Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low dietary folate and deficiency of methylenetetrahydrofolate reductase (Mthfr) were reported to increase the risk for congenital heart defects, but contributory mechanisms have not been elucidated. Because low folate and absent MTHFR activity were shown to affect proliferation and apoptosis in developing neural tissue, we examined these processes in the myocardium of embryos from Mthfr +/+ and Mthfr +/- mice fed control diets (CD) or folic acid-deficient diets (FADD). Mice consumed the designated diets for 8 wk, from weaning and through pregnancy until they were killed. Embryos were assessed on gestational day 12.5 for myocardial proliferation by 5-bromo-2'-deoxyuridine (BrdU) labeling and for apoptosis by TdT-mediated dUTP nick end labeling staining and caspase 3/7 activity assays. FADD-treated dams had significantly higher resorption rates than CD-treated dams. Embryonic lengths and weights from FADD-treated dams were significantly lower than those from CD-treated dams; the smallest embryos were those of the Mthfr +/- dams that consumed the FADD, with effect of genotype tending to be significant (P = 0.09). The thickness of cardiac ventricular compact walls of embryos from FADD-treated dams was significantly reduced, and embryonic myocardium from FADD-treated dams had significantly fewer BrdU-labeled cells compared with CD-treated dams, with no differences in apoptosis due to the diets. Genotype did not affect proliferation or apoptosis. Our results suggest that proliferation of embryonic myocardium is sensitive to maternal dietary folate and that folate supplementation during pregnancy is important for normal heart development and prevention of heart defects.
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PMID:Maternal folate deficiency affects proliferation, but not apoptosis, in embryonic mouse heart. 1677 36

Folates are essential for DNA synthesis and methylation reactions. The antifolate methotrexate (MTX) is a widely used chemotherapeutic drug which inhibits DNA synthesis and induces apoptosis. Changes in activity of a critical folate-metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR), might alter the chemosensitivity to MTX, as the MTHFR substrate is required for nucleotide synthesis and its product is used in homocysteine remethylation to methionine. Mild MTHFR deficiency is common in many populations due to a polymorphism at bp 677. We previously showed that altered expression of MTHFR enhanced MTX-induced myelosuppression in mice. To determine the cause of the impaired hematopoietic profile in mice with decreased or increased MTHFR expression, we evaluated MTX-induced apoptosis in the major hemolytic organ, spleen, using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining and caspase-3/7 activity assays, in MTHFR-deficient mice and in MTHFR-overexpressing mice after MTX administration. Decreased or increased expression of MTHFR in mice significantly increased TUNEL-positive cells and caspase-3/7 activities in MTX-treated spleen, compared with that of wild-type littermates. Plasma homocysteine levels correlated with apoptotic index in MTX-treated MTHFR-deficient mice and dUTP/dTTP ratios correlated with apoptotic index in MTX-treated MTHFR-overexpressing mice. The increased apoptosis may therefore relate to hyperhomocysteinemia and deoxyribonucleotide pool imbalances, respectively. Our results suggest that MTHFR underexpression and overexpression enhances MTX-induced apoptosis and myelosuppression, and that genotyping for the MTHFR polymorphism may have therapeutic implications.
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PMID:Methotrexate-induced apoptosis is enhanced by altered expression of methylenetetrahydrofolate reductase. 1959 6