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Effect of lead acetate on rats fed diets containing low levels of folic acid.

Nutritional factors such as deficiencies of calcium, iron, and protein alter susceptibility to the toxic effects of lead. While the suggestion has been made that vitamins may also influence lead toxicity, possible interactions have not been well documented. The present studies were performed to determine if a dietary deficiency of folic acid enhances the susceptibility to rats of the toxic effects of lead acetate. Lead exposure during the development of folate deficiency resulted in alterations in two of the parameters diagnostic of the individual conditions. Decreases in erythrocyte mean corpuscular volume (MCV) occur during lead poisoning, while increases occur during the development of folate deficiency. In the present study, significant reductions in MCV were observed in both the control + lead and in the low folate + lead groups. The increased MCV characteristic of folate deficiency was prevented by the concomitant lead exposure. Elevations in free erythrocyte protoporphyrin (FEP) levels are characteristic of lead intoxication; in contrast, FEP levels decline during folate deficiency. In the present study, FEP levels were significantly elevated only in the control + lead group. Values in the low folate + lead group were intermediate between those of the control and the control + lead groups, but did not differ significantly from those in the low folate group. The expected lead-induced elevation in FEP levels was diminished by the reduced erythropoiesis characteristic of folate deficiency.

Aminolevulinic Acid↗

A modified fecal excretion test for assaying intestinal absorption of 3H-folic acid.

A method for determination of the intestinal absorption of folic acid is described. It is based on the principle of double tracer technique in assay of fecal samples using gas proportional counting for 3H determinations. As the procedure is simple, reliable, and inexpensive, it is considered to be of value for laboratories without advanced equipment for radiochemical assay.

Cobalt Radioisotopes↗

Folic acid.

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Folic Acid↗

Folic acid dependent hypersarcosinaemia.

Hypersarcosinaemia is a rare inborn error of metabolism, caused by a deficiency of the sarcosine dehydrogenase complex with tetrahydrofolate as a formaldehyde acceptor needed for the sarcosine-glycine conversion. Prolonged therapy with folic acid on a hypersarcosinaemic patient resulted in a significant effect on the urinary excretion of sarcosine, leading to the conclusion that the patient has a folic acid dependent hypersarcosinaemia.

Amino Acid Metabolism, Inborn Errors↗

Disposable microfluidic ELISA for the rapid determination of folic acid content in food products.

A micro-analytical system for rapid and quantitative analysis by inhibition immunoassay is presented and applied to the detection of folic acid. Eight polymer microchannels of 65-nL volume each and containing microelectrodes are embedded in a cartridge so that they can be operated simultaneously. All fluidic steps as well as the amperometric detection in the channels are operated by an instrument and software developed in-house. The fluidic steps of the immunoassay occur through hydrodynamic loading of the different solutions through the channels. The speed and duration of the flow and incubation parameters can thus be adapted to the biological and testing requirements. The effectiveness of the system was demonstrated by analysing folic acid concentrations in real infant formula samples within 5 min. In an effort to get a fully monitored assay, each fluidic step is monitored thanks to continuous amperometric detection of oxygen in the microchannel.

Alkaline Phosphatase↗

An audit of methotrexate and folic acid for rheumatoid arthritis. Experience from a teaching centre.

We describe an audit of 158 patients with RA treated with weekly methotrexate and 5 mg of folic acid 24 h later. Our aim was to assess the safety and efficacy of this regime in our hands compared with published clinical trials of methotrexate in RA, and to examine patient outcomes. Treatment improved ESR, but only 69% of patients continuing therapy for prolonged periods believed their arthritis to be better on treatment. Health Assessment Questionnaire and Hospital Anxiety and Depression questionnaire scores in prospectively studied patients were not significantly altered by treatment. Toxicity occurred frequently (59% in those continuing and 89% in those ceasing therapy) and cessation of therapy solely due to lack of efficacy was rare. The probability of patients continuing with methotrexate and folic acid after 1, 2, 3 and 4 yr was 87, 76, 74 and 74%, respectively, figures that are at the upper end of the reported range for methotrexate alone.

Adult↗

Folic acid and homocysteine in age-related disease.

It has been known for decades that babies born to women that have a dietary deficiency in folic acid (folate) are at increased risk for birth defects, and that the nervous system is particularly susceptible to such defects. Folate deficiency in adults can increase risk of coronary artery disease, stroke, several types of cancer, and possibly Alzheimer's and Parkinson's diseases. Recent findings have begun to reveal the cellular and molecular mechanisms whereby folate counteracts age-related disease. An increase in homocysteine levels is a major consequence of folate deficiency that may have adverse effects on multiple organ systems during aging. Humans with inherited defects in enzymes involved in homocysteine metabolism, including cystathionine beta-synthase and 5,10-methylenetetrahydrofolate reductase, exhibit features of accelerated aging and a marked propensity for several age-related diseases. Homocysteine enhances accumulation of DNA damage by inducing a methyl donor deficiency state and impairing DNA repair. In mitotic cells such DNA damage can lead to cancer, while in postmitotic cells such as neurons it promotes cell death. The emerging data strongly suggest that elevated homocysteine levels increase the risk of multiple age-related diseases, and point to dietary supplementation with folate as a primary means of normalizing homocysteine levels and increasing healthspan.

Aged↗

Ribosomal protein S6 kinase is activated after folic acid injury and epidermal growth factor administration but not after unilateral nephrectomy in the rat kidney.

Following loss of functional renal mass induced by a single parenteral injection of folic acid, the increased proliferation of tubular epithelium to replace injured and necrotic cells was associated with S6 kinase activation and enhanced phosphorylation of this ribosomal protein in vitro, EGF administered 1.5 h after folic acid promoted the phosphorylation of S6 protein and accelerated the regenerative repair process. In contrast, the hypertrophic response of the kidney following uninephrectomy was not associated with S6 kinase activation. The results of this study suggest a close correlation between levels of S6 protein phosphorylation and the degree of cell proliferation in the rat kidney.

Animals↗

Effect of folic acid treatment in the fragile X syndrome.

The effect of folic acid intake on the frequency of fragile X positive cells and some behavioural characteristics were evaluated in 5 boys and 4 adult males with the fragile X syndrome. The expression of fragile X was nullified in 6 and decreased in 3 of the 9 patients. Behavioural and motor ability were considered to have improved in 4 of the 5 boys but not in the 4 adults with fragile X syndrome.

Adolescent↗

Intake of fruits, vegetables, folic acid and related nutrients and risk of breast cancer in postmenopausal women.

OBJECTIVE: To determine the role of fruit and vegetable consumption and dietary intake of folic acid and related nutrients such as methionine, cysteine and alcohol in the aetiology of breast cancer. DESIGN: Population based case-control study. SETTING: Part of the European Community Multicentre Study on Antioxidants, Myocardial Infarction, and Cancer of the Breast (EURAMIC) in Berlin, Germany. SUBJECTS: As part of the EURAMIC study, dietary intake data were collected in 43 postmenopausal women diagnosed with breast cancer between 1991 and 1992 in Berlin, Germany, and compared to 106 population-based controls. RESULTS: Odds ratios (ORs) adjusted for major risk factors of breast cancer but not for total energy intake showed a non-significant inverse association between a high intake of vegetables (OR=0.76, 95% CI=0.48-1.20) and fruits (OR=0.74, 95% CI=0.48-1.15) and breast cancer. Once results were adjusted for total energy intake the associations became much weaker (vegetables: R=0.86, 95% CI=0.51-1.46; fruits: OR=0.82, 95% CI=0.51-1.32). For all nutrients, the effect of energy adjustment was more profound and the inverse associations disappeared when results were adjusted for energy intake (total folate-not energy adjusted: OR = 0.79, 95% CI=0.51-1.21; energy adjusted: OR=1.14, 95% CI=0.73-1.79; folate equivalents-not energy adjusted: OR=0.81, 95% CI=0.53-1.23; energy adjusted: OR=1.16, 95% CI=0.78-1.74; methionine-not energy adjusted: OR=0.60, 95% CI=0.35-1.03; energy adjusted: OR=1.29, 95% CI=0.76-2.19; cysteine-not energy adjusted: OR=0.52, 95% CI=0.29-0.94; energy adjusted: OR=1.22, 95% CI=0.75-1.97). Alcohol intake was inversely associated with breast cancer in a non-significant way, possibly due to the relatively low alcohol intake of the study population. CONCLUSIONS: The results of this study do not provide firm evidence that a high intake of fruits and vegetables, folic acid, methionine or cysteine reduces the risk of getting breast cancer.

Adult↗

Heritable fragile sites on human chromosomes. VIII. Preliminary population cytogenetic data on the folic-acid-sensitive fragile sites.

The incidence of the autosomal folic-acid-sensitive fragile sites in 524 institutionalized retardates (.0095) was found to be significantly higher than in 1,019 unselected neonates (.00098), suggesting that heterozygosity for these fragile sites may not be as harmless as previously thought. When one of the parents of an index case was found to carry the fragile site, that parent was always the mother. The fragile site at Xq27 was not found among the neonates studied, but was present in 1.6% of the institutionalized retarded males examined; if this fragile site occurs in normal males, then it does so rarely. Further cytogenetic studies of fragile sites are required on both normal and abnormal populations.

Adolescent↗

Competitive inhibition of folic acid absorption in rat jejunum by triamterene.

Triamterene, a diuretic agent, has been reported to cause megaloblastic anemia in some patients. Because this drug is a pteridine derivative, we investigated its effect on folic acid absorption in the rat jejunum. In an in vivo intestinal loop method, triamterene inhibited the intestinal absorption of folic acid in a dose-dependent fashion, with 50% inhibition of systemic absorption occurring at a luminal concentration of 0.01 mmol/L of triamterene. Kinetic analysis using the influx chamber method demonstrated that triamterene is a competitive inhibitor of intestinal folate transport, with a Ki of 0.125 mmol/L. Because therapeutic doses can result in luminal concentration of the drug approximating or exceeding the Ki, the interaction between triamterene and folate absorption is potentially of clinical interest.

Animals↗

Arsenate-induced neural tube defects not influenced by constant rate administration of folic acid.

Serious suggestions have been made that dietary supplementation with folic acid (FA) and perhaps other vitamins during pregnancy may reduce the incidence of neural tube defect (NTD) in human newborns. The purpose of these experiments was to evaluate the effect of continuous infusion of FA on the incidence of NTDs induced by arsenate. This teratogen induces NTDs in up to 90% of golden hamster fetuses when administered acutely during critical stages of embryogenesis. FA was administered by subcutaneously implanted osmotic minipumps beginning on the 6th day of gestation, 48 h before an acutely administered dose of sodium arsenate. The protective effect of FA was examined at three teratogenic dose levels of arsenate: optimal, with 905 NTDs, intermediate, with 38% NTDs, and low, with 20% NTDs. Fetuses were recovered at day 13 of gestation and examined for NTDs and other malformations. Maternal red cell folate levels were determined on day 8, 48 h after implantation of the pumps. The results show that the maternal red blood cell level of FA can be significantly increased within 48 h by chronic infusion to levels which are almost two times (550 ng/ml) control levels. There was no significant protection against arsenate-induced NTDs following FA supplementation at any of three levels of this teratogen.

Animals↗

Chemistry and antitumor evaluation of selected classical 2,4-diaminoquinazoline analogues of folic acid.

A series of six 2,4-diaminoquinazoline analogues of folic acid which bear close structural resemblance to methotrexate, 1a, were synthesized by unequivocal routes. Three of these have not been described previously, while complete structural characterization of the remaining compounds is presented for the first time. Each of the compounds was a potent inhibitor of dihydrofolate reductase (DHFR) from rat liver or L1210 leukemia cells having I50 values in a range similar to that of 1a. However, a wide divergence in inhibitory activity toward the growth of human gastrointestinal adenocarcinoma or L1210 leukemia cells in vitro was observed. Compounds having a normal folate configuration at positions 9 and 10 were more inhibitory than their isomeric reversed-bridge counterparts. The N-formyl modifications were the least active of the compounds studied. Unsubstituted or N-methyl modifications competed effectively with tritiated 1a for uptake into L1210 leukemia cells, while N-formyl modifications did not. Against an L1210 cell line resistant to 1a by virtue of altered transport and overproduction of DHFR, partial but not complete cross-resistance was observed for certain analogues. Of the three compounds selected for in vivo evaluation against L1210 leukemia in mice, two had a similar level of antitumor activity to that of 1a. The compound 5,8-dideazamethopterin, 2b, however, was slightly more active than 1a but at substantially reduced dose levels.

Adenocarcinoma↗

High- but not low-dose folic acid improves endothelial function in coronary artery disease.

BACKGROUND: While folic acid (FA) reduces plasma homocysteine (Hcy), whether the simultaneous improvement in endothelial function is dependent on Hcy lowering per se is questionable. In the present study the relationship between FA dose, Hcy lowering and endothelial function in patients with coronary artery disease (CAD) was investigated. MATERIALS AND METHODS: Eighty-four patients with CAD received either 400 microg FA or 5 mg placebo daily for a 6-week treatment period. A further 44 patients with CAD received either 100 mg kg(-1) day(-1) of betaine or placebo for a 6-week treatment period. Flow-mediated dilatation (FMD), a measure of endothelial function, was assessed before and after the 6-week periods. Isometric tension and Western blotting were used to investigate the effect of FA on endothelial function and endothelial nitric oxide synthase (eNOS) dimerization in isolated rabbit aortic rings and cultured porcine aortic endothelial cells (PAEC), respectively. RESULTS: Both 400 micro g day(-1) and 5 mg day(-1) FA significantly increased plasma folate and decreased plasma Hcy. The FMD improved significantly after 6 weeks' treatment of 5 mg day(-1) FA but did not correlate with the reduction in Hcy. There was no change in FMD in either the 400 micro g FA or placebo group. In a subgroup analysis of 11 patients in the betaine group, despite a reduced Hcy, a significant impairment in FMD was observed. In the in vitro studies FA, but not betaine, reversed methionine-induced endothelial dysfunction. Moreover, the FA promoted eNOS dimerization in cultured PAEC. CONCLUSIONS: These data suggest that FA dose-dependently improves endothelial function in CAD via a mechanism independently of Hcy lowering. It may involve promotion of eNOS dimerization.

Aged↗