Risk of colorectal cancer associated with the C677T polymorphism in 5,10-methylenetetrahydrofolate reductase in Portuguese patients depends on the intake of methyl-donor nutrients

Background: Polymorphisms located in genes involved in the metabolism of folate and some methyl-related nutrients are implicated in colorectal cancer (CRC). Objective: We evaluated the association of 3 genetic polymorphisms [C677T MTHFR (methylene tetrahydrofolate reductase), A2756G MTR (methionine synthase), and C1420T SHMT (serine hydroxymethyltransferase)] with the intake of methyl-donor nutrients in CRC risk. Design: Patients withCRC(n 196) and healthy controls (n 200) matched for age and sex were evaluated for intake of methyl-donor nutrients and the 3 polymorphisms. Results: Except for folate intake, which was significantly lower in patients (P 0.02), no differences were observed in the dietary intake of other methyl-donor nutrients between groups. High intake of folate ( 406.7 g/d) was associated with a significantly lower risk of CRC (odds ratio: 0.67; 95% CI: 0.45, 0.99). The A2756G MTR polymorphism was not associated with the risk of developing CRC. In contrast, homozygosity for the C677TMTHFRvariant (TT) presented a 3.0-fold increased risk of CRC (95% CI: 1.3, 6.7). Similarly, homozygosity for the C1420T SHMT polymorphism also had a 2.6-fold increased risk (95% CI: 1.1, 5.9) of developing CRC. When interactions between variables were studied, low intake of all methyl-donor nutrients was associated with an increased risk ofCRC in homozygous participants for the C677T MTHFR polymorphism, but a statistically significant interaction was only observed for folate (odds ratio: 14.0; 95% CI: 1.8, 108.5). No significant associations were seen for MTR or SHMT polymorphisms. Conclusion: These results show an association between the C677T MTHFR variant and different folate intakes on risk of CRC.

Regulation of antioxidant enzymes gene expression in the yeast Saccharomyces cerevisiae during stationary phase

Gene expression of three antioxidant enzymes, Mn superoxide dismutase (MnSOD), Cu,Zn superoxide dismutase (Cu,ZnSOD), and glutathione reductase (GR) was investigated in stationary phase Saccharomyces cerevisiae during menadione-induced oxidative stress. Both GR and Cu,ZnSOD mRNA steady state levels increased, reaching a plateau at about 90 min exposure to menadione. GR mRNA induction was higher than that of Cu,ZnSOD (about 14-fold and 9-fold after 90 min, respectively). A different pattern of response was obtained for MnSOD mRNA, with a peak at about 15 min (about 8-fold higher) followed by a decrease to a plateau approximately 4-fold higher than the control value. However, these increased mRNA levels did not result in increased protein levels and activities of these enzymes. Furthermore, exposure to menadione decreased MnSOD activity to half its value, indicating that the enzyme is partially inactivated due to oxidative damage. Cu,ZnSOD protein levels were increased 2-fold, but MnSOD protein levels were unchanged after exposure to menadione in the presence of the proteolysis inhibitor phenylmethylsulfonyl fluoride. These results indicate that the rates of Cu,ZnSOD synthesis and proteolysis are increased, while the rates of MnSOD synthesis and proteolysis are unchanged by exposure to menadione. Also, the translational efficiency for both enzymes is probably decreased, since increases in protein levels when proteolysis is inhibited do not reflect the increases in mRNA levels. Our results indicate that oxidative stress modifies MnSOD, Cu,ZnSOD, and GR gene expression in a complex way, not only at the transcription level but also at the post-transcriptional, translational, and post-translational levels.

Formação contínua: relatos e reflexões

Neste volume, intitulado “FORMAÇÃO CONTÍNUA: RELATOS E REFLEXÕES”, reúnem-se diversos tipos de documentos produzidos no âmbito do projeto “Qualificação dos Professores em Países Lusófonos” (Programa EU-ACP – EDULINK – ID Number 9 – ACP – RPR – 118#28) – que decorreu entre 31 de dezembro de 2008 e 31 de dezembro de 2011. O objetivo do projeto foi o de “dotar as Instituições do Ensino Superior (IES) de competências que lhes permitissem desenvolver um programa de formação contínua (FC) de professores para o Ensino Básico, de qualidade e culturalmente específico, em países onde o Português é a língua de ensino”. Participaram no projeto as Escolas Superiores de Educação de Lisboa e de Viana do Castelo (Portugal), a Universidade de Cabo Verde (Cabo Verde), o Instituto Superior Politécnico (São Tomé e Príncipe), a Universidade Pedagógica (Moçambique) e a Universidade Nacional de Timor (Timor Lorosae). A ONGD portuguesa Engenho e Obra participou com o estatuto de “associada”. De entre todas as ações desenvolvidas devem destacar-se os Seminários realizados em Portugal (Lisboa e Viana do Castelo), Cabo Verde (Cidade da Praia) e Moçambique (Maputo), intercalados com Visitas Intercalares às IES participantes. De realçar também, que cada IES desenvolveu, no seu país, um Programa de Formação Contínua de Professores. Constituiu- se ainda uma rede de aprendizagem online onde todos os materiais científicos e pedagógicos desenvolvidos foram disponibilizados. Trabalharam-se quatro áreas de formação: Qualidade da Educação e Desenvolvimento (QED); Ensino das Ciências (EC); Ensino da Matemática (EM); e Tecnologias da Informação e Comunicação (TIC). Este volume divide-se em três partes: – Na primeira, estão contidos os documentos estruturantes do projeto – o Sumário Executivo e o Quadro Lógico. Estes representam a filosofia subjacente e as ações que foram previstas e implementadas; – Na segunda, incluem-se textos de cada uma das quatro áreas de formação (QED; EC; EM; TIC), produzidos pelos participantes e que procuram ou relatar experiências e boas-práticas desenvolvidas durante a 6 Formação contínua – relatos e reflexões implementação local dos programas de formação contínua ou contextualizar a formação com reflexão teórico-prática adicional; – Na terceira, estão textos de conferências proferidas nos três Seminários e que procuraram contextualizar alguns dos problemas relativos aos processos e modelos de formação de professores, frequentemente com uma preocupação de estudo mais aprofundado da realidade dos países onde os Seminários decorreram. – Em anexo apresentam-se, os Planos de Trabalho que foram seguidos nos Seminários bem como uma lista de participantes. Os conteúdos dos textos são de exclusiva responsabilidade dos autores.

Cholesterol 24S-Hydroxylase overexpression inhibits the liver X receptor (LXR) pathway by activating small guanosine triphosphate-binding proteins (sGTPases) in neuronal cells

The neuronal-specific cholesterol 24S-hydroxylase (CYP46A1) is important for brain cholesterol elimination. Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal long-term potentiation, suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway. Conversely, transgenic mice overexpressing CYP46A1 show an improved cognitive function. These results raised the question of whether CYP46A1 expression can modulate the activity of proteins that are crucial for neuronal function, namely of isoprenylated small guanosine triphosphate-binding proteins (sGTPases). Our results show that CYP46A1 overexpression in SH-SY5Y neuroblastoma cells and in primary cultures of rat cortical neurons leads to an increase in 3-hydroxy-3-methyl-glutaryl-CoA reductase activity and to an overall increase in membrane levels of RhoA, Rac1, Cdc42 and Rab8. This increase is accompanied by a specific increase in RhoA activation. Interestingly, treatment with lovastatin or a geranylgeranyltransferase-I inhibitor abolished the CYP46A1 effect. The CYP46A1-mediated increase in sGTPases membrane abundance was confirmed in vivo, in membrane fractions obtained from transgenic mice overexpressing this enzyme. Moreover, CYP46A1 overexpression leads to a decrease in the liver X receptor (LXR) transcriptional activity and in the mRNA levels of ATP-binding cassette transporter 1, sub-family A, member 1 and apolipoprotein E. This effect was abolished by inhibition of prenylation or by co-transfection of a RhoA dominant-negative mutant. Our results suggest a novel regulatory axis in neurons; under conditions of membrane cholesterol reduction by increased CYP46A1 expression, neurons increase isoprenoid synthesis and sGTPase prenylation. This leads to a reduction in LXR activity, and consequently to a decrease in the expression of LXR target genes.