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PubMed1999

Folic acid inhibits homocysteine-induced proliferation of human arterial smooth muscle cells.

PURPOSE: An elevated plasma homocysteine level has been identified as an independent risk factor for atherosclerosis. Whether this represents a marker for vascular disease or a direct effect on the vasculature remains unclear. Because vascular smooth muscle cells (VSMCs) play an integral role in the atherosclerotic process, we studied the effect of homocysteine on human infragenicular VSMC proliferation and the role of folic acid in reversing the homocysteine effect. METHODS: Human infragenicular VSMCs harvested from amputation specimens were studied. Various cell groups were exposed to physiologic (6.25 micromol/L and 12.5 micromol/L) and pathologic (25 micromol/L to 500 micromol/L) concentrations of homocysteine. Similar groups were simultaneously exposed to 20 nmol/L of folic acid. Cell counts and DNA synthesis, as reflected by [methyl-(3)H]-thymidine incorporation, were performed at 6 days and 24 hours, respectively. Additional groups were exposed to various combinations of folic acid (20 nmol/L), vitamin B(6) (145 nmol/L), and vitamin B(12) (0.45 nmol/L) in the presence of homocysteine (25, 50, and 250 micromol/L). RESULTS: Homocysteine resulted in a dose-dependent increase in DNA synthesis and cell proliferation. Cell counts increased significantly at homocysteine concentrations ranging from 25 micromol/L to 500 micromol/L (P <.05), with a maximal increase of 98% at 500 micromol/L of homocysteine. The addition of 20 nmol/L folic acid resulted in significant inhibition of cell proliferation at all homocysteine concentrations studied (P <.001). Maximal inhibition of 70% occurred in the cells exposed to 50 micromol/L of homocysteine. The increases in [methyl-(3)H]-thymidine incorporation ranged from 36% at 6 micromol/L homocysteine to a maximum of 247% at 500 micromol/L homocysteine. All increases were statistically significant (P <.05). The addition of 20 nmol/L folic acid resulted in significant inhibition of DNA synthesis (P <.002). Vitamins B(6) and B(12) did not demonstrate significant antiproliferative properties. CONCLUSION: A possible role of homocysteine in the formation of atherosclerotic lesions is through a direct proliferative effect on VSMCs in a dose-dependent fashion. Folic acid intake at levels available in dietary supplements may prove protective in hyperhomocysteinemia-induced atherosclerosis. Vitamins B(6) and B(12) alone do not appear to exhibit a substantial inhibitory effect in the setting of elevated homocysteine levels.

Cell Division↗
PubMed1997

Inadequate calcium, folic acid, vitamin E, zinc, and selenium intake in rheumatoid arthritis patients: results of a dietary survey.

OBJECTIVES: To determine the adequacy of calcium, folic acid, vitamin E, zinc, and selenium intake in patients with rheumatoid arthritis (RA). METHODS: We conducted an observational study on 48 patients (13 men, 35 women; mean age, 64.5 years) with RA attending a specialty clinic in New Zealand comparing their dietary intake as measured by a 5-day dietary survey with recommended dietary intake (RDI) guidelines. Information on disease activity, functional ability, and drug therapy also was obtained. RESULTS: The percentage of patients who achieved the RDI was 23% for calcium, 46% for folic acid, 29% for vitamin E, 10% for zinc, and only 6% for selenium. Patients on methotrexate had a significantly reduced intake of folic acid as a percentage of RDI (P < .05) compared with those on other therapies. In contrast, dietary intake of iron and protein was largely adequate and unrelated to anemia. CONCLUSIONS: Patients with RA should receive dietary education or supplementation to bring their intake of calcium, folic acid, vitamin E, zinc, and selenium up to the RDI.

Adult↗
PubMed1980

Histochemical localization of folic acid in the cells.

Smears, fresh cryotome sections (dried at 4 degrees C for 24 h), and deparaffinized sections were used for the "in situ" localization of folic acid. After irradiation with ultraviolet light, folic acid breaks down into a pteridine and a diazotizable amine. After oxidation and a brief hydrolysis, glyoxylic acid formed from the pteridine can be vizualized by a coupling agent, indicating the sites of folic acid in the cell.

Animals↗
PubMed2006

Effect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: community-based, cluster-randomised, placebo-controlled trial.

INTRODUCTION: Iron deficiency is widespread in the developing world and is especially common in young children who live on the Indian subcontinent. Supplementation with iron and folic acid alleviates severe anaemia and enhances neurodevelopment in deficient populations, but little is known about the risks of mortality and morbidity associated with supplementation. METHODS: We did a community-based, cluster-randomised, double-masked, placebo-controlled, 2x2 factorial trial in children aged 1-36 months and residing in southern Nepal. We randomly assigned children daily oral supplementation to age 36 months with: iron (12.5 mg) and folic acid (50 microg; n=8337), zinc alone (10 mg), iron, folic acid, and zinc (n=9230), or placebo (n=8683); children aged 1-11 months received half the dose. Our primary outcome measure was all-cause mortality, and our secondary outcome measures included cause-specific mortality and incidence and severity of diarrhoea, dysentery, and acute respiratory illness. Analyses were by intention to treat. This study is registered at , number NCT00109551. FINDINGS: The iron and folic acid-containing groups of the study were stopped early in November, 2003, on the recommendation of the data and safety monitoring board; mortality in these groups did not differ from placebo and there was low power to detect positive or negative effects by the time enrollment was completed. We continued to enroll children to the placebo and zinc alone groups. 25,490 children participated and analyses are based on 29,097.3 person-years of follow-up. There was no difference in mortality between the groups who took iron and folic acid without or with zinc when compared with placebo (HR 1.03, 95% CI 0.78-1.37, and 1.00, 0.74-1.34, respectively). There were no significant differences in the attack rates for diarrhoea, dysentery, or respiratory infections between groups, although all the relative risks except one indicated modest, non-significant protective effects. INTERPRETATION: Daily supplementation of young children in southern Nepal with iron and folic acid with or without zinc has no effect on their risk of death, but might protect against diarrhoea, dysentery, and acute respiratory illness.

Anemia, Iron-Deficiency↗
PubMed1986

Role of sodium ion in transport of folic acid in the small intestine.

The effect of sodium on folate transport across the intestinal luminal membrane was analyzed using two techniques: the "influx" chamber and isolated brush-border membrane vesicles. Preincubation of tissue in Na+-free medium did not have a consistent effect on folic acid influx provided that Na+ was present in the test solution. Replacement of Na+ in the test solution by choline+ resulted in a significant reduction of folic acid influx. However, when intestinal sheets that had been equilibrated in Na+-free solution were exposed to test solution containing either Na+, Li+, K+, Rb+, Cs+, Tris+, or guanidinium+ as main cations, folic acid influx was not significantly decreased. Concentration-dependence studies showed that replacement of Na+ by Rb+ did not affect the saturable mechanism of folate transport. Rather, a decrease in nonsaturable folic acid uptake accounted for the slightly reduced influx observed in the presence of Rb+. Experiments with brush-border membrane vesicles revealed that methotrexate uptake was significantly higher in the presence of external Na+ than in the presence of K+, but was not different from uptake in the presence of K+ plus valinomycin. These data suggest that the saturable component of folate transport is not Na+ dependent, and nonsaturable transport of folic acid across the luminal membrane occurs in part through a conductive pathway that involves a negatively charged species of folate and a cation whose membrane permeability affects the rate of folate transport. The importance of Na+ in this process in vivo derives from the fact that Na+ is the most permeant cation available at the absorptive site in the small intestine.

Animals↗
PubMed1987

Differential effects of stimulus termination on excitation and desensitization of folic acid receptors and guanylate cyclase in Dictyostelium discoideum.

The response of guanylate cyclase to addition of extracellular stimuli is well documented. Here we report for the first time the response of guanylate cyclase to removal of stimuli. Three methods were employed to terminate rapidly a stimulus of folic acid. (1) Addition of a highly active folate deaminase preparation, or (2) 12-fold dilution of the stimulated cell suspension, or (3) addition of an excess concentration of a non-agonistic derivative of folic acid, i.e., 2-deaminofolic acid, which chases the folate agonist from its cell-surface receptors. Accumulation of cGMP terminated instantaneously upon addition of deaminase, but degradation of the synthesized cGMP was not observed until 10-12 s after stimulation. Also in a cGMP phosphodiesterase-lacking 'streamer' mutant an instantaneous termination of further cGMP accumulation was observed upon stimulus removal. This suggests that the termination of cGMP accumulation is due to inactivation of guanylate cyclase instead of a steady state of cGMP synthesis and degradation. Further accumulation of cGMP was approx. 75% reduced upon dilution of a cell suspension after stimulation with both agonists. Stimulation by 300 nM folic acid or by 30 nM N10-methylfolic acid (a more potent agonist) yielded identical results. However, upon addition of deaminofolic acid the accumulation of cGMP continued normally if the cells had been stimulated with N10-methylfolic acid, but only slightly in the case of a folic acid stimulus. The effect of stimulus duration on desensitization was monitored; it was observed that 50% desensitization was induced by stimulation for 1 s, while 4 s was sufficient for maximal desensitization. Short stimuli were observed to elicit high levels of desensitization without much excitation of guanylate cyclase. A desensitization-like process was observed at the level of the folate-binding chemotactic receptors as well. Relationships between the cGMP response data and folic acid receptor kinetics are discussed.

Aminohydrolases↗
PubMed2004

[Homocysteine-induced apoptosis of endothelial cell and its antagonism by folic acid--the roles of caspase3, c-IAP1 and c-IAP2].

OBJECTIVE: The present study addresses the question how Hcy induces endothelial apoptosis and how folic acid antagonizes the proapoptotic effects of Hcy. METHODS: Human umbilical vein endothelial cells (HUVEC) were treated with Hcy, with or without folic acid, for 24 hours. Cell apoptosis was evaluated by Annexin V staining and flow cytometery, as well as agarose gel analysis for genomic DNA ladder. The mRNA and protein levels of caspase3, c-IAP1, and c-IAP2 were analyzed by RT-PCR and Western blot, respectively. RESULTS: Treatment with both low (0.3 mmol/L) and high (3.0 mmol/L) concentrations of Hcy induced HUVEC apoptosis, with higher apoptotic rate at the latter case. Hcy-induced HUVEC apoptosis was accompanied by an increased level of caspase3 expression and activation, together with decreased c-IAP2 level. Folic acid upregulated c-IAP2 expression while attenuating Hcy-induced apoptosis and caspase3 activation. CONCLUSION: Hcy may induce HUVEC apoptosis via a pathway involving caspase3, which can be partially antagonized by folic acid, possibly through upregulated c-IAP2 expression.

Apoptosis↗
PubMed1997

A dual-label stable-isotopic protocol is suitable for determination of folate bioavailability in humans: evaluation of urinary excretion and plasma folate kinetics of intravenous and oral doses of [13C5] and [2H2]folic acid.

Stable isotopic protocols for the study of folate absorption were conducted to determine the following: (1) the equivalence of the [13C5] and [2H2] forms of folic acid, and (2) the merits of short-term plasma kinetics from injected and oral doses vs. urinary excretion of [13C5] and [2H2]folates. Another objective was to evaluate the merits of protocols not involving "saturation" of subjects with nonlabeled folate. Oral administration of [13C5] and [2H2]folic acid ( approximately 500 nmol each) to adult subjects (n = 4) yielded an equivalent 24-h urinary excretion of approximately 2% of each dose (molar ratio of urinary [13C5]/[2H2]folates = 0.96 +/- 0.055; mean +/- SEM). Expression of urinary excretion as a ratio of [13C5]/[2H2]folates yielded less within-group variability than seen for absolute excretion of each form of labeled folate. In the second study, subjects received 226 nmol of [2H2]folic acid intravenously and 1010 nmol of [13C5]folic acid orally. Isotopic enrichment of plasma [2H2]folates rose rapidly and returned to near basal values by approximately 2 h postdose. In contrast, enrichment of plasma [13C5]folates was detected until 4 h after dose, whereas enrichment values were far lower than seen with [2H2]folate. Adjusting for the difference in dose, the molar response of plasma area under the curve for isotopic enrichment was 15- to 20-fold greater for injected folates. In view of this very limited short-term plasma response even with a relatively large oral dose, presumably due to hepatic first-pass uptake, these findings suggest that plasma kinetics would be of limited usefulness in assessing the relative bioavailability of nutritionally relevant oral doses of labeled folate.

Administration, Oral↗
PubMedDate not supplied

Severity of tenosynovitis in reovirus-infected chickens fed various dietary levels of choline, folic acid, manganese, biotin, or niacin.

Five experiments were conducted to determine the incidence and severity of tenosynovitis in tendons distal to the tarsal joint in 4-, 6-, and 8-week-old reovirus WVU 2937-infected chickens fed diets containing 20%, 100%, or 200% of the 1977 National Research Council nutrient requirements (NCR-77) of manganese, biotin, niacin, choline, or folic acid. Male chickens, but not female chickens, fed 20% or 100% or the NRC-77 level of folic acid had consistently higher lesion scores of tenosynovitis than male chickens fed the 200% NRC-77 level of folic acid. Increasing dietary manganese levels from 20% to 200% NRC-77 reduced the severity of tendon swelling in 6- and 8-week-old male chickens and appeared to increase the severity of tendon swelling in 8-week-old female chickens. Male chickens fed 20% of the NRC-77 required level of biotin had numerically more severe tenosynovitis at 6 weeks of age and significantly more severe tenosynovitis at 8 weeks of age than male chickens fed 100% and 200% of the NRC-77 level of biotin. Increasing dietary choline levels from 20% to 200% of the NCR-77 required level increased the severity of tenosynovitis numerically at 6 weeks of age and significantly at 8 weeks of age. When data were pooled across diet, male chickens had significantly more severe tenosynovitis than female chickens at 4, 6, and 8 weeks of age in the choline experiment and at 4 and 6 weeks of age in the folic acid experiment. Differences in the severity of tenosynovitis of individual treatment means (sex X diet X infection interaction means) occurred at only the 20% or 100% NRC-77 level of choline or folic acid. Male chickens also had more severe tenosynovitis than female chickens when fed 20% of the NRC-77 required level of manganese for 6 or 8 weeks.

Age Factors↗
PubMed1992

[Changes in serum folic acid and vitamin B12 levels in liver cirrhosis and its clinical significance].

The levels of serum folic acid and vitamin B12 were determined in 40 cases of liver cirrhosis with radioimmunoassay. It was shown that in 87.5% of the patients folic acid level was lower than that of a control group and in 67.5% serum vitamin B12 level was higher than that of the control group (P less than 0.05). The correlation between liver cirrhosis and dysbolism of folic acid and vitamin B12 and the megaloblastic changes and clinical significance were discussed.

Adult↗
PubMed2002

Folic acid supplementation on red kidney bean-induced diarrhoea and enteric bacterial translocation into mesenteric lymph nodes in rats: a pilot study.

UNLABELLED: Deaths following childhood diarrhoea, a major health problem in developing countries, are often associated with malnutrition and septicaemic complications. Folic acid has been used in the treatment of acute and chronic diarrhoea in the tropics. Using a rat model, we evaluated the protective effect of large doses of folic acid on diarrhoea, small intestinal bacterial overgrowth and translocation of enteric bacteria into mesenteric lymph nodes induced by a raw red kidney bean-based diet containing lectin (phytohemagglutinin). Long-Evans rats in 2 groups of 5 each (60 g to 70 g in weight, 28 d old) were used. All 10 rats, individually kept in metabolic cages, received a raw red kidney bean-based diet for 10 d, and 5 of them also received a daily folic acid supplement (160 microg/g feed) both during and for 10 d before the experiment. The faecal weight was measured and a quantitative aerobic bacterial culture of the small intestinal mucosal scrapings and of the mesenteric lymph nodes was made. Folic acid supplementation did not reduce faecal output nor did it prevent loss of body weight associated with lectin-induced diarrhoea. However, the mean total count of enteric bacteria translocated to the mesenteric lymph nodes was significantly reduced in the supplemented rats (1.27 +/- 0.61 vs 2.66 +/- 0.84, p = 0.028) and a trend towards reduced bacterial count in the small intestinal mucosal scrapings (0.40 +/- 0.89 vs 1.42 +/- 1.31, p = 0.16) was documented. A significant positive correlation was also seen between the bacterial count in the jejunal mucosal scrapings and in the mesenteric lymph nodes. CONCLUSION: Although large-dose folic acid supplementation did not prevent diarrhoea and malnutrition induced by a lectin-based diet, it substantially reduced the count of enteric bacteria translocated into the mesenteric lymph nodes and showed a trend towards a reduction in indigenous bacteria adhering to jejunal mucosa. These findings could be of relevance in the prevention of septicaemic complications following many clinical conditions, including diarrhoea with malnutrition in children known to have bacteraemic and septicaemic complications.

Animals↗
PubMed2004

MTHFR C677T polymorphism, folic acid and hyperhomocysteinemia in levodopa treated patients with Parkinson's disease.

Certain mutations (TT homozygous; CT heterozygous; CC wild-type) of the methylenetetrahydrofolate (MTHFR) gene and long-term levodopa application in patients with Parkinson's disease (PD) support onset of hyperhomocysteinemia. Total plasma homocysteine (t-hcys) depends on B6, B12, folic acid, all of which support remyelination from t-hcys to methionine. Objective of this trial were to compare B6, B12, folic acid and t-hcys levels in plasma of 83 levodopa treated PD patients and 44 controls. PD patients with the CT or TT genotype had significant higher t-hcys levels than controls or PD patients with the CC allele. Concentrations of B6 or B12 did not differ, but folic acid was significant higher in PD patients with the CT mutation. We recommend MTHFR genotyping, t-hcys monitoring and early vitamin supplementation in PD patients. The folic acid increase in PD patients with the CT allele is hypothetically due to an endogenous upregulation of folic acid absorption to decrease t-hcys.

Adult↗
PubMed1999

[Antagonism of folic acid on the toxicity of aspirin in yolk sac of rats].

The antagonistic effects of folic acid to aspirin on the development of rat yolk sac and embryos were studied during early organogenesis by using whole embryo culture technique and electron microscopy. The results showed that when treated with aspirin, the diameter of yolk sac and the body length of embryo were much shorter, the frequencies of abnormal embryos were significantly higher, and the yolk sac became thinner than those without treatment. The number of blood islands and capillaries decreased, the differentiation and development of blood vessel were retarded in the treated group. Ultrastructure observation also showed that the numbers of microvilli and capillaries were greatly decreased, and the structure and the numbers of lysosomes, endoplasmic reticula and ribosomes significantly changed in the treated group. When aspirin was added with high folic acid serum, the toxicity on yolk sac decreased or disappeared. The results suggested that the protection of yolk sac would be related to the antagonism of folic acid to aspirin.

Animals↗
PubMed2006

Folic acid supplementation during methotrexate immunosuppression is not associated with early toxicity, risk of acute graft-versus-host disease or relapse following hematopoietic transplantation.

Methotrexate (MTX) is used as an immunosuppressive agent for acute graft-versus-host disease (GVHD) prophylaxis following hematopoietic cell transplantation (HCT). Concerns that folate intake may impair MTX effectiveness or selectively rescue leukemic cells have led to variations in clinical practice regarding supplemental folic acid during MTX administration. A retrospective, observational study was undertaken to determine the association between folic acid intake (days 0-18 post transplant) and MTX toxicity and efficacy following HCT. The study population consisted of 311 adult patients who received a myeloablative HCT for chronic myelogenous leukemia, all four scheduled doses of MTX, and did not require leucovorin rescue. Multiple linear regression models were used to assess the relationships between folic acid intake (days 0-18 post-HCT) and oral mucositis index (OMI) scores, time to engraftment and risk of detectable acute GVHD. No statistically significant differences in mean OMI scores, time to engraftment, risk of acute GVHD, days to acute GVHD, risk of relapse or survival were observed when comparing patients taking, on average, <400 (14%), 400 (58%) or >400 microg (28%) folic acid per day. Our results suggest that concurrent folic acid supplementation does not change MTX effectiveness or toxicity in this patient population.

Acute Disease↗
PubMed2005

Bacterially synthesized folate and supplemental folic acid are absorbed across the large intestine of piglets.

A large pool of folate exists in the large intestine of humans. Preliminary evidence, primarily in vitro, suggests that this folate may be bioavailable. The purpose of this study was to test the hypothesis that supplemental folic acid and bacterially synthesized folate are absorbed across the large intestine of piglets. The pig was used as an animal model because it resembles the human in terms of folate absorption, at least in the small intestine. A tracer of [3H]-folic acid or [3H]-para-aminobenzoic acid ([3H]-PABA), a precursor of bacterially synthesized folate, was injected into the cecum of 11-day-old piglets. Feces and urine were collected for 3 days. Thereafter, piglets were killed, and livers and kidneys harvested. [3H]-Folate was isolated from biological samples by affinity chromatography using immobilized milk folate binding proteins and counted using a scintillation counter. In piglets injected with [3H]-folic acid, the feces, liver, urine and kidneys accounted for 82.1%, 12.3%, 3.9% and 1.7% of recovered [3H]-folate, respectively. In piglets injected with [3H]-PABA, the amount of recovered bacterially synthesized folate in the feces, liver and urine was 85.1%, 0.4% and 14.6%, respectively. Twenty-three percent and 13% of tritium were recovered in samples examined (liver, kidney, fecal and urine) from piglets injected with [3H]-folic acid and [3H]-PABA, respectively. Using our estimates of [3H]-folic acid absorption and the total and percent monoglutamyl folate content of piglet feces, we predict that at least 18% of the dietary folate requirement for the piglet could be met by folate absorption across the large intestine.

4-Aminobenzoic Acid↗
PubMed2005

Industry experience in promoting weekly iron-folic acid supplementation in the Philippines.

After participating in a pilot project under a government-industry partnership to promote the adoption of weekly iron-folic acid supplementation among women of reproductive age in the Philippines in 1998, United Laboratories (UNILAB), the Philippines' largest private pharmaceutical company, decided in April 2002 to launch a weekly iron-folic acid supplement for pregnant and non-pregnant women under the brand name Femina. The business objective set for the Femina brand was to build the category of preventive iron-folic acid supplements in line with the Philippine Department of Health's advocacy on weekly supplementation as an alternate to daily dosing to reduce the prevalence of anemia in the country. The brand was supported with an integrated mix of traditional advertising media with complementary direct-to-consumer educational programs that aimed to create awareness of iron-deficiency anemia, its causes and effects, and the role of weekly intake of iron-folic acid in preventing the condition. Aggressive marketing support for 1 year was successful in creating awareness among the target women. Significant lessons derived from consumers identified opportunity areas that can be further addressed in developing advocacy programs on weekly iron supplementation implemented on a nationwide scale in the future.

Adolescent↗
PubMed2004

Serum total homocysteine levels and the prevalence of folic acid deficiency and C677T mutation at the MTHFR gene in an indigenous population of Amazonia: the relationship of homocysteine with other cardiovascular risk factors.

Hyperhomocysteinemia is a risk factor for cardiovascular disease. C677T mutation at the MTHFR gene and deficiencies of folic acid and vitamin B-12 may account for elevation of total homocysteine (tHcy). Ninety Brazilian Parkatêjê Indians (90.0% of the population without admixture, aged > or = 20 years) were studied. Hyperhomocysteinemia was observed in 26.7% of the Indians. No case of vitamin B-12 deficiency was detected. Folic acid deficiency was found in 43.3% of the subjects. Rates of mutated allele 677T and TT genotype were 40.7% and 14.0%, respectively. Prevalence of hypertension, dyslipidemia, smoking, WHR > or = 0.9, BMI > or = 25 kg/m2 and chronic alcohol use were 4.4%, 44.4%, 25.6%, 72.2%, 67.8%, and 0.0%, respectively. All creatinine values were normal. Natural logarithmic (ln) tHcy showed no correlation with age, but was positively correlated with systolic (r = 0.22) and diastolic (r = 0.21) blood pressure and triglycerides (r = 0.39) and inversely correlated with folic acid (r = -0.40) adjusted for age and sex. Total homocysteine (tHcy) was higher among TT genotype (P < .001). The multiple linear regression model, containing variables for sex, folic acid, TT genotype, and triglycerides, explained 50.0% of the variation of the ln tHcy. In summary, high rates of cardiovascular risk factors were discovered. C667T mutation and folic acid deficiency can explain, at least in part, the observed hyperhomocysteinemia.

Adult↗