Metabolism and gene polymorphisms of the folate pathway in Brazilian women with history of recurrent abortion / Metabolismo e polimorfismos gênicos da via do folato em mulheres brasileiras com história de aborto recorrente

PURPOSE: To investigate the association between polymorphisms in genes that encode enzymes involved in folate- and vitamin B12-dependent homocysteine metabolism and recurrent spontaneous abortion (RSA). METHODS: We investigated the C677T and A1298C polymorphisms of the methylenetetrahydrofalate reductase gene (MTHFR), the A2756G polymorphism of the methionine synthase gene (MS) and the 844ins68 insertion of the cystathionine beta synthetase gene (CBS). The PCR technique followed by RFLP was used to assess the polymorphisms; the serum levels of homocysteine, vitamin B12 and folate were investigated by chemiluminescence. The EPI Info Software version 6.04 was used for statistical analysis. Parametric variables were compared by Student's t-test and nonparametric variables by the Wilcoxon rank sum test. RESULTS: The frequencies of gene polymorphisms in 89 women with a history of idiopathic recurrent miscarriage and 150 controls were 19.1 and 19.6% for the C677T, insertion, 20.8 and 26% for the A1298C insertion, 14.2 and 21.9% for the A2756G insertion, and 16.4 and 18% for the 844ins68 insertion, respectively. There were no significant differences between case and control groups in any of the gene polymorphisms investigated. However, the frequency of the 844ins68 insertion in the CBS gene was higher among women with a history of loss during the third trimester of pregnancy (p=0.003). Serum homocysteine, vitamin B12 and folate levels id not differ between the polymorphisms studied in the case and control groups. However, linear regression analysis showed a dependence of serum folate levels on the maintenance of tHcy levels. CONCLUSION: The investigated gene polymorphisms and serum homocysteine, vitamin B12 and folate levels were not associated with idiopathic recurrent miscarriage in the present study. Further investigations are needed in order to confirm the role of the CBS 844ins68 insertion in recurrent miscarriage. .

OBJETIVO: Investigar a associação entre polimorfismos nos genes que codificam enzimas envolvidas no metabolismo da homocisteína dependente de folato e vitamina B12 e aborto espontâneo recorrente. MÉTODOS: Investigamos os polimorfismos C677T e A1298C no gene methilenotetrahidrofalato redutase (MTHFR); o polimorfismo A2756G no gene metionina sintase (MS) e a inserção 844ins68 no gene da cistationina beta-sintetase (CBS). A técnica de PCR seguido por RFLP foi utilizada para investigar os polimorfismos. Os níveis séricos de homocisteína, vitamina B12 e de folato foram investigados pela técnica de quimioluminescência. O Software Epi Info versão 6.04 foi utilizado para realizar a análise estatística. As variáveis paramétricas foram comparadas pelo teste t de Student e as variáveis não paramétricas pelo teste de Wilcoxon rank sum. RESULTADOS: As frequências dos polimorfismos gênicos em 89 mulheres com história de aborto recorrente idiopático e 150 controles foram de 19,1 e 19,6% para o C677T; 20,8 e 26% para o A1298C; 14,2 e 21,9% para o A2756G e 16,4 e 18% para a inserção 844ins68, respectivamente. Não houve diferenças significantes entre os grupos caso e controle em todos os polimorfismos dos genes investigados. No entanto, a frequência da inserção 844ins68 no gene CBS foi maior entre mulher com histórico de perdas no terceiro trimestre da gravidez p=0.003). Os níveis de homocisteína, vitamina B12 e folato séricos não foram diferentes entre os polimorfismos estudados nos grupos casos e controles. No entanto, a análise de regressão linear mostrou dependência dos níveis séricos de folato na manutenção dos níveis de homocisteína. CONCLUSÃO: Os polimorfismos gênicos investigados, assim como homocisteína, vitamina B12 e os níveis séricos de folato não foram associados com abortos recorrentes idiopático no presente estudo. Novas investigações devem ser realizados a fim de confirmar o papel da inserção 844ins68-CBS nos abortos recorrentes. .

Roles and causes of abnormal DNA methylation in gastrointestinal cancers.

Evidence now suggests that epigenetic abnormalities, particularly altered DNA methylation, play a crucial role in the development and progression of human gastrointestinal malignancies. Two distinct DNA methylation abnormalities are observed together in cancer. One is an overall genome-wide reduction in DNA methylation (global hypomethylation) and the other is regional hypermethylation within the CpG islands of specific gene promoters. Global hypomethylation is believed to induce proto-oncogene activation and chromosomal instability, whereas regional hypermethylation is strongly associated with transcriptional silencing of tumor suppressor genes. To date, genes involved in regulation of the cell cycle, DNA repair, growth signaling, angiogenesis, and apoptosis, are all known to be inactivated by hypermethylation. Recently developed techniques for detecting changes in DNA methylation have dramatically enhanced our understanding of the patterns of methylation that occur as cancers progress. One of the key contributors to aberrant methylation is aging, but other patterns of methylation are cancer-specific and detected only in a subset of tumors exhibiting the CpG island methylator phenotype (CIMP). Although the cause of altered patterns of DNA methylation in cancer remains unknown, it is believed that epidemiological factors, notably dietary folate intake, might strongly influence DNA methylation patterns. Recent studies further suggest that polymorphisms of genes involved in folate metabolism are causally related to the development of cancer. Identifying epidemiological factors responsible for epigenetic changes should provide clues for cancer prevention in the future.

Vitamin B12 and folate depletion in cognition: a review.

In cross-sectional studies, low levels of folate and B12 have been shown to be associated with cognitive decline and dementia Evidence for the putative role of folate, vitamin B12 in neurocognitive and other neurological functions comes from reported cases of severe vitamin deficiencies, particularly pernicious anemia, and homozygous defects in genes that encode for enzymes of one-carbon metabolism. The neurological alterations seen in these cases allow for a biological role of vitamins in neurophysiology. Results are quite controversial and there is an open debate in literature, considering that the potential and differential role of folate and B12 vitamin in memory acquisition and cognitive development is not completely understood or accepted. What is not clear is the fact that vitamin B12 and folate deficiency deteriorate a pre-existing not overt pathological situation or can be dangerous even in normal subjects. Even more intriguing is the interaction between B12 and folate, and their role in developing hyperhomocysteinemia. The approach to the rehabilitation of the deficiency with adequate vitamin supplementation is very confusing. Some authors suggest it, even in chronic situations, others deny any possible role. Starting from these quite confusing perspectives, the aim of this review is to report and categorize the data obtained from the literature. Despite the plausible biochemical mechanism, further studies, based on clinical, neuropsychological, laboratory and (lastly) pathological features will be necessary to better understand this fascinating biochemical riddle.

Acido fólico: nutriente redescubierto / Folic acid: nutrient rediscover

Las funciones que en el organismo humano ejercen los folatos referentes a la formación de eritrocitos y leucocitos en la médula ósea y a la prevención de daños en el desarrollo del tubo neural del niño durante la gestación, han sido bien estudiadas. En los últimos años se han venido identificando funciones relacionadas con la salud cardiovascuar y el desarrollo de enfermedad tumoral de los individuos. A este respecto, en esta revisión la autora pretende resaltar las funciones que ejercen los folatos en la salud humana, relacionadas con los niveles de homocisteína en suero y con la síntesis y preparación del ADN, lo cual ha sido relacionado respectivamente con el desarrollo de enfermedades cuardiovasculares y algunos tipos de cáncer en humanos. Descriptores: Folatos, ácido fólico, homocisteína, enfermedad cardiovascular, enfermedad tumoral.

Acido Folico y depresion / Folic acid and major depressive disorder

La asociación entre deficiencia de ácido fólico y trastornos psiquiátricos ha sido estudiada y debatida desde el descubrimiento de esta vitamina en la década del 40. La relevancia clínica de esta deficiencia continúa siendo motivo de permanente investigación y ha sido inferida a partir de observaciones clínicas y de un mejor entendimiento del rol del folato en las vías metabólicas cerebrales. Este artículo hace una breve descripción de las características del acido fólico y su metabolismo, especialmente a nivel cerebral, así como una revisión de la literatura médica sobre la relación del ácido fólico y varios trastornos psiquiátricos, haciendo énfasis en el trastorno depresivo mayor

Acido Fólico y Vitamina B12 en la nutrición humana / Folic acid and vitamin B12 in human nutrition

La malnutrición es la causa más común de la defiencia de ácido fólico y cobalamina. La magnitud real de la deficiencia de folato no es bien conocida y la mayoría de las cifras están derivadas de la frecuencia de anemia en el embarazo; la deficiencia de cobalamina tiene mayor incidencia en los vegetarianos estrictos. Se estima que sólo la mitad del folato total de la dieta está disponible para ser absorbido. La cocción de los alimentos en grandes volúmenes de líquido destruye el folato de los vegetales verdes y de la carne, también se pueden perder así cantidades significativas de cobalamina. Por su implicación en las síntesis de ADN, ARN y el metabolismo de algunos aminoácidos, la defiencia de ácido fólico en el embarazo, principalmente antes del cierre del tubo neural, puede ocasionar daños en la formación de la médula espinal y el cerebro conduciendo a la aparición de anencefalia, espina bífida y encefalocele. La homocisteína como metabolito intermediario de la metionina y que requiere ácido fólico y cobalimina, se ha descrito como factor de riesgo para las enfermedades cardiovasculares. El envejecimiento está acompañado por un incremento del riesgo de deficiencia de cobalamina. Muchos adultos mayores sin antecedentes de anemia perniciosa tienen deficiencias clínicas o subclínicas de cobalamina, aparentemente debido a otros problemas de absorción

Partial characterization of folate uptake in microvillous membrane vesicles isolated from human placenta

The purpose of the present study was to determine biochemical parameters of folate uptake, and the putative contribution of the membrane-anchored folate receptor in microvillous membrane vesicles obtained from the syncytiotrophoblast of human term placenta. Uptake of [3H]-pteroylglutamic acid (PGA) by microvillous membrane vesicles was pH dependent with a maximum at pH 6.0, and attained equilibrium at 60 min of incubation. Uptake was higher in the presence of an inward pH gradient (pHout = 6.0; pHin = 7.5) than in the absence of the gradient (pHout = pHin = 6.0). The effect of changes in medium osmolality showed that both binding to the vesicular membrane and internalization contributed to the measured [3H]-PGA uptake. Equilibrium uptake experiments using [3H]-PGA concentrations within the physiological range of folate in blood serum showed that saturation was achieved at 30 nM and revealed a single class of binding sites with a Kd of 1.8 nM for [3H]-PGA. Cleavage of the glycosyl-phosphatidylinositol moiety of the folate receptor, which anchors the receptor to the membrane, with phosphatidylinositolspecific phospholipase C resulted in a reduction of about 80 per cent in [3H]-PGA uptake. In conclusion, our results showed that the folate uptake in the maternally facing membrane of the human placenta presents a saturable component and is mediated by the folate receptor to ensure an adequate maternal-fetal folate transfer.