosed CML patients and 170 normal controls were examined using PCR followed by Restriction Fragment Length Polymorphism [RFLP]. Results showed that the frequency of the C677T TT homozygous mutant genotype in patients with CML was significantly higher compared to controls [OR - 2.84, 95% CI: 1.24-6.50, .P-value - 0.014]. No such association was shown for the heterozygous C677T CT genotype [OR = 1.52, 95% CI: 0.95-2.41, P-value - 0.081]. As for the A1298C genotypes, a statistically significant higher frequency of the mutant homozygous genotype 1298CC was also detected in CML patients compared to the control group [OR - 2.18, 95% CI: 1.01-4.69, P-value - 0.046]. No such statistical significance was demonstrable for the heterozygote genotype 1298AC [OR = 1.08, 95% CI: 0.68-1.73, P-value = 0.743]. This is the first report to suggest that both mutated MTHFR genotypes, specifically the homozygous 677TT and 1298CC polymorphisms, can be associated with a higher risk of developing CML

Defectos del tubo neural: estado actual / Neural tube defects: current status

Las malformaciones congénitas constituyen la segunda causa de mortalidad infantil en nuestro medio, lo cual significa que nuestro comportamiento en términos de salud pública, es muy similar a los países desarrollados. Hay malformaciones de alto costo médico social en las cuales afortunadamente se puede intervenir eficazmente con medidas de prevención primaria o secundaria. Los defectos del tubo neural son una de ellas y en el mundo curiosamente, no son muchos los países que lo hacen. Afortunadamente, Chile ha tenido una actitud pionera en América con la implementación de un programa de fortificación de harinas que ha significado una disminución cercana al 50 por ciento en las tasas de frecuencia de la enfermedad. Los mecanismos bioquímicos exactos de la prevención no están claramente descritos, pero un papel importante juega el ácido fólico en la síntesis del ADN y en el metabolismo de la metionina/homocisteina, vías metabólicas claves del neuro desarrollo inicial. Lo más importante sin embargo, es que la prevención actúa sólo para aquellos casos típicamente dependientes de la neurulacion primaria y no para todos los defectos cráneo encefálicos.

Congenital anomalies are the second cause of infant mortality in Chile, which is similar to the findings in developed countries. The medical-social burden of some of these malformations is high, but some of them are able to undergo primary or secondary prevention. Neural tube defects are among them and unfortunately, a. global prevention is not the rule. Chile has been one of the pioneer countries with supplementation of folic acid fortification, which has resulted in a reduction in the prevalence of open neural tube defects in about 50 percent. The exact mechanisms involved in the prevention of open neural tube defects are not clear, but an important role has been ascribed to folic acid in the synthesis of DNA and metabolism of metionin-homocistein, key pathways for the early development of the neural tube. An important point is that fortification with folic acid only works in those defects associated with the primary neurulation and not to all cranio-encephalic defects.

Genetic polymorphisms involved in folate metabolism and elevated plasma concentrations of homocysteine: maternal risk factors for Down syndrome in Brazil

The aim of the present study was to investigate the effect of polymorphisms C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene, A2756G in methionine synthase reductase (MTR) gene and A80G in reduced folate carrier 1 (RFC1) gene, and plasma homocysteine (Hcy), on the maternal risk for Down syndrome (DS). Seventy-two DS mothers and 194 mothers who had no children with DS were evaluated. The investigation of the MTHFR C677T, MTR A2756G and RFC1 A80G polymorphisms was performed by polymerase chain reaction and enzyme digestion and the MTHFR A1298C polymorphism by allele-specific polymerase chain reaction. Hcy quantification was carried out by liquid chromatography-tandem mass spectrometry. The median number of polymorphic alleles for the four loci tested was greater in DS mothers compared to the control group, and the presence of three or more polymorphic alleles increased the risk for having a child with DS 1.74 times. Elevated maternal risk for DS was also observed when plasma Hcy three or more polymorphic alleles for MTHFR C677T, MTHFR A1298C, MTR A2756G, and RFC1 A80G, and plasma Hcy concentrations higher than 4.99 mi mol/L are maternal risk factors for DS.