Disruptions in folate metabolism are known to increase the risk for neural tube defects (NTD) and this is preventable by folic acid supplementation. However, the relationship between folate metabolism and cardiac development remains unclear. The interaction between other folate pathway nutrients, choline and riboflavin, and folate metabolism was studied in a murine model of methylenetetrahydrofolate reductase (MTHFR) deficiency. Maternal choline deficiency, riboflavin deficiency and MTHFR deficiency adversely affected embryonic or heart development. The promoters of MTHFR were also examined for interactions with GATA-4, TBX5, MEF2A and NKX-2.5, known transcription factors of cardiac development. Upstream promoter activity was increased in the presence of GATA-4 and this interaction was further enhanced upon the addition of MEF2A. TBX5 appeared to decrease upstream promoter activity. GATA-4 modestly increased downstream promoter activity. These results highlight the importance of adequate nutrient intake during pregnancy and provide a link between folate metabolism and cardiac development.

Folate deficiency, a prevalent vitamin deficiency in America, can stem from environmental and/or genetic causes. The most common inborn error of folate metabolism is deficiency of methylenetetrahydrofolate reductase (MTHFR), which catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Severe MTHFR deficiency results in hyperhomocysteinemia and homocystinuria; patients present with developmental delay, and various neurological and vascular disorders. This thesis describes three mutations identified in the MTHFR locus in patients with severe deficiency: 1025T→C (M→T), 1027T→G (W→G), and 1768G→A (E→K). Genotype-phenotype correlations are described, along with biochemical characterization of three mutations (983A→G (N→S), 1025T→C, 1027T→G). All three mutations exert their effect by decreasing Vmax without changing the enzyme's affinity for its substrate, 5-methyltetrahydrofolate. The 983A→G variant also conferred decreased affinity for FAD, a cofactor. / The more common and mild deficiency observed in the general healthy population is probably due in part to insufficient dietary intake of folate. Folate deficiency has been associated with increased risk for colon cancer. In a pilot study presented here, the impact of altered folate intake on tumor multiplicity in the Min mouse, a model for multiple intestinal neoplasia, was assessed. Folate deficient diets did not produce a consistent change in tumor numbers. However, a linear correlation between S-adenosylmethionine and S-adenosylhomocysteine content of preneoplastic tissue and tumor multiplicity was identified. / This thesis contributes to our understanding of the impact of genetic- and/or dietary-induced folate deficiency on cellular and organismal functions.

Orientadores: Carmen Silvia Passos Lima, Maria de Lourdes Setsuko Ayrizono / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T01:40:41Z (GMT). No. of bitstreams: 1 Guimaraes_JoseLuizMiranda_D.pdf: 4302732 bytes, checksum: 2d6604590176d72460b4a606d6ba2dd6 (MD5) Previous issue date: 2012 / Resumo: O desenvolvimento de câncer colorretal (CCR) é resultado de uma complexa interação de variáveis, incluindo elementos externos, como a exposição a agentes ambientais e dietéticos, e fatores internos, de natureza somática ou hereditária. Não está estabelecido se genótipos de polimorfismos de baixa penetrância em genes relacionados com o metabolismo do ácido fólico, como o metilenotetrahidrofolato redutase (MTHFR C677T e MTHFR A1298C), o metionina sintase (MTR A2756G), o metionina sintase redutase (MTRR A66G) e o timidilato sintase (TS 2R3R), estão associados com o risco de ocorrência da doença ou com suas manifestações clínicas. Portanto, o objetivo deste estudo foi verificar se esses polimorfismos gênicos influenciam o risco de ocorrência do adenocarcinoma colorretal esporádico (ACRE) e suas manifestações clínicas e biológicas em pacientes da região sudeste do Brasil. Foram avaliados 113 pacientes com ACRE e 188 controles, considerando os aspectos clínicos como a idade, o sexo, a raça, a localização, o grau de diferenciação do tumor, o estágio e os genótipos de cada gene. Os genótipos dos polimorfismos dos genes MTHFR, MTR, MTRR e TS foram avaliados por meio da reação em cadeia da polimerase (PCR) seguida ou não por digestão enzimática. O significado estatístico das diferenças entre grupos foi calculado por meio do teste da probabilidade exata de Fisher ou qui-quadrado. As determinações dos riscos de ocorrência do ACRE, a que pacientes e controles foram submetidos, foram obtidas por meio das razões das chances (ORs) e calculadas considerando um intervalo de confiança de 95%. Portadores dos genótipos MTRR 66AG+GG, do MTHFR 1298AC+CC+677CT+TT, do MTHFR 677CT+TT+MTR 2756AG+GG, do MTHFR 1298AC+CC + 677CT+TT + MTR 2756AG+GG e MTHFR 1298AC+CC + 677CT+TT + MTRR 66AG+GG apresentaram riscos 1,99, 3,26, 2,22, 10,92 e 14,88 vezes maiores, respectivamente, de desenvolver ACRE do que os outros. Além disso, os indivíduos com o genótipo MTHFR 677CT+TT e os genótipos MTR 2756AG+GG tiveram um risco de 2,12 e 1,42 vezes maior de desenvolver ACRE com idade menor do que 50 anos. Afro-Brasileiros com o genótipo GG do polimorfismo MTRR A66G tiveram risco 1,98 vezes maior de desenvolver ACRE, e indivíduos com o genótipo MTR 2756AG+GG e os genótipos MTHFR 677CT+TT estiveram sob risco 2,11 e risco 1,62 vezes maiores de ocorrência de tumores indiferenciados e avançados, respectivamente, do que os demais. Portadores dos genótipos MTHFR 1298AC+CC e MTHFR 1298AC+CC + MTRR 66AG+GG estiveram sob riscos 1,42 e 3,07 vezes maiores de tumor no reto, respectivamente, enquanto que portadores dos genótipos MTHFR 677CT+TT e MTHFR 677CT+TT + TS 2R3R+3R3R estiveram sob riscos 1,55 e 5,39 vezes maiores de tumor de cólon, respectivamente, do que portadores dos genótipos selvagens. Estes dados sugerem que polimorfismos dos genes MTHFR, MTR, MTRR e TS, que codificam enzimas que participam do metabolismo do ácido fólico, especialmente em combinação, têm papéis consistentes para o risco de desenvolver ACRE em indivíduos da região sudeste do Brasil / Abstract: The development of colorectal cancer (CRC) is the result of a complex interaction of variables, including external factors such as exposure to environmental agents and dietary factors and internal factors, whether somatic or hereditary. Is not been established genotypes with low penetrance polymorphisms in genes related to metabolism of folic acid such as methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase (TS 2R3R), are associated with the risk of the disease or its clinical manifestations. Therefore, the aim of this study was to determine whether these genetic polymorphisms influence the risk of sporadic colorectal adenocarcinoma (SCA) and their clinical and biological manifestations in patients from southeast Brazil. For this, we analyzed 113 patients with SCA and 188 controls, considering the clinical aspects such as age, sex, race, location, stage, degree of tumor differentiation and the genotypes of each gene described above. The genotypes of the polymorphisms of the MTHFR, MTR, MTRR and TS were assessed by polymerase chain reaction (PCR) and enzyme digestion. The statistical significance of differences between groups was calculated using the probability test of Fisher's exact or chi-square. Determination of the risks of SCA, the patients and controls were submitted, was obtained through the odds ratios (ORs) and calculated assuming a range of 95%. Carriers of the MTRR 66AG + GG, the MTHFR 1298AC+CC + 677CT+TT, the MTHFR 677CT+TT + MTR 2756AG+GG, the MTHFR 1298AC+CC + 677CT+TT + MTR 2756AG+GG, and the MTHFR 1298AC+CC + 677CT+TT + MTRR 66AG+GG genotypes had a 1.99, a 3.26, a 2.22, a 10.92 and a 14.88-fold increased risks for SCA than others, respectively. In addition, individuals with the MTHFR 677CT+TT and the MTR 2756AG+GG genotypes had a 2.12 and a 1.42-fold increased risks for SCA diagnosed under 50 years. African-Brazilians with the MTRR 66GG genotype had a 1.98-fold increased risk for SCA, and individuals with the MTR 2756AG+GG and the MTHFR 677CT+TT genotypes were under a 2.11 and a 1.62-fold increased risks for undifferentiated and advanced tumors, respectively, than others. Carriers of the MTHFR 1298AC+CC and the MTHFR 1298AC+CC + MTRR 66AG+GG genotypes had a 1.42 and a 3.07-fold increased risks for rectal tumor, respectively, while carriers of the MTHFR 677CT+TT and the MTHFR 677CT+TT + TS 2R3R+3R3R genotypes had a 1.55 and a 5.39-fold increased risks for colon tumor, respectively, than carriers of the wild genotypes. This data suggest that polymorphisms of genes MTHFR, MTR, MTRR and TS, which encode folate-dependent enzymes, particularly in combination, have consistent roles for SCA risk in southeastern Brazil / Doutorado / Fisiopatologia Cirúrgica / Doutor em Ciências

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<p>Cilj ovog istraživanja je bio da se utvrdi nivo folne kiseline u serumu (fiziolo&scaron;ka vrednost je od 16,31 do 34,88 nmol/l) i proceni težina kliničke slike instrumentima kliničke procene (HAMD 17 i 21, MADRS i CGI skala) u populaciji bolnički lečenih pacijenata, koji boluju od te&scaron;ke depresivne epizode, ili rekurententog depresivnog poremećaja, i njihov odgovor na inicijalnu antidepresivnu terapiju sprovođenu prema smernicama nacionalnog vodiča. Odgovor na antidepresivnu terapiju je određivan nakon četiri i osam nedelja lečenja u odnosu na nivo folne kiseline i prema nadoknadi folne kiseline u dozi od 15 mg dnevno (kod pacijenata koji nisu adekvatno odreagovali na terapiju). Smatrano je da je antidepresivni odgovor adekvatan ukoliko je utvrđena redukcija skora na HAMD (17, 21) i MADRS za 50%. Istraživanje je obuhvatilo 102 pacijenata (69 osoba ženskog pola i 33 osobe mu&scaron;kog pola) starosti između 18 i 70 godina života. Utvrđeno je da je snižen nivo folne kiseline u krvi imalo 41,2% pacijenata.<em> X</em>² testom je ustanovljeno da postoje značajne razlike nivoa folne kiseline u krvi u odnosu na pol. Snižen nivo folne kiseline je zastupljeniji kod osoba mu&scaron;kog pola. Pacijenati sa sniženim nivoom folne kiseline su imali inicijalno značajno vi&scaron;e skorove na skalama kliničke procene i izostanak adekvatnog terapijskog odgovora u četvrtoj nedelji lečenja. U osmoj nedelji lečenja se ta razlika u terapijskom odgovoru izgubila. Utvrđena je statistički značajna razlika u skorovima na HAMD (17) i MADRS u tri merenja u zavisnosti od nivoa folne kiseline i nadoknade uz upotrebu vi&scaron;esmerne me&scaron;ovite analize varijanse (ANOVA). Utvrđeno je da postoji značajan glavni efekat merenja (skorovi se značajno razlikuju od merenja do merenja), i značajan efekat interakcije merenja i nadoknade.</p> / <p>The aim of this paper is to establish the levels of folic acid in serum (physiological values is from 16.31 to 34.88 nmol/l) and the assessment of seriousness of clinical picture by clinical assessment instruments (HAMD 17 and 21, MADRS and CGI scales) in the population of hospitalized patients suffering from severe depressive episodes, or recurrent depressive disorder, and their response to the initial anti-depressant therapy administered according to national guidelines. The response to anti-depressant therapy was determined after four or eight weeks of treatment in relation to the levels of folic acid and according to recuperation of folic acid in the dose of 15 mg daily (in patients who did not react adequately to the therapy). It was believed that the anti-depressive response was satisfying in case of the established score reduction on HAMD (17, 21) and MADRS for 50%. The research encircled 102 patients (69 of whom female patients and 33 males) aged between 18 and 70. A reduced level of folic acid in blood was found in 41.2% of the patients. By<em> X</em>² test determined that there were significant differences in the levels of folic acid in relation to the patient gender. A reduced level was more found in male patients. The patients with reduced levels of folic acid had initially significantly higher scores on clinical assessment scales and the lack of an adequate therapeutic response in the fourth week of the treatment. In the eighth week of the treatment that difference vanished in therapeutic response. A statistically significant difference was determined on HAMD (17) and MADRS during three measurements depending on the levels of folic acid and its recuperation by using a multiway diverse analysis of variance (ANOVA). It was determined that there is a significant central effect of measurements (scores significantly differ from measurement to measurement), as well as an effect of interaction of measurements and the recuperation.</p>

Anemia and micronutrient deficiencies in infancy are common in low-income settings. These are partly due to maternal malnutrition and may impair child health and development. We studied the impact of maternal food and micronutrient supplementation, duration of exclusive breastfeeding (EBF), growth and infection on infant anemia and micronutrient status. In the MINIMat trial in Matlab, Bangladesh, pregnant women were randomized to Early or Usual promotion of enrolment in a food supplementation program and to one of three daily micronutrient supplements. Capsules containing 400µg folic acid and (a) 30 mg iron (Fe30Fol), (b) 60 mg iron (Fe60Fol), (c) 30 mg iron and other micronutrients (MMS) were provided from week 14 of gestation. Capsule intake was assessed with the eDEM device recording supplement container openings. Blood samples (n=2377) from women at week 14 and 30 were analyzed for hemoglobin (Hb). Duration of EBF and infant morbidity was based on monthly maternal recalls. Infants were weighed and measured monthly. Blood samples (n=1066) from 6-months-old infants were analyzed for Hb and plasma ferritin, zinc, retinol, vitamin B12 and folate. In women, Hb increase per capsule reached a plateau at 60 Fe60Fol capsules, indicating that nine weeks of daily supplementation produced maximum Hb response. Anemia was common (36%) at capsule intakes &gt;60 indicating other causes of anemia than iron deficiency. In infants, vitamin B12 deficiency prevalence was lower in the MMS (26.1%) than in the Fe30Fol group (36.5%), (p=0.003) and zinc deficiency prevalence was lower in the Usual than in the Early group. There were no other differential effects of food or micronutrient supplementation on infant anemia or micronutrient status. Infants exclusively breast-fed for 4-6 months had a higher mean plasma zinc concentration (9.9±2.3 µmol/L) than infants exclusively breast-fed for &lt;4 months (9.5±2.0 µmol/L), (p&lt; 0.01). No other differences in anemia, iron or zinc status were observed between EBF categories. Infection, low birth weight and iron deficiency were independent risk factors for infant anemia. Regardless of studied interventions, prevalence of anemia (43%), deficiency of zinc (56%), vitamin B12, vitamin A (19%) and iron (22%) in infancy was high and further preventive strategies are needed. / MINIMat

Diss. (sammanfattning) Linköping : Univ., 2004. / Härtill 4 uppsatser.

Dissertation (D.P.H.)--University of Michigan.