Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA-1 but not VLA-4 integrin mediated human T-cell adhesion.

Regulated adhesion of T cells by the integrins LFA-1 (lymphocyte function-associated antigen-1) and VLA-4 (very late antigen-4) is essential for T-cell trafficking. The small GTPase Rap1 is a critical activator of both integrins in murine lymphocytes and T-cell lines. Here we examined the contribution of the Rap1 regulatory pathway in integrin activation in primary CD3(+) human T cells.

Regulation of folate-mediated one-carbon metabolism by 10-formyltetrahydrofolate dehydrogenase.

10-Formyltetrahydrofolate dehydrogenase (FDH) catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to CO(2) and tetrahydrofolate (THF) and is an abundant high affinity folate-binding protein. Although several activities have been ascribed to FDH, its metabolic role in folate-mediated one-carbon metabolism is not well understood. FDH has been proposed to: 1) inhibit purine biosynthesis by depleting 10-formyl-THF pools, 2) maintain cellular folate concentrations by sequestering THF, 3) deplete the supply of folate-activated one-carbon units, and 4) stimulate the generation of THF-activated one-carbon unit synthesis by channeling folate cofactors to other folate-dependent enzymes.

Chronic cigarette smoking is associated with diminished folate status, altered folate form distribution, and increased genetic damage in the buccal mucosa of healthy adults.

Background: Smoking causes genetic damage in buccal cells and increases the risk of oral cancer. Because folate is instrumental in DNA synthesis and repair, it is a determinant of genetic stability and therefore might attenuate the genotoxic effects of smoking.

Objective: Our aim was to compare the presence of folate metabolites and select indicators of genetic damage in the mouths of chronic smokers and nonsmokers.

Homocysteine synthesis is elevated but total remethylation is unchanged by the methylenetetrahydrofolate reductase 677C->T polymorphism and by dietary folate restriction in young women.

The effects of folate status and the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism on the kinetics of homocysteine metabolism are unclear. We measured the effects of dietary folate restriction on the kinetics of homocysteine remethylation and synthesis in healthy women (20-30 y old) with the MTHFR 677 C/C or T/T genotypes (n = 9/genotype) using i.v.

The methylenetetrahydrofolate reductase 677C->T polymorphism and dietary folate restriction affect plasma one-carbon metabolites and red blood cell folate concentrations and distribution in women.

Whether folate status and the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism interact to affect methionine-cycle metabolite concentrations is uncertain. We evaluated the effects of dietary folate restriction on relations among folate status indices and plasma concentrations of methionine cycle metabolites in women with the MTHFR 677 C/C and T/T genotypes. Healthy, normohomocysteinemic women (n = 18; 20-30 y old) of adequate B vitamin status, and equally divided according to MTHFR 677C-->T genotype (9 C/C and 9 T/T) were recruited.

Methylenetetrahydrofolate reductase 677C->T polymorphism and folate status affect one-carbon incorporation into human DNA deoxynucleosides.

The methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism is thought to influence the partitioning of 1-carbon units between methylation and other components of 1-carbon metabolism and to influence the risk and etiology of several major cancers and cardiovascular disease. Our objective was to determine the effect of the MTHFR 677C-->T polymorphism and folate status on the relative rate and extent of in vivo synthesis of DNA precursors. Adequately nourished, healthy women (9 CC, 9 TT) were infused with [3-(13)C]serine and [(13)C(5)]methionine for 9 h before and after 7 wk of consumption of a low-folate diet.

Mice deficient in methylenetetrahydrofolate reductase exhibit tissue-specific distribution of folates.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), which is used for homocysteine remethylation to methionine, the precursor of S-adenosylmethionine (SAM). Impairment of MTHFR will increase homocysteine levels and compromise SAM-dependent methylation reactions. Mild MTHFR deficiency is common in many populations due to a polymorphism at bp 677.

Vitamin B-12 deficiency induces anomalies of base substitution and methylation in the DNA of rat colonic epithelium.

Derangements of one-carbon metabolism can directly affect the integrity of the genome by producing inappropriate uracil insertion into DNA and by altering patterns of DNA methylation. Vitamin B-12, a one-carbon nutrient, serves as a cofactor in the synthesis of precursors of biological methylation and in nucleotide synthesis. We therefore examined whether vitamin B-12 deficiency can induce these molecular anomalies in the colonic mucosa of rats.

Methenyltetrahydrofolate synthetase regulates folate turnover and accumulation.

Cellular folate deficiency impairs one-carbon metabolism, resulting in decreased fidelity of DNA synthesis and inhibition of numerous S-adenosylmethionine-dependent methylation reactions including protein and DNA methylation. Cellular folate concentrations are influenced by folate availability, cellular folate transport efficiency, folate polyglutamylation, and folate turnover specifically through degradation. Folate cofactors are highly susceptible to oxidative degradation in vitro with the exception of 5-formyltetrahydrofolate, which may be a storage form of folate.

Distribution of plasma folate forms in hemodialysis patients receiving high daily doses of L-folinic or folic acid.

Background: We have previously reported that a daily oral high dose of l-folinic acid for the treatment of hyperhomocysteinemia in hemodialysis patients does not provide significantly greater reduction in fasting total homocysteine (tHcy) levels than an equimolar dose of folic acid. The present study uses the affinity/HPLC method to analyze the distribution of plasma folate forms in patients who received l-folinic acid versus those who received folic acid. This was done to investigate claims that renal insufficiency is associated with impaired folate interconversion, a stance that is supportive of the premise that tHcy lowering in these patients is more efficacious with folinic acid and other reduced folates, than folic acid.

Plasma vascular endothelial growth factor in sleep apnea syndrome: effects of nasal continuous positive air pressure treatment.

Sleep apnea syndrome is associated with recurrent episodic hypoxia during sleep, which has been implicated in the development of cardiovascular morbidity. Hypoxia is the major stimulus of vascular endothelial growth factor (VEGF), which is a potent angiogenic cytokine. In the present article we describe the results of three experiments in which plasma concentrations of VEGF were measured in patients with sleep apnea.

Folate status and age affect the accumulation of L-isoaspartyl residues in rat liver proteins.

Formation of atypical L-isoaspartyl residues in proteins and peptides is a common, spontaneous and nonenzymatic modification of aspartyl and asparaginyl sites. The enzyme protein-L-isoaspartyl methyltransferase (PIMT) catalyzes the transfer of the methyl group of S-adenosyl-L-methionine (SAM) to these L-isoaspartyl sites, thereby allowing reisomerization and restoration of the original alpha peptide linkage. Because SAM is in part a product of folate metabolism, the present study was undertaken to determine the effects of folate deficiency on the presence of L-isoaspartyl residues in hepatic proteins.