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1

Mutagenic Studies of Folic Acid Antagonists1  

PubMed Central

Compounds that compete with folic acid (folic acid antagonists [FAAs]) become limited in their usefulness in the treatment of leukemia, malaria, and bacterial infections by the rapid development of resistance. Assays of the plasma levels of certain of these FAAs led to the observation, in about 25% of the determinations, that a higher density of growth of Streptococcus faecium var. durans (ATCC 8043) was obtained at an FAA concentration just below the completely inhibitory level than at one-half this concentration. This and other considerations suggested that FAAs may act not only as selective agents for resistant organisms but also as mutagens. Seven FAAs including amethopterin, pyrimethamine, trimethoprim, chlorguanide triazine, an experimental quinazoline, WR-158,122, and two experimental triazines, WR-99,210 and WR-38,839, were tested for mutagenicity in the Salmonella reversion assay developed by Ames et al. (1975). All were found to be negative for strains TA1535, TA1537, TA1538, TA98, and TA100, both with and without microsomal activation. These compounds were then tested as mutagens for three traits in the folic acid-requiring S. faecium. FAAs were shown to cause mutations to folic acid independence, rifampin resistance, and FAA resistance. It is postulated that the FAAs induce mutations by causing thymine deprivation in the folic acid-requiring host. Images PMID:329758

Genther, C. S.; Schoeny, R. S.; Loper, J. C.; Smith, C. C.

1977-01-01

2

The Biochemical, Cellular, and Pharmacological Action and Effects of the Folic Acid Antagonists  

Microsoft Academic Search

SUMMARY A brief survey of biochemical and pharmacological information on the action of the 4-amino folic acid antagonists is presented. An attempt is made to organize most of these facts into a coherent description of the mechanism of action of these drugs. It is concluded that, although their biochemical action is clearly a result of inhibition of the enzyme folic

WILLIAM C. WERKHEISER

3

Folic acid in diet  

MedlinePLUS

... leafy vegetables Dried beans and peas (legumes) Citrus fruits and juices Fortified means that vitamins have been added to the food. Many foods are now fortified with folic acid, including enriched breads, cereals, flours, cornmeals, pastas, rice, ...

4

Folic acid transport by mammalian small intestine.  

PubMed

The unidirectional influx of folic acid across the mucosal border of hamster duodenum and rat jejunum was determined. Influx follows saturation kinetics, is sodium-dependent, and is inhibited by methotrexate and is sodium-dependent, and is inhbited by methotrexate and folinic acid in the mucosal bathing solution. In hamster duodenum, the maximal influx is 1.2 nmol/(cm2.h), and the folic acid concentration required to give a half maximal influx (Km) is 7.2 micron.. At mucosal folic acid concentration of 1.5 micron, influx is reduced at least 65% by removal of sodium from the bathing solution. The influx process is significantly inhibited by cyanide and 2,4-dinitrophenol. The possibility was evaluated that the acidic microclimate at the brush border regulates the rate of folic acid transport and that inhibition of transmural transport by sodium-free media, ouabain, and methotrexate is brought about indirectly by an increase in pH of the microclimate. The data favor the alternative concept of a sodium-dependent carrier mechanism for entry of folic acid into the cells. The information presented is consistent with active transport of folic acid by a sodium-gradient mechanism, but additional information will be necessary to substantiate such a model. PMID:736128

Rose, R C; Koch, M J; Nahrwold, D L

1978-12-01

5

[Folic acid fortification of bread recommendable].  

PubMed

Folic acid supplementation was recommended in the Netherlands after it had been demonstrated that periconceptional use of folic acid protected against foetal neural tube defects; this recommendation led to a slight decrease in prevalence only. According to the Dutch Health Council, fortification of bread should now be considered. Policy-making is complicated by uncertainties regarding potential side effects, such as adverse effects in children, for which scientific evidence is lacking however. PMID:18712224

Cornel, M C; de Smit, D J; de Jong-van den Berg, L T W

2008-07-12

6

21 CFR 862.1295 - Folic acid test system.  

Code of Federal Regulations, 2010 CFR

...measure the vitamin folic acid in plasma and serum. Folic acid measurements are used in the diagnosis and treatment of megaloblastic anemia, which is characterized by the presence of megaloblasts (an abnormal red blood cell series) in the bone marrow....

2010-04-01

7

Periconceptional folic acid containing multivitamin supplementation  

Microsoft Academic Search

Objective: A summary about the final results of the Hungarian double-blind placebo controlled randomised trial of periconceptional folic acid containing multivitamin and trace element supplementation. Results: The major finding is a significant prevention of the first occurrence of neural-tube defect, urinary tract and cardiovascular defects, in addition a decrease in the rate of limb deficiencies and congenital hypertrophic pyloric stenosis.

Andrew E. Czeizel

1998-01-01

8

Neural tube defects, folic acid and methylation.  

PubMed

Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects. PMID:24048206

Imbard, Apolline; Benoist, Jean-François; Blom, Henk J

2013-09-01

9

21 CFR 172.345 - Folic acid (folacin).  

Code of Federal Regulations, 2013 CFR

21 Food and Drugs 3 2013-04-01...2013-04-01 false Folic acid (folacin). 172...Section 172.345 Food and Drugs FOOD AND DRUG ADMINISTRATION...of the Federal Food, Drug, and Cosmetic Act...the addition of folic acid. (d) Folic...

2013-04-01

10

21 CFR 172.345 - Folic acid (folacin).  

Code of Federal Regulations, 2012 CFR

21 Food and Drugs 3 2012-04-01...2012-04-01 false Folic acid (folacin). 172...Section 172.345 Food and Drugs FOOD AND DRUG ADMINISTRATION...of the Federal Food, Drug, and Cosmetic Act...the addition of folic acid. (d) Folic...

2012-04-01

11

21 CFR 172.345 - Folic acid (folacin).  

21 Food and Drugs 3 2014-04-01...2014-04-01 false Folic acid (folacin). 172...Section 172.345 Food and Drugs FOOD AND DRUG ADMINISTRATION...of the Federal Food, Drug, and Cosmetic Act...the addition of folic acid. (d) Folic...

2014-04-01

12

21 CFR 172.345 - Folic acid (folacin).  

Code of Federal Regulations, 2011 CFR

21 Food and Drugs 3 2011-04-01...2011-04-01 false Folic acid (folacin). 172...Section 172.345 Food and Drugs FOOD AND DRUG ADMINISTRATION...of the Federal Food, Drug, and Cosmetic Act...the addition of folic acid. (d) Folic...

2011-04-01

13

Estimates of Total Dietary Folic Acid Intake in the Australian Population Following Mandatory Folic Acid Fortification of Bread  

PubMed Central

Mandatory folic acid fortification of wheat flour for making bread was implemented in Australia in September 2009, to improve the dietary folate status of women of child-bearing age, and help reduce the incidence of neural tube defects in the population. This paper presents estimates of folic acid intake in the target population and other subgroups of the Australian population following implementation of the mandatory folic acid fortification standard. In June/July 2010 one hundred samples from seven bread categories were purchased from around the country and individually analysed for the amount of folic acid they contained. A modification to the triple enzyme microbiological method was used to measure folic acid in the individual bread samples. The folic acid analytical values together with national food consumption data were used to generate estimates of the population's folic acid intake from fortified foods. Food Standards Australia New Zealand's (FSANZ) custom-built dietary modelling program (DIAMOND) was used for the estimates. The mean amount of folic acid found in white bread was 200??g/100?g which demonstrated that folic-acid-fortified wheat flour was used to bake the bread. The intake estimates indicated an increase in mean folic acid intake of 159??g per day for the target group. Other sub-groups of the population also showed increases in estimated mean daily intake of folic acid. PMID:22957218

Dugbaza, Jacinta; Cunningham, Judy

2012-01-01

14

21 CFR 862.1295 - Folic acid test system.  

Code of Federal Regulations, 2013 CFR

...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1295 Folic acid test system. (a)...

2013-04-01

15

21 CFR 862.1295 - Folic acid test system.  

Code of Federal Regulations, 2011 CFR

...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1295 Folic acid test system. (a)...

2011-04-01

16

21 CFR 862.1295 - Folic acid test system.  

...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1295 Folic acid test system. (a)...

2014-04-01

17

Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia: The Folic Acid Clinical Trial Study  

PubMed Central

Preeclampsia (PE) is hypertension with proteinuria that develops during pregnancy and affects at least 5% of pregnancies. The Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia: the Folic Acid Clinical Trial (FACT) aims to recruit 3,656 high risk women to evaluate a new prevention strategy for PE: supplementation of folic acid throughout pregnancy. Pregnant women with increased risk of developing PE presenting to a trial participating center between 80/7 and 166/7 weeks of gestation are randomized in a 1?:?1 ratio to folic acid 4.0?mg or placebo after written consent is obtained. Intent-to-treat population will be analyzed. The FACT study was funded by the Canadian Institutes of Health Research in 2009, and regulatory approval from Health Canada was obtained in 2010. A web-based randomization system and electronic data collection system provide the platform for participating centers to randomize their eligible participants and enter data in real time. To date we have twenty participating Canadian centers, of which eighteen are actively recruiting, and seven participating Australian centers, of which two are actively recruiting. Recruitment in Argentina, UK, Netherlands, Brazil, West Indies, and United States is expected to begin by the second or third quarter of 2013. This trial is registered with NCT01355159. PMID:24349782

Champagne, Josee; Rennicks White, Ruth; Coyle, Doug; Fraser, William; Smith, Graeme; Fergusson, Dean; Walker, Mark C.

2013-01-01

18

Folic acid to reduce neonatal mortality from neural tube disorders  

PubMed Central

Background Neural tube defects (NTDs) remain an important, preventable cause of mortality and morbidity. High-income countries have reported large reductions in NTDs associated with folic acid supplementation or fortification. The burden of NTDs in low-income countries and the effectiveness of folic acid fortification/supplementation are unclear. Objective To review the evidence for, and estimate the effect of, folic acid fortification/supplementation on neonatal mortality due to NTDs, especially in low-income countries. Methods We conducted systematic reviews, abstracted data meeting inclusion criteria and evaluated evidence quality using adapted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Where appropriate, meta-analyses were performed. Results Meta-analysis of three randomized controlled trials (RCTs) of folic acid supplementation for women with a previous pregnancy with NTD indicates a 70% [95% confidence interval (CI): 35–86] reduction in recurrence (secondary prevention). For NTD primary prevention through folic acid supplementation, combining one RCT with three cohort studies which adjusted for confounding, suggested a reduction of 62% (95% CI: 49–71). A meta-analysis of eight population-based observational studies examining folic acid food fortification gave an estimated reduction in NTD incidence of 46% (95% CI: 37–54). In low-income countries an estimated 29% of neonatal deaths related to visible congenital abnormalities are attributed to NTD. Assuming that fortification reduces the incidence of NTDs, but does not alter severity or case-fatality rates, we estimate that folic acid fortification could prevent 13% of neonatal deaths currently attributed to congenital abnormalities in low-income countries. Discussion Scale-up of periconceptional supplementation programmes is challenging. Our final effect estimate was therefore based on folic acid fortification data. If folic acid food fortification achieved 100% population coverage the number of NTDs in low-income countries could be approximately halved. Conclusion The evidence supports both folic acid supplementation and fortification as effective in reducing neonatal mortality from NTDs. PMID:20348114

Blencowe, Hannah; Cousens, Simon; Modell, Bernadette; Lawn, Joy

2010-01-01

19

The neurology of folic acid deficiency.  

PubMed

The metabolism of folic acid and the metabolism of vitamin B12 are intimately linked such that deficiency of either vitamin leads to an identical megaloblastic anemia. The neurologic manifestations of folate deficiency overlap with those of vitamin B12 deficiency and include cognitive impairment, dementia, depression, and, less commonly, peripheral neuropathy and subacute combined degeneration of the spinal cord. In both deficiency states there is often dissociation between the neuropsychiatric and the hematologic complications. There is a similar overlap and dissociation between neurologic and hematologic manifestations of inborn errors of folate and vitamin B12 metabolism. Low folate and raised homocysteine levels are risk factors for dementia, including Alzheimer's disease, and depression. Even when folate deficiency is secondary to psychiatric illness due to apathy or poor diet it may eventually aggravate the underlying disorder in a vicious circle effect. Clinical responses to treatment with folates are usually slow over weeks and months, probably due to the efficient blood-brain barrier mechanism for the vitamin, perhaps in turn related to the experimentally demonstrated excitatory properties of folate derivatives. The inappropriate administration of folic acid in the presence of vitamin B12 deficiency may lead to both neurologic and, later, hematologic relapse. Impaired maternal folate intake and status increases the risk of neural tube defects. Periconceptual prophylactic administration of the vitamin reduces, but does not eliminate the risk of neural tube defects even in the absence of folate deficiency. Folates and vitamin B12 have fundamental roles in central nervous system function at all ages, especially in purine, thymidine, neucleotide, and DNA synthesis, genomic and nongenomic methylation and, therefore, in tissue growth, differentiation and repair. There is interest in the potential role of both vitamins in the prevention of disorders of central nervous system development, mood, dementia, including Alzheimer's disease, and aging. PMID:24365361

Reynolds, E H

2014-01-01

20

Liquid chromatographic determination of folic acid in multivitamin preparations.  

PubMed

A reversed-phase high-performance liquid chromatographic method is described for a stability-indicating assay of folic acid in multivitamin preparations. This method shows excellent recovery and precision characteristics, allows the determination of folic acid to levels of 0.1 microgram/mL, is simple to execute, and is suitable for high volume routine work. A good correlation was demonstrated between the HPLC method and the currently used bioassay. PMID:3559929

Paveenbampen, C; Lamontanaro, D; Moody, J; Zarembo, J; Rehm, C

1986-12-01

21

The Basis of Differential Responses to Folic Acid Supplementation  

Microsoft Academic Search

Background\\/Aims: Elevated levels of total homocysteine (tHcy) are associated with an increased risk of many common diseases. Supplementation with folic acid has been shown to significantly reduce tHcy levels. We used the classical twin model to partition the variability in changes in plasma tHcy levels through folic acid supplementation into genetic, environmental, and confounding epidemiological factors. Methods: We carried out

Ioana Cotlarciuc; Toby Andrew; Tracy Dew; Gail Clement; Raj Gill; Gabriela Surdulescu; Roy Sherwood; Kourosh R. Ahmadi

2011-01-01

22

Formation of polydopamine nanofibers with the aid of folic Acid.  

PubMed

Polydopamine (PDA) generated by the oxidative self-polymerization of dopamine shows great potential for surface modification. Observed PDA nanostructures are nanoparticles and thin films. The formation mechanism of PDA is still unclear; thus, the manipulation of PDA nanostructures is a big challenge. In this study, we first demonstrated that folic acid shows a dramatic effect on the PDA nanostructure: New aggregated nanostructures of PDA, nanobelts and nanofibers, were generated in a dopamine/folic acid system. We hypothesized that folic acid may be involved in the stacking of protomolecules of PDA by ?-? interactions and hydrogen bonding. Herein we describe the first experimental strategy to manipulate the aggregation of PDA by using small molecules. This study not only provides a new method for generating PDA nanofibers, which are proposed bioorganic electronic materials, but also a possible way to understand the formation mechanism of PDA and its analogues in nature, melanins. PMID:25146565

Yu, Xiang; Fan, Hailong; Wang, Le; Jin, Zhaoxia

2014-11-10

23

Benefits and risks of folic acid to the nervous system  

PubMed Central

During three decades of neurological practice I have witnessed a remarkable change in attitudes to the benefits and risks of folic acid therapy in nervous system disorders. In the 1960s all that was known and taught was that folic acid was harmful to the nervous system, especially in precipitating or exacerbating the neurological complications of vitamin B12 deficiency. So deeply held was this view that the possibility of neuropsychological benefits from this vitamin was initially viewed with considerable scepticism.1 PMID:11971038

Reynolds, E

2002-01-01

24

Studies on the folic acid activity of human serum  

Microsoft Academic Search

A method for the measurement of serum folic acid activity is described, which is a modification of previous methods.The material in serum with activity for L. casei is made up of a stable and a labile component. The amount of stable component in normal subjects and patients with megaloblastic anaemia is similar. The amount of labile component varies. In patients

A. H. Waters; D. L. Mollin; Josephine Pope; Thurl Towler

1961-01-01

25

Periconceptional folic acid\\/multivitamin supplementation and twin pregnancy  

Microsoft Academic Search

ObjectiveResults of our previous randomized controlled trial suggested an increase of twin pregnancies that was associated with the use of a multivitamin that contained folic acid during the periconceptional period. These findings were confirmed by US and Swedish studies, but not in the Chinese population. The aim of this analysis is to evaluate this possible association in a population-based data

Andrew E. Czeizel; Peter Vargha

2004-01-01

26

Epidemiology of neural tube defects and folic acid  

PubMed Central

This review article combines four disparate observations about Neural Tube Defects (NTDs). They are the worldwide decline in the birth incidence that began prior to prenatal diagnosis; family recurrence risks; the effect of prenatal diagnosis and termination of affected pregnancies; and the effect of folic acid. PMID:15679939

Shurtleff, David B

2004-01-01

27

Physicians' Knowledge of Alcohol, Tobacco and Folic Acid in Pregnancy  

ERIC Educational Resources Information Center

Objective: To assess: (1) physicians' knowledge and clinical confidence regarding problematic substance use in pregnancy compared to folic acid, and (2) physicians' desire for education in this area and their preferred learning modalities tools. Design: Self-administered survey. Setting: "Family Medicine Forum 2004" in Toronto, Canada.…

Lefebvre, L. G.; Ordean, A.; Midmer, D.; Kahan, M.; Tolomiczenko, G.

2007-01-01

28

Role of Folic Acid on Symptoms of Chronic Arsenic Toxicity  

PubMed Central

Background: Chronic arsenic toxicity (Arsenicosis) due to drinking of arsenic contaminated ground water is a global problem. However, its treatment is unsatisfactory. Methylation of arsenic facilitates its urinary excretion. Persons with relatively lower proportion of urinary dimethyl arsenic acid (DMA) are found to have at greater risk of developing symptoms of arsenicosis including its complications. The biochemical pathway responsible for methylation of arsenic is a folate-dependent pathway. Studies in rodents and humans suggest that folate nutritional status influences the metabolism of arsenic. Methods: The present study compares the effect of giving folic acid on 32 arsenicosis patients during a 6-month period and comparing the results with clinical effect of taking only arsenic-free safe water on 45 age and sex-matched arsenic-affected people for the same period. Results: There was significant improvement of arsenical skin lesion score of both patients treated with folic acid (2.96 ± 1.46 to 1.90 ± 0.90, P < 0.001) and arsenic free safe water (2.91 ± 1.26 to 1.62 ± 1.05, P < 0.001) for a period of 6 months. Significant improvement in systemic disease score was also observed from the baseline systemic score in folic acid treated group (4.78 ± 3.43 to 1.00 ± 1.56, P < 0.001) and the group treated with arsenic-free water (1.87 ± 2.11 to 0.82 ± 1.62, P < 0.001). However, there was a significant increased improvement of systematic disease score in the folic acid treated group compared to the control group taking arsenic free water (P < 0.001). Conclusions: This study provides evidence that folic acid treatment in arsenicosis cases could help in reducing clinical symptoms of arsenicosis. PMID:24554997

Ghose, Nelima; Majumdar, Kunal Kanti; Ghose, A. K.; Saha, C. K.; Nandy, A. K.; Mazumder, D. N. Guha

2014-01-01

29

Predicted contribution of folic acid fortification of corn masa flour to the usual folic acid intake for the US population: National Health and Nutrition Examination Survey 2001-20041-3  

Microsoft Academic Search

Background: Folic acid can prevent up to 70% of neural tube defects (NTDs) if taken before pregnancy. Compared with other race-ethnicities, Hispanic women have higher rates of NTDs, lower rates of folic acid supplement use, and lower total folic acid intakes. Objective: The objective was to assess potential effects of fortify- ing corn masa flour with folic acid on Mexican

Heather C Hamner; Joseph Mulinare; Mary E Cogswell; Alina L Flores; Coleen A Boyle; Christine E Prue; Chia-Yih Wang; Alicia L Carriquiry; Owen Devine

30

Folic acid supplementation during pregnancy protects against lipopolysaccharide-induced neural tube defects in mice.  

PubMed

Folic acid is a water-soluble B-complex vitamin. Increasing evidence demonstrates that physiological supply of folic acid during pregnancy prevents folic acid deficiency-related neural tube defects (NTDs). Previous studies showed that maternal lipopolysaccharide (LPS) exposure caused NTDs in rodents. The aim of this study was to investigate the effects of high-dose folic acid supplementation during pregnancy on LPS-induced NTDs. Pregnant mice were intraperitoneally injected with LPS (20 ?g/kg/d) from gestational day (GD) 8 to GD12. As expected, a five-day LPS injection resulted in 19.96% of fetuses with NTDs. Interestingly, supplementation with folic acid (3mg/kg/d) during pregnancy significantly alleviated LPS-induced NTDs. Additionally, folic acid significantly attenuated LPS-induced fetal growth restriction and skeletal malformations. Additional experiment showed that folic acid attenuated LPS-induced glutathione (GSH) depletion in maternal liver and placentas. Moreover, folic acid significantly attenuated LPS-induced expression of placental MyD88. Additionally, folic acid inhibited LPS-induced c-Jun NH2-terminal kinase (JNK) phosphorylation and nuclear factor kappa B (NF-?B) activation in placentas. Correspondingly, folic acid significantly attenuated LPS-induced tumor necrosis factor (TNF)-?, interleukin (IL)-1? and IL-6 in placentas, maternal serum and amniotic fluid. In conclusion, supplementation with high-dose folic acid during pregnancy protects against LPS-induced NTDs through its anti-inflammatory and anti-oxidative effects. PMID:24177262

Zhao, Mei; Chen, Yuan-Hua; Chen, Xue; Dong, Xu-Ting; Zhou, Jun; Wang, Hua; Wu, Shu-Xian; Zhang, Cheng; Xu, De-Xiang

2014-01-13

31

Knowledge of periconceptional folic acid use among pregnant women at Ain Shams University Hospital, Cairo, Egypt.  

PubMed

Egypt has a high incidence of neural tube defects. Folic acid supplementation in the periconceptional period is known to lower the risk of such defects. This cross-sectional study aimed to measure the level of knowledge about periconceptional folic acid use among pregnant women attending for antenatal care at Ain Shams University Hospital, Cairo, Egypt in 2012. Questionnaires were filled through personal interviews with 660 pregnant women. Of the respondents, 62.4% had heard of folic acid and 39.2% knew about the role of folic acid supplementation in prevention of congenital anomalies. Knowledge about using folic acid before and in the first trimester of pregnancy was highest among university-educated women and those working in professional occupations. Only 18.8% of women reported taking folic acid, and 8.8% had used it before conception. Awareness campaigns are suggested to improve knowledge about folic acid among women in the childbearing period in Egypt. PMID:25343469

Al-Darzi, W; Al-Mudares, F; Farah, A; Ali, A; Marzouk, D

2014-09-01

32

Occurrence of Crithidia Factors and Folic Acid in Various Bacteria  

PubMed Central

Crithidia factors and folic acid were found to be widely distributed in culture fluids and in cells of 27 species of bacteria, when cultured under aerobic conditions into the stationary phase. Most bacteria excreted more Crithidia factors and folic acid than they retained in their cells. One Crithidia factor produced by Serratia indica and one produced by Bacillus cereus differed from biopterin in their chromatographic behavior. The factor excreted by S. indica appeared to be a 2-amino-4-hydroxy-6-substituted pteridine on the basis of KMnO4 oxidation and ultraviolet absorption spectra. One of the folate compounds excreted by this organism was shown to be identical to 5,10-methylidynetetrahydrofolic acid by bioautography. PMID:5473887

Iwai, K.; Kobashi, M.; Fujisawa, H.

1970-01-01

33

Preventive Effects of Folic Acid Supplementation on Adverse Maternal and Fetal Outcomes  

PubMed Central

Although there is accumulating evidence regarding the additional protective effect of folic acid against adverse pregnancy outcomes other than neural tube defects, these effects have not been elucidated in detail. We evaluated whether folic acid supplementation is associated with favorable maternal and fetal outcomes. This was a secondary analysis of 215 pregnant women who were enrolled in our prior study. With additional data from telephone interviews regarding prenatal folic acid supplementation, existing demographic, maternal and fetal data were statistically analyzed. The concentration of folic acid in maternal blood was significantly higher following folic acid supplementation (24.6 ng/mL vs.11.8 ng/mL). In contrast, homocysteine level in maternal blood decreased with folic acid supplementation (5.5 µmol/mL vs. 6.8 µmol/mL). The rates of both preeclampsia (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.09–0.76) and small for gestational age (SGA; 9.2% vs. 20.0%; OR, 0.42; 95% CI, 0.18–0.99) were lower in the folic acid supplementation group than those in the control group. Other pregnancy outcomes had no association with folic acid supplementation. The findings indicate that folic acid supplementation may help to prevent preeclampsia and SGA. Further studies are warranted to elucidate the favorable effects of folic acid supplementation on pregnancy outcomes. PMID:24842467

Kim, Min Woo; Ahn, Ki Hoon; Ryu, Ki-Jin; Hong, Soon-Cheol; Lee, Ji Sung; Nava-Ocampo, Alejandro A.; Oh, Min-Jeong; Kim, Hai-Joong

2014-01-01

34

Folic Acid Supplementation Promotes Mammary Tumor Progression in a Rat Model  

PubMed Central

Folic acid supplementation may prevent the development of cancer in normal tissues but may promote the progression of established (pre)neoplastic lesions. However, whether or not folic acid supplementation can promote the progression of established (pre)neoplastic mammary lesions is unknown. This is a critically important issue because breast cancer patients and survivors in North America are likely exposed to high levels of folic acid owing to folic acid fortification and widespread supplemental use after cancer diagnosis. We investigated whether folic acid supplementation can promote the progression of established mammary tumors. Female Sprague-Dawley rats were placed on a control diet and mammary tumors were initiated with 7,12-dimethylbenza[a]anthracene at puberty. When the sentinel tumor reached a predefined size, rats were randomized to receive a diet containing the control, 2.5x, 4x, or 5x supplemental levels of folic acid for up to 12 weeks. The sentinel mammary tumor growth was monitored weekly. At necropsy, the sentinel and all other mammary tumors were analyzed histologically. The effect of folic acid supplementation on the expression of proteins involved in proliferation, apoptosis, and mammary tumorigenesis was determined in representative sentinel adenocarcinomas. Although no clear dose-response relationship was observed, folic acid supplementation significantly promoted the progression of the sentinel mammary tumors and was associated with significantly higher sentinel mammary tumor weight and volume compared with the control diet. Furthermore, folic acid supplementation was associated with significantly higher weight and volume of all mammary tumors. The most significant and consistent mammary tumor-promoting effect was observed with the 2.5x supplemental level of folic acid. Folic acid supplementation was also associated with an increased expression of BAX, PARP, and HER2. Our data suggest that folic acid supplementation may promote the progression of established mammary tumors. The potential tumor-promoting effect of folic acid supplementation in breast cancer patients and survivors needs further clarification. PMID:24465421

Deghan Manshadi, Shaidah; Ishiguro, Lisa; Sohn, Kyoung-Jin; Medline, Alan; Renlund, Richard; Croxford, Ruth; Kim, Young-In

2014-01-01

35

Imaging Pancreatic Cancer with Folic Acid Terminated Luminescent Silicon Nanocrystals  

NASA Astrophysics Data System (ADS)

Quantum dots have great potential for visualization of medically relevant targets such as cancer. However, potential toxicity, stemming from the use of heavy metal based semidonductor materials, has been a major impediment to use of quantum dots in vivo. Silicon is an inherently non-toxic element. By combining the unique optical properties of silicon quantum dots with fundamentals of cancer biology, we can develop probes that safely target and enable the visualization of cancer cells. Many cancer cells overexpress folate receptors, making the folate receptors a suitable target for cancer imaging evaluations. Here, we report the synthesis of folic acid coated silicon quantum dots for targeting pancreatic cancer cells. Folic acid on the silicon quantum dots improves selectivity and may decrease possible negative side effects. This demonstration adds to the evidence that silicon can be sucessfully used for biological imaging.

Erogbogbo, Folarin; Swihart, Mark T.

2010-10-01

36

Folic acid deaminase activity during development in Dictyostelium discoideum.  

PubMed Central

Folic acid attracts vegetative amoebae of Dictyostelium discoideum. Secreted by bacteria, it may act as a food-seeking device. The inactivation of this attractant is catalyzed by a deaminase. As assay has been developed to measure the folic acid deaminase activity. In addition to cell-surface an intracellular deaminase, the amoebae of D. discoideum release the enzyme into the medium. The pH optimum of the extracellular enzyme was 6.0, and higher for the cell-associated deaminases. The extracellular enzyme was secreted maximally by vegetative amoebae, and its activity diminished during cell differentiation. The cell-surface bound enzyme was less active than the extracellular enzyme, and its activity decreased twofold during a 6-h starvation period. The enzyme activity of homogenates and 48,000 x g pellets diminished during this period 35 to 40%. The supernatant of a homogenate had a higher deaminase activity than the homogenate itself or its pellet; this suggests the presence of an inhibitor in the particulate fraction. The underlying mechanism for inactivation of folic acid has similar characteristics as that for inactivation of cyclic adenosine monophosphate. PMID:7400095

Kakebeeke, P I; de Wit, R J; Konijn, T M

1980-01-01

37

Folic acid supplementation and IVF pregnancy outcome in women with unexplained infertility.  

PubMed

Folic acid supplements are commonly used by infertile women which leads to a positive folate status. However, the effect of folic acid supplements on pregnancy outcome in women with unexplained infertility has not been well investigated. This study evaluated folic acid supplement use and folate status in women with unexplained infertility in relation to IVF pregnancy outcome. In addition, use of folic acid supplements and folate status were compared between women with unexplained infertility and fertile, nonpregnant control women. Women with unexplained infertility used significantly more folic acid supplements and had higher median total folic acid intake from supplements compared with fertile control women (both P < 0.001). Women with unexplained infertility also had significantly higher median plasma folate and lower median plasma homocysteine concentrations than fertile women (both P < 0.001), but folic acid supplementation or folate status were not related to pregnancy outcome in women with unexplained infertility. In conclusion, folic acid supplementation or good folate status did not have a positive effect on pregnancy outcome following infertility treatment in women with unexplained infertility. Folate is one of the B vitamins which has been suggested to be related to infertility. Folic acid is an artificial form of folate which is commonly used in dietary supplements. Folic acid supplementation has been shown to increase folate concentrations and decrease concentrations of the amino acid homocysteine in the blood. Folic acid supplementation is commonly used by infertile women, but the effect on pregnancy outcome in women with a diagnosis of unexplained infertility has not been thoroughly investigated. In the present study, folic acid supplement use and folate status (concentrations of folate and homocysteine) in women with unexplained infertility were evaluated in relation to pregnancy outcome. In addition, the use of folic acid supplements and folate status were compared between women with unexplained infertility and fertile control women. Our results showed that women with unexplained infertility used considerably more folic acid supplements and had higher total folic acid intake from supplements compared with fertile control women. Women with unexplained infertility had better blood folate and homocysteine concentrations than fertile women, but folic acid supplementation or folate status were not related to pregnancy outcome following the infertility treatment. In conclusion, high folic acid intake or good folate status did not increase the possibility of a birth of a healthy baby after infertility treatment in women with unexplained infertility. PMID:24745837

Murto, T; Skoog Svanberg, A; Yngve, A; Nilsson, T K; Altmäe, S; Wånggren, K; Salumets, A; Stavreus-Evers, A

2014-06-01

38

Economic burden of neural tube defects and impact of prevention with folic acid: a literature review  

Microsoft Academic Search

Neural tube defects (NTDs) are the second most common group of serious birth defects. Although folic acid has been shown to\\u000a reduce effectively the risk of NTDs and measures have been taken to increase the awareness, knowledge, and consumption of\\u000a folic acid, the full potential of folic acid to reduce the risk of NTDs has not been realized in most

Yunni Yi; Marion Lindemann; Antje Colligs; Claire Snowball

39

Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally  

Microsoft Academic Search

SummaryWomen are advised to take folic acid before they conceive as a precaution against neural-tube defects. However, the use of folic acid in preventing orofacial clefts is unknown. We investigated whether a woman's periconceptional use of multivitamins containing folic acid was associated with a reduced risk of orofacial clefts.We derived data from a population-based case-control study of fetuses and liveborn

G. M Shaw; C. R Wasserman; C. D O'Malley; M. M Tolarova; E. J Lammer

1995-01-01

40

A relationship between vitamin B sub 12 , folic acid, ascorbic acid, and mercury uptake and methylation  

SciTech Connect

Ingestion of megadoses of certain vitamins appears to influence the in vivo methylation of mercuric chloride in guinea pigs. The addition of megadoses of vitamin B{sub 12} fed either singularly or in combination with folic acid resulted in increased methylmercury concentrations in the liver. Moreover, percent methylmercury levels were significantly increased with B{sub 12} treatment in the liver (B{sub 12} only and B{sub 12}/folic acid) and brain (B{sub 12}/vitamin C). Incorporation of high levels of folic acid into the dietary regime also increased the methylmercury concentration particularly in the liver and hair tissues. The addition of vitamin C in the diet, particularly in combination with B{sub 12} (brain) or folic acid (muscle) resulted in increased methylmercury levels in these tissues and percent methylmercury values with B{sub 12} in the muscle and brain tissue.

Zorn, N.E.; Smith, J.T. (Univ. of Tennessee, Knoxville (USA))

1990-01-01

41

Factors contributing to the success of folic acid public health campaigns  

PubMed Central

Background Studies in the 1990s have found that periconceptional dietary folate, supplementation of folic acid or supplemental multivitamins containing folic acid, help prevent neural tube defect (NTDs) if taken at the right time. This literature review assesses the extant folic acid public health campaigns literature and identifies some common variables used in folic acid consumption campaign evaluations. Methods This review was part of a larger study that searched PUBMED, PsycINFO and Embase from 1976 to 2010 to identify articles related to the psychosocial and economic impact of NTDs (especially spina bifida) on patients and caregivers. Results Awareness of folic acid levels prior to conception improved post-campaign from 6 to 41%. Knowledge about consumption and correct periconceptional use of folic acid also improved. However, in most studies more than 50% of women did not take folic acid as prescribed. Many factors were associated with or without taking folic acid post-campaign, including incomplete outreach, prior awareness and knowledge, closeness to pregnancy, demographics and other personal characteristics. Conclusions Sustained campaigning to maintain awareness about and promote periconceptional consumption of folic acid in order to reduce the incidence of NTDs is clearly needed. Additional initiatives could complement existing public health strategies. PMID:21727078

Rofail, D.; Colligs, A.; Abetz, L.; Lindemann, M.; Maguire, L.

2012-01-01

42

Evaluation of Educational Materials from a Social Marketing Campaign to Promote Folic Acid Use Among Hispanic Women: Insight from Cuban and Puerto Rican Ethnic Subgroups  

Microsoft Academic Search

Current data indicate significant disparities in awareness and use of folic acid between Hispanic and non-Hispanic women.\\u000a Hispanic women are less likely to have heard about folic acid, to know that folic acid can prevent birth defects, to take\\u000a folic acid daily, and to take folic acid before pregnancy. “Three Sisters\\/Las Tres Hermanos” is a folic acid social marketing\\u000a campaign

Gwendolyn P. Quinn; Kamilah B. Thomas; Kimberlea Hauser; Nydia Y. Rodríguez; Nazach Rodriguez-Snapp

2009-01-01

43

Maternal B vitamin status in pregnancy week 18 according to reported use of folic acid supplements  

PubMed Central

Scope Epidemiological studies on the association between pregnancy outcomes and use of periconceptional folic acid are often based on maternal reported intake. Use of folic acid during pregnancy is associated with a higher socioeconomic status known to have an impact on diet quality. We have studied plasma B vitamin status according to reported use of folic acid supplements during the periconceptional period in Norwegian women. Methods and results Plasma levels of folate, cobalamin, pyridoxal 5?-phosphate (vitamin B6), riboflavin and the metabolic markers total homocysteine, methylmalonic acid and 3-hydroxykynurenine were measured in pregnancy week 18 and related to reported intake of folic acid from 4 weeks prior to conception throughout week 18 in 2911 women from the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. Being a folic acid user during the periconceptional period was associated with a better socioeconomic status, and a higher intake of several micronutrients, including vitamins, trace-metals and omega 3 fatty acids. Folic acid users had a significantly better plasma B vitamin status. Conclusions Epidemiological data based on maternal reported intake of folic acid supplements during pregnancy, should take into account the numerous nutritional implications, in addition to higher blood folate levels, of being a folic acid user. PMID:23001761

Bj?rke-Monsen, Anne Lise; Roth, Christine; Magnus, Per; Midttun, ?ivind; Nilsen, Roy M.; Reichborn-Kjennerud, Ted; Stoltenberg, Camilla; Susser, Ezra; Vollset, Stein Emil; Ueland, Per Magne

2013-01-01

44

Maternal and Cord Blood Homocysteine and Folic Acid Levels in Smoking and Nonsmoking Pregnant Women  

Microsoft Academic Search

Introduction: The homocysteine level in blood is affected by gender, diet, smoking, folic acid and B-complex vitamins. It is known that higher than normal homocysteine levels in plasma may cause vascular endothelium dysfunction, resulting in the promotion of thrombus formation. In our study, we aimed to assess the effects of smoking during pregnancy on the homocysteine and folic acid levels

Isil Coker; Ayfer Colak; Aybike Gunaslan Hasturk; Omur Yildiz; Hakan Turkon; Oya Halicioglu

2011-01-01

45

Folic Acid Enhances Early Functional Recovery in a Piglet Model of Pediatric Head Injury  

Microsoft Academic Search

For stroke and spinal cord injury, folic acid supplementation has been shown to enhance neurodevelopment and to provide neuroprotection. We hypothesized that folic acid would reduce brain injury and improve neurological outcome in a neonatal piglet model of traumatic brain injury (TBI), using 4 experimental groups of 3- to 5-day-old female piglets. Two groups were intubated, anesthetized and had moderate

Maryam Y. Naim; Stuart Friess; Colin Smith; Jill Ralston; Karen Ryall; Mark A. Helfaer; Susan S. Margulies

2010-01-01

46

Awareness and Use of Folic Acid among Women in the Lower Mississippi Delta  

ERIC Educational Resources Information Center

Context: National and state efforts to increase folic acid awareness and use may not be reaching large segments of the population. Purpose: This study examines folic acid awareness and use among women of childbearing age in a representative, economically at-risk rural sample and identifies factors that influence awareness and use. Methods: A…

Robbins, James M.; Hopkins, Sarah E.; Mosley, Bridget S.; Casey, Patrick H.; Cleves, Mario A.; Hobbs, Charlotte A.

2006-01-01

47

Promoting PreConceptional Use of Folic Acid to Hispanic Women: A Social Marketing Approach  

Microsoft Academic Search

Objective: To develop a culturally appropriate communication initiative in an effort to promote the use of pre-conceptional folic acid among Hispanic women of childbearing age. The materials were designed to communicate information about the risks of neural tube defects and the value of folic acid supplementation before conception. Methods: The initiative was developed using a social marketing approach. A series

Gwendolyn P. Quinn; Kimberlea Hauser; Bethany A. Bell-Ellison; Nydia Y. Rodriguez; Jaime L. Frías

2006-01-01

48

Folic acid fortification of grain: an economic analysis.  

PubMed Central

OBJECTIVES. The purpose of this study was to compare the economic costs and benefits of fortifying grain with folic acid to prevent neural tube defects. METHODS. A cost-benefit analysis based on the US population, using the human capital approach to estimate the costs associated with preventable neural tube defects, was conducted. RESULTS. Under a range of assumptions about discount rates, baseline folate intake, the effectiveness of folate in preventing neural tube defects, the threshold dose that minimizes risk, and the cost of surveillance, fortification would likely yield a net economic benefit. The best estimate of this benefit is $94 million with low-level (140 micrograms [mcg] per 100 g grain) fortification and $252 million with high-level (350 mcg/100 g) fortification. The benefit-to-cost ratio is estimated at 4.3:1 for low-level and 6.1:1 for high-level fortification. CONCLUSIONS. By averting costly birth defects, folic acid fortification of grain in the United States may yield a substantial economic benefit. We may have underestimated net benefits because of unmeasured costs of neural tube defects and unmeasured benefits of higher folate intake. We may have overestimated net benefits if the cost of neurologic sequelae related to delayed diagnosis of vitamin B12 deficiency exceeds our projection. PMID:7733427

Romano, P S; Waitzman, N J; Scheffler, R M; Pi, R D

1995-01-01

49

Use of vitamins containing folic acid among women of childbearing age--United States, 2004.  

PubMed

Neural tube defects (NTDs) are serious birth defects of the spine (spina bifida) and brain (anencephaly), affecting approximately 3,000 pregnancies each year in the United States. Periconceptional consumption of the B vitamin folic acid reduces the occurrence of NTDs by 50%-70%. To prevent these defects, the U.S. Public Health Service (1992) and Institute of Medicine (1998) issued separate recommendations that all women capable of becoming pregnant consume 400 micro g of folic acid daily, and the Food and Drug Administration mandated fortification of cereal grain products with folic acid to increase women's daily intake. Fortification of the U.S. food supply with folic acid has resulted in a 26% reduction in NTDs. However, even with fortification, not all women receive adequate levels of folic acid from their diets. Therefore, increasing the use of vitamins containing folic acid remains an important component of NTD prevention. To monitor the use of vitamins containing folic acid among women of childbearing age, the Gallup Organization has conducted a series of surveys for the March of Dimes Birth Defects Foundation since 1995. This report presents results from the 2004 survey, which indicated that although no substantial increase in the proportion of women who use vitamins containing folic acid daily occurred during 1995-2003, a substantial increase was observed in 2004, with 40% of women aged 18-45 years reporting daily consumption of a vitamin containing folic acid. This report also presents information about women's dieting behaviors. Regardless of dieting status, public health programs should stress the importance of women in their childbearing years consuming 400 micro g of folic acid daily through supplements, fortified foods, and a diet containing folate-rich foods. PMID:15371968

2004-09-17

50

High Dosage Folic Acid Supplementation, Oral Cleft Recurrence and Fetal Growth  

PubMed Central

Objectives: To evaluate the effects of folic acid supplementation on isolated oral cleft recurrence and fetal growth. Patients and Methods: The study included 2,508 women who were at-risk for oral cleft recurrence and randomized into two folic acid supplementation groups: 0.4 and 4 mg per day before pregnancy and throughout the first trimester. The infant outcome data were based on 234 live births. In addition to oral cleft recurrence, several secondary outcomes were compared between the two folic acid groups. Cleft recurrence rates were also compared to historic recurrence rates. Results: The oral cleft recurrence rates were 2.9% and 2.5% in the 0.4 and 4 mg groups, respectively. The recurrence rates in the two folic acid groups both separately and combined were significantly different from the 6.3% historic recurrence rate post the folic acid fortification program for this population (p = 0.0009 when combining the two folic acid groups). The rate of cleft lip with palate recurrence was 2.9% in the 0.4 mg group and 0.8% in the 4 mg group. There were no elevated fetal growth complications in the 4 mg group compared to the 0.4 mg group. Conclusions: The study is the first double-blinded randomized clinical trial (RCT) to study the effect of high dosage folic acid supplementation on isolated oral cleft recurrence. The recurrence rates were similar between the two folic acid groups. However, the results are suggestive of a decrease in oral cleft recurrence compared to the historic recurrence rate. A RCT is still needed to identify the effect of folic acid on oral cleft recurrence given these suggestive results and the supportive results from previous interventional and observational studies, and the study offers suggestions for such future studies. The results also suggest that high dosage folic acid does not compromise fetal growth. PMID:23380913

Wehby, George L.; Felix, Temis Maria; Goco, Norman; Richieri-Costa, Antonio; Chakraborty, Hrishikesh; Souza, Josiane; Pereira, Rui; Padovani, Carla; Moretti-Ferreira, Danilo; Murray, Jeffrey C.

2013-01-01

51

[Does 5-methyltetrahydrofolate offer any advantage over folic acid?].  

PubMed

Almost half of the women do not follow the guidelines around folate suppletion before and during pregnancy, despite the proven benefit in the prevention of neural tube defects, miscarriages and premature births. The Belgian Superior Health Council recommends a minimum of 400 micrograms of folic acid or folate suppletion per day from 4 weeks before conception to 8 weeks thereafter. Many studies point to the importance of a wider intake period, more particularly at least 3 months before conception and throughout pregnancy and lactation. In high-risk women 4 mg is recommended until after the first 3 months of pregnancy. Afterwards the usual dose of 400 micrograms is sufficient. About half of the European population appears to have a gene mutation on the gene coding for the production of methylenetetrahydrofolate reductase, the enzyme that is involved in the formation of 5-methyltetrahydrofolate, which is, in his turn, responsible for the conversion of the toxic homocysteine in methionine. Women with such a gene polymorphism have a significantly higher risk to have a miscarriage or a baby with neural tube defects. For this reason, a search for an alternative form of synthetic folic acid supplement "pteroylmonoglutamic acid (PMG)" was conducted, particularly the calcium salt of 5-methyltetrahydrofolate (Metafolin). This offers the possibility to deliver the reduced folate immediately, which no longer needs to be converted by the reductase enzyme. Furthermore, this avoids free PMG in the circulation, lowers the risk for drug interactions and a vitamin B2 deficiency will not be masked. Despite clear guidelines regarding dietary supplements before and during pregnancy, their implementation is poor. Not only gynecologists but also GPs and pharmacists, should make more efforts to provide women of childbearing age with personal information. Especially risk groups such as adolescents, low-skilled or less well-off women and immigrants deserve special attention. PMID:23350208

Leemans, L

2012-12-01

52

Knowledge, Attitudes, and Practice among Women and Doctors Concerning the Use of Folic Acid  

PubMed Central

Background and Objective. Daily folic acid intake, prior to conception and in early pregnancy, significantly reduces neural tube defects (NTDs). We compared folic acid consumption among Jewish and Bedouin women and the recommendations of family physicians and gynecologists. Methods. We compared 64 Muslim Bedouin women and 65 Jewish women. We also compared 39 gynecologists and 60 family physicians. Results. Fifty-one Jewish women (78.5%) took folic acid during pregnancy, but only seven (10.8%) before conception. Sixty Bedouin women (93.75%) took folic acid during pregnancy, but only four (6.25%) before conception (P < .05). Five Jewish women (7.7%) and two Bedouin women (3.1%) took folic acid three months before conception. Thirty-three gynecologists (87%) recommend preconception folic acid compared with thirty-six family physicians (60%) (P < .05). Conclusions. The majority of women use folic acid during pregnancy, but only few do so to prevent NTDs. There is a significant difference between doctors' recommendations and actual practice. PMID:21647220

Auriel, Eithan; Biderman, Aya; Belmaker, Ilana; Freud, Tamar; Peleg, Roni

2011-01-01

53

Knowledge, Attitudes, and Practice among Women and Doctors Concerning the Use of Folic Acid.  

PubMed

Background and Objective. Daily folic acid intake, prior to conception and in early pregnancy, significantly reduces neural tube defects (NTDs). We compared folic acid consumption among Jewish and Bedouin women and the recommendations of family physicians and gynecologists. Methods. We compared 64 Muslim Bedouin women and 65 Jewish women. We also compared 39 gynecologists and 60 family physicians. Results. Fifty-one Jewish women (78.5%) took folic acid during pregnancy, but only seven (10.8%) before conception. Sixty Bedouin women (93.75%) took folic acid during pregnancy, but only four (6.25%) before conception (P < .05). Five Jewish women (7.7%) and two Bedouin women (3.1%) took folic acid three months before conception. Thirty-three gynecologists (87%) recommend preconception folic acid compared with thirty-six family physicians (60%) (P < .05). Conclusions. The majority of women use folic acid during pregnancy, but only few do so to prevent NTDs. There is a significant difference between doctors' recommendations and actual practice. PMID:21647220

Auriel, Eithan; Biderman, Aya; Belmaker, Ilana; Freud, Tamar; Peleg, Roni

2011-01-01

54

Folic acid - vitamin and panacea or genetic time bomb?  

PubMed

We live in a health-conscious age - many of us supplement our diet with essential micronutrients through the discretionary use of multivitamin pills or judicious selection of foods that have a health benefit beyond that conferred by the nutrient content alone - the so-called 'functional foods'. Indeed, the citizens of some nations have little choice, with a mandatory fortification policy in place for certain vitamins. But do we ever stop to consider the consequences of an increased exposure to micronutrients? We examine this issue in relation to the B-group vitamin folic acid, and ask whether supplementation with this vitamin could introduce a strong genetic selection pressure - one that has the side effect of increasing the prevalence of some of the most significant, human life-threatening diseases. Are we affecting our genetics - is this a case of human evolution in progress by altering our diet? PMID:15738964

Lucock, Mark; Yates, Zoë

2005-03-01

55

Folic acid and neural tube defect: can't we come to closure?  

PubMed Central

In a series of nonrandomized and randomized intervention trials and case-control and cohort studies, women using multivitamins or folic acid supplements during the first 6 weeks of pregnancy experienced a three- to fourfold reduction in neural tube defects among their offspring. Viewed collectively, these data provide strong evidence that an important subset of US women do not receive sufficient folic acid to minimize their risk of a defective pregnancy. Further, the amounts of folic acid contained in multivitamins (usually 200-400 micrograms per day) appear adequate to greatly reduce, and probably eliminate, the excess risk. PMID:1566943

Willett, W C

1992-01-01

56

Ethanol-Induced Inhibition of Human Intestinal Enzyme Activities: Reversal by Folic Acid.  

National Technical Information Service (NTIS)

In 10 normal volunteer subjects on a constant or an ad libitum mixed diet ethanol decreased jejunal glycolytic enzymes. Folate increased the jejunal glycolytic enzymes. Ethanol and folic acid given together antagonized the action of each other. (Author)

H. L. Greene, F. B. Stifel, R. H. Herman, Y. F. Herman, N. S. Rosensweig

1973-01-01

57

The impact of folic acid intake on the association between diabetes, obesity, and spina bifida  

PubMed Central

Objective To investigate the relationship between spina bifida and two established risk factors, pregestational diabetes and obesity, in both the presence and absence of the recommended daily folic acid intake in the periconceptional period. Study Design Cases of spina bifida (n=1154) and controls (n=9439) from the Slone Epidemiology Center Birth Defects Study (1976–2011) were included. Information on preexisting diabetes (collected 1976+) and obesity (collected 1993+), defined as BMI ?30 kg/m2, were collected through interviews conducted within six months of delivery. Periconceptional folic acid intake was calculated using both dietary and supplement information. Mothers were classified as consuming more or less than 400µg/day of folic acid, with food folate included at a 30% discount for its lower bioavailability. Logistic regression models, adjusted for maternal race, education, and study site, were used to calculate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the joint effects of low folic acid intake coupled with diabetes or obesity. Results Mothers of cases were more likely to have diabetes or be obese (0.7% and 19.0%, respectively) than control mothers (0.4% and 10.8%, respectively). The joint effect of diabetes and lower folic acid intake on spina bifida was larger (aOR:3.95; CI: 1.56, 10.00) than that of diabetes and higher folic acid intake (aOR:1.31; CI: 0.17, 10.30). Folic acid intake made little difference on the association between obesity and spina bifida. Conclusion Our findings suggest that folic acid further attenuates, though does not eliminate, the risk of spina bifida associated with diabetes, than that with obesity. PMID:23711668

Parker, Samantha E; Yazdy, Mahsa M; Tinker, Sarah C; Mitchell, Allen A; Werler, Martha M

2013-01-01

58

Folic acid supplementation during early pregnancy and the risk of gestational hypertension and preeclampsia.  

PubMed

Emerging evidence has suggested that folic acid-containing multivitamins may markedly reduce the risk of gestational hypertension or preeclampsia. We examined whether maternal supplementation with folic acid alone during early pregnancy can prevent the occurrence of gestational hypertension and preeclampsia. The data are from a large population-based cohort study established to evaluate the effectiveness of the campaign to prevent neural tube defects with folic acid supplementation in China. We selected participants who were registered in 2 southern provinces, had exact information on folic acid use, and were not affected by chronic hypertension or diabetes mellitus before 20 weeks gestation. A logistic regression model was used to adjust for the effects of the main potential confounders, including age, body mass index, education, occupation, parity, and multiple births. The study size had 99.9% power (?=0.05) to detect a decrease of 10% over the unexposed rate of 9.4% for gestational hypertension. Among the 193 554 women (47.9% took folic acid, 52.1% did not), the overall incidence of gestational hypertension and preeclampsia was 9.5% and 2.5%, respectively. The incidence of gestational hypertension and preeclampsia was 9.7% and 2.5% for women who took folic acid, and 9.4% and 2.4% for women who did not use it. The adjusted risk ratio associated with folic acid use was 1.08 (95% confidence interval, 1.04-1.11) for gestational hypertension and 1.11 (95% confidence interval, 1.04-1.18) for preeclampsia. Our findings suggest that daily consumption of 400 ?g folic acid alone during early pregnancy cannot prevent the occurrence of gestational hypertension and preeclampsia. PMID:23399716

Li, Zhiwen; Ye, Rongwei; Zhang, Le; Li, Hongtian; Liu, Jianmeng; Ren, Aiguo

2013-04-01

59

Awareness of the benefits of folic acid and prevalence of the use of folic acid supplements to prevent neural tube defects among Thai women  

Microsoft Academic Search

Objective  To determine the level of knowledge about the usefulness of periconceptional folic acid supplementation among pregnant women.\\u000a \\u000a \\u000a \\u000a Materials and methods  An anonymous questionnaire was completed by selected subjects to assess folic acid awareness. The questionnaire was administered\\u000a to pregnant women who were seeking antenatal care at King Chulalongkorn Memorial Hospital May to December 2005. The questions\\u000a covered their knowledge and use

Katika Nawapun; Vorapong Phupong

2007-01-01

60

Synergistic embryotoxicity of combination pyrimethamine and folic acid in rats.  

PubMed

The increased embryotoxicity of pyrimethamine (PYM) with concomitant oral dosing of folic acid (FA) was examined in rats. The preventive effects of folinic acid (FNA) on PYM embryotoxicity were also examined. Six groups were constructed: PYM I (PYM 1.2 mg/kg/day), FA (FA 50 mg/kg/day), PYM I+FA (1.2 and 50 mg/kg/day, respectively), PYM II (2.7 mg/kg/day), PYM II+FNA (2.7 and 12 mg/kg/day, respectively), and a vehicle control group. The agents were administered for 11 days from day 7 throughout 17 of gestation. PYM and FA were administered by gavage and FNA was administered intraperitoneally. Visceral and skeletal malformations were observed in the fetuses of both PYM I+FA and PYM II groups; these included dilatation of the lateral ventricle and fused ribs. No malformed fetuses were observed in the fetuses of the other four groups. External malformations were observed only in the fetuses of PYM II groups; these included cleft palate, cleft lips, and brachygnathia, among others. These results show that the concomitant gavage dosing of FA augments PYM embryotoxicity. The preventive effects of FNA were also confirmed. PMID:8274822

Chung, M K; Han, S S; Roh, J K

1993-01-01

61

The Effect of Multiple Single Nucleotide Polymorphisms in the Folic Acid Pathway Genes on Homocysteine Metabolism  

PubMed Central

Objective. To investigate the joint effects of the single nucleotide polymorphisms (SNPs) of genes in the folic acid pathway on homocysteine (Hcy) metabolism. Methods. Four hundred women with normal pregnancies were enrolled in this study. SNPs were identified by MassARRAY. Serum folic acid and Hcy concentration were measured. Analysis of variance (ANOVA) and support vector machine (SVM) regressions were used to analyze the joint effects of SNPs on the Hcy level. Results. SNPs of MTHFR (rs1801133 and rs3733965) were significantly associated with maternal serum Hcy level. In the different genotypes of MTHFR (rs1801133), SNPs of RFC1 (rs1051266), TCN2 (rs9606756), BHMT (rs3733890), and CBS (rs234713 and rs2851391) were linked with the Hcy level adjusted for folic acid concentration. The integrated SNPs scores were significantly associated with the residual Hcy concentration (RHC) (r = 0.247). The Hcy level was significantly higher in the group with high SNP scores than that in other groups with SNP scores of less than 0.2 (P = 0.000). Moreover, this difference was even more significant in moderate and high levels of folic acid. Conclusion. SNPs of genes in the folic acid pathway possibly affect the Hcy metabolism in the presence of moderate and high levels of folic acid. PMID:24524080

Liang, Shuang; Zhou, Yuanpeng; Wang, Huijun; Qian, Yanyan; Ma, Duan; Tian, Weidong; Persaud-Sharma, Vishwani; Yu, Chen; Ren, Yunyun; Zhou, Shufeng; Li, Xiaotian

2014-01-01

62

Women’s awareness and periconceptional use of folic acid: data from a large European survey  

PubMed Central

Objective To investigate the awareness and use of folic acid in European women of child-bearing age, particularly in the setting of pregnancy and pregnancy planning. Methods Between November 2009 and December 2009, women aged 15–49 years old from 18 European countries completed a 30-minute structured questionnaire either online or via face-to-face interviews. To achieve nationally representative samples for each country quotas were set for age, education, income, and regional distribution. Results A total of 22,925 women participated in the survey. Of the respondents, 58% had at least one biological child, and of these 38% reported that their first pregnancy was not planned. Nearly 60% of women who planned their pregnancy indicated that they had stopped using their method of contraception without first consulting a doctor or another health care professional. Overall, 70% reported that they had heard of folic acid and 40% stated that they knew the benefits of folic acid. However, when prompted to indicate which diseases and/or birth defects folic acid can protect against, only 17% knew that folic acid can reduce the risk of neural tube defects/spina bifida. Conclusions A large proportion of European women of child-bearing age in this survey were unaware that periconceptional folic acid supplementation reduces the risk of birth defects. PMID:23658501

Bitzer, Johannes; von Stenglin, Ariane; Bannemerschult, Ralf

2013-01-01

63

Use of dietary supplements containing folic acid among women of childbearing age--United States, 2005.  

PubMed

Neural tube defects (NTDs) are serious birth defects of the spine (spina bifida) and brain (anencephaly), affecting approximately 3,000 pregnancies each year in the United States. Daily periconceptional consumption of 400 mug of folic acid, as recommended by the Public Health Service (PHS) since 1992, reduces the occurrence of NTDs by 50%-70%. The Food and Drug Administration ordered mandatory fortification with folic acid of U.S. cereal grain products, beginning in 1998. However, despite a 26% reduction in NTDs, not all women of childbearing age receive adequate levels of folic acid from their diets. Therefore, increasing the number of women who take dietary supplements containing 400 mug of folic acid daily remains an important component of NTD prevention. This report summarizes results from the 2005 March of Dimes Gallup survey, which determined a decrease in the proportion of childbearing-aged women who reported taking folic acid in dietary supplements daily, from 40% in 2004 to 33% in 2005, returning to a level consistent with that reported during 1995-2003. These results emphasize the need for innovative programs to increase folic acid consumption to further reduce NTDs. PMID:16195694

2005-09-30

64

Use of supplements containing folic acid among women of childbearing age--United States, 2007.  

PubMed

Neural tube defects (NTDs) are serious birth defects of the brain (anencephaly) and spine (spina bifida) that affect approximately 3,000 pregnancies each year in the United States. In 1992, the U.S. Public Health Service recommended that all women of childbearing age in the United States capable of becoming pregnant consume 400 microg of folic acid daily to reduce their risk for having a pregnancy affected by NTDs. To assess awareness, knowledge, and behavior related to folic acid among women of childbearing age (aged 18-45 years), CDC analyzed the results of a national survey conducted annually by the Gallup Organization during the period 2003-2007. This report summarizes the results of that analysis, which indicated that, among all women of childbearing age, those aged 18-24 years had the least awareness regarding folic acid consumption (61%), the least knowledge regarding when folic acid should be taken (6%), and the lowest reported daily use of supplements containing folic acid (30%). Because women in this age group account for nearly one third of all births in the United States, promotion of folic acid consumption should be targeted to this population. PMID:18185493

2008-01-11

65

Folic acid handling by the human gut: implications for food fortification and supplementation123  

PubMed Central

Background: Current thinking, which is based mainly on rodent studies, is that physiologic doses of folic acid (pterylmonoglutamic acid), such as dietary vitamin folates, are biotransformed in the intestinal mucosa and transferred to the portal vein as the natural circulating plasma folate, 5-methyltetrahydrofolic acid (5-MTHF) before entering the liver and the wider systemic blood supply. Objective: We tested the assumption that, in humans, folic acid is biotransformed (reduced and methylated) to 5-MTHF in the intestinal mucosa. Design: We conducted a crossover study in which we sampled portal and peripheral veins for labeled folate concentrations after oral ingestion with physiologic doses of stable-isotope–labeled folic acid or the reduced folate 5-formyltetrahydrofolic acid (5-FormylTHF) in 6 subjects with a transjugular intrahepatic porto systemic shunt (TIPSS) in situ. The TIPSS allowed blood samples to be taken from the portal vein. Results: Fifteen minutes after a dose of folic acid, 80 ± 12% of labeled folate in the hepatic portal vein was unmodified folic acid. In contrast, after a dose of labeled 5-FormylTHF, only 4 ± 18% of labeled folate in the portal vein was unmodified 5-FormylTHF, and the rest had been converted to 5-MTHF after 15 min (postdose). Conclusions: The human gut appears to have a very efficient capacity to convert reduced dietary folates to 5-MTHF but limited ability to reduce folic acid. Therefore, large amounts of unmodified folic acid in the portal vein are probably attributable to an extremely limited mucosal cell dihydrofolate reductase (DHFR) capacity that is necessary to produce tetrahydrofolic acid before sequential methylation to 5-MTHF. This process would suggest that humans are reliant on the liver for folic acid reduction even though it has a low and highly variable DHFR activity. Therefore, chronic liver exposure to folic acid in humans may induce saturation, which would possibly explain reports of systemic circulation of unmetabolized folic acid. This trial was registered at clinicaltrials.gov as NCT02135393. PMID:24944062

Patanwala, Imran; King, Maria J; Barrett, David A; Rose, John; Jackson, Ralph; Hudson, Mark; Philo, Mark; Dainty, Jack R; Wright, Anthony JA; Finglas, Paul M; Jones, David E

2014-01-01

66

Folic acid attenuates hyperhomocysteinemia-induced glomerular damage in rats.  

PubMed

The present study investigated whether lowering plasma homocysteine (Hcy) with folic acid (FA) could attenuate hyperhomocysteinemia (HHcy)-associated glomerular damage and possible mechanisms. The HHcy animal model was established by intragastric administration with l-methionine in rats. FA was also given intragastrically. Plasma Hcy and creatinine and urinary albumin were measured. Histological and ultrastructural changes were observed by light and electron microscopes. The expression of alpha-smooth muscle actin (?-SMA), proliferating cell nuclear antigen (PCNA) and transforming growth factor-beta1 (TGF-?1) in the kidney was examined by immunohistochemical staining and western blot analysis. The administration of l-methionine induced HHcy in rats. The HHcy rats developed glomerulosclerosis and fibrosis. Plasma creatinine concentration and urinary albumin excretion were also significantly increased in HHcy rats. Effacement and extensively fusion of podocyte foot process was observed in HHcy rats, which was associated with decreased expression of nephrin protein in renal cortex of HHcy rats. Supplementation with FA lowered plasma Hcy significantly. Plasma creatinine concentration and urinary albumin excretion were also significantly attenuated by FA. Morphologically, HHcy-associated glomerulosclerosis, fibrosis, podocyte foot process effacement and loss of podocyte nephrin, were significantly improved by FA. The expressions of ?-SMA, PCNA and TGF-?1 were increased in renal cortex of HHcy rats, and which were also partially reversed by FA. These data suggest that elevated plasma Hcy is an important pathogenic factor for glomerular damage. Lowering plasma Hcy by FA can inhibit TGF-?1 expression and attenuate HHcy-induced glomerular damage. PMID:23859838

Cao, Lu; Lou, Xiaoying; Zou, Zhaoxia; Mou, Nana; Wu, Weikang; Huang, Xiongqing; Tan, Hongmei

2013-09-01

67

Folic Acid Supplementation and Preterm Birth: Results from Observational Studies  

PubMed Central

Introduction. Folic acid (FA) supplementation is recommended worldwide in the periconceptional period for the prevention of neural tube defects. Due to its involvement in a number of cellular processes, its role in other pregnancy outcomes such as miscarriage, recurrent miscarriage, low birth weight, preterm birth (PTB), preeclampsia, abruptio placentae, and stillbirth has been investigated. PTB is a leading cause of perinatal mortality and morbidity; therefore its association with FA supplementation is of major interest. The analysis of a small number of randomized clinical trials (RCTs) has not found a beneficial role of FA in reducing the rate of PTBs. Aim of the Study. The aim of this review was to examine the results from recent observational studies about the effect of FA supplementation on PTB. Materials and Methods. We carried out a search on Medline and by manual search of the observational studies from 2009 onwards that analyzed the rate of PTB in patients who received supplementation with FA before and/or throughout pregnancy. Results. The results from recent observational studies suggest a slight reduction of PTBs that is not consistent with the results from RCTs. Further research is needed to better understand the role of FA supplementation before and during pregnancy in PTB. PMID:24724083

Franchi, Massimo

2014-01-01

68

Maternal folic acid supplementation to dams on marginal protein level alters brain fatty acid levels of their adult offspring.  

PubMed

Studies on fetal programming of adult diseases have highlighted the importance of maternal nutrition during pregnancy. Folic acid and long-chain essential polyunsaturated fatty acids (LC-PUFAs) have independent effects on fetal growth. However, folic acid effects may also involve alteration of LC-PUFA metabolism. Because marginal deficiency of LC-PUFAs during critical periods of brain growth and development is associated with risks for adult diseases, it is highly relevant to investigate how maternal supplementation of such nutrients can alter brain fatty acid levels. We examined the impact of folic acid supplementation, conventionally used in maternal intervention, on brain essential fatty acid levels and plasma corticosterone concentrations in adult offspring at 11 months of age. Pregnant female rats from 4 groups (6 in each) were fed with casein diets either with 18 g protein/100 g diet (control diet) or treatment diets that were marginal in protein (MP), such as 12 g protein/100 g diet supplemented with 8 mg folic acid (FAS/MP), 12 g protein/100 g diet without folic acid (FAD/MP), or 12 g protein/100 g diet (MP) with 2 mg folic acid. Pups were weaned to a standard laboratory diet with 18 g protein/100 g diet. All male adult offspring in the FAS/MP group showed lower docosahexaenoic acid (P<.05) as compared with control adult offspring (6.04+/-2.28 vs 10.33+/-0.86 g/100 g fatty acids) and higher n-6/n-3 ratio (P<.05). Docosahexaenoic acid levels in FAS/MP adult offspring were also lower (P<.05) when compared with the MP group. Plasma corticosterone concentrations were higher (P<.05) in male adult offspring from the FAS/MP group compared with control as well as the MP adult offspring. Results suggest that maternal folic acid supplementation at MP intake decreased brain docosahexaenoic acid levels probably involving corticosterone increase. PMID:16631439

Rao, Shobha; Joshi, Sadhana; Kale, Anvita; Hegde, Mahabaleshwar; Mahadik, Sahebarao

2006-05-01

69

Folic acid and primary prevention of birth defects.  

PubMed

Birth defects (BDs) are an important public health problem, due to their overall incidence, occurring in 2-3% of live births in European Union. Neural tube defects (NTDs) are among major NTDs, due to their severity and relatively high incidence; in the meanwhile NTDs are also the most effectively preventable BDs to date. In particular, an adequate folic acid (FA) intake reduces both the occurrence and the recurrence of NTDs; FA is the synthetic form of folates, naturally occurring vitamins in a number of foods, especially vegetables. The daily intake of 0.4 mg of FA should be recommended to all women of childbearing age who plan to become pregnant. The Italian Network for Primary Prevention of BDs through FA Promotion has achieved a significant improvement in FA awareness and use in the periconceptional period. Nevertheless, primary prevention of BDs needs to make further progress; the Italian National Centre for Rare Diseases participates in european sureveillance of congenital anomalies (EUROCAT) Joint Action as coordinator of activities on the effectiveness of BDs prevention. Mandatory food fortification with FA has not been introduced in any European country. The health benefits of FA in reducing the risk of NTDs are undisputed; however mechanistic and animal studies suggest a relationship between high FA intakes and increased cancer promotion, while human studies are still inconsistent and inconclusive. A Working Group organized by the European Food Safety Authority pointed out significant uncertainties about fortification safety and the need for more studies; currently, FA intake from fortified foods and supplements should not exceed 1 mg/day in adults. In conclusion, based on up-to-date scientific evidence, the Italian Network strategy pivots on periconceptional supplementation integrated with promotion of healthy eating habits, support to health education, enhancing the role of women in managing life choices about their health and pregnancy and increasing the scientific knowledge about BDs primary prevention. PMID:21915935

Taruscio, Domenica; Carbone, Pietro; Granata, Orietta; Baldi, Francesca; Mantovani, Alberto

2011-01-01

70

Using CD-ROM technology to increase folic acid knowledge among physician assistant students.  

PubMed

The purpose of this study was to examine the effectiveness of incorporating CD-ROM technology to increase the knowledge of folic acid among physician assistant students. Participants included 76 first-year physician assistant students enrolled in a Women's Health course. A pretest and posttest was used to evaluate the knowledge gain after viewing the CD-ROM over a 2-week period. Of the 76 students in the course, 73 completed the pretest and the post-test. Posttest scores were significantly better than pretest scores (t = -11.83; p < or = 0.001), with means 68.63% and 46.18%. Knowledge scores increased by 22.45% from pre-test to posttest. Student evaluation results suggested that the CD-ROM (1) provided folic acid information in a clear and effective manner, (2) adequately covered the folic acid information, (3) increased student awareness and knowledge about folic acid, and (4) may promote early commitment by students to recommend daily folic acid intake to their patients. PMID:15503753

Morgan, Christine; Klein, Diane Austrin; Selbst, Melissa

2004-01-01

71

Quantum dot-folic acid conjugates as potential photosensitizers in photodynamic therapy of cancer.  

PubMed

This study examined the in vitro potential of bioconjugated quantum dots (QDs) as photosensitizers for photodynamic therapy (PDT). According to our previous approaches using photosensitizers, folic acid appears to be an optimal targeting ligand for selective delivery of attached therapeutic agents to cancer tissues. We synthesized hydrophilic near infrared emitting CdTe(S)-type QDs conjugated with folic acid using different spacers. Photodynamic efficiency of QDs conjugated or not with folic acid was evaluated on KB cells, acting as a positive control due to their overexpression of FR-?, and HT-29 cells lacking FR-?, as negative control. A design of experiments was suggested as a rational solution to evaluate the impacts of each experimental factor (QD type and concentration, light fluence and excitation wavelength, time of contact before irradiation and cell phenotype). We demonstrated that, for concentrations lower than 10 nM, QDs displayed practically no cytotoxic effect without light exposure for both cell lines. Whereas QDs at 2.1 nM displayed a weak photodynamic activity, a concentration of 8 nM significantly enhanced the photodynamic efficiency characterized by a light dose-dependent response. A statistically significant difference in photodynamic efficiency between KB and HT-29 cells was evidenced in the case of folic acid-conjugated QDs. Optimal conditions led to an enhanced photocytotoxicity response, allowing us to validate the ability of QDs to generate a photodynamic effect and of folic acid-conjugated QDs for targeted PDT. PMID:21479314

Morosini, Vincent; Bastogne, Thierry; Frochot, Céline; Schneider, Raphaël; François, Aurélie; Guillemin, François; Barberi-Heyob, Muriel

2011-05-01

72

Folic Acid and Risk of Prostate Cancer: Results From a Randomized Clinical Trial  

PubMed Central

Data regarding the association between folate status and risk of prostate cancer are sparse and conflicting. We studied prostate cancer occurrence in the Aspirin/Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas conducted between July 6, 1994, and December 31, 2006. Participants were followed for up to 10.8 (median = 7.0, interquartile range = 6.0–7.8) years and asked periodically to report all illnesses and hospitalizations. Aspirin alone had no statistically significant effect on prostate cancer incidence, but there were marked differences according to folic acid treatment. Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group (age-adjusted hazard ratio = 2.63, 95% CI = 1.23 to 5.65, Wald test P = .01). In contrast, baseline dietary folate intake and plasma folate in nonmultivitamin users were inversely associated with risk of prostate cancer, although these associations did not attain statistical significance in adjusted analyses. These findings highlight the potential complex role of folate in prostate cancer and the possibly different effects of folic acid–containing supplements vs natural sources of folate. PMID:19276452

Grau, Maria V.; Haile, Robert W.; Sandler, Robert S.; Summers, Robert W.; Bresalier, Robert S.; Burke, Carol A.; McKeown-Eyssen, Gail E.; Baron, John A.

2009-01-01

73

Factors affecting the use of folic acid supplements in pregnant women in Glasgow.  

PubMed Central

BACKGROUND: Use of folic acid supplements preconception, and during the first trimester, is associated with a reduced incidence of first and subsequent neural tube defects. The Department of Health guidelines recommend the use of folic acid supplements by all women planning a pregnancy. AIM: To ascertain the proportion using folic acid supplements and the factors affecting their use. METHOD: Questionnaires were distributed postpartum to the 515 women who delivered normal babies in three maternity units in Glasgow over a four-week period. RESULTS: Forms were completed by 487 (95%) women. Only 57% took supplements at some point during their pregnancy, and only 21% took them before conception. Failure to take supplements was significantly associated with unplanned pregnancy, younger age, and previous pregnancies. Lack of awareness of the potential benefits associated with folic acid use was the commonest reason cited by women for not taking supplements. CONCLUSIONS: Increased health education through health care professionals and mass media campaigns can improve awareness and thereby increase the use of supplements in planned pregnancies. However, 42% of women in our study had unplanned pregnancies. Intake of folic acid supplements in this group can only be increased by improvements in dietary intake within the population as a whole, and by fortification of commonly ingested foods. PMID:9474827

McGovern, E; Moss, H; Grewal, G; Taylor, A; Bjornsson, S; Pell, J

1997-01-01

74

Impact of folic acid supplementation on single- and double-stranded RNA degradation in human colostrum and mature milk.  

PubMed

Sufficient intake of folic acid is necessary for normal embryogenesis, fetal, and neonatal development. Folic acid facilitates nucleic acid internalization, and protects cellular DNA from nuclease degradation. Human milk contains enzymes, antimicrobial proteins, and antibodies, along with macrophages, that protect against infections and allergies. However, little to no information is available on the effects of folic acid supplementation on degradation of nucleic acids in human milk. In the present study, we aimed to determine the RNase activity (free and inhibitor-bound) in colostrum and mature milk, following folic acid supplementation. The study design included a total of 59 women, 27 of whom received 400 ?g of folic acid daily periconceptionally and after. Folic acid supplementation increased the free RNase and polyadenylase activity following lactation. However, the increased RNase activity was not due to de novo enzyme synthesis, as the inhibitor-bound (latent) RNase activity was significantly lower and disappeared after one month. Folic acid reduced RNase activity by using double-stranded RNA as substrate. Data suggests that folic acid supplementation may improve viral RNAs degradation and mRNA degradation, but not dsRNA degradation, preserving in this way the antiviral defense. PMID:24650098

Kocic, Gordana; Bjelakovic, Ljiljana; Bjelakovic, Bojko; Jevtoci-Stoimenov, Tatjana; Sokolovic, Dusan; Cvetkovic, Tatjana; Kocic, Hristina; Stojanovic, Svetlana; Langerholc, Tomaz; Jonovic, Marina

2014-07-01

75

[Integral bread development with soybean, chia, linseed, and folic acid as a functional food for women].  

PubMed

Six bread formulations were developed, using different proportions of whole-wheat flour, chia seeds and flaxseed flour. All of our formulations were added with folic acid. Sensorial and texture evaluations were performed, showing good acceptance of the products. Proximal chemical analysis was carried out; in addition, the following parameters were determined: calcium, phosphorus, total dietary fiber, folic acid, water hydration capacity, Glucose Dialysis Retardation Index (GDRI) and fatty acids. The results obtained showed higher protein levels in the developed breads (23.23-30.24 (g/100g dry matter) as compared to a control (21.00% of proteins in bread elaborated without chia or flaxseed). Furthermore, the breads contained 10.07-12.15 of lipids (g/100g dry matter) (linoleic acid: 2.43-4.05%; linolenic acid: 1.12-4.46 %; oleic acid: 2.93-6.13 %), GDRI values were between 89.1 and 98.1 % and folic acid was in the range 699.44 - 991.3 (microg/100g dry matter). The same parameters were determined in the chia seed and in the flaxseed flour. It was concluded that; due to their high levels of protein, insaturated fatty acids (omega-3 and omega-6), dietary fiber and folic acid, these breads have a high nutritional value, so they could have special benefits for woman. PMID:17824203

Justo, Mayela Bautista; Alfaro, Alejandra Denisse Castro; Aguilar, Ernesto Camarena; Wrobel, Katarzyna; Wrobel, Kazimierz; Guzmán, Guadalupe Alanís; Sierra, Zeferino Gamiño; Zanella, Victor Da Mota

2007-03-01

76

Preschool iron-folic acid and zinc supplementation in children exposed to iron-folic acid in utero confers no added cognitive benefit in early school-age.  

PubMed

In Nepal, antenatal iron-folic acid supplementation improved aspects of intellectual, executive, and fine motor function among school-age children. We examined the impact of added zinc to the maternal antenatal supplement (M-IFAZn) and preschool supplementation from 12 to 36 mo with iron-folic acid (C-IFA) ± zinc (C-IFAZn) on cognitive outcomes compared to maternal iron-folic acid (M-IFA) alone. Children 7-9 y old (n = 780) who participated in early childhood micronutrient supplementation trial during 2001-2004 and whose mothers participated in an antenatal micronutrient supplementation between 1999 and 2001 were followed for cognitive assessments in 2007-2009. Using multivariate analysis of variance and adjusting for confounders, M-IFA with child supplementation (either C-IFA or C-IFAZn) did not impact scores on the tests of general intelligence (Universal Nonverbal Intelligence Test), and executive function (Stroop and go/no go tests) relative to the M-IFA alone. However, children in the C-IFAZn group had slightly lower scores on the backward digit span (-0.29, 95% CI: -0.55, -0.04) and Movement Assessment Battery for Children (1.33, 95% CI: 0.26, 2.40) relative to the referent group, whereas both C-IFA (-1.92, 95% CI: -3.12, -0.71) and C-IFAZn (-1.78, 95% CI: -2.63, -0.92) produced somewhat lower finger tapping test scores (fine motor skills). The combination of M-IFAZn and C-IFA or C-IFAZn did not lead to any outcome differences relative to M-IFA alone. Preschool iron-folic acid ± zinc to children exposed to iron-folic acid in utero or addition of zinc to maternal iron-folic acid conferred no additional benefit to cognitive outcomes assessed in early school age. The late timing of supplementation during preschool may explain the lack of impact of iron and/or zinc. PMID:21956955

Christian, Parul; Morgan, Mary E; Murray-Kolb, Laura; LeClerq, Steven C; Khatry, Subarna K; Schaefer, Barbara; Cole, Pamela M; Katz, Joanne; Tielsch, James M

2011-11-01

77

Effect of supplemental folic acid on valproic acid-induced embryotoxicity and tissue zinc levels in vivo.  

PubMed

Valproic acid (VPA) is an anti-convulsant drug known to cause spina bifida in humans. Administration of the vitamin, folic acid, has been shown to decrease the recurrence and possibly also the occurrence of neural tube defects, primarily spina bifida, in humans. Additionally, treatment with a derivative (folinic acid) of folic acid has been reported to decrease the frequency of VPA-induced exencephaly in mice treated with the drug in vivo. A protective effect by folinic acid has not been observed in vitro. The purpose of this investigation was to reexamine the ability of folinic acid to decrease the incidence of VPA-induced neural tube defects in vivo. We also examined the effect of increased intake of folic acid on zinc levels in various maternal and embryonic tissues. Folinic acid, whether administered by intraperitoneal injection or in osmotic mini-pumps, did not decrease the number of mouse fetuses with VPA-induced exencephaly. Dietary supplementation with 10-20 times the daily required intake of folic acid in rodents also failed to decrease the embryotoxicity of VPA. Such dietary supplementation had no effect on zinc levels in maternal liver, brain, or kidney, nor in embryonic tissues. These results indicate that folic acid is not able to reverse the embryotoxicity induced by the anticonvulsant, that there is no apparent effect of high dietary folate intake on maternal or embryonic zinc levels and suggest that folate is probably not involved in the mechanism of VPA-induced embryotoxicity. PMID:8838251

Hansen, D K; Grafton, T F; Dial, S L; Gehring, T A; Siitonen, P H

1995-11-01

78

Protective effect of ligand-binding proteins against folic acid loss due to photodecomposition.  

PubMed

The B group vitamin known as folates is essential for a variety of physiological processes and plays an important role in the prevention of neural tube defects. However, it decomposes when exposed to UV light. In this study, the response of the synthetic form of folates known as folic acid to UV irradiation in the presence of ?-lactoglobulin (?-LG), bovine serum albumin (BSA) and ?-lactalbumin (?-LA) was investigated using circular dichroism, absorbance and fluorescence spectroscopy. Photodecomposition of folic acid was delayed in the presence of the proteins, which ranked in the order ?-LG>BSA>?-LA in terms of effectiveness. Protein unfolding or decomposition occurred at the same time, due to interaction with folic acid photodecomposition products. The results suggest potential uses of ligand-binding proteins as carriers of water-soluble active compounds for nutraceutical applications. PMID:23790844

Liang, Li; Zhang, Jie; Zhou, Peng; Subirade, Muriel

2013-11-15

79

Fortification of Corn Masa Flour With Folic Acid in the United States  

PubMed Central

Food fortification is an effective public health tool for addressing micronutrient deficiencies. The mandatory fortification of enriched cereal grains (e.g., wheat flour) with folic acid, which began in the United States in 1998, is an example of a successful intervention that significantly reduced the rate of neural tube defects (NTDs). However, despite the drop in NTD rates across all racial/ethnic groups after fortification, Hispanics continue to have the highest rates of this condition. One possible way to reduce this disparity is to fortify corn masa flour to increase the overall intake of folic acid in Hispanic women. We present the available evidence in favor of this approach, address possible safety issues, and outline next steps in the fortification of corn masa flour with folic acid in the United States. PMID:21680940

Oinuma, Motoko

2011-01-01

80

Folic acid and human reproduction—ten important issues for clinicians  

PubMed Central

This article presents data on the current best evidence-based clinical practices and controversies surrounding folic acid supplementation/fortification for the prevention of neural tube defects (NTDs) during early pregnancy. Formatted as a series of ten clinical questions, answers and extensive discussion are provided for each point. We assess the history and evidence behind supplementation and fortification, racial/ethnic disparities in NTDs on a global scale, and present information on risk factors for NTDs other than dietary folic acid deficiency. Also discussed are public health challenges, including disparities in NTD rates, population-wide monitoring of NTDs, and tracking safety data in the post-fortification era. Emerging data are also reviewed regarding the role folic acid may play in malignant processes, cardiovascular disease, male fertility, and other medical conditions. PMID:21991291

Dunlap, Beth; Shelke, Kantha; Salem, Shala A.; Keith, Louis G.

2011-01-01

81

Folic acid supplementation reduces oxidative stress and hepatic toxicity in rats treated chronically with ethanol  

PubMed Central

Folate deficiency and hyperhomocysteinemia are found in most patients with alcoholic liver disease. Oxidative stress is one of the most important mechanisms contributing to homocysteine (Hcy)-induced tissue injury. However it has not been examined whether exogenous administration of folic acid attenuates oxidative stress and hepatic toxicity. The aim of this study was to investigate the in vivo effect of folic acid supplementation on oxidative stress and hepatic toxicity induced by chronic ethanol consumption. Wistar rats (n = 32) were divided into four groups and fed 0%, 12%, 36% ethanol, or 36% ethanol plus folic acid (10 mg folic acid/L) diets. After 5 weeks, chronic consumption of the 36% ethanol diet significantly increased plasma alanine transaminase (ALT) (P < 0.05) and aspartate transaminase (AST) (P < 0.05), triglycerides (TG) (P < 0.05), Hcy (P < 0.001), and low density lipoprotein conjugated dienes (CD) (P < 0.05) but decreased total radical-trapping antioxidant potential (TRAP) (P < 0.001). These changes were prevented partially by folic acid supplementation. The 12% ethanol diet had no apparent effect on most parameters. Plasma Hcy concentration was well correlated with plasma ALT (r = 0.612**), AST (r = 0.652*), CD (r = 0.495*), and TRAP (r = -0.486*). The results indicate that moderately elevated Hcy is associated with increased oxidative stress and liver injury in alcohol-fed rats, and suggests that folic acid supplementation appears to attenuate hepatic toxicity induced by chronic ethanol consumption possibly by decreasing oxidative stress. PMID:22259676

Lee, Soo-Jung; Kang, Myung-Hee

2011-01-01

82

Antiapoptotic efficacy of folic acid and vitamin B?? against arsenic-induced toxicity.  

PubMed

Earlier, we proposed that the ability of folic acid and vitamin B?? to preserve systemic and mitochondrial function after short-term exposure to arsenic may prevent further progression to more permanent injury and pathological changes leading to cell death. To elucidate its mechanism, the present study examined the antiapoptotic efficacy of folic acid and vitamin B?? against short-term arsenic exposure-induced hepatic mitochondria oxidative stress and dysfunction. Sixteen to eighteen weeks old male albino rats weighing 140-150 × g were divided into five groups: Control (A), Arsenic-treated (B), Arsenic + folic acid (C), Arsenic +vitamin B?? (D), and Arsenic + folic acid + vitamin B?? (E). Data generated indicated that folic acid and vitamin B?? separately or in combination can give significant protection against alterations in oxidative stress and apoptotic marker parameters and downstream changes in mitochondria, namely pro-oxidative (NO, TBARS, OH?) and antioxidative defense (SOD, CAT, GSH) markers, iNOS protein expression, mitochondrial swelling, cytochrome c oxidase and Ca²?-ATPase activity, Ca²? content, caspase-3 activity. Additionally, results of hepatic cell DNA fragmentation, arsenic load of blood, hepatic tissue and urine, and histological observations, all strongly support that both these supplements have efficacy in preventing apoptotic changes and cellular damage. As the mechanisms of actions of both of these supplements are methylation related, a combined application was more effective. Results further reveal new molecular targets through which folic acid and vitamin B?? separately or in combination work to alleviate one critical component of arsenic-induced liver injury: mitochondria dysfunction. PMID:22566245

Majumdar, Sangita; Maiti, Anasuya; Karmakar, Subhra; Das, Asankur Sekhar; Mukherjee, Sandip; Das, Dolan; Mitra, Chandan

2012-05-01

83

Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics.  

PubMed

There is a large body of evidence to suggest that improving periconceptional folate status reduces the risk of neonatal neural tube defects. Thus increased folate intake is now recommended before and during the early stages of pregnancy, through folic acid supplements or fortified foods. Furthermore, there is growing evidence that folic acid may have a role in the prevention of other diseases, including dementia and certain types of cancer. Folic acid is a synthetic form of the vitamin, which is only found in fortified foods, supplements and pharmaceuticals. It lacks coenzyme activity and must be reduced to the metabolically active tetrahydrofolate form within the cell. L-5-methyl-tetrahydrofolate (L-5-methyl-THF) is the predominant form of dietary folate and the only species normally found in the circulation, and hence it is the folate that is normally transported into peripheral tissues to be used for cellular metabolism. L-5-methyl-THF is also available commercially as a crystalline form of the calcium salt (Metafolin(R)), which has the stability required for use as a supplement. Studies comparing L-5-methyl-THF and folic acid have found that the two compounds have comparable physiological activity, bioavailability and absorption at equimolar doses. Bioavailability studies have provided strong evidence that L-5-methyl-THF is at least as effective as folic acid in improving folate status, as measured by blood concentrations of folate and by functional indicators of folate status, such as plasma homocysteine. Intake of L-5-methyl-THF may have advantages over intake of folic acid. First, the potential for masking the haematological symptoms of vitamin B(12) deficiency may be reduced with L-5-methyl-THF. Second, L-5-methyl-THF may be associated with a reduced interaction with drugs that inhibit dihydrofolate reductase. PMID:20608755

Pietrzik, Klaus; Bailey, Lynn; Shane, Barry

2010-08-01

84

Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malaria  

Microsoft Academic Search

Whether children with malarial anaemia should receive supplementation with iron or folic acid is uncertain. Therefore, the effects of supplementary treatment with iron or folic acid, given together with chloroquine or pyrimethamine-sulfadoxine (Fansidar®), has been assessed in 600 Gambian children with uncomplicated falciparum malaria. After one month, haematological recovery was significantly better in the group treated with Fansidar® than in

Michaël Boele van Hensbroek; Stephen Morris-Jones; Sarah Meisner; Shabbar Jaffar; Lang Bayo; Raduwan Dackour; Christine Phillips; Brian M. Greenwood

1995-01-01

85

A folate-rich diet is as effective as folic acid from supplements in decreasing plasma homocysteine concentrations  

Microsoft Academic Search

st tr ra ac ct t Background & Aims: At least 500 µg of folic acid are required daily to treat hyperhomocysteinemia. To reach this amount by dietary changes alone may be difficult because food has a low folic acid content and bioavailability. No studies have compared the effects of similar amounts of additional folate derived from a combination of

M. Antonia Vilaseca; Susana Balcells; Rafael Artuch; Emili Corbella; José F. Meco; Ramon Vila; Ramon Pujol; Daniel Grinberg

2005-01-01

86

Periconceptional folic acid use and the prevalence of positional plagiocephaly.  

PubMed

The incidence of positional plagiocephaly (PP) has increased during the last 2 decades in the Netherlands. Although this is generally solely attributed to the advice to put babies on the back during their sleep, other factors might be of influence. Because the advice to take folic acid (FA) was initiated in the same period as the sleeping advice, this study was undertaken to evaluate the effect of FA on PP. It is known that a daily intake of 400 microg of FA around the time of conception is advised in periconceptive women to prevent development of neural tube defects. The maximal daily dietary folate intake is considered to be 250 mg with a bioavailability of 50% to 70%. However, periconceptional women may take a multivitamin containing pteroylmonoglutamine in addition to a FA supplement (isolated pteroylmonoglutamine). Therefore, the daily intake of FA will exceed 1 mg daily, which is considered the upper limit of daily folate ingestion. Data from the "Maastricht Cohort and Intervention study about pregnancy related girdlepain" were used to study the amount of folate containing supplemental intake of all the 7526 women. In this study, women were prospectively questioned about their FA intake. The entire cohort, considered the control group, was compared with a subgroup of women within this cohort with children with PP, treated by a plastic surgeon, considered the PP group. Double use, defined as isolated FA preparations in addition to folate containing supplements (vitamins), was seen more frequently in women giving birth to children with PP. In the PP group, double use was seen in 33.3% of the women compared to 13.2% in the control group. Although no statistical analysis could be made because the PP group was too small, the use of too high dosages of FA might have an adverse effect in causing more PP. This article does not want to discuss the beneficial effect of FA during pregnancy. However, we observed a potential empirical relation between PP and FA double intake requiring attention in more extensive studies. PMID:18216662

Michels, Alice; El Bakkali, Nadia; Bastiaenen, Caroline H; De Bie, Rob A; Colla, Carlo G; Van der Hulst, Rene R

2008-01-01

87

Investigation, using rat embryo culture, of the role of methionine supply in folic acid-mediated prevention of neural tube defects  

Microsoft Academic Search

Peri-conceptional folic acid supplementation has become a well established way to prevent neural tube defects (NTDs) and such supplementation reduces the prevalence of these defects by approximately 70%. However, the mechanism of the preventive effect of folic acid is not clear. This overview focuses on the biochemical basis of folic acid-preventable NTDs and on the results obtained with whole embryo

L. A. G. J. M. Vanaerts

1995-01-01

88

A folic acid conjugated silica-titania porous hollow nanosphere for improved topical photodynamic therapy.  

PubMed

The folic acid conjugated hollow nanosphere is used to encapsulate protoporphyrin IX and is utilized for photodynamic therapy. This system represents a 3.33 times higher photodynamic efficiency than previous protoporphyrin IX-based systems. The result proposes a new opportunity for effective photodynamic therapy of folate receptor positive tumor cells. PMID:25348554

Jang, Yoonsun; Kim, Sojin; Oh, Wan-Kyu; Kim, Chanhoi; Lee, Inkyu; Jang, Jyongsik

2014-12-18

89

Response of Broilers Performance to Dietary Betaine and Folic Acid at Different Methionine Levels  

Microsoft Academic Search

2 Abstract: Two experiments were designed to estimate the effect of methionine levels (0.33 and 0.45%) with betaine and folic acid on broiler performance. A total of 648 unsexed one week old Arbor Acres broiler chicks was randomly divided into two experiments according to dietary methionine level. Each experiment divided into nine treatment groups of 12 birds each with three

O. M. El-Husseiny; M. A. Abo-El-Ella; M. O. Abd-Elsamee; Magda M. Abd-Elfattah

2007-01-01

90

Effect of folic acid fortification on the characteristics of lemon yogurt  

Microsoft Academic Search

Development of dairy products with new flavors and health benefits helps the dairy industry increase sales of products as well as provide consumers with products they enjoy. Folic acid is used in the prevention of neural tube defects, heart defects, facial clefts, urinary tract abnormalities, and limb deficiencies. The objective of this study was to determine the effect of different

C. A. Boeneke; K. J. Aryana

2008-01-01

91

Effect of Lipid Peroxides on Fat Absorption and Folic Acid Status in the Rat  

Microsoft Academic Search

Addition of oxidized linoleate to the diet of rats resulted in a decreased rate of weight gain, an increased calorie requirement for each gram of weight gained, an impairment of fat absorption and an increase in the weight and length of the small intestine. The white cell count, blood haemoglobin levels and the concentration of folic acid in serum and

M. G. Cutler; M. A. Hayward

1974-01-01

92

Folic Acid Promotion for Hispanic Women in Florida: A Vitamin Diary Study  

ERIC Educational Resources Information Center

Objective: To assess the barriers and benefits of taking multivitamins among Hispanic women exposed to a folic acid social marketing campaign in Florida, USA. Design and setting: Evaluation of non-pregnant women aged 18-35 from multiple Hispanic subgroups. Method: For 6 months, participants exposed to social marketing campaign educational…

Thomas, Kamilah B.; Hauser, Kimberlea; Rodriguez, Nydia Y.; Quinn, Gwendolyn P.

2010-01-01

93

Multi-institute study finds folic acid may reduce some childhood cancers  

Cancer.gov

Folic acid fortification of foods may reduce the incidence of the most common type of kidney cancer and a type of brain tumors in children, finds a new study from the University of Minnesota and Washington University in St. Louis. Incidence reductions were found for Wilms' tumor, a type of kidney cancer, and primitive neuroectodermal tumors (PNET), a type of brain cancer.

94

Harvard study finds folic acid, vitamins B6 and 12 do not affect colorectal adenoma risk  

Cancer.gov

Combined folic acid, vitamin B6 and vitamin B12 supplements had no statistically significant effect on the risk of colorectal adenoma among women who were at high risk for cardiovascular disease, according to a Harvard Medical School study published October 12 in the Journal of the National Cancer Institute. The Harvard Medical School is a component of the Dana-Farber Cancer Institute.

95

Determination of folate/folic acid level in milk by microbiological assay, immuno assay and high performance liquid chromatography.  

PubMed

A concurrent determination of folate versus folic acid in milk by microbiological assay (MA) with Lactobacillus rhamnosus as the assay organism, Enzyme Linked Immuno Sorbent Assay (ELISA) by competitive binding rapid ELISA kit (RIDASCREEN®) and high-pressure-liquid chromatography (HPLC) was done for detection of the folate form and its level. MA gave total folate content as Lb. rhamnosus showed similar response to most folate isomers formed by the tri-enzyme treatment in comparison with the other two methods which specifically estimated the folic acid. In case of ELISA, specificity was apparently limited to folic acid and dihydro folic acid and thereby showed a lower response for other folate derivatives. Estimation by HPLC with UV detector was highly specific and hence only folic acid could be detected without any cross reactivity. Among the different methods HPLC was observed to be the most sensitive method for determination of folic acid and hence can efficiently determine the folic acid fortification level while MA remained highly efficient, sensitive and reproducible method for estimation of total folate indicating its potential use for dietary folate estimation. PMID:23506679

Iyer, Ramya; Tomar, Sudhir Kumar

2013-05-01

96

Folic acid supplementation changes the fate of neural progenitors in mouse embryos of hyperglycemic and diabetic pregnancy.  

PubMed

Folic acid has been shown to decrease the incidence of neural tube defects (NTDs) in normal and hyperglycemic conditions, but the influence of folic acid on the development of central nervous system is not fully understood. Here, we aimed to explore the effects of folic acid, especially high dose of folic acid, on the characteristics of neural progenitors in embryos of hyperglycemic and diabetic mouse. Hyperglycemic and diabetic pregnant mice were given 3 mg/kg or 15 mg/kg folic acid from embryonic day 0.5 (E0.5) and were euthanased on E11.5, E13.5 or E18.5. The incidence of NTDs at E13.5 was counted. The proliferation, apoptosis and differentiation of neural progenitors and neuronal migration were determined using BrdU incorporation assay, TUNEL assay, immunofluorescence, Western blot and real-time reverse transcriptase polymerase chain reaction. Both normal and high doses of folic acid decreased the incidence of NTDs, promoted proliferation and reduced apoptosis of neuroepithelial cells in embryos of hyperglycemic and diabetic mice. Importantly, folic acid, especially at high dose, might affect the premature differentiation of neural progenitors in embryos of hyperglycemic and diabetic pregnancy. This may be attributed to changes of messenger RNA expression levels of some basic-helix-loop-helix transcription factors. In addition, folic acid might be involved in regulating neuronal migration in embryos of hyperglycemic and diabetic pregnancy. These findings suggest that periconceptional supplementation of folic acid, especially at high dose, may be a double-edged sword because it may result in undesirable outcomes affecting both the neuronal and glial differentiation in hyperglycemic and diabetic pregnancy. PMID:23260036

Yuan, Qiuhuan; Zhao, Shidou; Liu, Shangming; Zhang, Yanmin; Fu, Jie; Wang, Fuwu; Liu, Qian; Ling, Eng-Ang; Hao, Aijun

2013-07-01

97

Characterization of the folic acid C9-N10-cleaving enzyme of Dictyostelium minutum V3.  

PubMed Central

Folic acid is a chemoattractant for the slime mold Dictyostelium minutum V3. The activity of extracellular folic acid is regulated by a folic acid C9-N10 splitting enzyme (FAS). The products were identified as pterin-6-aldehyde and p-amino-benzoylglutamic acid. The enzyme was stabilized by EDTA. For the extracellular enzyme, the Km was 10(-7) M, and the optimal pH was 4.0. During starvation, FAS activity was mainly secreted into the medium; after 3 h, a plateau was reached. The membrane-bound activity was constant, but only 12% of the extracellular activity at 3 h. Intracellular activity also increased up to 3 h to a level of 23% of the extracellular FAS. The substrate recognition of FAS was found to be based on 4-O or N3 or both, N5 or N8 or both, N10, and the p-aminobenzoic acid moiety, whereas 2-NH2, N1, and the glutamic acid moiety were not recognized. Other slime mold species were found to secrete FAS with 20-fold or more reduced activity than D. minutum V3. PMID:6841318

De Wit, R J; van der Velden, R J; Konijn, T M

1983-01-01

98

Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids  

Microsoft Academic Search

Folic acid deficiency represents a vitamin deficiency that may be due either to an inadequacy of the dietary supply or to an increased requirement. It leads to a number of abnormalities including hematological, neurological and cardiovascular disorders. In this study, we investigated whether folic acid deficiency would influence platelet and macrophage activities. For 6 weeks, rats were fed a test

Philippe Durand; Michel Prost; Denis Blache

1996-01-01

99

The effect of folic acid, protein energy and multiple micronutrient supplements in pregnancy on stillbirths  

PubMed Central

Background Pregnancy is a state of increased requirement of macro- and micronutrients, and malnourishment or inadequate dietary intake before and during pregnancy, can lead to adverse perinatal outcomes including stillbirths. Many nutritional interventions have been proposed during pregnancy according to the nutritional status of the mother and baseline risk factors for different gestational disorders. In this paper, we have reviewed three nutritional interventions including peri-conceptional folic acid supplementation, balanced protein energy supplementation and multiple micronutrients supplementation during pregnancy. This paper is a part of a series to estimate the effect of interventions on stillbirths for input to Live Saved Tool (LiST) model. Methods We systematically reviewed all published literature to identify studies evaluating effectiveness of peri-conceptional folic acid supplementation in reducing neural tube defects (NTD), related stillbirths and balanced protein energy and multiple micronutrients supplementation during pregnancy in reducing all-cause stillbirths. The primary outcome was stillbirths. Meta-analyses were generated where data were available from more than one study. Recommendations were made for the Lives Saved Tool (LiST) model based on rules developed by the Child Health Epidemiology Reference Group (CHERG). Results There were 18 studies that addressed peri-conceptional folic acid supplementation for prevention of neural tube defects (NTDs). Out of these, 7 studies addressed folic acid supplementation while 11 studies evaluated effect of folic acid fortification. Pooled results from 11 fortification studies showed that it reduces primary incidence of NTDs by 41 % [Relative risk (RR) 0.59; 95 % confidence interval (CI) 0.52-0.68]. This estimate has been recommended for inclusion in the LiST as proxy for reduction in stillbirths. Pooled results from three studies considered to be of low quality and suggest that balanced protein energy supplementation during pregnancy could lead to a reduction of 45% in stillbirths [RR 0.55, 95 % CI 0.31-0.97]. While promising, the intervention needs more effectiveness studies before inclusion in any programs. Pooled results from 13 studies evaluating role of multiple micronutrients supplementation during pregnancy showed no significant effect in reducing stillbirths [RR = 0.98; 95% CI: 0.88 – 1.10] or perinatal mortality [RR = 1.07; 95% CI: 0.92 – 1.25; random model]. No recommendations have been made for this intervention for inclusion in the LiST model. Conclusions Peri-conceptional folic acid supplementation reduces stillbirths due to NTDs by approximately 41%, a point estimate recommended for inclusion in LiST. PMID:21501455

2011-01-01

100

Effects of folic acid on epithelial apoptosis and expression of Bcl2 and p53 in premalignant gastric lesions  

Microsoft Academic Search

Abstract Abstract Abstract Abstract Abstract AIM: To evaluate,the effects, of folic acid on epithelial apoptosis and expression of Bcl-2 and p53 in the tissues of premalignant gastric lesions. METHODS: Thirty-eight patients, with premalignant gastric

Da-Zhong Cao; Wei-Hao Sun; Xi-Long Ou; Qian Yu; Ting Yu; You-Zhen Zhang; Zi-Ying Wu; Qi-Ping Xue; Yun-Lin Cheng

2005-01-01

101

Folic acid supplementation, dietary folate intake during pregnancy and risk for spontaneous preterm delivery: a prospective observational cohort study  

PubMed Central

Background Health authorities in numerous countries recommend periconceptional folic acid to pregnant women to prevent neural tube defects. The objective of this study was to examine the association of folic acid supplementation during different periods of pregnancy and of dietary folate intake with the risk of spontaneous preterm delivery (PTD). Methods The Norwegian Mother and Child Cohort Study is a population-based prospective cohort study. A total of 65,668 women with singleton pregnancies resulting in live births in 1999–2009 were included. Folic acid supplementation was self-reported from 26 weeks before pregnancy until week 24 during pregnancy. At gestational week 22, the women completed a food frequency questionnaire, which allowed the calculation of their average total folate intake from foods and supplements for the first 4–5 months of pregnancy. Spontaneous PTD was defined as the spontaneous onset of delivery between weeks 22+0 and 36+6 (n?=?1,628). Results The median total folate intake was 266 ?g/d (interquartile range IQR 154–543) in the overall population and 540 ?g/d (IQR 369–651) in the supplement users. Eighty-three percent reported any folic acid supplementation from <8 weeks before to 24 weeks after conception while 42% initiated folic acid supplementation before their pregnancy. Cox regression analysis showed that the amount of folate intake from the diet (hazard ratio HR 1.16; confidence interval CI 0.65-2.08) and from the folic acid supplements (HR 1.04; CI 0.95-1.13) was not significantly associated with the risk of PTD. The initiation of folic acid supplementation more than 8 weeks before conception was associated with an increased risk for PTD (HR 1.19; CI 1.05-1.34) compared to no folic acid supplementation pre-conception. There was no significant association with PTD when supplementation was initiated within 8 weeks pre-conception (HR 1.01; CI 0.88-1.16). All analyses were adjusted for maternal characteristics and socioeconomic, health and dietary variables. Conclusions Our findings do not support a protective effect of dietary folate intake or folic acid supplementation on spontaneous PTD. Pre-conceptional folic acid supplementation starting more than 8 weeks before conception was associated with an increased risk of PTD. These results require further investigation before discussing an expansion of folic acid supplementation guidelines. PMID:23937678

2013-01-01

102

Electropolymerized molecularly imprinted polymer films of a bis-terthiophene dendron: folic acid quartz crystal microbalance sensing.  

PubMed

A folic acid sensor was prepared via an electropolymerized molecularly imprinted polymer (E-MIP) film of a bis-terthiophene dendron on a quartz crystal microbalance (QCM). The cyclic voltammetry (CV) electrodeposition of the imprinted polymer film was monitored by electrochemical QCM or E-QCM, enabling in situ monitoring and characterization of E-MIP film formation and the viscoelastic behavior of the film. A key component of the E-MIP process is the use of a bifunctional monomer design to precomplex with the template and function as a cross-linker. The complex was electropolymerized and cross-linked by CV to form a polythiophene matrix. Stable cavities were formed that specifically fit the size and shape of the folic acid template. The same substrate surface was used for folic acid sensing. The predicted geometry of the 1:2 folic acid/terthiophene complex was obtained through semiempirical AM1 quantum calculations. The analytical performance, expressed through the figures of merit, of the sensor in aqueous solutions of the analyte was investigated. A relatively good linearity, R(2) = 0.985, was obtained within the concentration range 0-100 ?M folic acid. The detection limit was found to be equal to 15.4 ?M (6.8 ?g). The relative cross selectivity of the folic acid imprinted polymer against the three molecules follows this trend: pteroic acid (= 50%) > caffeine (= 41%) > theophylline (= 6%). The potential and limitations of the E-MIP method were also discussed. PMID:21080660

Apodaca, Dahlia C; Pernites, Roderick B; Ponnapati, Ramakrishna R; Del Mundo, Florian R; Advincula, Rigoberto C

2011-02-01

103

Effect of methionine, methionine hydroxy analogue, vitamin B?? and folic acid on blood and liver glutathione content in chicks  

E-print Network

~ GF METHIOEIEE~ METHIOEIEE ZQRGKY AEALOGUE~ ~ B~ AED FOLIC ACID OE BLOOD AED LXVER GAGEE COETEET IE CHICKS A Thesis Approved ss o tyle and. content by: / irmgn Q C~ttee Nsy 1954 LIBRARY 4 & N COLLEGE OF TEXAS ~ OF NETBIOEIEE, NETBIONINE... HYDROXY AEALOGUE~ VITAlGTI BIB AND FOLIC ACID 05 BLOOD AHD LIVER GIVBLHBOTIE COTITERT III CHICKS A Thesis Sabit Gsbsy Submitted to the Graduate School of the Agricultural and Mechanical College of Texas in partial fulfillment of the requirements...

Gabay, Sabit

2012-06-07

104

Enhanced Reduction of Fasting Total Homocysteine Levels With Supraphysiological Versus Standard Multivitamin Dose Folic Acid Supplementation in Renal Transplant Recipients  

Microsoft Academic Search

The mild fasting hyperhomocysteinemia commonly observed in chronic (ie, $6 months posttransplantation) renal transplant recipients (RTRs) can be effectively treated with combined B-vitamin supplementation featuring supraphysiological doses of folic acid. There are no controlled data evaluating the comparative efficacy of supraphysiological versus standard multivitamin dose folic acid supplementation in reducing fasting total homocysteine (tHcy) levels among RTRs. We block-randomized 60

Andrew J. Beaulieu; Reginald Y. Gohh; Haewook Han; David Hakas; Paul F. Jacques; Jacob Selhub; Andrew G. Bostom

105

Biogenic gold nanoparticles as fotillas to fire berberine hydrochloride using folic acid as molecular road map.  

PubMed

Use of biologically modified gold nanoparticles (GNPs) as molecular vehicle to ferry potential anti-cancer drug berberine hydrochloride (BHC) using folic acid (FA) as targeting molecule is reported in this work. A tropical fruit peel, Trapa bispinosa is used to fabricate highly monodispersed GNPs, passivated with essential functional groups which were used as linkers to attach FA and BHC via amide linkage. Flocculation Parameter (FP) of biologically synthesized GNPs was calculated under different salt concentrations which were found to be very ideal under a physiological condition. Various statistical models were used to find drug release profile out of which Higuchi was found to be the most ideal. GNP-FA-BHC complexes were found to be active against folic acid expressing HeLa cells. PMID:23910269

Pandey, Sunil; Mewada, Ashmi; Thakur, Mukeshchand; Shah, Ritu; Oza, Goldie; Sharon, Madhuri

2013-10-01

106

Folic Acid-conjugated Graphene Oxide loaded with Photosensitizers for Targeting Photodynamic Therapy  

PubMed Central

Photodynamic therapy (PDT) has emerged as an alternative and promising noninvasive treatment for cancer as well as non-cancer diseases, which involves the uptake of photosensitizers (PSs) by cancer cells followed by irradiation. The use of nanomaterials as carriers of PSs is a very promising approach to improve the development of PDT in clinical medicine. In this study, a novel folic acid-conjugated graphene oxide (GO) was strategically designed and prepared as targeting drug delivery system to achieve higher specificity. The second generation photosensitizer (PS) Chlorin e6 (Ce6) was effectively loaded into the system via hydrophobic interactions and ?-? stacking. The nanocarriers can significantly increase the accumulation of Ce6 in tumor cells and lead to a remarkable photodynamic efficacy on MGC803 cells upon irradiation. These suggested that folic acid-conjugated GO loaded Ce6 had great potential as effective drug delivery system in targeting PDT. PMID:21562631

Huang, Peng; Xu, Cheng; Lin, Jing; Wang, Can; Wang, Xiansong; Zhang, Chunlei; Zhou, Xuejiao; Guo, Shouwu; Cui, Daxiang

2011-01-01

107

Characteristics of Dispersed ZnO-Folic acid Conjugate in Aqueous Medium  

E-print Network

The focus of this article is based on the aqueous dispersed state properties of inorganic ZnO nanoparticles (average size lessthan or equal to 4 nm), their surface modification and bio-functionalization with folic acid at physiological pH ~ 7.5, suitable for bio-imaging and targeted therapeutic application. While TEM studies of the ZnO nano-crystallites have been performed to estimate their size and morphology in dry state, the band gap properties of the freshly prepared samples, the hydrodynamic size in aqueous solution phase and the wide fluorescence range in visible region have been investigated to establish the fact that the sol is particularly suitable for the bio-medical purpose in the aqueous dispersed state. Key words: ZnO nanoparticle; folic acid; band gap; hydrodynamic size; fluorescence.

Sreetama Dutta; Bichitra Nandi Ganguly

2013-12-04

108

Effect of Iron/Folic Acid Supplementation on the Outcome of Malaria Episodes Treated with Sulfadoxine-Pyrimethamine  

PubMed Central

Folic acid supplementation may potentially alter the efficacy of sulfadoxine-pyrimethamine (SP) treatment in children with malaria. However, there is lack of evidence from randomized controlled trials and effects of folic acid supplementation on clinical efficacy of SP therapy remain moderately understood among children. In a double masked, placebo-controlled trial among preschool children in Pemba Island (Tanzania), iron and folic acid supplementation (Fe/FA) showed an increased risk of hospitalizations and death. In the present paper, we evaluated if folic acid supplementation reduced the efficacy of malaria treatment and thereby contributed to observed adverse effects. During the study, 1648 children had confirmed malarial episodes and received either sulphadoxine-pyrimethamine (SP) treatment and iron folic acid or SP treatment and placebo. These children were evaluated for recovery and incidence of hospitalization during the next 15, 30, and 140 days. Two groups did not differ in malarial episode or hospitalization rate on subsequent 15, 30, and 140 days. Altered efficacy of SP by folic acid was not observed and did not contribute to adverse events in the previous trial. This trial is registered with Controlled-trials.com ISRCTN59549825. PMID:24575311

Black, Robert E.; Kabole, Ibrahim; Dhingra, Usha; Ramsan, Mahdi

2014-01-01

109

Effect of iron/folic Acid supplementation on the outcome of malaria episodes treated with sulfadoxine-pyrimethamine.  

PubMed

Folic acid supplementation may potentially alter the efficacy of sulfadoxine-pyrimethamine (SP) treatment in children with malaria. However, there is lack of evidence from randomized controlled trials and effects of folic acid supplementation on clinical efficacy of SP therapy remain moderately understood among children. In a double masked, placebo-controlled trial among preschool children in Pemba Island (Tanzania), iron and folic acid supplementation (Fe/FA) showed an increased risk of hospitalizations and death. In the present paper, we evaluated if folic acid supplementation reduced the efficacy of malaria treatment and thereby contributed to observed adverse effects. During the study, 1648 children had confirmed malarial episodes and received either sulphadoxine-pyrimethamine (SP) treatment and iron folic acid or SP treatment and placebo. These children were evaluated for recovery and incidence of hospitalization during the next 15, 30, and 140 days. Two groups did not differ in malarial episode or hospitalization rate on subsequent 15, 30, and 140 days. Altered efficacy of SP by folic acid was not observed and did not contribute to adverse events in the previous trial. This trial is registered with Controlled-trials.com ISRCTN59549825. PMID:24575311

Sazawal, Sunil; Black, Robert E; Kabole, Ibrahim; Dutta, Arup; Dhingra, Usha; Ramsan, Mahdi

2014-01-01

110

Vitamin B12 and Folic Acid Imbalance Modifies NK Cytotoxicity, Lymphocytes B and Lymphoprolipheration in Aged Rats  

PubMed Central

Different vitamin B12 and folic acid concentrations could exacerbate the immune response. The aim was to evaluate different dietary folic acid and vitamin B12 levels on the immune response in aged rats. Male Sprague Dawley aged rats were assigned to three folic acid groups (deficient, control, supplemented) each in absence of vitamin B12 for 30 days. Several parameters of innate and acquired immune responses were measured. Serum and hepatic folate levels increased according to folic acid dietary level, while vitamin B12 levels decreased. There was a significant decrease in natural killer cell-mediated cytotoxicity in the spleen for the vitamin B12 deficient diet and folic acid control diet groups. Significant changes in CD45 lymphocyte subsets were also observed according to dietary imbalance. Lymphoproliferative response to concanavalin A and phytohemagglutinin did not differ significantly between groups. The spleen response to lipopolysaccharide increased significantly, but was unmodified for the other organs. An imbalance between dietary vitamin B12 and folic acid concentrations alters some immunological parameters in aged rats. Therefore, the ratio between folate and vitamin B12 could be as important as their absolute dietary concentrations. PMID:24288024

Partearroyo, Teresa; Ubeda, Natalia; Montero, Ana; Achon, Maria; Varela-Moreiras, Gregorio

2013-01-01

111

Folic acid reduces adhesion molecules VCAM-1 expession in aortic of rats with hyperhomocysteinemia  

Microsoft Academic Search

To investigate effects of supplementation of folic acid on the expression of adhesion molecules VCAM-1 in the aortas of rats with hyperhomocysteinemia. Thirty male SD rats (200±20 g) were invided into 3 groups (n=10 for each group): control group(Control), high Met group(Met) and Met plus Folate group(Met+Folate), fed. for 45 days.Plasma Hcy levels were higher with the high-methionine diet (140.68±36.87

Ming Li; Jian Chen; Yu-Shu Li; Yi-Bai Feng; Xiang Gu; Chun-Zhi Shi

2006-01-01

112

Homocysteine mediated decrease in bone blood flow and remodeling: Role of Folic Acid  

PubMed Central

Deficiencies in folate lead to increased serum concentrations of homocysteine (Hcy), which is known as hyperhomocysteinemia (HHcy), is associated with bone disorders. Although, homocysteine (Hcy) accumulates collagen in bone and contribute to decrease in bone strength. The mechanism of Hcy induced bone loss and remodeling is unclear. Therefore, the present study was aimed to determine the role of folic acid in genetically HHcy associated decrease in bone blood flow and remodeling. Wildtype (WT) and cystathionine-?-synthase heterozygous (CBS+/?) mice were used in this study and supplemented with or without folic acid (FA 300 mg/kg, Hcy reducing agent) in drinking water for 6 weeks. The tibial bone blood flow was measured by laser Doppler and ultrasonic flow probe method. The tibial bone density was assessed by dual energy X-ray absorptiometry. The bone homogenates were analyzed for oxidative stress,NOX-4 as oxidative marker and thioredoxin-1 (Trx-1) as anti-oxidant marker, bone remodeling (MMP-9) and bio-availability of nitric oxide (eNOS/iNOS/NO) by Western blot method. The results suggested that there was decrease in tibial blood flow in CBS+/? mice. The bone density was also reduced in CBS+/? mice. There was an increase in NOX-4, iNOS, MMP -9 protein as well as MMP-9 activity in CBS+/? mice and decrease in Trx-1, eNOS protein levels, in part by decreasing NO bio-availability in CBS+/? mice. Interestingly, these effects were ameliorated by folic acid and suggested that folic acid supplementation may have therapeutic potential against genetically HHcy induced bone loss. PMID:21469179

Tyagi, Neetu; Kandel, Madhavi; Munjal, Charu; Vacek, Jonathan C.; Qipshidze, Natia; SB, Pushpakumar; Metreveli, Naria; Tyagi, Suresh C.

2013-01-01

113

Effects of dietary supplements of folic acid and vitamin B12 on metabolism of dairy cows in early lactation.  

PubMed

The present experiment was undertaken to determine the effects of dietary supplements of folic acid and vitamin B12 given from 3 wk before to 8 wk after calving on lactational performance and metabolism of 24 multiparous Holstein cows assigned to 6 blocks of 4 cows each according to their previous milk production. Supplementary folic acid at 0 or 2.6 g/d and vitamin B12 at 0 or 0.5 g/d were used in a 2 x 2 factorial arrangement. Supplementary folic acid increased milk production from 38.0 +/- 0.9 to 41.4 +/- 1.0 kg/d and milk crude protein yield from 1.17 +/- 0.02 to 1.25 +/- 0.03 kg/d. It also increased plasma Gly, Ser, Thr, and total sulfur AA, decreased Asp, and tended to increase plasma Met. Supplementary B12 decreased milk urea N, plasma Ile, and Leu and tended to decrease Val but increased homocysteine, Cys, and total sulfur AA. Liver concentration of phospholipids was higher in cows fed supplementary B12. Plasma and liver concentrations of folates and B12 were increased by their respective supplements, but the increase in plasma folates and plasma and liver B12 was smaller for cows fed the 2 vitamins together. In cows fed folic acid supplements, supplementary B12 increased plasma glucose and alanine, tended to decrease plasma biotin, and decreased Km of the methylmalonyl-coenzyme A mutase in hepatic tissues following addition of deoxyadenosylcobalamin, whereas it had no effect when cows were not fed folic acid supplements. There was no treatment effect on plasma nonesterified fatty acids as well as specific activity and gene expression of Met synthase and methylmalonyl-coenzyme A mutase in the liver. Ingestion of folic acid supplements by cows fed no supplementary B12 increased total lipid and triacylglycerols in liver, whereas these supplements had no effect in cows supplemented with B12. The increases in milk and milk protein yields due to folic acid supplements did not seem to be dependent on the vitamin B12 supply. However, when vitamin B12 was given in combination with folic acid, utilization of the 2 vitamins seems to be increased, probably more so in extrahepatic tissues. Metabolic efficiency seems also to be improved as suggested by similar lactational performance and dry matter intake for cows fed supplementary folic acid but increased plasma glucose and decreased hepatic lipids in cows fed folic acid and vitamin B12 together. PMID:17582128

Graulet, B; Matte, J J; Desrochers, A; Doepel, L; Palin, M-F; Girard, C L

2007-07-01

114

Effects of High-Dose Folic Acid and Pyridoxine on Plasma and Erythrocyte Sulfur Amino Acids in Hemodialysis Patients  

Microsoft Academic Search

In this investigation, sulfur amino acids (sAA) and sulfhydryls were determined in the plasma and erythrocytes (RBC) of 10 uremic patients on regular hemodialysis (HD) treatment and 10 healthy subjects, before and after supplemen- tation with 15 mg\\/d of folic acid and 200 mg\\/d of pyridoxine for 4 wk. The basal total plasma concentrations of homocys- teine (Hcy), cysteine (Cys),

MOHAMED E. SULIMAN; JOS ´ E C. DIVINO FILHO; ORN ANDERSTAM; BENGT LINDHOLM

1999-01-01

115

Transcriptomic responses provide a new mechanistic basis for the chemopreventive effects of folic acid and tributyrin in rat liver carcinogenesis.  

PubMed

The steady increase in the incidence and mortality of hepatocellular carcinoma (HCC) signifies a crucial need to understand better its pathogenesis to improve clinical management and prevention of the disease. The aim of this study was to investigate molecular mechanisms for the chemopreventive effects of folic acid and tributyrin alone or in combination on rat hepatocarcinogenesis. Male Wistar rats were subjected to a classic "resistant hepatocyte" model of liver carcinogenesis and treated with folic acid and tributyrin alone or in combination for 5 weeks during promotion stage. Treatment with folic acid and tributyrin alone or in combination strongly inhibited the development of glutathione-S-transferase placental form (GSTP)-positive foci. Microarray analysis showed significant changes in gene expression. A total of 498, 655 and 940 of differentially expressed genes, involved in cell cycle, p53-signaling, angiogenesis and Wnt pathways, was identified in the livers of rats treated with folic acid, tributyrin or folic acid and tributyrin. A detailed analysis of these differentially expressed genes revealed that treatments inhibited angiogenesis in the preneoplastic livers. This was evidenced by the fact that 30 out of 77 differentially expressed genes common to all three treatments are involved in the regulation of the angiogenesis pathway. The inhibition of angiogenesis was confirmed by reduced levels of CD34 protein. In conclusion, the tumor-suppressing activity of folic acid and tributyrin is associated with inhibition of angiogenesis at early stages of rat liver carcinogenesis. Importantly, the combination of folic acid and tributyrin has stronger chemopreventive effect than each of the compounds alone. PMID:24302446

Guariento, Aline H; Furtado, Kelly S; de Conti, Aline; Campos, Adriana; Purgatto, Eduardo; Carrilho, Jéssica; Shinohara, Elvira Maria Guerra; Tryndyak, Volodymyr; Han, Tao; Fuscoe, James C; Ross, Sharon A; Beland, Frederick A; Pogribny, Igor P; Moreno, Fernando S

2014-07-01

116

Methionine, folic acid, vitamin B b12 sand unidentified factors in the nutrition of the growing chick  

E-print Network

to determine the vitamin B12 ~ biotin, pantothenic acid and folic acid content of same. The microbiolcgical assay procedure of Skegg et al. (1". 50) wi. th ~~~ ~~~ ~ (A. T. C. C. ) as the test organism was used to determine the vitamin B12 content... to determine the vitamin B12 ~ biotin, pantothenic acid and folic acid content of same. The microbiolcgical assay procedure of Skegg et al. (1". 50) wi. th ~~~ ~~~ ~ (A. T. C. C. ) as the test organism was used to determine the vitamin B12 content...

Welch, Billy E

2012-06-07

117

Periconceptional bread intakes indicate New Zealand's proposed mandatory folic acid fortification program may be outdated: results from a postpartum survey  

PubMed Central

Background In September 2009, a folic acid fortification mandate (135 ?g/100 g bread) was to be implemented in New Zealand. However, due to political and manufacturer objection, fortification was deferred until May 2012. Based on estimates of bread consumption derived from a 1997 nationally representative survey, this program was intended to deliver a mean additional intake of 140 ?g folic acid/d to women of childbearing age. Little is known about current bread consumption patterns in this target group. The aim of this study was to assess bread consumption among women prior to and during pregnancy with the intent to estimate periconceptional folic acid intakes that would be derived from bread if mandatory fortification were implemented as currently proposed. Methods A retrospective survey of 723 postpartum women in hospitals and birthing centres across New Zealand was conducted using a self-administered questionnaire on bread intake prior to and during pregnancy and maternal socio-demographic and obstetric characteristics. Results Median bread intake before conception (2 slices/d) was below that of previous data upon which the current fortification proposal was modeled (3-4 slices/d). If mandatory fortification is implemented as proposed, only 31% (95% CI = 24%-37%) of childbearing-age women would attain an additional folic acid intake of ? 140 ?g/d, with a mean of 119 ?g/d (95% CI = 107 ?g/d-130 ?g/d). Based on these data, a fortification level of 160 ?g/100 g bread is required to achieve the targeted mean of 140 ?g folic acid/d. Nonetheless, under the current proposal additional folic acid intakes would be greatest among the least advantaged segments of the target population: Pacific and indigenous M?ori ethnic groups; those with increased parity, lower income and education; younger and single mothers; and women with unplanned pregnancies. Subgroups predicted to derive less than adequate folic acid intakes from the proposed policy were women of Asian descent and those with a postgraduate education. Conclusions This study provides insight on the ability of a fortification policy to benefit the groups at highest risk of poor folate intakes in a population. However, bread consumption among the target group of childbearing women appears to have declined since the data used in previous dietary modeling were collected. Thus, it seems prudent to re-model dietary folic acid intakes based on more recent national survey data prior to the implementation of a mandatory folic acid fortification policy. PMID:22333513

2012-01-01

118

The micronutrient supplements, zinc sulphate and folic acid, did not ameliorate sperm functional parameters in oligoasthenoteratozoospermic men.  

PubMed

We investigated the effects of folic acid and zinc sulphate supplementation on the improvement of sperm function in subfertile oligoasthenoteratozoospermic (OAT) men. Eighty-three OAT men participated in a 16-week intervention randomised, double-blind clinical trial with daily treatment of folic acid (5 mg day(-1) ) and zinc sulphate (220 mg day(-1) ), or placebo. Before and after treatment, semen and blood samples were obtained for determining sperm concentration, motility, and morphology, sperm viability, sperm mitochondrial function, sperm chromatin status using toluidine blue, aniline blue, acridine orange and chromomycin A3 staining; and semen and blood folate, zinc, B12 , total antioxidant capacity (TAC) and malondialdehyde (MDA) concentrations. Sperm concentration (×10(6)  ml(-1) ) increased in subfertile men receiving the combined treatment of folic acid and zinc sulphate and also in the group receiving only folic acid treatment; however, it was not statistically significant (P = 0.056 and P = 0.05, respectively). Sperm chromatin integrity (%) increased significantly in subfertile men receiving only zinc sulphate treatment (P = 0.048). However, this improvement in sperm quality was not significant after adjusting placebo effect. This study showed that zinc sulphate and folic acid supplementation did not ameliorate sperm quality in infertile men with severely compromised sperm parameters, OAT. Male infertility is a multifactorial disorder, and also nutritional factors play an important role in results of administration of supplementation on sperm parameters. However, these results should be confirmed by multiple studies in larger populations of OAT men. PMID:24147895

Raigani, M; Yaghmaei, B; Amirjannti, N; Lakpour, N; Akhondi, M M; Zeraati, H; Hajihosseinal, M; Sadeghi, M R

2014-11-01

119

Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: A report from the National Down Syndrome Project  

PubMed Central

Both a lack of maternal folic acid supplementation and the presence of genetic variants that reduce enzyme activity in folate pathway genes have been linked to meiotic nondisjunction of chromosome 21; however, the findings in this area of research have been inconsistent. To better understand these inconsistencies, we asked whether maternal use of a folic acid-containing supplement before conception reduces risk for chromosome 21 nondisjunction. Using questionnaire data from the National Down Syndrome Project, a population-based case-control study, we compared the use of folic acid-containing supplements among mothers of infants with full trisomy 21 due to maternal nondisjunction (n=702) and mothers of infants born with no major birth defects (n=983). Using logistic regression, adjusting for maternal age, race/ethnicity, and infant age at maternal interview, we found no evidence of an association between lack of folic acid supplementation and maternal nondisjunction among all case mothers (OR=1.16; 95% CI: 0.90–1.48). In analyses stratified by meiotic stage and maternal age (<35 years or ? 35 years), we found an association among older mothers experiencing meiosis II nondisjunction errors (OR=2.00; 95% CI: 1.08–3.71). These data suggest that lack of folic acid supplementation may be associated specifically with MII errors in the aging oocyte. If confirmed, these results could account for inconsistencies among previous studies, as each study sample may vary by maternal age structure and proportion of meiotic errors. PMID:23401135

HOLLIS, NaTasha D.; ALLEN, Emily G.; OLIVER, Tiffany Renee; TINKER, Stuart W.; DRUSCHEL, Charlotte; HOBBS, Charlotte A.; O'LEARY, Leslie A.; ROMITTI, Paul A.; ROYLE, Marjorie H.; TORFS, Claudine P.; FREEMAN, Sallie B.; SHERMAN, Stephanie L.; BEAN, Lora J. H.

2012-01-01

120

The Effect of Folic Acid on Menopausal Hot Flashes: A Randomized Clinical Trial  

PubMed Central

Introduction: The use of alternative therapies for the treatment of menopausal hot flashes has increased due to the serious risk of hormone therapy. Most alternative therapies have not been accepted by women. Therefore, conducting a study to find effective treatment, which has a low rate of complications and is more acceptable, is necessary. The aim of this study was to assess the effects of folic acid on menopausal hot flashes. Methods: In the present study 70 menopausal women were placed into two groups of 35 with random allocation, and were treated with folic acid 1 mg tablets and placebo tablets once a day during four weeks. Information was gathered by questionnaire, interviews, and hot flash diary during five stages. Comparisons of within-group Results were performed by ANOVA and between-group results were performed using ANCOVA. Data were analyzed by SPSS for Windows. Results: There was a significant difference between mean severity, duration, and frequency of hot flashes before and after treatment within both groups. In comparing the results between the groups, mean hot flash severity in second, third, and fourth weeks were significantly different. The mean hot flash frequency was significantly different in third and fourth weeks, and the mean hot flash duration was significantly different in the fourth week. Conclusion: The results of the present study indicated that folic acid was effective in reducing the severity, duration, and frequency of hot flashes during menopause. Therefore, it can be recommended as an affordable and accessible method for treating menopausal hot flash for women. PMID:25276719

Bani, Soheila; Hasanpour, Shirin; Farzad Rik, Leila; Hasankhani, Hadi; Sharami, Seiedeh Hajar

2013-01-01

121

Microwave-assisted polyol synthesis of carbon nitride dots from folic acid for cell imaging  

PubMed Central

A green, one-step microwave-assisted polyol synthesis was employed to prepare blue luminescent carbon nitride dots (CNDs) using folic acid molecules as both carbon and nitrogen sources. The as-prepared CNDs had an average size of around 4.51 nm and could be well dispersed in water. Under excitation at 360 nm, the CNDs exhibited a strong blue luminescence and the quantum yield was estimated to be 18.9%, which is greater than that of other reported CNDs. Moreover, the CNDs showed low cytotoxicity and could efficiently label C6 glioma cells, demonstrating their potential in cell imaging. PMID:25382977

Guan, Weiwei; Gu, Wei; Ye, Ling; Guo, Chenyang; Su, Su; Xu, Pinxiang; Xue, Ming

2014-01-01

122

Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease  

Microsoft Academic Search

Recent epidemiological and clinical data suggest that persons with low folic acid levels and elevated homocysteine levels are at increased risk of Alzheimer's disease (AD), but the underlying mechanism is unknown. We tested the hypothesis that im- paired one-carbon metabolism resulting from folic acid defi- ciency and high homocysteine levels promotes accumulation of DNA damage and sensitizes neurons to amyloid

Inna I. Kruman; T. S. Kumaravel; Althaf Lohani; Ward A. Pedersen; Roy G. Cutler; Yuri Kruman; Norman Haughey; Jaewon Lee; Michele Evans; Mark P. Mattson

2002-01-01

123

Evaluation of educational materials from a social marketing campaign to promote folic acid use among Hispanic women: insight from Cuban and Puerto Rican ethnic subgroups.  

PubMed

Current data indicate significant disparities in awareness and use of folic acid between Hispanic and non-Hispanic women. Hispanic women are less likely to have heard about folic acid, to know that folic acid can prevent birth defects, to take folic acid daily, and to take folic acid before pregnancy. "Three Sisters/Las Tres Hermanos" is a folic acid social marketing campaign designed for Mexican-American women. To determine the effectiveness of the materials on other Hispanic sub groups, women of childbearing age from Cuba and Puerto Rico were recruited to evaluate the materials. Participants were asked five pre-test questions about folic acid knowledge and were then provided with the folic acid educational materials that included either a photo-novella and a low literacy brochure, or a video-novella in English or Spanish. Once the participants reviewed the materials, they were asked 10 post-test questions about the materials. The results of the evaluation are discussed. PMID:18561023

Quinn, Gwendolyn P; Thomas, Kamilah B; Hauser, Kimberlea; Rodríguez, Nydia Y; Rodriguez-Snapp, Nazach

2009-10-01

124

Nonrandom distribution of methotrexate-induced aberrations on human chromosomes. Detection of further folic acid sensitive fragile sites  

Microsoft Academic Search

Eleven folic acid sensitive fragile sites (3p14, 7p13, 7q31.1, 7q32, 9q32, 11p13, 14q23, 15q22, 16q23, Xp22.2, Xq22) were detected in one individual, eight of them previously unknown. These sites seem to bear each its specific sensitivity to folic acid deficiency. Six of the sites were observed simultaneously on both homologous chromosomes in at least one cell. Each of these 11

G. Barbi; P. Steinbach; W. Vogel

1984-01-01

125

Primary prevention of neural-tube defects and some other congenital abnormalities by folic acid and multivitamins: history, missed opportunity and tasks  

PubMed Central

The history of intervention trials of periconception folic acid with multivitamin and folic acid supplementation in women has shown a recent breakthrough in the primary prevention of structural birth defects, namely neural-tube defects and some other congenital abnormalities. Recently, some studies have demonstrated the efficacy of this new method in reducing congenital abnormalities with specific origin; for example, in the offspring of diabetic and epileptic mothers, and in pregnancy with high fever. The benefits and drawbacks of four possible uses of periconception folate/folic acid and multivitamin supplementation are discussed: we believe there has been a missed opportunity to implement this preventive approach in medical practice. The four methods are as follows: (i) dietary intake of folate and other vitamins, (ii) periconception folic acid/multivitamin supplementation, (iii) food fortification with folic acid, and (iv) the combination of oral contraceptives with 6S-5-methytetrahydrofolate (‘folate’). PMID:25083211

Bártfai, Zoltán; Bánhidy, Ferenc

2011-01-01

126

Megaloblastic anemia in patients receiving total parenteral nutrition without folic acid or vitamin B12 supplementation.  

PubMed

Pancytopenia developed in four patients receiving postoperatively total parenteral nutrition (TPN). Symptoms and signs were related mainly to underlying bowel disease. Hematologic abnormalities, first noted from 4 to 7 weeks following institution of TPN, consisted of normocytic anemia (mean decrease in hemoglobin value, 2.2 g/dL), occasional macrocytes being noted, leukopenia (range of leukocyte counts, 1.2 to 3.6 X 10(9) L), some hypersegmented neutrophils being detected, and clinically significant thrombocytopenia (range of platelet counts, 25 to 52 X 10(9)/L). In all patients the bone marrow showed megaloblastic changes, with ring sideroblasts, although pyridoxine was included in the TPN regimens. Serum vitamin B12 values were normal in one patient and at the lower limit of normal in the other two patients in whom it was measured, while serum or erythrocyte folate values, or both, were reduced in three patients. Full hematologic response was observed in the four patients after folic acid replacement therapy; leukocytosis and thrombocytosis were noted in three. Thus, folic acid and possibly vitamin B12 should be added routinely to TPN regimens to prevent deficiency of either substance. PMID:406033

Denburg, J; Bensen, W; Ali, M A; McBride, J; Ciok, J

1977-07-23

127

Folic acid--the scientific debate as a base for public health policy.  

PubMed

Randomized controlled trials have proven that periconceptional folic acid intake reduces the risk of neural tube defects (NTDs). This lead to different public health policies: fortification of foods in many countries and supplementation in some others. We concentrate here on pro's and con's of fortification policies. Meanwhile, new beneficial but also potential adverse effects are being hypothesized. Highest level evidence is available for the protective effect of folic acid on NTDs. Lower level evidence suggests other protective effects, but also some potential adverse effects, such as masking Vitamin B-12 deficiency, increasing twinning rates and an 'acceleration phenomenon' in pre-existing malignant neoplasms. While observational studies show lower cancer rates associated with increased folate intake, some case reports and animal experiments suggest opposite effects. Thus, public health policy makers are facing the question of balancing beneficial and potential adverse effects repeatedly. We propose that the scientific debate no longer focuses on NTDs alone, but that a comprehensive evaluation be undertaken by a public health authority with experience in complex meta-analyses and technology assessment. PMID:15978774

Cornel, M C; de Smit, D J; de Jong-van den Berg, L T W

2005-01-01

128

Double-Blind Therapeutic Trial in Angelman Syndrome Using Betaine and Folic Acid  

PubMed Central

Angelman syndrome (AS) is caused by reduced or absent expression of the maternally inherited ubiquitin protein ligase 3A gene (UBE3A), which maps to chromosome 15q11–q13. UBE3A is subject to genomic imprinting in neurons in most regions of the brain. Expression of UBE3A from the maternal chromosome is essential to prevent AS, because the paternally inherited gene is not expressed, probably mediated by antisense UBE3A RNA. We hypothesized that increasing methylation might reduce expression of the antisense UBE3A RNA, thereby increasing UBE3A expression from the paternal gene and ameliorating the clinical phenotype. We conducted a trial using two dietary supplements, betaine and folic acid to promote global levels of methylation and attempt to activate the paternally inherited UBE3A gene. We performed a number of investigations at regular intervals including general clinical and developmental evaluations, biochemical determinations on blood and urine, and electroencephalographic studies. We report herein the data on 48 children with AS who were enrolled in a double-blind placebo-controlled protocol using betaine and folic acid for 1 year. There were no statistically significant changes between treated and untreated children; however, in a small subset of patients we observed some positive trends. PMID:20635355

Peters, Sarika U.; Bird, Lynne M.; Kimonis, Virginia; Glaze, Daniel G.; Shinawi, Lina M.; Bichell, Terry Jo; Barbieri-Welge, Rene; Nespeca, Mark; Anselm, Irina; Waisbren, Susan; Sanborn, Erica; Sun, Qin; O’Brien, William E.; Beaudet, Arthur L.; Bacino, Carlos A.

2011-01-01

129

Knowledge and periconceptional use of folic acid for the prevention of neural tube defects in ethnic communities in the United Kingdom: Systematic review and meta-analysis  

PubMed Central

BACKGROUND: It is widely accepted that periconceptional supplementation with folic acid can prevent a significant proportion of neural tube defects (NTDs). The present study evaluated how folic acid knowledge and periconceptional use for NTD prevention varies by ethnicity in the United Kingdom (U.K.). METHODS: A literature search was conducted to identify studies that included assessment of folic acid knowledge or use in U.K. women of different ethnicities. Only research and referenced sources published after 1991, the year of the landmark Medical Research Council’s Vitamin Study, were included. A meta-analysis was performed of studies that assessed preconceptional folic acid use in Caucasians and non-Caucasians. RESULTS: Five studies met the inclusion criteria for assessment of knowledge and/or use of folic acid supplements in U.K. women including non-Caucasians. The available evidence indicates that South Asians specifically have less knowledge and lower periconceptional use of folic acid than Caucasians; one study found that West Indian and African women also had lower folic acid uptake. A synthesis of results from three of the studies, in a meta-analysis, shows that Caucasians are almost three times more likely to take folic acid before conception than non-Caucasians. CONCLUSION: From the limited evidence available, U.K. women of non-Caucasian ethnicity appear to have less knowledge and a lower uptake of folic acid supplementation than Caucasians during the periconceptional period. Implementing targeted, innovative education campaigns together with a mandatory fortification policy, including the fortification of ethnic minority foods, will be required for maximum prevention of folic acid–preventable NTDs across different ethnic groups. Birth Defects Research (Part A) 97:444–451, 2013. © 2013 Wiley Periodicals, Inc. PMID:23873812

Peake, Jordana N; Copp, Andrew J; Shawe, Jill

2013-01-01

130

Folic Acid  

MedlinePLUS

... Statement on Complementary and Alternative Methods of Cancer Management References Clarke R. Halsey J, Lewington S, et al. Effects of lowering homocystein levels with B vitamins on cardiovascular disease, cancer, and ...

131

Inhibitors of folic acid synthesis in the treatment of experimental Pneumocystis carinii pneumonia.  

PubMed

Inhibitors of folic acid synthesis were compared alone and in different combinations in the therapy of pneumocystosis in immunosuppressed rats. Sulfonamides (sulfamethoxazole, sulfadiazine, and sulfadoxine) and sulfones (dapsone) used alone were very active against Pneumocystis carinii, as judged by histologic examination of the lungs and by organism quantitation. Improved efficacy could not be demonstrated by the addition of an inhibitor of dihydrofolate reductase to the regimen. Dihydrofolate reductase inhibitors (trimethoprim, diaveridine, and pyrimethamine) used alone were ineffective against P. carinii. All drugs were well tolerated except pyrimethamine, which caused bone marrow depression; folinic acid ameliorated this adverse reaction but did not interfere with P. carinii treatment. These data have potential clinical implications but need to be interpreted with caution and in light of other systems of P. carinii drug evaluation. PMID:3258144

Walzer, P D; Kim, C K; Foy, J M; Linke, M J; Cushion, M T

1988-01-01

132

Cancer Therapy: Folic Acid Functionalized Surface Highlights 5-Methylcytosine-Genomic Content within Circulating Tumor Cells (Small 21/2014).  

PubMed

A folic acid (FA)-functionalized surface, able to selectively entrap circulating tumor cell (CTC)-expressing folic receptors, is developed by E. Di Fabrizio and co-workers on page 4324. Since FA represents a good transducer highlighting the CTC global 5-methylcytosine content, this functionalized surface represents an important tool to profile cellular methylation changes in tumor monitoring strategies. The image shows CTCs under a scanning electron microscope after fixation and metallization. Image credit: M. Orlando, R. Ruffilli, and V. Shalabaeva. PMID:25378072

Malara, Natalia; Coluccio, Maria Laura; Limongi, Tania; Asande, Monica; Trunzo, Valentina; Cojoc, Gheorghe; Raso, Cinzia; Candeloro, Patrizio; Perozziello, Gerardo; Raimondo, Raffaella; De Vitis, Stefania; Roveda, Laura; Renne, Maria; Prati, Ubaldo; Mollace, Vincenzo; Di Fabrizio, Enzo

2014-11-01

133

Is Weekly Iron and Folic Acid Supplementation as Effective as Daily Supplementation for Decreasing Incidence of Anemia in Adolescent Girls?  

Microsoft Academic Search

T HIS CLINICAL TRIAL1 compared the effective- ness of weekly vs daily administration of iron plus folic acid for the treatment of anemia in adolescent Nepalese girls, a population with an extremely high prevalence of ane- mia. The study was conducted in a single government- run school in Dharan, an urban foothill town in Nepal. Girls from the 8th to

DIMITRI A. CHRISTAKIS; HAROLD P. LEHMANN

134

Dietary Intake of Vitamin B12 and Folic Acid Is Associated With Lower Blood Pressure in Japanese Preschool Children  

Microsoft Academic Search

BackgroundAn elevated plasma homocysteine level is an independent risk factor for high blood pressure and cardiovascular disease, and its level is regulated by three vitamins; vitamin B6, B12, and folic acid. Until now, the association between the intake of these vitamins and blood pressure has been examined only in adult populations. We purposed to examine the association between dietary intake

Yuya Tamai; Keiko Wada; Michiko Tsuji; Kozue Nakamura; Yukari Sahashi; Kaori Watanabe; Keiko Yamamoto; Kyoko Ando; Chisato Nagata

2011-01-01

135

The Interactions between L-tyrosine based nanoparticles decorated with folic acid and cervical cancer cells under physiological flow.  

PubMed

Many anticancer drugs have been established clinically, but their efficacy can be compromised by nonspecific toxicity and an inability to reach the desired cancerous intracellular spaces. In order to address these issues, researchers have explored the use of folic acid as a targeted moiety to increase specificity of chemotherapeutic drugs. To expand upon such research, we have conjugated folic acid to functionalized poly(ethylene glycol) and subsequently decorated the surface of l-tyrosine polyphosphate (LTP) nanoparticles. These nanoparticles possess the appropriate size (100-500 nm) for internalization as shown by scanning electron microscopy and dynamic light scattering. Under simulated physiological flow, LTP nanoparticles decorated with folic acid (targeted nanoparticles) show a 10-fold greater attachment to HeLa, a cervical cancer cell line, compared to control nanoparticles and to human dermal fibroblasts. The attachment of these targeted nanoparticles progresses at a linear rate, and the strength of this nanoparticle attachment is shown to withstand shear stresses of 3.0 dyn/cm(2). These interactions of the targeted nanoparticles to HeLa are likely a result of a receptor-ligand binding, as a competition study with free folic acid inhibits the nanoparticle attachment. Finally, the targeted nanoparticles encapsulated with a silver based drug show increased efficacy in comparison to nondecorated (plain) nanoparticles and drug alone against HeLa cells. Thus, targeted nanoparticles are a promising delivery platform for developing anticancer therapies that overexpress the folate receptors (FRs). PMID:22957928

Ditto, Andrew J; Shah, Kush N; Robishaw, Nikki K; Panzner, Matthew J; Youngs, Wiley J; Yun, Yang H

2012-11-01

136

Periconceptional folic acid and multivitamin supplementation for the prevention of neural tube defects and other congenital abnormalities.  

PubMed

The pioneering studies of Smithells et al. showed the reduction of recurrent neural-tube defects (NTD) after periconceptional folic acid-containing multivitamin supplementation. The Hungarian Periconceptional Service was established in 1984, and this primary health care system offered a chance to organize a randomized controlled trial to check whether the supplementation of a multivitamin containing 0.8 mg of folic acid during the periconceptional period is appropriate for the reduction of a first occurrence of NTD in the family. This found a reduction of approximately 90% of primary NTD. An unexpected finding was a significant reduction in the rate of congenital abnormalities overall: 20.6 per 1000 in the 'multivitamin' group, and 40.6 per 1000 in the 'trace-element-like' placebo group (RR = 0.53, 95% CI: 0.35-0.70). When the 6 cases of NTD were excluded, this difference in the rates of major congenital abnormalities between the two study-groups remained very highly significant (p < 0.0001). Cardiovascular malformations and urinary tract defects were particularly affected. These findings were confirmed in the Hungarian cohort-controlled trial and by observational studies in other countries. Two questions remain to be answered. Is folic acid better alone or with multivitamins? What is the optimal dose of folic acid? Overall, the Hungarian experiences of periconceptional care have shown not only primary prevention of several severe congenital abnormalities but also a good cost-benefit balance. PMID:19161162

Czeizel, Andrew E

2009-04-01

137

Efficacy of methylcobalamin on lowering total homocysteine plasma concentrations in haemodialysis patients receiving high-dose folic acid supplementation  

Microsoft Academic Search

Background. Hyperhomocysteinaemia, which is con- sidered to be induced by impairment of the remethyl- ation pathway in patients with chronic renal failure (CRF), cannot be cured solely by folic acid therapy. In the present study, we investigated the additional benefit of administration of methylcobalamin, which is a co-enzyme in the remethylation pathway, on lower- ing total homocysteine (tHcy) plasma concentrations

Katsushi Koyama; Takeshi Usami; Oki Takeuchi; Kunio Morozumi; Genjiro Kimura

138

Insights into prevention of human neural tube defects by folic acid arising from consideration of mouse mutants.  

PubMed

Almost 30 years after the initial study by Richard W. Smithells and coworkers, it is still unknown how maternal periconceptional folic acid supplementation prevents human neural tube defects (NTDs). In this article, questions about human NTD prevention are considered in relation to three groups of mouse models: NTD mutants that respond to folate, NTD mutants and strains that do not respond to folate, and mutants involving folate-pathway genes. Of the 200 mouse NTD mutants, only a few have been tested with folate; half respond and half do not. Among responsive mutants, folic acid supplementation reduces exencephaly and/or spina bifida aperta frequency in the Sp(2H), Sp, Cd, Cited2, Cart1, and Gcn5 mutants. Prevention ranges from 35 to 85%. The responsive Sp(2H) (Pax3) mutant has abnormal folate metabolism, but the responsive Cited2 mutant does not. Neither folic nor folinic acid reduces NTD frequency in Axd, Grhl3, Fkbp8, Map3k4, or Nog mutants or in the curly tail or SELH/Bc strains. Spina bifida frequency is reduced in Axd by methionine and in curly tail by inositol. Exencephaly frequency is reduced in SELH/Bc by an alternative commercial ration. Mutations in folate-pathway genes do not cause NTDs, except for 30% exencephaly in folate-treated Folr1. Among folate-pathway mutants, neural tube closure is normal in Cbs, Folr2, Mthfd1, Mthfd2, Mthfr, and Shmt1 mutants. Embryos die by midgestation in Folr1, Mtr, Mtrr, and RFC1 mutants. The mouse models point to genetic heterogeneity in the ability to respond to folic acid and also to heterogeneity in genetic cause of NTDs that can be prevented by folic acid. PMID:19117321

Harris, Muriel J

2009-04-01

139

Nutri-epigenetics Ameliorates Blood-Brain Barrier Damage and Neurodegeneration in Hyperhomocysteinemia: Role of Folic Acid  

PubMed Central

Epigenetic mechanisms underlying nutrition (nutrition epigenetics) are important in understanding human health. Nutritional supplements, for example folic acid, a cofactor in one-carbon metabolism, regulate epigenetic alterations and may play an important role in the maintenance of neuronal integrity. Folic acid also ameliorates hyperhomocysteinemia, which is a consequence of elevated levels of homocysteine. Hyperhomocysteinemia induces oxidative stress that may epigenetically mediate cerebrovascular remodeling and leads to neurodegeneration; however, the mechanisms behind such alterations remain unclear. Therefore, the present study was designed to observe the protective effects of folic acid against hyperhomocysteinemia-induced epigenetic and molecular alterations leading to neurotoxic cascades. To test this hypothesis, we employed 8-weeks-old male wild-type (WT) cystathionine-beta-synthase heterozygote knockout methionine-fed (CBS+/?+Met), WT, and CBS+/?+Met mice supplemented with folic acid (FA) [WT+FA and CBS+/?+ Met+FA, respectively, 0.0057-?g g?1 day?1 dose in drinking water/4 weeks]. Hyperhomocysteinemia in CBS+/?+Met mouse brain was accompanied by a decrease in methylenetet-rahydrofolate reductase and an increase in S-adenosylho-mocysteine hydrolase expression, symptoms of oxidative stress, upregulation of DNA methyltransferases, rise in matrix metalloproteinases, a drop in the tissue inhibitors of metallo-proteinases, decreased expression of tight junction proteins, increased permeability of the blood–brain barrier, neuro-degeneration, and synaptotoxicity. Supplementation of folic acid to CBS+/?+Met mouse brain led to a decrease in the homocysteine level and rescued pathogenic and epigenetic alterations, showing its protective efficacy against homocysteine-induced neurotoxicity. PMID:24122186

Kalani, Anuradha; Kamat, Pradip K.; Givvimani, Srikanth; Brown, Kasey; Metreveli, Naira; Tyagi, Suresh C.

2014-01-01

140

Relative bioavailability of iron and folic acid from a new powdered supplement compared to a traditional tablet in pregnant women  

PubMed Central

Background Deficiencies of iron and folic acid during pregnancy can lead to adverse outcomes for the fetus, thus supplements are recommended. Adherence to current tablet-based supplements is documented to be poor. Recently a powdered form of micronutrients has been developed which may decrease side-effects and thus improve adherence. However, before testing the efficacy of the supplement as an alternate choice for supplementation during pregnancy, the bioavailability of the iron needs to be determined. Our objective was to measure the relative bioavailability of iron and folic acid from a powdered supplement that can be sprinkled on semi-solid foods or beverages versus a traditional tablet supplement in pregnant women. Methods Eighteen healthy pregnant women (24 – 32 weeks gestation) were randomized to receive the supplements in a crossover design. Following ingestion of each supplement, the changes (over baseline) in serum iron and folate over 8 hours were determined. The powdered supplement contained 30 mg of iron as micronized dispersible ferric pyrophosphate with an emulsifier coating and 600 ?g folic acid; the tablet contained 27 mg iron from ferrous fumarate and 1000 ?g folic acid. Results Overall absorption of iron from the powdered supplement was significantly lower than the tablet (p = 0.003). There was no difference in the overall absorption of folic acid between supplements. Based on the differences in the area under the curve and doses, the relative bioavailability of iron from powdered supplement was lower than from the tablet (0.22). Conclusion The unexpected lower bioavailability of iron from the powdered supplement is contrary to previously published reports. However, since pills and capsules are known to be poorly accepted by some women during pregnancy, it is reasonable to continue to explore alternative micronutrient delivery systems and forms of iron for this purpose. Trial Registration ClinicalTrials.gov NCT00789490 PMID:19635145

Hartman-Craven, Brenda; Christofides, Anna; O'Connor, Deborah L; Zlotkin, Stanley

2009-01-01

141

Degradation of folic acid in fortified vitamin juices during long term storage.  

PubMed

Folic acid (FA) concentrations of nine fortified vitamin juices were determined with the aim to study the FA degradation and to investigate the deviation from the declared label value. The juices were received shortly after bottling and were analyzed monthly during controlled storage conditions (light and dark) over one year. The analyses were performed by HPLC-MS/MS, which included a fast "dilute and shoot" sample preparation. Average decreases in FA concentration of 46% were observed after one year. Fresh juices (shortly after bottling) showed the highest deviations from the declared label value (up to+89%). Label values did not reflect the actual concentration of FA in these products, making it difficult to determine the intake of this vitamin. PMID:24767034

Frommherz, Lara; Martiniak, Yvonne; Heuer, Thorsten; Roth, Alexander; Kulling, Sabine E; Hoffmann, Ingrid

2014-09-15

142

Folic acid supplementation in pregnancy and implications in health and disease  

PubMed Central

Maternal exposure to dietary factors during pregnancy can influence embryonic development and may modulate the phenotype of offspring through epigenetic programming. Folate is critical for nucleotide synthesis, and preconceptional intake of dietary folic acid (FA) is credited with reduced incidences of neural tube defects in infants. While fortification of grains with FA resulted in a positive public-health outcome, concern has been raised for the need for further investigation of unintended consequences and potential health hazards arising from excessive FA intakes, especially following reports that FA may exert epigenetic effects. The objective of this article is to discuss the role of FA in human health and to review the benefits, concerns and epigenetic effects of maternal FA on the basis of recent findings that are important to design future studies. PMID:25135350

2014-01-01

143

Effects of folic acid and folinic acid on cognitive and motor behaviors in 20-month-old rats.  

PubMed

Old rats had lower plasma concentrations of folates but not of vitamin B12 than young rats. Old rats injected with pharmacological doses of folic acid (5 mg/kg) or folinic acid (2.5 mg/kg) every 2 days for a 32-day period spontaneously alternated above chance levels at the 0-min retention interval whereas old rats injected with placebo did not. Rats injected with folinic acid that had plasma folate concentrations above the median for that group alternated at the 3-min retention interval whereas none of the other subgroups did. These results indicate that supplementation with folinic acid at pharmacological doses may decrease perseverative responding and improve spatial memory in old rats. However, neither vitamin group was improved in motor coordination, grip strength, or spatial learning in a water maze. There was no hyperactivity or loss of body weight following vitamin supplementation. PMID:8451272

Lalonde, R; Joyal, C C; Botez, M I

1993-03-01

144

Formulation and evaluation of niosomal nasal drug delivery system of folic acid for brain targeting.  

PubMed

Nasal mucosa offers advantages to deliver drugs to brain via olfactory route thus provides rapid onset of drug action and hence faster therapeutic effect. Therefore, various strategies have been proposed to improve the delivery of different drugs to brain including liposomes, colloidal drug carriers, micelles, chimeric peptide technology and nanotechnology through nasal route. The low blood level of folates is the primary cause of depression in Alzheimer's disease. Folic acid is a water soluble vitamin showing difficulty in crossing the blood brain barrier and thus was formulated as niosomal nasal drug delivery systems to target the brain. In the present work, folic acid niosomes were prepared using different nonionic surfactants i.e., span 20, span 60, span 80, tween 20, tween 80 and cholesterol by using lipid layer hydration technique. These were evaluated for particle size, viscosity, osmotic shock, entrapment efficiency and in vitro drug release. The influence of different formulation variables such as surfactant type, surfactant concentration, and cholesterol concentration was optimized for required size distribution, viscosity, entrapment efficiency and in vitro release. The prepared niosomes were in the size range of 3.05-5.625 µm. Niosomes prepared with span 60 and cholesterol in the ratio of 1:1 (50 mg: 50 mg) shown higher entrapment efficiency of 69.42% and better in vitro drug release of 64.2% at the end of 12 hrs and therefore considered as optimized formulation. The stability studies were carried out by storing niosomes at 4±1°C and 25±1°C and showed good stability over the period of storage. The release of drug from niosomes followed anomalous diffusion and obeyed first order release kinetics. Ex-vivo perfusion studies were also performed by using rat model, about 48.15% of drug was found to be absorbed through nasal cavity at the end of 6 hrs. PMID:23863098

Ravouru, Nagaraju; Kondreddy, Pallavi; Korakanchi, Deepthy; Haritha, M

2013-12-01

145

Preschool Iron-Folic Acid and Zinc Supplementation in Children Exposed to Iron-Folic Acid in Utero Confers No Added Cognitive Benefit in Early School-Age123  

PubMed Central

In Nepal, antenatal iron-folic acid supplementation improved aspects of intellectual, executive, and fine motor function among school-age children. We examined the impact of added zinc to the maternal antenatal supplement (M-IFAZn) and preschool supplementation from 12 to 36 mo with iron-folic acid (C-IFA) ± zinc (C-IFAZn) on cognitive outcomes compared to maternal iron-folic acid (M-IFA) alone. Children 7–9 y old (n = 780) who participated in early childhood micronutrient supplementation trial during 2001–2004 and whose mothers participated in an antenatal micronutrient supplementation between 1999 and 2001 were followed for cognitive assessments in 2007–2009. Using multivariate analysis of variance and adjusting for confounders, M-IFA with child supplementation (either C-IFA or C-IFAZn) did not impact scores on the tests of general intelligence (Universal Nonverbal Intelligence Test), and executive function (Stroop and go/no go tests) relative to the M-IFA alone. However, children in the C-IFAZn group had slightly lower scores on the backward digit span (?0.29, 95% CI: ?0.55, ?0.04) and Movement Assessment Battery for Children (1.33, 95% CI: 0.26, 2.40) relative to the referent group, whereas both C-IFA (?1.92, 95% CI: ?3.12, ?0.71) and C-IFAZn (?1.78, 95% CI: ?2.63, ?0.92) produced somewhat lower finger tapping test scores (fine motor skills). The combination of M-IFAZn and C-IFA or C-IFAZn did not lead to any outcome differences relative to M-IFA alone. Preschool iron-folic acid ± zinc to children exposed to iron-folic acid in utero or addition of zinc to maternal iron-folic acid conferred no additional benefit to cognitive outcomes assessed in early school age. The late timing of supplementation during preschool may explain the lack of impact of iron and/or zinc. PMID:21956955

Christian, Parul; Morgan, Mary E.; Murray-Kolb, Laura; LeClerq, Steven C.; Khatry, Subarna K.; Schaefer, Barbara; Cole, Pamela M.; Katz, Joanne; Tielsch, James M.

2011-01-01

146

A Review of the Benefits of Nutrient Supplements during Pregnancy: From Iron-Folic-Acid to Long-Chain Polyunsaturated Fatty Acids to Probiotics  

Microsoft Academic Search

This review summarizes current knowledge on the effectiveness of prenatal nutrient supplements ranging from iron-folic-acid (IFA), which is standard of care in many parts of the world, to more novel ones such as ?–3 fatty acids and probiotics in improving maternal and child health outcomes. Randomized controlled trials have shown that prenatal IFA supplements reduce the risk of anemia and

Usha Ramakrishnan

2010-01-01

147

Effects of Altered Maternal Folic Acid, Vitamin B12 and Docosahexaenoic Acid on Placental Global DNA Methylation Patterns in Wistar Rats  

PubMed Central

Potential adverse effects of excess maternal folic acid supplementation on a vegetarian population deficient in vitamin B12 are poorly understood. We have previously shown in a rat model that maternal folic acid supplementation at marginal protein levels reduces brain omega-3 fatty acid levels in the adult offspring. We have also reported that reduced docosahexaenoic acid (DHA) levels may result in diversion of methyl groups towards DNA in the one carbon metabolic pathway ultimately resulting in DNA methylation. This study was designed to examine the effect of normal and excess folic acid in the absence and presence of vitamin B12 deficiency on global methylation patterns in the placenta. Further, the effect of maternal omega 3 fatty acid supplementation on the above vitamin B12 deficient diets was also examined. Our results suggest maternal folic acid supplementation in the absence of vitamin B12 lowers plasma and placental DHA levels (p<0.05) and reduces global DNA methylation levels (p<0.05). When this group was supplemented with omega 3 fatty acids there was an increase in placental DHA levels and subsequently DNA methylation levels revert back to the levels of the control group. Our results suggest for the first time that DHA plays an important role in one carbon metabolism thereby influencing global DNA methylation in the placenta. PMID:21423696

Kulkarni, Asmita; Dangat, Kamini; Kale, Anvita; Sable, Pratiksha; Chavan-Gautam, Preeti; Joshi, Sadhana

2011-01-01

148

Assessment of tailor-made prevention of atherosclerosis with folic acid supplementation: randomized, double-blind, placebo-controlled trials in each MTHFR C677T genotype  

Microsoft Academic Search

This study aimed at assessing the effect of folic acid supplementation quantitatively in each MTHFR C677T genotype and considered the efficiency of tailor-made prevention of atherosclerosis. Study design was genotype-stratified, randomized, double-blind, placebo-controlled trials. The setting was a Japanese company in the chemical industry. Subjects were 203 healthy men after exclusion of those who took folic acid or drugs known

Koichi Miyaki; Mitsuru Murata; Haruhito Kikuchi; Izumi Takei; Takeo Nakayama; Kiyoaki Watanabe; Kazuyuki Omae

2005-01-01

149

Possible preventive effect of high doses of folic acid for isolated hypospadias: A national population-based case-control study.  

PubMed

Hypospadias is a common structural birth defect (congenital abnormality) of the male genital organ. The objective of this study was to test the hypothesis regarding the possible preventive effect of folic acid for isolated hypospadias (IH). Folic acid use was compared in 3,038 cases with IH and 24,814 male controls without any defects in the national population-based Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. In Hungary only one kind of folic acid tablet, containing 3?mg/tablet was available during the study period. Hungarian obstetricians recommended daily use of 1-3 tablets, that is, 3-9?mg of folic acid during pregnancy; the estimated daily dose was 5.7 or 5.6?mg in the mothers of cases with IH and controls, respectively. Of 3,038 mothers of cases 1,474 (48.5%) were supplemented with high doses of folic acid during pregnancy and 13,509/24,814 mothers of controls (54.9%) as reference were supplemented at this level as well (OR 95% CI: 0.79, 0.73-0.85). If only medically recorded folic acid use in the critical period of IH was evaluated, the preventive effect was more apparent (OR 95% CI: 0.36, 0.32-0.41). The intake of folic acid among mothers of infants with severe IH was lower than among mothers of infants with mild IH, suggesting a dose-response relationship. In conclusion, this study suggests that high doses of folic acid are associated with a reduced risk of IH. However, this analysis was based on observational data; therefore, confirmation in a well-controlled study is needed. © 2014 Wiley Periodicals, Inc. PMID:25257620

Mavrogenis, Stelios; Urban, Róbert; Czeizel, Andrew E; Acs, Nándor

2014-12-01

150

Periconceptional Maternal Folic Acid Use of 400 ug per Day Is Related to Increased Methylation of the IGF2 Gene in the Very Young Child  

PubMed Central

Background Countries worldwide recommend women planning pregnancy to use daily 400 µg of synthetic folic acid in the periconceptional period to prevent birth defects in children. The underlying mechanisms of this preventive effect are not clear, however, epigenetic modulation of growth processes by folic acid is hypothesized. Here, we investigated whether periconceptional maternal folic acid use and markers of global DNA methylation potential (S-adenosylmethionine and S-adenosylhomocysteine blood levels) in mothers and children affect methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in the child. Moreover, we tested whether the methylation of the IGF2 DMR was independently associated with birth weight. Methodology/Principal Findings IGF2 DMR methylation in 120 children aged 17 months (SD 0.3) of whom 86 mothers had used and 34 had not used folic acid periconceptionally were studied. Methylation was measured of 5 CpG dinucleotides covering the DMR using a mass spectrometry-based method. Children of mother who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to folic acid (49.5% vs. 47.4%; p?=?0.014). IGF2 DMR methylation of the children also was associated with the S-adenosylmethionine blood level of the mother but not of the child (+1.7% methylation per SD S-adenosylmethionine; p?=?0.037). Finally, we observed an inverse independent association between IGF2 DMR methylation and birth weight (?1.7% methylation per SD birthweight; p?=?0.034). Conclusions Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use. PMID:19924280

Steegers-Theunissen, Regine P.; Obermann-Borst, Sylvia A.; Kremer, Dennis; Lindemans, Jan; Siebel, Cissy; Steegers, Eric A.; Slagboom, P. Eline; Heijmans, Bastiaan T.

2009-01-01

151

A Combined Supplementation of Omega-3 Fatty Acids and Micronutrients (Folic Acid, Vitamin B12) Reduces Oxidative Stress Markers in a Rat Model of Pregnancy Induced Hypertension  

PubMed Central

Objectives Our earlier studies have highlighted that an altered one carbon metabolism (vitamin B12, folic acid, and docosahexaenoic acid) is associated with preeclampsia. Preeclampsia is also known to be associated with oxidative stress and inflammation. The current study examines whether maternal folic acid, vitamin B12 and omega-3 fatty acid supplementation given either individually or in combination can ameliorate the oxidative stress markers in a rat model of pregnancy induced hypertension (PIH). Materials and Methods Pregnant Wistar rats were assigned to control and five treatment groups: PIH; PIH + vitamin B12; PIH + folic acid; PIH + Omega-3 fatty acids and PIH + combined micronutrient supplementation (vitamin B12 + folic acid + omega-3 fatty acids). L-Nitroarginine methylester (L-NAME; 50 mg/kg body weight/day) was used to induce hypertension during pregnancy. Blood Pressure (BP) was recorded during pregnancy and dams were dissected at d20 of gestation. Results Animals from the PIH group demonstrated higher (p<0.01 for both) systolic and diastolic BP; lower (p<0.01) pup weight; higher dam plasma homocysteine (p<0.05) and dam and offspring malondialdehyde (MDA) (p<0.01), lower (p<0.05) placental and offspring liver DHA and higher (p<0.01) tumor necrosis factor–alpha (TNF–?) levels as compared to control. Individual micronutrient supplementation did not offer much benefit. In contrast, combined supplementation lowered systolic BP, homocysteine, MDA and placental TNF-? levels in dams and liver MDA and protein carbonyl in the offspring as compared to PIH group. Conclusion Key constituents of one carbon cycle (folic acid, vitamin B12 and DHA) may play a role in reducing oxidative stress and inflammation in preeclampsia. PMID:25405347

Kemse, Nisha G.; Kale, Anvita A.; Joshi, Sadhana R.

2014-01-01

152

Fabrication of folic acid sensor based on the Cu doped SnO2 nanoparticles modified glassy carbon electrode.  

PubMed

A novel folic acid biosensor has been fabricated using Cu doped SnO2 nanoparticles (NPs) synthesized by a simple microwave irradiation method. Powder XRD and TEM studies confirmed that both the pure and Cu doped SnO2 (Cu: 0, 10, 20wt%) crystallized in tetragonal rutile-type structure with spherical morphology. The average crystallite size of pure SnO2 was estimated to be around 16 nm. Upon doping, the crystallite sizes decreased to 9 nm and 5 nm for 10 and 20wt% Cu doped SnO2 respectively. XPS studies confirmed the electronic state of Sn and Cu to be 4+ and 2+ respectively. Cu (20wt%) doped SnO2 NPs are proved to be a good sensing element for the determination of folic acid (FA). Cu-SnO2 NPs (20wt%) modified glassy carbon electrode (GCE) exhibited the lowest detection limit of 0.024 nM over a wide folic acid concentration range of 1.0 × 10(-10) to 6.7 × 10(-5) M at physiological pH of 7.0. The fabricated sensor is highly selective towards the determination of FA even in the presence of a 100 fold excess of common interferent ascorbic acid. The sensor proved to be useful for the estimation of FA content in pharmaceutical sample with satisfactory recovery. PMID:24981704

Lavanya, N; Radhakrishnan, S; Sudhan, N; Sekar, C; Leonardi, S G; Cannilla, C; Neri, G

2014-07-25

153

Critical micronutrients in pregnancy, lactation, and infancy: considerations on vitamin D, folic acid, and iron, and priorities for future research.  

PubMed

The Early Nutrition Academy and the European Commission-funded EURRECA Network of Excellence jointly sponsored a scientific workshop on critical micronutrients in pregnancy, lactation, and infancy. Current knowledge and unresolved questions on the supply of vitamin D, folic acid, and iron for pregnant women, lactating women, and infants, and their health effects were discussed. The question was addressed of whether, and under which circumstances, supplementation with these micronutrients in addition to usual dietary intakes is advisable. The workshop participants concluded that public health strategies for improving supplementation with these micronutrients in pregnancy, lactation, and infancy are required. Further research priorities should focus on adequately powered human intervention trials to obtain a stronger evidence base for the amounts of vitamin D, folic acid, and iron that have optimal effects on health. The conclusions of the workshop should help to inform the scientific community as well as public health policy strategies. PMID:22123630

Hermoso, Maria; Vollhardt, Christiane; Bergmann, Karin; Koletzko, Berthold

2011-01-01

154

Folate Deficiency and Folic Acid Supplementation: The Prevention of Neural-Tube Defects and Congenital Heart Defects  

PubMed Central

Diet, particularly vitamin deficiency, is associated with the risk of birth defects. The aim of this review paper is to show the characteristics of common and severe neural-tube defects together with congenital heart defects (CHD) as vitamin deficiencies play a role in their origin. The findings of the Hungarian intervention (randomized double-blind and cohort controlled) trials indicated that periconceptional folic acid (FA)-containing multivitamin supplementation prevented the major proportion (about 90%) of neural-tube defects (NTD) as well as a certain proportion (about 40%) of congenital heart defects. Finally the benefits and drawbacks of three main practical applications of folic acid/multivitamin treatment such as (i) dietary intake; (ii) periconceptional supplementation; and (iii) flour fortification are discussed. The conclusion arrived at is indeed confirmation of Benjamin Franklin’s statement: “An ounce of prevention is better than a pound of care”. PMID:24284617

Czeizel, Andrew E.; Dudás, Istvan; Vereczkey, Attila; Bánhidy, Ferenc

2013-01-01

155

Online pre-column derivatization with chromatographic separation to determine folic acid.  

PubMed

A simple, sensitive, and selective online pre-column derivatization high-performance liquid chromatographic method was developed and validated for the first time to determine trace levels of folic acid (FA). An oxidant cerium (IV) trihydroxyhydroperoxide packed reactor was used for pre-column oxidation and was combined by column switching with a C18 analytical column for sample enrichment and separation. The method was based on oxidative cleavage of FA into highly fluorescence products, 2-amino-4-hydroxypteridine-6-carboxaldehyde and the corresponding 2-amino-4-hydroxypteridine-6-carboxylic acid, during the flow of 0.04 M phosphate buffer (pH 3.5) containing the analyte through packed reactor at a flow rate of 0.2 mL/min and 40°C. The fluorescent products were enriched on the head of the analytical column for the final separation. The separation was performed at room temperature using a mobile phase consisting of phosphate buffer (0.04 M, pH 3.5) and acetonitrile (90:10, v/v). The eluents were monitored at emission and excitation wavelengths of 463 and 367 nm, respectively. The method showed excellent recovery, precision and accuracy with detection limits of 0.067 ng/mL from 500 µL of sample FA. The developed method was successfully applied to the determination of FA in pharmaceutical formulations and showed a recovery of 99.31% and a relative standard deviation of 1.72%. PMID:23097580

Emara, Samy; Masujima, Tsutomu; Zarad, Walaa; Kamal, Maha; Ei-Bagary, Ramzia

2013-07-01

156

LC/MS/MS identification of some folic acid degradation products after E-beam irradiation  

NASA Astrophysics Data System (ADS)

Folates belong to the B vitamin group based on the parental compound folic acid (FA). They are involved in important biochemical processes like DNA synthesis and repair. FA is composed of a pteridine ring, p-aminobenzoic acid and glutamate moieties. The human metabolism is not able to synthesize folates and therefore obtain them from diet. FA, a synthetic vitamin, is used as a food fortificant because of its low price, relative stability and increased bioavailability compared to natural folate forms. FA is known to be a sensitive compound easily degradable in aqueous solution by ultraviolet and visible light towards various by-products. Irradiation is a process for preservation of foods that uses accelerated electrons, gamma rays or X-rays. Irradiation is proposed for the treatment of various food products, eliminating or reducing pathogens and insects, increasing the storage time and replacing chemical fumigants. This study concerns the identification of degradation products of FA after E-beam irradiation. FA aqueous solutions were irradiated with a Van de Graaff electrons beam accelerator (2 MeV, 100 ?A current, 20 cm scan width, dose rate about 2 kGy/s). Applied doses were between 0 (control) and 10.0 kGy. Absorbed doses were monitored with FWT 60.00 radiochromic dosimeters.

Araújo, M. M.; Marchioni, E.; Zhao, M.; Kuntz, F.; Di Pascoli, T.; Villavicencio, A. L. C. H.; Bergaentzle, M.

2012-08-01

157

No Effect of Folic Acid Supplementation on Global DNA Methylation in Men and Women with Moderately Elevated Homocysteine  

PubMed Central

A global loss of cytosine methylation in DNA has been implicated in a wide range of diseases. There is growing evidence that modifications in DNA methylation can be brought about by altering the intake of methyl donors such as folate. We examined whether long-term daily supplementation with 0.8 mg of folic acid would increase global DNA methylation compared with placebo in individuals with elevated plasma homocysteine. We also investigated if these effects were modified by MTHFR C677T genotype. Two hundred sixteen participants out of 818 subjects who had participated in a randomized double-blind placebo-controlled trial were selected, pre-stratified on MTHFR C677T genotype and matched on age and smoking status. They were allocated to receive either folic acid (0.8 mg/d; n?=?105) or placebo treatment (n?=?111) for three years. Peripheral blood leukocyte DNA methylation and serum and erythrocyte folate were assessed. Global DNA methylation was measured using liquid chromatography-tandem mass spectrometry and expressed as a percentage of 5-methylcytosines versus the total number of cytosine. There was no difference in global DNA methylation between those randomized to folic acid and those in the placebo group (difference?=?0.008, 95%CI?=??0.05,0.07, P?=?0.79). There was also no difference between treatment groups when we stratified for MTHFR C677T genotype (CC, n?=?76; CT, n?=?70; TT, n?=?70), baseline erythrocyte folate status or baseline DNA methylation levels. In moderately hyperhomocysteinemic men and women, long-term folic acid supplementation does not increase global DNA methylation in peripheral blood leukocytes. ClinicalTrials.gov NCT00110604 PMID:21966393

Jung, Audrey Y.; Smulders, Yvo; Verhoef, Petra; Kok, Frans J.; Blom, Henk; Kok, Robert M.; Kampman, Ellen; Durga, Jane

2011-01-01

158

Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and pre-natal folic acid intake  

PubMed Central

Background Incidence of unilateral retinoblastoma varies globally suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is inversely associated with risk of retinoblastoma in offspring. Methods Using a case-control study design, we examined the association between retinoblastoma risk and maternal variations in the folate-metabolizing genes, methylenetetrahydrofolate reductase (MTHFR677C>T, rs1801133) and dihydrofolate reductase (DHFR 19base pair deletion of intron 1a [DHFR19bpdel], rs70991108). In central Mexico, we enrolled 103 mothers of children with newly diagnosed unilateral retinoblastoma and 97 control mothers who had healthy children in an IRB approved study. Mothers were interviewed regarding perinatal characteristics including use of prenatal vitamin supplements and gave peripheral blood samples used for PCR-based genotyping of rs1801133 and rs70991108. Results The risk of having a child with unilateral retinoblastoma were associated with maternal homozygosity for DHFR19bpdel (OR=3.78, 95%CI:1.89,7.55; p=0.0002), even after controlling for child’s DHFR19bpdel genotype (OR=2.81, 95%CI:1.32,5.99; p=0.0073). In a subgroup of 167 mothers with data on prenatal intake of supplements containing folic acid (a synthetic form of folate), DHFR19bpdel-associated risk was significantly elevated only among those who reported taking folic acid supplements. Maternal MTHFR genotype was unrelated to risk of having a child with retinoblastoma. Conclusion Maternal homozygosity for a polymorphism in the DHFR gene necessary for converting synthetic folic acid into biological folate is associated with increased risk for retinoblastoma. Prenatal ingestion of synthetic folic acid supplements may be associated with increased risk for early childhood carcinogenesis in a genetically susceptible subset of the population. PMID:22648968

Orjuela, MA; Cabrera-Munoz, L; Paul, L; Ramirez-Ortiz, MA; Liu, X; Chen, J; Mejia-Rodriguez, F; Medina-Sanson, A; Diaz-Carreno, S; Suen, IH; Selhub, J; Ponce-Castaneda, MV

2012-01-01

159

Targeted delivery of Doxorubicin by folic Acid-decorated dual functional nanocarrier.  

PubMed

Doxorubicin (DOX) is one of the most commonly used antineoplastic agents, but its clinical application is oftentimes coupled with severe side effects. Selective delivery of DOX to tumors via nanosized drug carrier represents an attractive approach to this problem. Previously, we developed a dual functional nanomicellar carrier, PEG5K-embelin2 (PEG5K-EB2), which was able to deliver paclitaxel (PTX) selectively to tumors and to achieve an enhanced therapeutic effect. In the present study, we examined the utility of PEG5K-EB2 to deliver DOX to tumors. In addition, folic acid (FA) was coupled to the surface of the PEG5K-EB2 micelles (FA-PEG5K-EB2) to further improve the selective targetability of the system. DOX-loaded PEG5K-EB2 micelles were uniformly spherical particles with a diameter of approximately 20 nm. Incorporation of FA had minimal effect on the size of the particles. The DOX loading efficiency was as high as 91.7% and 93.5% for PEG5K-EB2 and FA-PEG5K-EB2, respectively. DOX formulated in PEG5K-EB2 micelles (with or without FA decoration) demonstrated sustained kinetics of DOX release compared to free DOX. FA-PEG5K-EB2 significantly facilitated the intracellular uptake of DOX over free DOX and PEGylated liposomal DOX (Doxil) in breast cancer cells, 4T1.2, and drug resistant cells, NCI/ADR-RES. P-gp ATPase assay showed that PEG5K-EB2 significantly inhibited the function of the P-gp efflux pump. The maximum tolerated dose of DOX-loaded PEG5K-EB2 micelles was 15 mg/kg in mice, which was 1.5-fold greater than that for free DOX. Pharmacokinetics (PK) and biodistribution studies showed that both types of DOX-loaded micelles, especially FA-PEG5K-EB2, were able to significantly prolong the blood circulation time of DOX and facilitate its preferential accumulation at the tumor tissue. Finally, DOX/PEG5K-EB2 mixed micelles demonstrated significantly enhanced tumor growth inhibitory effect with minimal toxicity in comparison to free DOX and Doxil and the antitumor activity was further enhanced after the decoration by folic acid. Our data suggest that FA-PEG5K-EB2 micelles represent a promising DOX delivery system that warrants more study in the future. PMID:25265550

Lu, Jianqin; Zhao, Wenchen; Huang, Yixian; Liu, Hao; Marquez, Rebecca; Gibbs, Robert B; Li, Jiang; Venkataramanan, Raman; Xu, Liang; Li, Shulin; Li, Song

2014-11-01

160

Iron and Folic Acid Consumption by the Ante-natal Mothers in a Rural Area of India in 2010  

PubMed Central

Background: The average rural Indian women enter her reproductive life, particularly in pregnancy, suffer from nutritional anemia due to iron deficiency. National program of India had implemented a strategy for supplementation of iron folic acid by means of iron folic acid (IFA) tablets at least 3 months during antenatal period. The study had been conducted to assess the proportion of pregnant mothers consumes the IFA tablets and the factors determine compliance. Methods: A cross-sectional, community-based study was conducted in rural area of India on 50 antenatal mothers by multistage sampling technique. The data were analyzed by using SPSS 16 (Statistical Package for the Social Sciences, ver. 16), Chicago, considering the level of significance at 95%. Results: The IFA tablet was adequately consumed by 62% mother among the study population. The consumption is more among the mother who were explained properly than those who were not explained by the health worker (?2= 4.529, P < 0.05). Conclusions: The compliance of iron folic acid tablets was still far behind to reach the National Goal though the service component are quite strong by the front line workers and health providers. An effort should be given at the level of front line health workers by training and re-training them to improve the compliance of IFA consumption. PMID:24319564

Pal, Partha Pratim; Sharma, Shilpi; Sarkar, Tarun Kumar; Mitra, Pevel

2013-01-01

161

Folic Acid Conjugated ?-Valerolactone-Poly(ethylene glycol) Based Triblock Copolymer as a Promising Carrier for Targeted Doxorubicin Delivery  

PubMed Central

The aim of this study is to test the hypothesis that the newly synthesized poly(?-valerolactone)/poly(ethylene glycol)/poly(?-valerolactone) (VEV) copolymer grafted with folic acid would impart targetability and further enhance the anti-tumor efficacy of doxorubicin (DOX). Here, folic acid conjugated VEV (VEV-FOL) was synthesized by a modified esterification method and characterized using IR and NMR. DOX loaded VEV-FOL micelles were synthesized using a novel solvent evaporation method and were obtained with a mean diameter of 97 nm with high encapsulation efficiency and sustained in vitro release profile. Comparative studies of polymer micelles with and without folate for cellular uptake and cytotoxicity were done on folate receptor-positive breast cancer cell line, MDAMB231. The intracellular uptake tests showed significant increase in folate micellar uptake when compared to non-folate-mediated micelles. MTT assay followed by apoptosis assays clearly indicated that folate decorated micelles showed significantly better cytotoxicity (IC50?=?0.014 µM) and efficiency to induce apoptosis than other treated groups. Moreover, a significant G2/M arrest was induced by DOX loaded VEV-FOL micelles at a concentration where free drug failed to show any activity. Thus, our results show that the folic acid-labeled VEV copolymer is a promising biomaterial with controlled and sustainable tumor targeting ability for anticancer drugs which can open new frontiers in the area of targeted chemotherapy. PMID:23990912

Nair K, Lekha; Jagadeeshan, Sankar; Nair S, Asha; Kumar, G. S. Vinod

2013-01-01

162

Folic acid-functionalized human serum albumin nanocapsules for targeted drug delivery to chronically activated macrophages.  

PubMed

Activated synovial macrophages play a key role in Rheumatoid Arthritis (RA). Recent studies have shown that folate receptor beta (FR?) is specifically expressed by activated macrophages. Therefore a folate-based nanodevice would provide the possibility of delivering therapeutic agents to activated macrophages without affecting normal cells and tissues. This study shows for the first time the sonochemical preparation of HSA nanocapsules avoiding toxic cross linking chemicals and emulsifiers used in other methods. Production of HSA nanocapsules was optimized leading to a diameter of 443.5 ± 9.0 nm and a narrow size distribution indicated by a polydispersity index (PDI) of 0.066 ± 0.080. Nanocapsules were surface modified with folic acid (FA) and the FA content was determined to be 0.38 and 6.42 molecules FA per molecule HSA, depending on the surplus of FA employed. Dynamic light scattering was used to determine size, PDI and zetapotential of the produced nanocapsules before and after surface modification. FA distribution on the surface of HSA nanocapsules was localized three-dimensionally after fluorescence labeling using confocal laser scanning microscopy (CLSM). Furthermore, specific binding and internalization of HSA nanocapsules by FR?-positive and FR?-negative macrophages, obtained from human peripheral blood mononuclear cells, was demonstrated by flow cytometry. FR?-expressing macrophages showed an increased binding for FA-modified capsules compared with those without FA. PMID:22374516

Rollett, Alexandra; Reiter, Tamara; Nogueira, Patricia; Cardinale, Massimiliano; Loureiro, Ana; Gomes, Andreia; Cavaco-Paulo, Artur; Moreira, Alexandra; Carmo, Alexandre M; Guebitz, Georg M

2012-05-10

163

Folic Acid Functionalized Surface Highlights 5-Methylcytosine-Genomic Content within Circulating Tumor Cells.  

PubMed

Although the detection of methylated cell free DNA represents one of the most promising approaches for relapse risk assessment in cancer patients, the low concentration of cell-free circulating DNA constitutes the biggest obstacle in the development of DNA methylation-based biomarkers from blood. This paper describes a method for the measurement of genomic methylation content directly on circulating tumor cells (CTC), which could be used to deceive the aforementioned problem. Since CTC are disease related blood-based biomarkers, they result essential to monitor tumor's stadiation, therapy, and early relapsing lesions. Within surface's bio-functionalization and cell's isolation procedure standardization, the presented approach reveals a singular ability to detect high 5-methylcytosine CTC-subset content in the whole CTC compound, by choosing folic acid (FA) as transducer molecule. Sensitivity and specificity, calculated for FA functionalized surface (FA-surface), result respectively on about 83% and 60%. FA-surface, allowing the detection and characterization of early metastatic dissemination, provides a unique advance in the comprehension of tumors progression and dissemination confirming the presence of CTC and its association with high risk of relapse. This functionalized surface identifying and quantifying high 5-methylcytosine CTC-subset content into the patient's blood lead significant progress in cancer risk assessment, also providing a novel therapeutic strategy. PMID:25044603

Malara, Natalia; Coluccio, Maria Laura; Limongi, Tania; Asande, Monica; Trunzo, Valentina; Cojoc, Gheorghe; Raso, Cinzia; Candeloro, Patrizio; Perozziello, Gerardo; Raimondo, Raffaella; De Vitis, Stefania; Roveda, Laura; Renne, Maria; Prati, Ubaldo; Mollace, Vincenzo; Di Fabrizio, Enzo

2014-11-01

164

Structural basis for molecular recognition of folic acid by folate receptors.  

PubMed

Folate receptors (FR?, FR? and FR?) are cysteine-rich cell-surface glycoproteins that bind folate with high affinity to mediate cellular uptake of folate. Although expressed at very low levels in most tissues, folate receptors, especially FR?, are expressed at high levels in numerous cancers to meet the folate demand of rapidly dividing cells under low folate conditions. The folate dependency of many tumours has been therapeutically and diagnostically exploited by administration of anti-FR? antibodies, high-affinity antifolates, folate-based imaging agents and folate-conjugated drugs and toxins. To understand how folate binds its receptors, we determined the crystal structure of human FR? in complex with folic acid at 2.8?Å resolution. FR? has a globular structure stabilized by eight disulphide bonds and contains a deep open folate-binding pocket comprised of residues that are conserved in all receptor subtypes. The folate pteroate moiety is buried inside the receptor, whereas its glutamate moiety is solvent-exposed and sticks out of the pocket entrance, allowing it to be conjugated to drugs without adversely affecting FR? binding. The extensive interactions between the receptor and ligand readily explain the high folate-binding affinity of folate receptors and provide a template for designing more specific drugs targeting the folate receptor system. PMID:23851396

Chen, Chen; Ke, Jiyuan; Zhou, X Edward; Yi, Wei; Brunzelle, Joseph S; Li, Jun; Yong, Eu-Leong; Xu, H Eric; Melcher, Karsten

2013-08-22

165

Excited-State Dynamics in Folic Acid and 6-CARBOXYPTERIN upon Uva Excitation  

NASA Astrophysics Data System (ADS)

The excited-state dynamics of folic acid (FA) and 6-carboxypterin (6CP) are poorly understood and work is needed to uncover the relaxation pathways that ultimately lead to their oxidative damage of DNA. In our approach, broad-band transient absorption spectroscopy was used to monitor the evolution of the excited states in FA and 6CP in basic aqueous solution upon excitation at 350 nm. In addition, quantum-chemical calculations were performed to assist in the interpretation of the experimental results and in the postulation of kinetic mechanisms. The combined experimental and computational results support a kinetic model where excitation of FA results in ultrafast charge separation (? = 0.6 ps), which decays back to the ground state primarily by charge recombination with a lifetime of 2.2 ps. A small fraction of the charge transfer state undergoes intersystem crossing to populate the lowest-energy triplet state with a lifetime of 200 ps. On the other hand, a large fraction of the initially excited singlet state in 6CP decays by fluorescence emission with a lifetime of 100 ps, while intersystem crossing to the triplet state occurs with a lifetime of 4.4 ns. The potential implications of these results to the oxidative damage of DNA by FA and 6CP will be discussed. Funding from the National Science Foundation is gratefully acknowledged (CHE-1255084).

Huang, Huijuan; Vogt, R. Aaron; Crespo-Hernandez, Carlos E.

2013-06-01

166

Synthesis and cellular uptake of folic acid-conjugated cellulose nanocrystals for cancer targeting.  

PubMed

Elongated nanoparticles have recently been shown to have distinct advantages over spherical ones in targeted drug delivery applications. In addition to their oblong geometry, their lack of cytotoxicity and numerous surface hydroxyl groups make cellulose nanocrystals (CNCs) promising drug delivery vectors. Herein we report the synthesis of folic acid-conjugated CNCs for the targeted delivery of chemotherapeutic agents to folate receptor-positive cancer cells. Folate receptor-mediated cellular binding/uptake of the conjugate was demonstrated on human (DBTRG-05MG, H4) and rat (C6) brain tumor cells. Folate receptor expression of the cells was verified by immunofluorescence staining. Cellular binding/uptake of the conjugate by DBTRG-05MG, H4, and C6 cells was 1452, 975, and 46 times higher, respectively, than that of nontargeted CNCs. The uptake mechanism was determined by preincubation of the cells with the uptake inhibitors chlorpromazine or genistein. DBTRG-05MG and C6 cells internalized the conjugate primarily via caveolae-mediated endocytosis, whereas H4 cells internalized the conjugate primarily via clathrin-mediated endocytosis. PMID:24716601

Dong, Shuping; Cho, Hyung Joon; Lee, Yong Woo; Roman, Maren

2014-05-12

167

Bioinformatic analysis of endothelial progenitor cells exposed to folic acid in type 1 diabetes mellitus.  

PubMed

We investigated the effects of type 1 diabetes mellitus (T1DM) on endothelial progenitor cells (EPCs) at the molecular level and assessed the therapeutic potential of folic acid (FA) in DM. We downloaded the gene expression profile of the EPCs from T1DM patients before and after treatment with FA and from healthy controls. We identified the differentially expressed genes (DEGs) in the EPCs from T1DM patients before and after a four-week period of FA treatment and compared them with those obtained from the healthy subjects by using limma package in R language. Then, functional annotation of the DEGs was performed using the online tool Database for Annotation, Visualization and Integrated Discovery (DAVID) based on the Kyoto Encyclopedia of Genes and Genomes database. The expression of 696 genes was altered in the EPCs from T1DM patients compared to those from the healthy controls. These genes were mainly involved in the pathways associated with immune response. FA can normalize majority of the altered gene expression profiles of EPCs from T1DM patients to resemble those of healthy subjects, albeit with some side effects. FA can be a potential therapeutic agent for the treatment of T1DM. However, focused efforts are required to ensure that the dose of FA falls within the permissible pharmacological range. PMID:24421150

Fang, D N; He, X D; Li, X H; Jia, H; Li, P Y; Lu, Q; Quan, Z; Wang, Q L

2014-01-01

168

Methoxistasis: Integrating the Roles of Homocysteine and Folic Acid in Cardiovascular Pathobiology  

PubMed Central

Over the last four decades, abnormalities in the methionine-homocysteine cycle and associated folate metabolism have garnered great interest due to the reported link between hyperhomocysteinemia and human pathology, especially atherothrombotic cardiovascular disease. However, clinical trials of B-vitamin supplementation including high doses of folic acid have not demonstrated any benefit in preventing or treating cardiovascular disease. In addition to the fact that these clinical trials may have been shorter in duration than appropriate for modulating chronic disease states, it is likely that reduction of the blood homocysteine level may be an oversimplified approach to a complex biologic perturbation. The methionine-homocysteine cycle and folate metabolism regulate redox and methylation reactions and are, in turn, regulated by redox and methylation status. Under normal conditions, a normal redox-methylation balance, or “methoxistasis”, exists, coordinated by the methionine-homocysteine cycle. An abnormal homocysteine level seen in pathologic states may reflect a disturbance of methoxistasis. We propose that future research should be targeted at estimating the deviation from methoxistasis and how best to restore it. This approach could lead to significant advances in preventing and treating cardiovascular diseases, including heart failure. PMID:23955381

Joseph, Jacob; Loscalzo, Joseph

2013-01-01

169

Efficacy of folic acid supplementation on endothelial function and plasma homocysteine concentration in coronary artery disease: A meta-analysis of randomized controlled trials  

PubMed Central

The aim of the present study was to conduct an updated meta-analysis of relevant randomized controlled trials (RCTs) in order to estimate the effect of folic acid supplementation on endothelial function and the concentration of plasma homocysteine in patients with coronary artery disease (CAD). An extensive search of PubMed was conducted to identify RCTs that compared folic acid with placebo therapy. The mean difference (MD) and 95% confidence interval (CI) were used as a measure of the correlation between folic acid supplementation and endothelial function/plasma homocysteine concentration. Of the 377 patients included in this analysis, 191 patients underwent folic acid supplementation and 186 individuals underwent placebo treatment. Compared with the use of a placebo, folic acid supplementation alone exhibited significant efficacy on increasing flow-mediated dilation (FMD; MD, 57.72 ?m; 95% CI, 50.14–65.31; P<0.05) and lowering the concentration of plasma homocysteine (MD, ?3.66 ?mol/l; 95% CI, ?5.44–?1.87; P<0.05; I2, 87%). There was no significant change in the response to end diastolic diameter, glyceryl-trinitrate diameter, heart rate, baseline and peak hyperemic flow and systolic and diastolic blood pressure between the folic acid and placebo groups (P>0.05). Therefore, the meta-analysis indicated that 5 mg folic acid daily supplementation for >4 weeks significantly improved FMD and lowered the concentration of plasma homocysteine in patients with CAD. However, more RCTs are required in order to confirm these observations. PMID:24940394

YI, XIN; ZHOU, YANLI; JIANG, DINGSHENG; LI, XIAOYAN; GUO, YI; JIANG, XUEJUN

2014-01-01

170

Trans-stimulation effects of folic acid derivatives on methotrexate transport by rat renal organic anion transporter, OAT-K1.  

PubMed

We examined the pharmacological role of the renal organic anion transporter OAT-K1, which localizes predominantly in the brush-border membranes of proximal straight tubules, in the urinary excretion of methotrexate and the possibility of its contribution to "folinic acid rescue." With Madin-Darby canine kidney (MDCK) cells stably transfected with OAT-K1 cDNA, OAT-K1-mediated methotrexate accumulation was inhibited in the presence of various folic acid derivatives. These derivatives included aminopterin, 5-methyltetrahydrofolic acid, unlabeled methotrexate, folinic acid (citrovorum factor, leucovorin), and folic acid with apparent inhibition constant values of 0.5, 1.2, 1.8, 8.2, and 14.1 microM, respectively. In contrast, 10 microM taurocholic acid and sulfobromophthalein did not inhibit OAT-K1-mediated methotrexate accumulation. In addition, methotrexate efflux was stimulated in the presence of inwardly directed gradients of aminopterin, 5-methyltetrahydrofolic acid, unlabeled methotrexate, folinic acid, and folic acid, but not of uric acid, taurocholic acid, and glutathione, indicating that OAT-K1-mediated methotrexate efflux is stimulated by a folic acid derivatives exchange. In conclusion, OAT-K1 was suggested to enhance the apical efflux of highly accumulated methotrexate in tubular epithelial cells and contribute at least in part to folinic acid rescue by exchanging intracellular methotrexate for extracellular folinic acid. PMID:10869408

Takeuchi, A; Masuda, S; Saito, H; Hashimoto, Y; Inui, K

2000-06-01

171

Folic Acid Mitigates Angiotensin-II-Induced Blood Pressure and Renal Remodeling  

PubMed Central

Clinical data suggests an association between systolic hypertension, renal function and hyperhomocysteinemia (HHcy). HHcy is a state of elevated plasma homocysteine (Hcy) levels and is known to cause vascular complications. In this study, we tested the hypothesis whether Ang II-induced hypertension increases plasma Hcy levels and contributes to renovascular remodeling. We also tested whether folic acid (FA) treatment reduces plasma Hcy levels by enhancing Hcy remethylation and thus mitigating renal remodeling. Hypertension was induced in WT mice by infusing Ang II using Alzet mini osmotic pumps. Blood pressure, Hcy level, renal vascular density, oxidative stress, inflammation and fibrosis markers, and angiogenic- and anti-angiogenic factors were measured. Ang II hypertension increased plasma Hcy levels and reduced renal cortical blood flow and microvascular density. Elevated Hcy in Ang II hypertension was associated with decreased 4, 5-Diaminofluorescein (DAF-2DA) staining suggesting impaired endothelial function. Increased expression of Nox-2, -4 and dihydroethidium stain revealed oxidative stress. Excess collagen IV deposition in the peri-glomerular area and increased MMP-2, and -9 expression and activity indicated renal remodeling. The mRNA and protein expression of asymmetric dimethylarginine (ADMA) was increased and eNOS protein was decreased suggesting the involvement of this pathway in Hcy mediated hypertension. Decreased expressions of VEGF and increased anti-angiogenic factors, angiostatin and endostatin indicated impaired vasculogenesis. FA treatment partially reduced hypertension by mitigating HHcy in Ang II-treated animals and alleviated pro-inflammatory, pro-fibrotic and anti-angiogenic factors. These results suggest that renovascular remodeling in Ang II-induced hypertension is, in part, due to HHcy. PMID:24386282

Pushpakumar, Sathnur B.; Kundu, Sourav; Metreveli, Naira; Sen, Utpal

2013-01-01

172

Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis.  

PubMed

Acute kidney injury (AKI) is a disease with mitochondrial dysfunction and a newly established risk factor for the development of chronic kidney disease (CKD) and fibrosis. We examined mitochondrial homeostasis in the folic acid (FA)-induced AKI model that develops early fibrosis over a rapid time course. Mice given a single dose of FA had elevated serum creatinine (3-fold) and urine glucose (2.2-fold) 1 and 2 d after injection that resolved by 4d. In contrast, peroxisome proliferator gamma coactivator 1? (PGC-1?) and mitochondrial transcription factor A (TFAM), critical transcriptional regulators of mitochondrial biogenesis (MB), were down-regulated ?80% 1d after FA injection and remained depressed through 14 d. Multiple electron transport chain and ATP synthesis genes were also down-regulated from 1 to 14 d after FA, including NADH dehydrogenase (ubiquinone) 1 beta subcomplex 8 (NDUF?8), ATP synthase subunit ? (ATPS-?), and cytochrome C oxidase subunit I (COXI). Mitochondrial DNA copy number was reduced ?50% from 2 to 14 d after FA injection. Protein levels of early fibrosis markers ?-smooth muscle actin and transforming growth factor ?1 were elevated at 6 and 14 d after FA. Picrosirius red staining and collagen 1A2 (COL1A2) IHC revealed staining for mature collagen deposition at 14 d. We propose that mitochondrial dysfunction induced by AKI is a persistent cellular injury that promotes progression to fibrosis and CKD, and that this model can be used to test mitochondrial therapeutics that limit progression to fibrosis and CKD. PMID:24275386

Stallons, L Jay; Whitaker, Ryan M; Schnellmann, Rick G

2014-01-30

173

Pharmacokinetics, biodistribution, and toxicity of folic Acid-coated antiretroviral nanoformulations.  

PubMed

The drug delivery platform for folic acid (FA)-coated nanoformulated ritonavir (RTV)-boosted atazanavir (FA-nanoATV/r) using poloxamer 407 was developed to enhance cell and tissue targeting for a range of antiretroviral drugs. Such formulations would serve to extend the drug half-life while improving the pharmacokinetic profile and biodistribution to reservoirs of human immunodeficiency virus (HIV) infection. To this end, we now report enhanced pharmacokinetics and drug biodistribution with limited local and systemic toxicities of this novel nanoformulation. The use of FA as a targeting ligand for nanoATV/r resulted in plasma and tissue drug concentrations up to 200-fold higher compared to equimolar doses of native drug. In addition, ATV and RTV concentrations in plasma from mice on a folate-deficient diet were up to 23-fold higher for mice administered FA-nanoATV/r than for mice on a normal diet. Compared to earlier nanoATV/r formulations, FA-nanoATV/r resulted in enhanced and sustained plasma and tissue ATV concentrations. In a drug interaction study, ATV plasma and tissue concentrations were up to 5-fold higher in mice treated with FA-nanoATV/r than in mice treated with FA-nanoATV alone. As observed in mice, enhanced and sustained plasma concentrations of ATV were observed in monkeys. NanoATV/r was associated with transient local inflammation at the site of injection. There were no systemic adverse reactions associated with up to 10 weeks of chronic exposure of mice or monkeys to FA-nanoATV/r. PMID:25288084

Gautam, Nagsen; Puligujja, Pavan; Balkundi, Shantanu; Thakare, Rhishikesh; Liu, Xin-Ming; Fox, Howard S; McMillan, JoEllyn; Gendelman, Howard E; Alnouti, Yazen

2014-12-01

174

Folic acid mitigates angiotensin-II-induced blood pressure and renal remodeling.  

PubMed

Clinical data suggests an association between systolic hypertension, renal function and hyperhomocysteinemia (HHcy). HHcy is a state of elevated plasma homocysteine (Hcy) levels and is known to cause vascular complications. In this study, we tested the hypothesis whether Ang II-induced hypertension increases plasma Hcy levels and contributes to renovascular remodeling. We also tested whether folic acid (FA) treatment reduces plasma Hcy levels by enhancing Hcy remethylation and thus mitigating renal remodeling. Hypertension was induced in WT mice by infusing Ang II using Alzet mini osmotic pumps. Blood pressure, Hcy level, renal vascular density, oxidative stress, inflammation and fibrosis markers, and angiogenic- and anti-angiogenic factors were measured. Ang II hypertension increased plasma Hcy levels and reduced renal cortical blood flow and microvascular density. Elevated Hcy in Ang II hypertension was associated with decreased 4, 5-Diaminofluorescein (DAF-2DA) staining suggesting impaired endothelial function. Increased expression of Nox-2, -4 and dihydroethidium stain revealed oxidative stress. Excess collagen IV deposition in the peri-glomerular area and increased MMP-2, and -9 expression and activity indicated renal remodeling. The mRNA and protein expression of asymmetric dimethylarginine (ADMA) was increased and eNOS protein was decreased suggesting the involvement of this pathway in Hcy mediated hypertension. Decreased expressions of VEGF and increased anti-angiogenic factors, angiostatin and endostatin indicated impaired vasculogenesis. FA treatment partially reduced hypertension by mitigating HHcy in Ang II-treated animals and alleviated pro-inflammatory, pro-fibrotic and anti-angiogenic factors. These results suggest that renovascular remodeling in Ang II-induced hypertension is, in part, due to HHcy. PMID:24386282

Pushpakumar, Sathnur B; Kundu, Sourav; Metreveli, Naira; Sen, Utpal

2013-01-01

175

BP, cardiovascular disease, and death in the Folic Acid for Vascular Outcome Reduction in Transplantation trial.  

PubMed

The optimal BP level in kidney transplant recipients remains uncertain. This post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial cohort assessed associations of BP with a pooled cardiovascular disease (CVD) outcome and with all-cause mortality. In 3474 prevalent kidney transplant patients, mean age was 52±9 years, 63% were men, 76% were white, 20% had a history of CVD, 40% had a history of diabetes mellitus, and the median time since transplant was 4.1 years (25th to 75th percentiles, 1.7-7.4); mean systolic BP was 136±20 mmHg and mean diastolic BP was 79±12 mmHg. There were 497 CVD events and 406 deaths. After adjustment for demographic and transplant characteristics and CVD risk factors, each 20-mmHg increase in baseline systolic BP associated with a 32% increase in subsequent CVD risk (hazard ratio [HR], 1.32; 95% confidence interval [95% CI], 1.19 to 1.46) and a 13% increase in mortality risk (HR, 1.13; 95% CI, 1.01 to 1.27). Similarly, after adjustment, at diastolic BP levels<70 mmHg, each 10-mmHg decrease in diastolic BP level associated with a 31% increase in CVD risk (HR, 1.31; 95% CI, 1.06 to 1.62) and a 31% increase in mortality risk (HR, 1.31; 95% CI, 1.03 to 1.66). However, at diastolic BP levels>70 mmHg, there was no significant relationship between diastolic BP and outcomes. Higher systolic BP strongly and independently associated with increased risk of CVD and all-cause mortality, without evidence of a J shape, whereas only lower levels of diastolic BP associated with increased risk of CVD and death in this trial. PMID:24627349

Carpenter, Myra A; John, Alin; Weir, Matthew R; Smith, Stephen R; Hunsicker, Lawrence; Kasiske, Bertram L; Kusek, John W; Bostom, Andrew; Ivanova, Anastasia; Levey, Andrew S; Solomon, Scott; Pesavento, Todd; Weiner, Daniel E

2014-07-01

176

Highly selective electrochemical biosensor for the determination of folic acid based on DNA modified-pencil graphite electrode using response surface methodology.  

PubMed

An electrochemical DNA biosensor was proposed as a screening device for the rapid analysis of folic acid using a pencil graphite electrode modified with salmon sperm ds-DNA. At first, immobilization of the ds-DNA on pencil graphite electrode was optimized using response surface methodology. Solution pH, DNA concentration, time of DNA deposition and potential of deposition was optimized each at three levels. The optimum combinations for the reaction were pH 4.8, DNA concentration of 24 ?g mL(-1), deposition time of 304 s, and deposition potential of 0.60 V, by which the adenine signal was recorded as 3.04 ?A. Secondly the binding of folic acid to DNA immobilized on a pencil graphite electrode was measured through the variation of the electrochemical signal of adenine. Folic acid could be measure in the range of 0.1-10.0 ?mol L(-1) with a detection limit of 1.06×10(-8) ?mol L(-1). The relative standard deviations for ten replicate differential pulse voltammetric measurements of 2.0 and 5.0 ?mol L(-1) folic acid were 4.6% and 4.3%, respectively. The biosensor was successfully used to measure folic acid in different real samples. PMID:23827633

Mirmoghtadaie, Leila; Ensafi, Ali A; Kadivar, Mahdi; Norouzi, Parviz

2013-04-01

177

Broadcasting behavior change: a comparison of the effectiveness of paid and unpaid media to increase folic acid awareness, knowledge, and consumption among Hispanic women of childbearing age.  

PubMed

Awareness about folic acid's effectiveness in reducing the risk of certain birth defects has increased among women in the United States; however, few Hispanic women are consuming enough folic acid daily. A 1998 survey conducted by the Gallup Organization for the National March of Dimes Birth Defects Foundation found that English-speaking Hispanic women had lower folic acid awareness (53% vs. 72%) and lower daily consumption (29% vs. 33%) than non-Hispanic White women. In 1999, the Centers for Disease Control and Prevention (CDC) conducted baseline surveys with Spanish-speaking Hispanic women in selected U.S. markets to measure folic acid awareness, knowledge, and consumption. A Spanish-language public service announcement (PSA) volunteer campaign and a paid Spanish-language media and community education campaign were conducted in 2000 and 2002, respectively. Comparisons of postcampaign surveys indicate that the paid media campaign was significantly more effective than the PSA campaign in increasing folic acid awareness, knowledge, and consumption among Spanish-speaking Hispanic women. PMID:17003248

Flores, Alina L; Prue, Christine E; Daniel, Katherine Lyon

2007-04-01

178

Equivalent absorption and in vivo kinetics of tritiated folic acid and 5-formyl-tetrahydrofolic acid in rats  

SciTech Connect

The intestinal absorption and in vivo turnover kinetics of ({sup 3}H)folic acid (FA) and (6S)-5-formyl-({sup 3}H)tetrahydrofolate (5-CHO-THF) were examined to determine whether differences exist in the inherent bioavailability of these forms of the vitamin. Following oral administration of 2 {mu}Ci/100 g body weight (in 50 mM sodium ascorbate, pH 7), a biphasic pattern of urinary tritium excretion was observed for each labeled folate. The following kinetic results were obtained (n=9). Little tritium was found in the GI tract after 8 hours, which indicated nearly complete absorption of each folate. HPLC analysis of urine revealed similar excretory patterns over 0-8 days post-dose for each folate administered, and the patterns of hepatic ({sup 3}H)folates were equivalent when examined after 8 hours and 4 days post-dose. These findings indicate that the bioavailability FA and 5-formyl-THF is equivalent.

Bhandari, S.D.; Gregory, J.F. (Univ. of Florida, Gainesville (United States))

1990-02-26

179

Utilization of folic acid and iron supplementation services by pregnant women attending an antenatal clinic at a regional referral hospital in Kenya.  

PubMed

To determine utilization of iron and folic acid supplementation services among pregnant women in Kenya. A cross sectional study was conducted at Nyeri Hospital, a regional referral hospital in central Kenya. Women attending the antenatal clinic were selected through systematic sampling. A semi-structured questionnaire was administered to collect information on utilization of folic acid and iron supplementation services. Women who ingested folic acid or iron supplements for >4 days in a week were considered "highly compliant". The health worker in-charge of the antenatal clinic was interviewed about the frequency of supplement stock-outs during the past year. Haemoglobin concentration was measured directly from one drop of capillary blood and measured using portable HEMOCUE B-Hb photometer. Of the 381 women interviewed, only 23.6 % obtained antenatal care in the first trimester; 69.3 and 51.2 % received folic acid and iron supplements, respectively. However, only half (45-58 %) received any information about supplementation. Most women were initiated on folic acid (80.7 %) or iron (67.7 %) after 12 and 16 weeks of gestation, respectively, well after the recommended time period. However, more than 80 % of those who received folic acid and iron were highly compliant. Stock-outs were common at the facility. Of 361 women tested for Hb level, the prevalence of anaemia (Hb levels < 11 g/dl) was 7.8 %. Health workers need to better explain the importance of supplements to pregnant women. Women who come late to antenatal clinic miss opportunities to start supplementation early in pregnancy. Problems with supply chain management exacerbate the problem. PMID:22907273

Maina-Gathigi, L; Omolo, J; Wanzala, P; Lindan, C; Makokha, A

2013-09-01

180

SYNTHESIS, CHARACTERIZATION, AND IN VITRO ASSAY OF FOLIC ACID CONJUGATES OF 3?-AZIDO-3?-DEOXYTHYMIDINE (AZT): TOWARD TARGETED AZT BASED ANTICANCER THERAPEUTICS  

PubMed Central

Conjugates of three components namely folic acid, poly(ethylene glycol) and 3?-azido-3?-deoxythymidine (AZT) are presented. Folate-PEG units were coupled to AZT to facilitate delivery of the nucleoside into the cell. A convenient separation of the polydisperse PEGylated-folic acid regioisomers produced upon conjugation is described. This is to select for the active ?-regioisomer over the inactive ?-regioisomer. In vitro cytotoxicity assays were conducted against an ovarian cell line (A2780/AD) that overexpresses the folate receptor (FR) and compared to a FR free control cell line. Compared to AZT a ~ 20-fold greater potency against the resistant ovarian line was observed for the conjugates. PMID:18205071

Vortherms, Anthony R.; Doyle, Robert P.; Gao, Dayuan; Debrah, Olivia; Sinko, Patrick J.

2009-01-01

181

[Environment and genetics in the etiology of cleft lip and cleft palate with reference to the role of folic acid].  

PubMed

The combined birth prevalence of cleft palate [CP] and cleft lip with or without cleft palate [CL(P)] in Europe is approximately one in 700 with characteristic regional variations. Orofacial clefting (OC) is therefore now one of the most frequent congenital anomalies, with a higher birth prevalence that Down's Syndrome or Neural Tube defects, but still lower than cardiovascular malformation. Babies with OC require a multidisciplinary medical approach, surgery and rehabilitative treatments over time. This means an important effort in terms of social organization as well as economical costs for the health care system. In Italy, the health care costs for approximately 800 children born with orofacial clefting per year has been estimated at around 150 billion Lire (80 million Euros). The etiology of OC is complex and heterogeneous both for isolated and associated defects; causes linked to environment, genetics and gene-environment interaction are known, although there is still a lot to do, especially in clarifying the role of genetics in producing susceptibility to the environment. Four categories of genes for which there are results suggestive of a genetic susceptibility to OCs are: 1) genes expressed in a particular area of the embryo or in a particular period of the palatine arch development, such as the transforming growth factors alpha and beta (TGF alpha, TGF beta 2, TGF beta 3); 2) genes having biological activities linked to the OC's pathogenesis without direct involvement (e.g. the retinoic acid receptor (RARA), the methylenetetrahydrofolate reductase receptor (MTHFR) and the folic acid receptor (FOLR1); 3) genes or locus identified in experimental animals as the homeotic genes MSX-1 and MSX-2; 4) genes involved in the interaction with the xenobiotics metabolism as those in P-450 cytochrome system. Several environmental factors have been implicated in the OC etiology; among those, the folic acid supplementation during the periconceptional period that was found effective in the prevention of neural tube defects. In fact, folic acid deficiency may be responsible for different malformations through a common mechanism that interferes with the embryonic development, depending on the maternal or embryo genotype. Further investigation is required to study in depth how the genotype would modify the role of environmental factors like folic acid. Well-designed and conducted epidemiological studies seem to be able to give worthwhile information. Studies carried out in Europe on these issues are a few, particularly those on gene-environment interaction. Recent results obtained in molecular biology and the availability of wealth of data can allow to perform ad hoc investigations, being important not only for the basic research but also for their public health implications. For this objective a specific scientific network at the European level has been set by the European Science Foundation (ESF), whose first step will be to establish consistent case ascertainment and data collection across Europe and to develop standardized protocols and methods of analysis. It is hoped that in the longer term such multicentre collaborative research will enable combined analysis and lead to the identification of genetic susceptibility to certain environmental factors, including nutrition. Such studies would inform the current debate about the efficacy of folic acid and other nutritional factors in prevention of disease in the developing embryo. Subsequent public health measures targeted according to risk might reduce the prevalence of disorders such as orofacial clefting. PMID:10748547

Bianchi, F; Calzolari, E; Ciulli, L; Cordier, S; Gualandi, F; Pierini, A; Mossey, P

2000-01-01

182

Apoptosis selectively induced in BEL-7402 cells by folic acid-modified magnetic nanoparticles combined with 100 Hz magnetic field  

PubMed Central

Objective To explore the effect of folic acid-modified magnetic nanoparticles (FA-MNPs) combined with a 100 Hz extremely low-frequency electromagnetic field (ELF-EMF) on the apoptosis of liver cancer BEL-7402 cells. Materials and methods MNPs (20 nm) were prepared by coprecipitation, and then folic acid was coated onto MNPs to prepare FA-MNPs. BEL-7402 cells and HL7702 cells were selected as liver cancer cells and normal liver cells, respectively. The ELF-EMF was generated from a solenoid coil. Cellular uptake of NPs was determined by inductively coupled plasma atomic emission spectroscopy. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to evaluate cell inhibition. Apoptosis was analyzed by flow cytometry. Statistical analyses were performed using two-way analysis of variance. Results FA-MNPs combined with a 100 Hz magnetic field significantly inhibited cell proliferation and induced higher apoptosis compared to either the ELF-EMF alone or FA-MNPs alone. FA-MNPs showed a better apoptosis effect and higher iron uptake in BEL-7402 cells compared to in HL7702 cells. On the basis of the ELF-EMF, higher doses of FA-MNPs brought higher apoptosis and higher iron uptake in either BEL-7402 cells or HL7702 cells. Conclusion These results suggest that FA-MNPs may induce apoptosis in a cellular iron uptake-dependent manner when combined with an ELF-EMF in BEL-7402 cells. PMID:24790442

Wen, Jian; Jiang, Shulian; Chen, Zhiqiang; Zhao, Wei; Yi, Yongxiang; Yang, Ruili; Chen, Baoan

2014-01-01

183

Synthesis of multifunctional Ag@Au@phenol formaldehyde resin particles loaded with folic acids for photothermal therapy.  

PubMed

Multifunctional Ag@Au@ phenol formaldehyde resin (PFR) particles loaded with folic acids (FA) have been designed for killing tumor cells through photothermy conversion under the irradiation of near-infrared (NIR) light. Possessing the virtue of good fluorescence, low toxicity, and good targeting, the nanocomposite consists of an Ag core, an Au layer, a PFR shell, and folic acids on the PFR shell. The Ag@PFR core-shell structure can be prepared with a simple hydrothermal method after preheating. We then filled the PFR shell with a layer of Au by heating and modified the shell with polyelectrolyte to change its surface charge state. To capture tumor cells actively, FA molecules were attached onto the surface of the Ag@Au@PFR particles in the presence of 1-ethyl-3-(3-dimethly aminopropyl) carbodiimide (EDAC) and N-hydroxysuccinimide (NHS). Owing to the excellent property of Au NPs and Ag NPs as photothermal conversion agents, the Ag@Au@ PFR@FA particles can be utilized to kill tumor cells when exposed to NIR light. PMID:22744779

Yang, Ping; Xu, Qi-Zhi; Jin, Sheng-Yu; Lu, Yang; Zhao, Yang; Yu, Shu-Hong

2012-07-23

184

Hif1? down-regulation is associated with transposition of great arteries in mice treated with a retinoic acid antagonist  

PubMed Central

Background Congenital heart defect (CHD) account for 25% of all human congenital abnormalities. However, very few CHD-causing genes have been identified so far. A promising approach for the identification of essential cardiac regulators whose mutations may be linked to human CHD, is the molecular and genetic analysis of heart development. With the use of a triple retinoic acid competitive antagonist (BMS189453) we previously developed a mouse model of congenital heart defects (81%), thymic abnormalities (98%) and neural tube defects (20%). D-TGA (D-transposition of great arteries) was the most prevalent cardiac defect observed (61%). Recently we were able to partially rescue this abnormal phenotype (CHD were reduced to 64.8%, p = 0.05), by oral administration of folic acid (FA). Now we have performed a microarray analysis in our mouse models to discover genes/transcripts potentially implicated in the pathogenesis of this CHD. Results We analysed mouse embryos (8.5 dpc) treated with BMS189453 alone and with BMS189453 plus folic acid (FA) by microarray and qRT-PCR. By selecting a fold change (FC) ? ± 1.5, we detected 447 genes that were differentially expressed in BMS-treated embryos vs. untreated control embryos, while 239 genes were differentially expressed in BMS-treated embryos whose mothers had also received FA supplementation vs. BMS-treated embryos. On the basis of microarray and qRT-PCR results, we further analysed the Hif1? gene. In fact Hif1? is down-regulated in BMS-treated embryos vs. untreated controls (FCmicro = -1.79; FCqRT-PCR = -1.76; p = 0.005) and its expression level is increased in BMS+FA-treated embryos compared to BMS-treated embryos (FCmicro = +1.17; FCqRT-PCR = +1.28: p = 0.005). Immunofluorescence experiments confirmed the under-expression of Hif1? protein in BMS-treated embryos compared to untreated and BMS+FA-treated embryos and, moreover, we demonstrated that at 8.5 dpc, Hif1? is mainly expressed in the embryo heart region. Conclusions We propose that Hif1? down-regulation in response to blocking retinoic acid binding may contribute to the development of cardiac defects in mouse newborns. In line with our hypothesis, when Hif1? expression level is restored (by supplementation of folic acid), a decrement of CHD is found. To the best of our knowledge, this is the first report that links retinoic acid metabolism to Hif1? regulation and the development of D-TGA. PMID:20846364

2010-01-01

185

Carbobenzoxy amino acids: Structural requirements for cholecystokinin receptor antagonist activity  

SciTech Connect

The authors used dispersed acini prepared from guinea pig pancreas to examine 28 carbobenzoxy (CBZ) amino acids for their abilities to function as cholecystokinin receptor antagonists. All amino acid derivatives tested, except for CBZ-alanine, CBZ-glycine, and N alpha-CBZ- lysine, were able to inhibit the stimulation of amylase secretion caused by the C-terminal octapeptide of cholecystokinin. In general, there was a good correlation between the ability of a carbobenzoxy amino acid to inhibit stimulated amylase secretion and the ability of the amino acid derivative to inhibit binding of /sup 125/I-cholecystokinin. The inhibition of cholecystokinin-stimulated amylase secretion was competitive, fully reversible, and specific for those secretagogues that interact with the cholecystokinin receptor. The potencies with which the various carbobenzoxy amino acids inhibited the action of cholecystokinin varied 100-fold and CBZ-cystine was the most potent cholecystokinin receptor antagonist. This variation in potency was primarily but not exclusively a function of the hydrophobicity of the amino acid side chain.

Maton, P.N.; Sutliff, V.E.; Jensen, R.T.; Gardner, J.D.

1985-04-01

186

IADR 2010: Karl Kingsley, Mark Keiserman, Christine Bergman Based upon evidence of human health outcomes correlated with folic acid intake, the US Food and Drug  

E-print Network

health outcomes correlated with folic acid intake, the US Food and Drug Administration adopted requirements for folate fortification of foods that increased mean dietary folate intake and concomitantly cancers. Determining the effects of dietary intake on the progression of oral cancers is an important

Ahmad, Sajjad

187

Supplementation with Micronutrients in Addition to Iron and Folic Acid Does Not Further Improve the Hematologic Status of Pregnant Women in Rural Nepal  

Microsoft Academic Search

Iron deficiency is one of the main causes of anemia during pregnancy, although other micronutrient deficiencies may play a role. We examined the effects of daily antenatal and postnatal supplementation with four combinations of micronutrients on maternal hematologic indicators in a double-masked randomized controlled community trial. Communities, called sectors, were randomly assigned to supplementation with folic acid (400 g),

Parul Christian; Jaibar Shrestha; Steven C. LeClerq; Subarna K. Khatry; Tianan Jiang; Tracey Wagner; Joanne Katz

188

Maternal high folic acid supplement promotes glucose intolerance and insulin resistance in male mouse offspring fed a high-fat diet.  

PubMed

Maternal nutrition may influence metabolic profiles in offspring. We aimed to investigate the effect of maternal folic acid supplement on glucose metabolism in mouse offspring fed a high-fat diet (HFD). Sixty C57BL/6 female mice were randomly assigned into three dietary groups and fed the AIN-93G diet containing 2 (control), 5 (recommended folic acid supplement, RFolS) or 40 (high folic acid supplement, HFolS) mg folic acid/kg of diet. All male offspring were fed HFD for eight weeks. Physiological, biochemical and genetic variables were measured. Before HFD feeding, developmental variables and metabolic profiles were comparable among each offspring group. However, after eight weeks of HFD feeding, the offspring of HFolS dams (Off-HFolS) were more vulnerable to suffer from obesity (p=0.009), glucose intolerance (p<0.001) and insulin resistance (p<0.001), compared with the controls. Off-HFolS had reduced serum adiponectin concentration, accompanied with decreased adiponectin mRNA level but increased global DNA methylation level in white adipose tissue. In conclusion, our results suggest maternal HFolS exacerbates the detrimental effect of HFD on glucose intolerance and insulin resistance in male offspring, implying that HFolS during pregnancy should be adopted cautiously in the general population of pregnant women to avoid potential deleterious effect on the metabolic diseases in their offspring. PMID:24736781

Huang, Yifan; He, Yonghan; Sun, Xiaowei; He, Yujie; Li, Ying; Sun, Changhao

2014-01-01

189

Folate receptor imaging with 125I labeled folic acid with a whole body small animal imaging device built with plastic scintillating optical fibers  

Microsoft Academic Search

A small animal whole body imaging cylindrical device was built with plastic scintillating fibers and position sensitive photomultipliers (Hamamatsu) and digitized using flash ADCs. A co-axial brass mesh collimator (septum thickness 1 mm) was used in combination with an electronic collimation scheme to enhance spatial resolution. Imaging studies with 125I labeled folic acid were performed in mice bearing folate receptor

P. V. Kulkarni; P. P. Antich; A. Constantinescu; J. Prior; T. Nguyen; J. Fernando; J. A. Anderson; S. D. Weitman; B. A. Kamen; R. W. Parkey; R. C. Chaney; E. J. Fenyves

1995-01-01

190

Investigation, using rat embryo culture, of the role of methionine supply in folic acid-mediated prevention of neural tube defects.  

PubMed

Peri-conceptional folic acid supplementation has become a well established way to prevent neural tube defects (NTDs) and such supplementation reduces the prevalence of these defects by approximately 70%. However, the mechanism of the preventive effect of folic acid is not clear. This overview focuses on the biochemical basis of folic acid-preventable NTDs and on the results obtained with whole embryo culture that may help to shed some light on the mechanisms that underlie the preventive effect of folic acid. Culturing gestational day (GD) 9.5 rat embryos on diet-induced folate-deficient rat serum resulted in many malformations, but no NTDs and this embryotoxicity could only partly be overcome by supplementation with N(5)-methyltetrahydrofolate(5-methylTHF). This indicates that there may be an indirect effect of folate deficiency. Besides an important role in purine and thymidine synthesis, folate drives the methylation cycle in which the methyl group of 5-methylTHF is transferred to numerous biomolecules. In this process homocysteine and methionine are constantly interconverted. It was hypothesized that folate deficiency might lead to a toxic accumulation of homocysteine. However, only homocysteine levels 100-fold higher than physiological levels were embryotoxic to cultured GD10 rat embryos. Moreover, 1 and 2 mm l-homocysteine could prevent NTDs in GD9.5 rat embryos when they were cultured in human serum. Addition of 100 mum methionine had the same preventive effect, but addition of 1 mm folinic acid could not prevent the NTDs. When embryos were cultured in cow or canine serum, methionine had a similar preventive effect. These results suggest folic acid mediated prevention of NTDs may be based on an increase of the methionine supply and possibly its supportive action towards the methylation cycle. PMID:20650144

Vanaerts, L A

1995-10-01

191

Effect of folic acid plus glycine supplement on uterine prostaglandin and endometrial granulocyte-macrophage colony-stimulating factor expression during early pregnancy in pigs.  

PubMed

The objective was to determine the effects of folic acid+glycine supplement on uterine metabolism of prostaglandin and mRNA expression of endometrial granulocyte-macrophage colony-stimulating factor (GM-CSF) in nulliparous (NYL) and multiparous Yorkshire-Landrace (YL) sows, and in multiparous Meishan-Landrace sows (ML). In each of these three groups, sows were randomly assigned to two treatments: 15 ppm folic acid+0.6% glycine or no supplement. The dietary supplement was given from the estrus before mating to slaughter on Day 25 of pregnancy. At slaughter, endometrial tissue was collected to determine endometrial expression levels of GM-CSF mRNA, cyclooxygenase-1 (COX1) and -2 (COX2) and to evaluate in vitro endometrial secretion of prostaglandin E2 (PGE2) secretion. Allantoic fluid samples were also collected to determine the concentration of PGE2, prostaglandin F2alpha (PGF2alpha), estradiol-17beta (E2), progesterone (P4), and transforming-growth factor-beta2 (TGF-beta2). The allantoic contents of PGF2alpha, E2 and P4, and endometrial in vitro secretion of PGE2 were not significantly influenced by the folic acid+glycine supplement. The folic acid+glycine supplement tended (P<0.07) to increase allantoic content of PGE2 and TGF-beta2 in all sows and increased (P<0.05) endometrial expression of COX2, especially in NYL sows. The endometrial expression of COX1 was decreased (P<0.05) by folic acid+glycine supplement, especially in multiparous YL sows. The allantoic contents of PGE2 and PGF2alpha were not significantly affected by sow type. However, NYL sows had higher (P<0.05) endometrial in vitro secretion of PGE2 and allantoic content of P4 than multiparous YL and ML sows. The allantoic content of E2 was also higher (P<0.05) in NYL sows than in multiparous ML sows only. The allantoic content of TGF-beta2 was lower (P<0.05) in multiparous ML than in multiparous YL only sows. Finally, in YL and NYL sows, folic acid+glycine supplement decreased (P<0.05) the endometrial expression of GM-CSF but not in ML sows. In summary, folic acid+glycine supplement altered endometrial expression of GM-CSF and uterine metabolism of prostaglandins during the post-attachment period of porcine embryos but some of these effects were manifest only in Meishan and nulliparous sows. PMID:14662146

Guay, Frédéric; Matte, J Jacques; Girard, Christiane L; Palin, Marie-France; Giguère, Alain; Laforest, Jean-Paul

2004-01-15

192

Concentrations of blood folate in Brazilian studies prior to and after fortification of wheat and cornmeal (maize flour) with folic acid: a review  

PubMed Central

Background In July 2004, the Brazilian Ministry of Health through the National Health Surveillance Agency made the fortification of wheat flour and cornmeal (maize flour) with iron and folic acid mandatory, with the intention of reducing the rate of diseases such as neural tube defects. Objective The aim of the study was to investigate the impact of the folic acid fortified wheat flour and cornmeal on serum and red blood cell folate levels and on the reduction of neural tube defects in different Brazilian studies. Methods In order to compare folate concentrations in the Brazilian population prior to and following the implementation of mandatory fortification of wheat and cornmeal, studies that involved blood draws between January 1997 and May 2004 (pre-fortification period), and from June 2004 to the present (post-fortification period) were chosen. The data search included PubMed and Scopus databases as well as the Brazilian Digital Library of Theses and Dissertations. The following keywords were employed for the query: folate, folic acid, fortification, Brazil, healthy population, the elderly, children and pregnant women. Results A total of 47 Brazilian studies were selected; 26 from the pre-fortification period and 22 after the fortification implementation. The studies were classified according to the cohort investigated (pregnant women, children, adolescents, adults and the elderly). After the implementation of flour fortification with folic acid in Brazil, serum folate concentrations increased in healthy populations (57% in children and adolescents and 174% in adults), and the incidence of neural tube defects dropped. Conclusion Folic acid fortification of wheat flour and cornmeal increased the blood folate concentrations and reduced the incidence of neural tube defects. PMID:25031167

Britto, Jessica Carrilho; Cancado, Rodolfo; Guerra-Shinohara, Elvira Maria

2014-01-01

193

Implementing preventive iron-folic acid supplementation among women of reproductive age in some Western Pacific countries: possibilities and challenges.  

PubMed

Lack of effective implementation mechanisms is identified as a major obstacle in the prevention and control of iron-deficiency anemia. This paper discusses experiences gained from implementing iron-folic acid supplementation in the Philippines, Vietnam, and Cambodia. The understanding of contextual elements is proposed as a foundation for planning interventions. Moreover, it is suggested that a social marketing framework should provide a way of thinking about how to influence related behaviors. The application of a social marketing framework applied using a "5 P's" approach: public relations and collaboration, product, price, place, and promotion, is described, as well as enabling factors (possibilities) and inhibiting factors (challenges) of this approach. Although a program to improve iron nutrition among women of reproductive age may not be simple to implement, it is essential to enhancing health, human development, and economic advancement in developing countries. PMID:16466083

Smitasiri, Suttilak; Solon, Florentino S

2005-12-01

194

Folic acid-conjugated silica capped gold nanoclusters for targeted fluorescence/X-ray computed tomography imaging  

PubMed Central

Background Gastric cancer is 2th most common cancer in China, and is still the second most common cause of cancer-related death in the world. Successful development of safe and effective nanoprobes for in vivo gastric cancer targeting imaging is a big challenge. This study is aimed to develop folic acid (FA)-conjugated silica coated gold nanoclusters (AuNCs) for targeted dual-modal fluorescent and X-ray computed tomography imaging (CT) of in vivo gastric cancer cells. Method AuNCs were prepared, silica was coated on the surface of AuNCs, then folic acid was covalently anchored on the surface of AuNCs, resultant FA-conjugated AuNCs@SiO2 nanoprobes were investigated their cytotoxicity by MTT method, and their targeted ability to FR(+) MGC803 cells and FR(?) GES-1 cells. Nude mice model loaded with MGC803 cells were prepared, prepared nanoprobes were injected into nude mice via tail vein, and then were imaged by fluorescent and X-ray computed tomography (CT) imaging. Results FA-conjugated AuNCs@SiO2 nanoprobes exhibited good biocompatibility, and could target actively the FR(+) MGC-803 cells and in vivo gastric cancer tissues with 5 mm in diameter in nude mice models, exhibited excellent red emitting fluorescence imaging and CT imaging. Conclusion The high-performance FA-conjugated AuNCs@SiO2 nanoprobes can target in vivo gastric cancer cells, can be used for fluorescent and CT dual-mode imaging, and may own great potential in applications such as targeted dual-mode imaging of in vivo early gastric cancer and other tumors with FR positive expression in near future. PMID:23718865

2013-01-01

195

[Cytogenetic effects in peripheral blood lymphocytes in the offspring of Chernobyl nuclear power plant accident liquidators under the influence of mitomycin C in vitro and folic acid in vivo].  

PubMed

The data on cytogenetic examination concerning the offspring of the Chernobyl accident liquidators (cleanup personnel) have been obtained. It has been established that spontaneous chromosomal aberrations level before folic acid administration was 1,8 times higher than that value after its employment (4,45 to 2,42 %, p < 0,01). In lymphocyte cultures treated with mitomycin C accompanied by folic acid it was 4,5 times higher before their administration (23,95 to 5,36 %, p < 0,001). The data obtained confirm a possibility of stabilization of genetic apparatus in offspring of the Chernobyl disaster liquidators after folic acid administration. PMID:23427614

Kovaleva, V I; Bagatskaia, N V

2013-01-01

196

Multiple point action mechanism of valproic acid-teratogenicity alleviated by folic acid, vitamin C, and N-acetylcysteine in chicken embryo model.  

PubMed

The teratogenicity of antiepilepsy drug valproic acid (VPA) mostly is found in genetic and somatic levels, causing teratogenesis involving neurotubular defects (NTDs), anencephaly, lumbosacral meningomyelocele, and leg dysfunction due to spina bifida aperta. A diversity of nutraceutics have been tried to alleviate the risk of VPA-teratogenicity. The effect was varying. In order to promote the preventive prescription, to find out its action mechanism can be rather crucial. We used chicken embryo model to try the effect of folic acid (FA), ascorbic acid (AA), and N-acetyl cysteine (NAC). VPA at 30mM showed the higher malformation rate (66.7%) with the least mortality (22.2%). Pathological findings indicated that the cervical muscle was more susceptible to VPA injury than the ankle muscle. VPA downregulated levels of superoxide dismutase (SOD), glutathione (GSH), histone deacetylase (HDAC) and folate, and upregulated H(2)O(2) and homocysteine. FA, AA, and NAC significantly upregulated SOD, but only AA alone activated GSH. AA and NAC downregulated H(2)O(2), while FA was totally ineffective. All three nutraceutics comparably rescued HDAC with simultaneously suppressed homocysteine accumulation and folate re-elevation, although less effectively by NAC. Based on these data, we conclude VPA possesses "Multiple Point Action Mechanism". In addition to affecting the cited transcription and translation levels, we hypothesize that VPA competitively antagonize the glutamic acid to couple with pteroic acid in biosynthesis of dihydrofolic acid (DHFA). H(2)O(2) directly destroyed the NADPH reducing system at dihydrofolate reductase (DHFR) and methylene tetrahydrofolate reductase (MTHFR) levels, while completely restored by AA, an implication in preservation of intact apoenzymes. In addition, the GSH-GSSG system is sandwiched between the reducing systems NADPH/NADP and DHA-AA, its net balance is highly dependent on in situ in vivo Redox state, hence folic acid transformation is varying. To rescue the VPA-induced teratogenicity, simultaneous multiple prescriptions are suggested. PMID:22051200

Hsieh, Chiu-Lan; Wang, Hui-Er; Tsai, Wan-Jane; Peng, Chiung-Chi; Peng, Robert Y

2012-01-27

197

A Novel Preparation Method for Camptothecin (CPT) Loaded Folic Acid Conjugated Dextran Tumor-Targeted Nanoparticles  

PubMed Central

In this study, folic-dextran-camptothecin (Fa-DEX-CPT) tumor-targeted nanoparticles were produced with a supercritical antisolvent (SAS) technique by using dimethyl sulfoxide (DMSO) as a solvent and carbon dioxide as an antisolvent. A factorial design was used to reveal the effect of various process parameters on the mean particle size (MPS) and morphology of the particles formed. Under the optimum operation conditions, Fa-DEX-CPT nanoparticles with a MPS of 182.21 nm were obtained. Drug encapsulation efficiency and loading efficiency were 62.13% and 36.12%, respectively. It was found that the concentrations of the camptothecin (CPT) and dextran solution had a major influence upon morphology and shape of the final product. In addition, the samples were characterized by Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) with the purpose of developing a suitable targeted drug delivery system for cancer chemotherapy. PMID:21845075

Zu, Yuangang; Wang, Dan; Zhao, Xiuhua; Jiang, Ru; Zhang, Qi; Zhao, Dongmei; Li, Yong; Zu, Baishi; Sun, Zhiqiang

2011-01-01

198

Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study123  

PubMed Central

Background: Periconceptional folate is essential for proper neurodevelopment. Objective: Maternal folic acid intake was examined in relation to the risk of autism spectrum disorder (ASD) and developmental delay (DD). Design: Families enrolled in the CHARGE (CHildhood Autism Risks from Genetics and Environment) Study from 2003 to 2009 were included if their child had a diagnosis of ASD (n = 429), DD (n = 130), or typical development (TD; n = 278) confirmed at the University of California Davis Medical Investigation of Neurodevelopmental Disorders Institute by using standardized clinical assessments. Average daily folic acid was quantified for each mother on the basis of dose, brands, and intake frequency of vitamins, supplements, and breakfast cereals reported through structured telephone interviews. Results: Mean (±SEM) folic acid intake was significantly greater for mothers of TD children than for mothers of children with ASD in the first month of pregnancy (P1; 779.0 ± 36.1 and 655.0 ± 28.7 ?g, respectively; P < 0.01). A mean daily folic acid intake of ?600 ?g (compared with <600 ?g) during P1 was associated with reduced ASD risk (adjusted OR: 0.62; 95% CI: 0.42, 0.92; P = 0.02), and risk estimates decreased with increased folic acid (P-trend = 0.001). The association between folic acid and reduced ASD risk was strongest for mothers and children with MTHFR 677 C>T variant genotypes. A trend toward an association between lower maternal folic acid intake during the 3 mo before pregnancy and DD was observed, but not after adjustment for confounders. Conclusions: Periconceptional folic acid may reduce ASD risk in those with inefficient folate metabolism. The replication of these findings and investigations of mechanisms involved are warranted. PMID:22648721

Schmidt, Rebecca J; Tancredi, Daniel J; Ozonoff, Sally; Hansen, Robin L; Hartiala, Jaana; Allayee, Hooman; Schmidt, Linda C; Tassone, Flora; Hertz-Picciotto, Irva

2012-01-01

199

The use of imidazolium ionic liquid/copper complex as novel and green catalyst for chemiluminescent detection of folic acid by Mn-doped ZnS nanocrystals.  

PubMed

A novel chemiluminescence (CL) method using water-soluble Mn-doped ZnS quantum dots (QDs) as CL emitter is proposed for the chemiluminometric determination of folic acid in pharmaceutical formulation. Water-soluble Mn-doped ZnS QDs were synthesized by using L-cysteine as stabilizer in aqueous solutions. The nanoparticles were structurally and optically characterized by X-ray powder diffraction (XRD), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), UV-Vis absorption spectroscopy and photoluminescence (PL) emission spectroscopy. The CL of ZnS QDs induced by directly chemical oxidation and its ionic liquid-sensitized effect in aqueous solution were then investigated. It was found that oxidants, especially hydrogen peroxide, could directly oxidize ZnS QDs to produce weak CL emission in basic conditions. In the presence of 1,3-dipropylimidazolium bromide/copper a drastic light emission enhancement is observed, related to a strong interaction between Cu(2+) and the imidazolium ring. Therefore, a new CL analysis system was developed for the determination of folic acid. Under the optimum conditions, there is a good linear relationship between the relative CL intensity and the concentration of folic acid in the range of 1×10(-9)-1×10(-)(6) M of folic acid with a correlation coefficient (R(2)) of 0.9991. The limit of detection of this system was found to be 1×10(-)(10) M. This method is not only simple, sensitive and low cost, but also reliable for practical applications. PMID:24322762

Azizi, Seyed Naser; Shakeri, Parmis; Chaichi, Mohammad Javad; Bekhradnia, Ahmadreza; Taghavi, Mehdi; Ghaemy, Mousa

2014-03-25

200

Maternal exposure to fluoxetine during gestation and lactation affects the DNA methylation programming of rat's offspring: modulation by folic acid supplementation.  

PubMed

Fluoxetine is an antidepressant that has been largely used for treatment of depression in pregnancy. In the present study we evaluated the effects of the exposure to fluoxetine during gestation and lactation on DNA methylation of rat brain regions. Female Wistar rats were treated with 5mg/kg of fluoxetine during pregnancy and lactation. In order to assess the effects of fluoxetine in the context of maternal folic acid supplementation we performed an additional combined treatment composed by folic acid (8 mg/kg/day) and fluoxetine (5 mg/kg/day). On the postnatal day 22, male rats were euthanized and hippocampus, cortex, hypothalamus, and periaqueductal gray area were removed. Global DNA methylation was quantified using a high-throughput ELISA-based method. Neurofunctional changes were addressed using validated behavioral tests: hot plate, elevated plus maze and open field. A decrease in the global DNA methylation profile of hippocampus was associated to the exposure to fluoxetine, whereas an increase in methylation was observed in cortex. The combined treatment induced an increase in the methylation of hippocampus indicating the potential of folic acid to modulate this epigenetic alteration. Increase in the latency to the thermal nociceptive response was observed in animals exposed to fluoxetine whereas this effect was abolished in animals from the combined treatment. In summary we demonstrated that exposure to fluoxetine during gestation and lactation affect the DNA methylation of brain and the nociceptive response of rats. Furthermore our data reveal the potential of folic acid to modulate epigenetic and functional changes induced by early exposure to fluoxetine. PMID:24583191

Toffoli, L V; Rodrigues, G M; Oliveira, J F; Silva, A S; Moreira, E G; Pelosi, G G; Gomes, M V

2014-05-15

201

The use of imidazolium ionic liquid/copper complex as novel and green catalyst for chemiluminescent detection of folic acid by Mn-doped ZnS nanocrystals  

NASA Astrophysics Data System (ADS)

A novel chemiluminescence (CL) method using water-soluble Mn-doped ZnS quantum dots (QDs) as CL emitter is proposed for the chemiluminometric determination of folic acid in pharmaceutical formulation. Water-soluble Mn-doped ZnS QDs were synthesized by using L-cysteine as stabilizer in aqueous solutions. The nanoparticles were structurally and optically characterized by X-ray powder diffraction (XRD), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), UV-Vis absorption spectroscopy and photoluminescence (PL) emission spectroscopy. The CL of ZnS QDs induced by directly chemical oxidation and its ionic liquid-sensitized effect in aqueous solution were then investigated. It was found that oxidants, especially hydrogen peroxide, could directly oxidize ZnS QDs to produce weak CL emission in basic conditions. In the presence of 1,3-dipropylimidazolium bromide/copper a drastic light emission enhancement is observed, related to a strong interaction between Cu2+ and the imidazolium ring. Therefore, a new CL analysis system was developed for the determination of folic acid. Under the optimum conditions, there is a good linear relationship between the relative CL intensity and the concentration of folic acid in the range of 1 × 10-9-1 × 10-6 M of folic acid with a correlation coefficient (R2) of 0.9991. The limit of detection of this system was found to be 1 × 10-10 M. This method is not only simple, sensitive and low cost, but also reliable for practical applications.

Azizi, Seyed Naser; Shakeri, Parmis; Chaichi, Mohammad Javad; Bekhradnia, Ahmadreza; Taghavi, Mehdi; Ghaemy, Mousa

2014-03-01

202

Reduction in mortality and teratogenicity following simultaneous administration of folic acid and vitamin E with antiepileptic, antihypertensive and anti-allergic drugs  

PubMed Central

Aim: The present study was designed to evaluate the teratogenic effects on breeding pattern in mice following administration of lamotrigine (LT) and levetiracetam (LV) and its combination with anti-hypertensive and anti-allergic drugs. Moreover, possibility of decrease in teratogenic effect was also evaluated upon simultaneous administration of these combinations with folic acid or vitamin E. Materials and Methods: The study was carried out on mature female mice housed in polycarbonate breeding cages. Drugs were administered continuously till the birth of neonates and pups were examined for any teratogenic potential of drugs. Results: The results of the study reveals that teratogenic effects of lamotrigine, methyldopa and loratadine (LTMLO) combination were seems to be reduced upon simultaneous administration with folic acid, while addition of vitamin E was found to be more effective in reducing the mortality rate of levetiracetam, methyldopa and loratadine combination. Conclusion: Teratogenic effects of LTMLO combination were better prevented by folic acid. However, further studies on large number of animals and humans are required before reaching to definite conclusion. PMID:25035638

Wahid, Shahana; Khan, Rafeeq Alam; Feroz, Zeeshan

2014-01-01

203

The association of idiopathic recurrent early pregnancy loss with polymorphisms in folic acid metabolism-related genes.  

PubMed

The aim of this study was to investigate the association between polymorphisms in folic acid metabolism-related genes and idiopathic recurrent early pregnancy loss (REPL). A prospective case-control study was performed on a cohort of 82 REPL patients and 166 healthy controls. Genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C was assessed by applying polymerase chain reaction for amplification followed by DNA sequencing, for methionine synthase reductase A66G, solute carrier family 19, member 1 (SLC19A1) G80A and C696T, and genotyping was done by utilizing the Sequenom MassARRAY system. The results revealed a significant association between MTHFR A1298C polymorphism and idiopathic REPL. Haplotype analysis indicated that the MTHFR 677C-MTHFR 1298C allele combination was associated with REPL (P < 0.001). The MTHFR 677C-MTHFR 1298A and SLC19A1 80G-SLC19A1 696C allele combinations had lower frequencies in patients with REPL, but with P > 0.05 (P = 0.093 and P = 0.084, respectively). PMID:24728915

Cao, Yunlei; Zhang, Zhaofeng; Zheng, Yanmin; Yuan, Wei; Wang, Jian; Liang, Hong; Chen, Jianping; Du, Jing; Shen, Yueping

2014-05-01

204

Effects of folic acid deficiency and MTHFRC677T polymorphisms on cytotoxicity in human peripheral blood lymphocytes  

SciTech Connect

Apoptosis (APO) and necrosis (NEC) are two different types of cell death occurring in response to cellular stress factors. Cells with DNA damage may undergo APO or NEC. Folate is an essential micronutrient associated with DNA synthesis, repair and methylation. Methylenetetrahydrofolate reductase (MTHFR) regulates intracellular folate metabolism. Folate deficiency and MTHFR C677T polymorphisms have been shown to be related to DNA damage. To verify the cytotoxic effects of folate deficiency on cells with different MTHFR C677T genotypes, 15 human peripheral lymphocyte cases with different MTHFR C677T genotypes were cultured in folic acid (FA)-deficient and -sufficient media for 9 days. Cytotoxicity was quantified using the frequencies of APO and NEC as endpoints, the nuclear division index (NDI), and the number of viable cells (NVC). These results showed that FA is an important factor in reducing cytotoxicity and increasing cell proliferation. Lymphocytes with the TT genotype proliferated easily under stress and exhibited different responses to FA deficiency than lymphocytes with the CC and CT genotypes. A TT individual may accumulate more cytotoxicity under cytotoxic stress, suggesting that the effects of FA deficiency on cytotoxicity are greater than the effects in individuals with the other MTHFR C677T variants.

Wu Xiayu; Liang Ziqing [School of Life Sciences, Yunnan Normal University, Kunming Yunnan 650092 (China); Zou Tianning [Thirdary Affiliated hospital of Kunming Medical College, Kunming Yunnan 650101 (China); Wang Xu [School of Life Sciences, Yunnan Normal University, Kunming Yunnan 650092 (China)], E-mail: wangxu@fudan.edu.cn

2009-02-13

205

Methionine, folic acid and vitamin B12 in growing-finishing pigs: impact on growth performance and meat quality.  

PubMed

Growth performance, metabolic variables, and meat quality were measured in 78 growing-finishing pigs using supplements of 0 (C), or 0.2% of DL-methionine (M), and three combinations of folic acid [mg/kg] and cyanocobalamin [microg/kg], respectively 0 and 0 (V0), 10 and 25 (V1), and 10 and 150 (V2) in a 2 x 3 factorial arrangement. Feed conversion was lower (p = 0.05) in M than in C pigs during the growing period (0-4 weeks). Both V1 and V2 treatments increased plasma vitamin B12 (p < 0.01) and decreased plasma homocysteine (p < 0.01). Plasma 5-methyl-tetrahydrofolates were the lowest, highest and intermediate in V0, V1 and V2 pigs (p < 0.04), respectively. In V2 meat, folates were 32% higher, vitamin B12, 55% higher and homocysteine, 28% lower than in V0 (p < 0.01). Oxidative stability of the fresh meat was similar among treatments during a storage period of 42 days. Therefore, methionine supplements improved growth performance during the growing period. Vitamin supplements interacted with the methionine cycle pathway, increased vitamin content of pork meat but did not improve oxidative stability of the fresh meat during storage. PMID:18610535

Giguére, Alain; Girard, Christiane L; Matte, J Jacques

2008-06-01

206

Explaining the effects of anticipated regret messages on young women's intention to consume folic acid: a moderated-mediation model.  

PubMed

This study tests a moderated-mediation model to explain the joint effects of consideration of future consequences and exposure to health messages containing an anticipated regret component on behavioral intention to consume folic acid. In an online survey-experiment conducted in March 2011, 245 women 18-35 years of age were randomized to 1 of 3 conditions (exposure to attitude-only message/exposure to attitude-plus-anticipated-regret message/no message exposure) in a between-participants design. Results showed a positive joint effect of consideration of future consequences and exposure to an attitude-plus-anticipated-regret message on anticipated regret (B = 0.89, SE = 0.41, p < .05). Among women high in consideration of future consequences, exposure to an attitude-plus-anticipated-regret message increased anticipated regret. Likewise, another positive joint effect of consideration of future consequences and anticipated regret on behavioral intention was observed (B = 0.28, SE = 0.12, p < .05). Anticipated regret was positively related to intention among women high in consideration of future consequences. Implications are discussed. PMID:24083394

Martinez, Lourdes S

2014-01-01

207

Folic acid functionalized silver nanoparticles with sensitivity and selectivity colorimetric and fluorescent detection for Hg2+ and efficient catalysis.  

PubMed

In this research, folic acid functionalized silver nanoparticles (FA-AgNPs) were selected as a colorimetric and a 'turn on' fluorescent sensor for detecting Hg(2+). After being added into Hg(2+), AgNPs can emit stable fluorescence at 440 nm when the excitation wavelength is selected at 275 nm. The absorbance and fluorescence of the FA-AgNPs could reflect the concentration of the Hg(2+) ions. Thus, we developed a simple, sensitive analytical method to detect Hg(2+) based on the colorimetric and fluorescence enhancement of FA-AgNPs. The sensor exhibits two linear response ranges between absorbance and fluorescence intensity with Hg(2+) concentration, respectively. Meanwhile, a detection limit of 1 nM is estimated based on the linear relationship between responses with a concentration of Hg(2+). The high specificity of Hg(2+) with FA-AgNPs interactions provided the excellent selectivity towards detecting Hg(2+) over other metal ions (Pb(2+), Mg(2+), Zn(2+), Ni(2+), Cu(2+), Co(2+), Ca(2+), Mn(2+), Fe(2+), Cd(2+), Ba(2+), Cr(6+) and Cr(3+)). This will provide a simple, effective and multifunctional colorimetric and fluorescent sensor for on-site and real-time Hg(2+) ion detection. The proposed method can be applied to the analysis of trace Hg(2+) in lake water. Additionally, the FA-AgNPs can be used as efficient catalyst for the reduction of 4-nitrophenol and potassium hexacyanoferrate (III). PMID:25116278

Su, Dongyue; Yang, Xin; Xia, Qingdong; Zhang, Qi; Chai, Fang; Wang, Chungang; Qu, Fengyu

2014-09-01

208

Disc Assay Method for Determination of Folic Acid Content of Milk, Cheese, and Other Foods1  

Microsoft Academic Search

A rapid disc assay method has been standardized for determination of folie acid content of several dairy products. The method involves measurement of the zone of growth stimulation of Strepto- coccus (aecalis around a disc containing £olic acid extract on ~ deficient agar me- dium. The diameter of the zone of growth bears a logarithmic relationship to the concentration of

J. R. Vakil; K. M. Shahani

1969-01-01

209

Folic acid-mediated inhibition of serum-induced activation of EGFR promoter in colon cancer cells.  

PubMed

Although accumulating evidence suggests a chemopreventive role for folic acid (FA) in colorectal carcinogenesis, the underlying mechanisms are largely unknown. Previously, we reported that supplemental FA inhibits the expression and activation of epidermal growth factor receptor (EGFR) in colon cancer cell lines. To determine the mechanism(s) by which FA affects EGFR function, we have examined whether and to what extent supplemental FA or its metabolites 5-methyltetrahydrofolate (MTF), dihydrofolate (DF), and tetrahydrofolate (TF) will modulate basal and serum-induced activation of the EGFR promoter in the HCT-116 colon cancer cell line. HCT-116 cells were preincubated with or without (control) FA or one of its metabolites (10 microg/ml) for 48 h, transfected with the EGFR promoter luciferase reporter construct, and incubated for 48 h with FA, DF, TF, or 5-MTF in the absence or presence of 10% FBS. Supplemental FA as well as its metabolites markedly inhibited EGFR promoter activity and its methylation status. Exposure of the cells to 10% FBS caused a marked stimulation of EGFR promoter activity and its expression, both of which were greatly abrogated by supplemental FA and 5-MTF. In contrast, serum-induced activation of c-fos promoter activity was unaffected by 5-MTF. The 5-MTF-induced inhibition of serum-mediated stimulation of EGFR promoter activity and EGFR expression was reversed when methylation was inhibited by 5-aza-2'-deoxycytidine. Our data suggest that FA and its metabolite 5-MTF inhibit EGFR promoter activity in colon cancer cells by enhancing methylation. This could partly be responsible for FA-mediated inhibition of growth-related processes in colorectal neoplasia. PMID:15075253

Nagothu, Kiran K; Rishi, Arun K; Jaszewski, Richard; Kucuk, Omer; Majumdar, Adhip P N

2004-09-01

210

Carboxymethyl-?-cyclodextrin conjugated nanoparticles facilitate therapy for folate receptor-positive tumor with the mediation of folic acid.  

PubMed

Currently, clinical operation treatments, chemotherapy and radiotherapy just could eliminate local tumor cells. However, chemotherapy and radiotherapy also injury normal cells and lead to serious side effects and toxicities. So, it is necessary to find an effective target cancer carrier that delivers the anticancer agents into tumor cells and reduces normal cells' injury. Folic acid (FA) is a classical targeting agent mediates internalization of chemical drugs into tumor cells which over-express folate receptor (FR) on their surface. We herein report that based on host-guest interaction, NPs decorated by novel folate enhance antitumor drug delivery. BSA-NPs were prepared by desolvation method and carboxymethyl-?-cyclodextrin (CM-?-CD) was conjugated to the surface of NPs by carbodiimide coupling to hold FA. From in vitro cytotoxicity assay, cell apoptosis study, intracellular ATP level assay and western blot, we can see that FA-CM-?-CD-BSA NPs as good monodispersity, negative charge, and homogenous particle size have a high encapsulation efficiency. The results showed that MTT and cell apoptosis demonstrated that FA-decorated NPs exhibit stronger inhibition rate and induce obvious apoptosis in FR positive Hela cells as compared to free drug and FA undecorated NPs. Moreover, 5-fluorouracil (5-Fu) loaded FA-CM-?-CD-BSA NPs down-regulate ATP levels and increase the expression of caspase-3. Taken together, FA-CM-?-CD-BSA NPs enhance FR receptor-mediated endocytosis and lead to more intracellular uptake of drug, inducing the higher apoptosis ratio of cells than free 5-Fu. PMID:25149123

Su, Chang; Li, Hongdan; Shi, Yijie; Wang, Guan; Liu, Liwei; Zhao, Liang; Su, Rongjian

2014-10-20

211

Consumption of folic acid-fortified bread improves folate status in women of reproductive age in Chile.  

PubMed

Since January 2000 the Chilean Ministry of Health has required the fortification of wheat flour with folic acid (FA) at a concentration of 2.2 mg FA/kg in order to reduce the risk of neural tube defects (NTD) in newborns. This policy was expected to result in a mean additional intake of approximately 400 microg FA/d. We assessed the effectiveness of the FA flour fortification program on bread folate content and on blood folate concentration in women of childbearing age in Santiago, Chile. The prefortification folate status of 751 healthy women of reproductive age was assessed. The folate content of 100 bread samples bought at retail bakeries was measured, average wheat flour consumption was estimated and postfortification FA dietary intake was calculated. The effect of flour fortification on blood folate concentration in this group of women (n = 605) was evaluated in a follow-up study. Blood folate concentrations of the 605 women in the follow-up group increased (P < 0.0001) following fortification. Before fortification the mean serum and red blood cell folate concentrations were 9.7 +/- 4.3 and 290 +/- 102 nmol/L, respectively, compared with 37.2 +/- 9.5 and 707 +/- 179 nmol/L postfortification, respectively. The mean FA content of bread was 2020 +/- 940 micro g/kg. The median FA intake of the group evaluated postfortification was 427 microg/d (95% CI 409-445) based on an estimated intake of 219 g/d (95% CI 201-229) of wheat flour, mainly as bread. Fortification of wheat flour substantially improved folate status in a population of women of reproductive age in Chile. The effect of the FA fortification program on the occurrence of NTD is currently being assessed. PMID:14519804

Hertrampf, Eva; Cortés, Fanny; Erickson, J David; Cayazzo, Marisol; Freire, Wilma; Bailey, Lynn B; Howson, Christopher; Kauwell, Gail P A; Pfeiffer, Christine

2003-10-01

212

Functional assessment of zinc nutriture using changes in plasma zinc after exercise in men supplemented with folic acid  

SciTech Connect

Recently, the authors proposed that changes in plasma zinc (Zn) and copper (Cu) content after maximal exercise could be a functional test of human trace element nutriture. To test this hypothesis, they studied the effect of folic acid (FA) supplements, previously shown to affect zinc absorption on the exercise-induced changes in plasma Zn and Cu in 7 men aged 28.6 +/- 1.2 yr (mean +/- SEM). The men were fed a constant diet with intakes of Cu (1.01 +/- 0.06 mg/d), Zn (12.7 +/- 0.3 mg/d) and FA (200 mg/d) for two 4 wk periods. This basal diet was supplemented with 400 or 800 mg/d FA and it was fed for 4 wk periods alternating with the unsupplemented diet. Pre and post-exercise hematocrit (Hct), hemoglobin (Hb), and plasma Zn and Cu were not affected by FA supplements. To correct for hemoconcentration during exercise, the van Beaumont quotient was calculated from pre and post-exercise Hct, Hb, and plasma Zn and Cu. When the basal diet was fed, the quotient for Zn was 3.4 +/- 1.4 and 2.3 +/- 1.4%, and it declined (p < 0.05) to -5.93 +/- 1.9% and -7.4 +/- 1.8% with 400 and 800 mg/d supplementation, resp. FA supplementation had no effect on the quotient for plasma Cu. These data suggest that Zn mobilization from stores during exercise is impaired with high intakes of FA.

Lukaski, H.C.; Bolonchuk, W.W.; Milne, D.B.

1986-03-05

213

Control of prostate cancer associated with withdrawal of a supplement containing folic acid, L-methyltetrahydrofolate and vitamin B12: a case report  

PubMed Central

Introduction This is the first report of possible direct stimulation of hormone-resistant prostate cancer or interference of docetaxel cytotoxicity of prostate cancer in a patient with biochemical relapse of prostatic-specific antigen. This observation is of clinical and metabolic importance, especially at a time when more than 80 countries have fortified food supplies with folic acid and some contemplate further fortification with vitamin B12. Case presentation Our patient is a 71-year-old Caucasian man who had been diagnosed in 1997 with prostate cancer, stage T1c, and Gleason score 3+4 = 7. His primary treatment included intermittent androgen deprivation therapy including leuprolide + bicalutamide + deutasteride, ketoconazole + hydrocortisone, nilandrone and flutamide to resistance defined as biochemical relapse of PSA. While undergoing docetaxel therapy to treat a continually increasing prostate-specific antigen level, withdrawal of 10 daily doses of a supplement containing 500 ?g of vitamin B12 as cyanocobalamin, as well as 400 ?g of folic acid as pteroylglutamic acid and 400 ?g of L-5-methyltetrahydrofolate for a combined total of 800 ?g of mixed folates, was associated with a return to a normal serum prostatic-specific antigen level. Conclusion This case report illustrates the importance of the effects of supplements containing large amounts of folic acid, L-5-methyltetrahydrofolate, and cyanocobalamin on the metabolism of prostate cancer cells directly and/or B vitamin interference with docetaxel efficacy. Physicians caring for patients with prostate cancer undergoing watchful waiting, hormone therapy, and/or chemotherapy should consider the possible acceleration of tumor growth and/or metastasis and the development of drug resistance associated with supplement ingestion. We describe several pathways of metabolic and epigenetic interactions that could affect the observed changes in serum levels of prostate-specific antigen. PMID:21867542

2011-01-01

214

Phosphinic acid analogues of GABA are antagonists at the GABAB receptor in the rat anococcygeus.  

PubMed Central

CGP 35348 (3-aminopropyl(diethoxymethyl)phosphinic acid) and 3-aminopropyl(n-hexyl)phosphinic acid (3-APHPA) were tested in the rat anococcygeus muscle against CGP 27492 (3-aminopropylphosphinic acid), a selective GABAB agonist, for their antagonist activity. Their antagonist potency was compared with that of 2-hydroxysaclofen. The pA2 values for CGP 35348, 3-APHPA and 2-hydroxysaclofen were 5.38, 4.86, 4.45 respectively in the rat anococcygeus muscle. These results confirm the previous reports of GABAB antagonist activity for these compounds and show a marginal improvement in potency over 2-hydroxysaclofen. PMID:1646062

Hills, J. M.; Sellers, A. J.; Mistry, J.; Broekman, M.; Howson, W.

1991-01-01

215

Metabolic interrelationships between folic acid, vitamin B12 and the citrovorum factor  

E-print Network

microorganisms and animals, including man, has become well established in the past few years. These findings have been summarized in several recent reviews (Pfiffner and Hogan, ? 46 ; Stokstad and Hutchings, f47; Day and Totter, f47 ; Welch, !47 ; Jukes... hand studies by Nichol and Welch ( f50) indicated an increased CP synthesis upon incubation of rat liver slices with PGA and ascorbic acid . In Chapter 3 evidence is pre? sented which offers an explanation for the above discrepancy and briefly...

Doctor, Vasant Manilal

2013-10-04

216

Structural elucidation of specific noncovalent association of folic acid with native cyclodextrins using an ion mobility mass spectrometry and theoretical approach.  

PubMed

The combination of ion mobility mass spectrometry studies and theoretical calculations including docking studies permitted a detailed structural description of noncovalent complexes of folic acid (FA) and native cyclodextrins (?-CD, ?-CD, and ?-CD). The mode of noncovalent association depended on the cavity size of the cyclodextrin. The structure of FA/?-CD represented the exclusion complex in which the aminobenzoic moiety and the aromatic pteridine ring of folic acid remain outside the cyclodextrin cavity, while the glutamate residue is anchored in the interior of the ?-cyclodextrin. A rotaxane-type structure was proposed for the FA/?-CD complex with the aminobenzoic part of FA being trapped in the central cavity of ?-CD. The glutamate residue and the aromatic pteridine ring interact with the primary and secondary rim hydroxyl residues, respectively, enhancing complex stability. Two possible structures of FA/?-CD were suggested, the first one being analogous to the FA/?-CD complex and the second one being more stable-in which the aromatic pteridine ring penetrates into the CD cavity while the glutamate residue with the aminobenzoic part of FA is exposed to the cone exterior of CD at its wider edge. Further insight into the association behavior of the folic acid toward cyclodextrins evaluated by thermodynamic calculations indicates that the process is highly exothermic. The complex stability increased in the order FA/?-CD < FA/?-CD < FA/?-CD. This order is consistent with the previously determined relative gas-phase stability established based on the dissociation efficiency curves of the FA/CD complexes. PMID:24712714

Zimnicka, Magdalena; Tro?, Anna; Ceborska, Magdalena; Jakubczak, Micha?; Koli?ski, Micha?; Danikiewicz, Witold

2014-05-01

217

Long-Term Weekly Iron-Folic Acid and De-Worming Is Associated with Stabilised Haemoglobin and Increasing Iron Stores in Non-Pregnant Women in Vietnam  

PubMed Central

Background The prevalence of anaemia and iron deficiency in women remains high worldwide. WHO recommends weekly iron-folic acid supplementation where anaemia rates in non-pregnant women of reproductive age are higher than 20%. In 2006, a demonstration project consisting of weekly iron-folic acid supplementation and regular de-worming was set up in two districts in a northern province in Vietnam where anaemia and hookworm rates were 38% and 76% respectively. In 2008 the project was expanded to all districts in the province, targeting some 250,000 women. The objectives of this study were to: 1) examine changes in haemoglobin, iron stores and soil transmitted helminth infection prevalence over three years and 2) assess women's access to and compliance with the intervention. Methods and Findings The study was a semi-cross-sectional, semi-longitudinal panel design with a baseline survey, three impact surveys at three-, twelve- and thirty months after commencement of the intervention, and three compliance surveys after ten weeks, eighteen and thirty six months. Results After thirty months, mean haemoglobin stabilised at 130.3 g/L, an increase of 8.2 g/L from baseline, and mean serum ferritin rose from 23.9 µg/L to 52 µg/L. Hookworm prevalence fell from 76% to 22% over the same period. After thirty six months, 81% of the target population were receiving supplements and 87% were taking 75% or more of the supplements they received. Conclusions Weekly iron-folic acid supplementation and regular de-worming was effective in significantly and sustainably reducing the prevalence of anaemia and soil transmitted helminth infections and high compliance rates were maintained over three years. PMID:21209902

Casey, Gerard J.; Jolley, Damien; Phuc, Tran Q.; Tinh, Ta T.; Tho, Dang H.; Montresor, Antonio; Biggs, Beverley-Ann

2010-01-01

218

Size control in the synthesis of 1-6 nm gold nanoparticles using folic acid-chitosan conjugate as a stabilizer  

NASA Astrophysics Data System (ADS)

We report a simple and practical method for the preparation of folic acid (FA)-chitosan functionalized gold nanoparticles (AuNPs) with a very small size (1-6 nm). Sodium borohydride was used as a reducing agent. The size of the AuNPs was controlled by adjusting the mass fraction of FA-chitosan conjugate to Au. The AuNPs were characterized using UV-vis spectroscopy and transmission electron microscopy (TEM). The results indicated that the size distribution of AuNPs decreased ranging from 6 nm to 1 nm with increasing the fraction of FA-chitosan conjugate in the reaction systems.

Liu, Lili; Zhang, Xianwen; Chaudhuri, Jharna

2014-09-01

219

A pH-sensitive gene delivery system based on folic acid-PEG-chitosan - PAMAM-plasmid DNA complexes for cancer cell targeting.  

PubMed

In this study, pH-sensitive biomaterials coated polymer/DNA nanocomplexes containing a high mobility group box 1 (HMGB1) were developed as an efficient non-viral gene delivery system. HMGB1 is a family of endogenous molecules that contains nuclear locating sequences (NSL). Polyethylene glycol tethered carboxylated chitosan modified with folic acid (FA-PEG-CCTS) was synthesized and its buffering capacity was determined by acid-base titration. A pH-sensitive core-shell system FA-PEG-CCTS/PAMAM/HMGB1/pDNA nanocomplexes (FPCPHDs), was prepared and characterized. Electrophoresis showed that FPCPHDs were resistant to heparin replacement and DNase I digestion. FPCPHDs exhibited only minor toxic effects on HepG2 and KB cells. The results of both luciferase activity assay and RFP fluorescence intensity analysis showed that FPCPHDs enhanced gene transfection and expression in KB cells. Moreover, gene transfection and expression in KB cells were inhibited by free folic acid. Intracellular trafficking of FPCPHDs in KB cells showed that FPCPHDs could rapidly escape from endo-lysosomes and become exclusively located in the nucleus at 3 h post transfection. In addition, FPCPHDs exhibited increased red fluorescence protein (RFP) expression at the tumor site of S180 xenograft nude mice. All results suggest that FPCPHDs is an efficient approach to improve the transfection and expression efficiency in most FR-positive cancer cells. PMID:24094823

Wang, Mingyue; Hu, Haiyang; Sun, Yuqi; Qiu, Lipeng; Zhang, Jie; Guan, Guannan; Zhao, Xiuli; Qiao, Mingxi; Cheng, Liang; Cheng, Lifang; Chen, Dawei

2013-12-01

220

Folic acid-conjugated core/shell ZnS:Mn/ZnS quantum dots as targeted probes for two photon fluorescence imaging of cancer cells.  

PubMed

This work presents a novel approach to producing water soluble manganese-doped core/shell ZnS/ZnS quantum dots (ZnS:Mn/ZnS). The Mn-doped ZnS core was prepared through a nucleation doping strategy and a ZnS shell was grown on ZnS:Mn d-dots by decomposition of Zn(2+)-3-mercaptopropionic acid (MPA) complexes at 100 °C. It was found that the Mn2+(4)T1?6A1 fluorescence emission at ?590 nm significantly increased after growth of the shell when the Mn2+ doping content was 4.0 at.%. A photoluminescence quantum yield of ?22% was obtained for core/shell nanocrystals. The nanoparticles were structurally and compositionally characterized by transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and dynamic light scattering. The surface MPA molecules favor the dispersion of ZnS:Mn/ZnS QDs in aqueous media and make possible conjugation with targeting folic acid molecules. The folate receptor-mediated delivery of folic acid-conjugated ZnS:Mn/ZnS QDs was demonstrated using confocal microscopy with biphotonic excitation. Bare and folate-conjugated QDs exhibit only weak cytotoxicity towards folate receptor-positive T47D cancer cells and MCF-7 cells, used as a reference, at high concentrations (mmolar range) after 72h incubation. PMID:20965282

Geszke, Malgorzata; Murias, Marek; Balan, Lavinia; Medjahdi, Ghouti; Korczynski, Jaroslaw; Moritz, Michal; Lulek, Janina; Schneider, Raphaël

2011-03-01

221

Folic acid-conjugated iron oxide porous nanorods loaded with doxorubicin for targeted drug delivery.  

PubMed

Iron oxide porous nanorods (IOPNR) with lengths ranging from 40nm to 60nm and pore diameters ranging from 5nm to 10nm were prepared, and further modified with NH2-PEG-FA (FA-PEG-IOPNR) for ligand targeting and modified with NH2-PEG-OCH3 (PEG-IOPNR) as a control. Instead of chemical bonding, doxorubicin (DOX), a low water solubility anticancer drug, was loaded in the pores of the modified IOPNR because of their porous structure and high porosity. The release of DOX in acidic PBS solution (pH 5.3) was faster than that in neutral (pH 7.4) solution. The analysis results from TEM, inductively coupled plasma emission spectroscopy, confocal laser scanning microscopy, and flow cytometry analyses indicated that the presence of FA on the surface of the nanorods increase the cellular uptake of nanorods in the case of HeLa cells, a folate receptor (FR)-positive cell line. In contrast, for COS 7 cells, a FR-negative cell line, FA ligand on the surface of the nanorods showed no effect on the cellular uptake. MTT assay indicated that the cytotoxicity of DOX loaded in FA-PEG-IOPNR to HeLa cells was higher than that of DOX in PEG-IOPNR. In the case of COS 7 cells, no significant difference between the cytotoxicity of DOX loaded in FA-PEG-IOPNR and PEG-IOPNR was found. These results suggested that FA-PEG-IOPNR had the potential for target delivery of chemotherapeutic into cancer cells. PMID:24907583

Yu, Ping; Xia, Xi-Ming; Wu, Ming; Cui, Can; Zhang, Yang; Liu, Lei; Wu, Bo; Wang, Cai-Xia; Zhang, Liu-Jie; Zhou, Xiang; Zhuo, Ren-Xi; Huang, Shi-Wen

2014-08-01

222

Folic acid-coupled nano-paclitaxel liposome reverses drug resistance in SKOV3/TAX ovarian cancer cells.  

PubMed

Chemotherapy could be used as an effective treatment for ovarian cancer and subsequent peritoneal metastasis. Administration of chemoagents in a targeted manner may bring the advantage of higher efficiency and lower drug resistance. In the present study, folate receptor (FR)-targeted nano-paclitaxel formulations were generated and tested for cytotoxicity in a peritoneal xenograft model of paclitaxel-resistant ovarian cancer and SKOV3/TAX cell lines. Immunocytochemical staining confirmed the expression of FR in both SKOV3 and SKOV3/TAX cells. The enrichment of the folic acid-coupled PEGylated nano-paclitaxel liposome (FA-NP) in FR-positive cells was visualized with fluorescence. The uptake of the FA-NP peaked at 4 h and was more robust than nontargeted PEGylated nano-paclitaxel liposome (NP). FA-NP but not NP markedly inhibited the growth of ovarian cancer cells and induced a two-fold increase in the doubling time. The cytotoxic effects of FA-NP were more potent than NP in both SKOV3 cells [50% of inhibition concentration (IC50), 5.67 vs. 50.2 ?g/ml, FA-NP vs. NP] and SKOV3/TAX cells (IC50, 0.38 vs. >200 ?g/ml, FA-NP vs. NP). FA-NP caused more G2-M cell cycle arrest and apoptotic changes in ovarian cancer cells than NP or regular paclitaxel. However, these effects were blunted in the presence of free FA, which competitively inhibited the receptor-mediated uptake of FA-NP particles. Intraperitoneal (i.p.) administration of FA-NP but not regular paclitaxel, NP, or vehicle significantly prolonged the survival and reduced tumor nodule number (2.9±0.3) in BALB/c nude mice. FA-NP also markedly enhanced the percentage of apoptotic cells in peritoneal xenografts of paclitaxel-resistant ovarian cancer cells (44.6±8.5 vs. 3.2±1.1% for vehicle, 22.4±5.9% for regular paclitaxel, and 35.2±7.7% for NP; P<0.05). However, intravenous administration of FA-NP at the same dose failed to induce apoptosis (20.1±6.2%; P<0.05) and inhibit tumor nodule number to the same extent as intraperitoneal administration. FA-NP reversed the drug resistance in paclitaxel-resistant SKOV3/TAX ovarian cancer cells both in vitro and in vivo. Localized and targeted administration of the FR-targeted chemoagents might prolong the survival time in patients with drug-resistant ovarian cancer. PMID:24275314

Tong, Lingxia; Chen, Wei; Wu, Jing; Li, Hongxia

2014-03-01

223

Comparison of (6 S)-5-methyltetrahydrofolic acid v. folic acid as the reference folate in longer-term human dietary intervention studies assessing the relative bioavailability of natural food folates: comparative changes in folate status following a 16-week placebo-controlled study in healthy adults.  

PubMed

Folic acid (pteroylmonoglutamic acid) has historically been used as the reference folate in human intervention studies assessing the relative bioavailability of dietary folate. Recent studies using labelled folates indicated different plasma response kinetics to folic acid than to natural (food) folates, thus obviously precluding its use in single-dose experiments. Since differences in tissue distribution and site of biotransformation were hypothesised, the question is whether folic acid remains suitable as a reference folate for longer-term intervention studies, where the relative bioavailability of natural (food) folate is assessed based on changes in folate status. Healthy adults aged 18-65 years (n 163) completed a 16-week placebo-controlled intervention study in which the relative bioavailability of increased folate intake (453 nmol/d) from folate-rich foods was assessed by comparing changes in plasma and erythrocyte folate concentration with changes induced by an equal reference dose of supplemental (6S)-5-methyltetrahydrofolic acid or folic acid. The relative increase in plasma folate concentration in the food group was 31 % when compared with that induced by folic acid, but 39 % when compared with (6S)-5-methyltetrahydrofolic acid. The relative increase in erythrocyte folate concentration in the food group when compared with that induced by folic acid was 43 %, and 40 % when compared with (6S)-5-methyltetrahydrofolic acid. When recent published observations were additionally taken into account it was concluded that, in principle, folic acid should not be used as the reference folate when attempting to estimate relative natural (food) folate bioavailability in longer-term human intervention studies. Using (6S)-5-methyltetrahydrofolic acid as the reference folate would avoid future results' validity being questioned. PMID:19852872

Wright, Anthony J A; King, Maria J; Wolfe, Caroline A; Powers, Hilary J; Finglas, Paul M

2010-03-01

224

EE-drospirenone-levomefolate calcium versus EE-drospirenone + folic acid: folate status during 24 weeks of treatment and over 20 weeks following treatment cessation  

PubMed Central

Background Adequate folate supplementation in the periconceptional phase is recommended to reduce the risk of neural tube defects. Oral contraceptives may provide a reasonable delivery vehicle for folate supplementation before conception in women of childbearing potential. This study aimed to demonstrate that a fixed-dose combination of an oral contraceptive and levomefolate calcium leads to sustainable improvements in folate status compared with an oral contraceptive + folic acid. Methods This was a double-blind, randomized, parallel-group study in which 172 healthy women aged 18–40 years received ethinylestradiol (EE)-drospirenone-levomefolate calcium or EE-drospirenone + folic acid for 24 weeks (invasion phase), and EE-drospirenone for an additional 20 weeks (folate elimination phase). The main objective of the invasion phase was to examine the area under the folate concentration time-curve for plasma and red blood cell (RBC) folate, while the main objective of the elimination phase was to determine the duration of time for which RBC folate concentration remained ? 906 nmol/L after cessation of EE-drospirenone-levomefolate calcium. Results Mean concentration-time curves for plasma folate, RBC folate, and homocysteine were comparable between treatment groups during both study phases. During the invasion phase, plasma and RBC folate concentrations increased and approached steady-state after about 8 weeks (plasma) or 24 weeks (RBC). After cessation of treatment with levomefolate calcium, folate concentrations decreased slowly. The median time to RBC folate concentrations falling below 906 nmol/L was 10 weeks (95% confidence interval 8–12 weeks) after cessation of EE-drospirenone-levomefolate calcium treatment. Plasma and RBC folate levels remained above baseline values in 41.3% and 89.3% of women, respectively, at the end of the 20-week elimination phase. Conclusion Improvements in folate status were comparable between EE-drospirenone-levomefolate calcium and EE-drospirenone + folic acid. Plasma and RBC folate levels remained elevated for several months following cessation of treatment with EE-drospirenone-levomefolate calcium. PMID:23610531

Diefenbach, Konstanze; Trummer, Dietmar; Ebert, Frank; Lissy, Michael; Koch, Manuela; Rohde, Beate; Blode, Hartmut

2013-01-01

225

Actions of excitatory amino acid antagonists on synaptic potentials of layer II\\/III neurons of the cat's visual cortex  

Microsoft Academic Search

Actions of excitatory amino acid (EAA) antagonists on the responses of cells in layers II\\/III and IV of the cat's visual cortex to stimulation of layer VI and the underlying white matter were studied in slice preparations. Antagonists used were 2-amino-5-phosphonovalerate (APV), a selective antagonist for the N-methyl-D-aspartate (NMDA) type of EAA receptors, and kynurenate, a broadspectrum antagonist for the

T. Shirokawa; A. Nishigori; F. Kimura; T. Tsumoto

1989-01-01

226

Folate Status of Reproductive Age Women and Neural Tube Defect Risk: The Effect of Long-Term Folic Acid Supplementation at Doses of 140 ug and 400 ug per Day  

PubMed Central

Primary prevention of most folate-responsive neural tube defects (NTDs) may not require 400 ?g folic acid/day but may be achieved by attaining a high maternal folate status. Using RBC folate ?906 nmol/L as a marker for NTD risk reduction, the study aimed to determine the change in blood folate concentrations in reproductive age women in response to long-term folic acid supplementation at 400 µg/day and 140 µg/day (dose designed to mimic the average daily folic acid intake received from New Zealand’s proposed mandatory bread fortification program). Participants were randomly assigned to a daily folic acid supplement of 140 µg (n = 49), 400 µg (n = 48) or placebo (n = 47) for 40 weeks. RBC folate concentrations were measured at baseline, and after 6, 12, 29 and 40 weeks. At 40 weeks, the overall prevalence of having a RBC folate <906 nmol/L decreased to 18% and 35% in the 400 µg and 140 µg groups, respectively, while remaining relatively unchanged at 58% in the placebo group. After 40 weeks, there was no evidence of a difference in RBC folate between the two treatment groups (P = 0.340), nor was there evidence of a difference in the odds of a RBC folate <906 nmol/L (P = 0.078). In conclusion, the average daily intake of folic acid received from the proposed fortification program would increase RBC folate concentrations in reproductive age women to levels associated with a low risk of NTDs. PMID:22254076

Hursthouse, Nicola A.; Gray, Andrew R.; Miller, Jody C.; Rose, Meredith C.; Houghton, Lisa A.

2011-01-01

227

Impact of a pharmacist-directed educational program on the long-term knowledge and use of folic acid among college women: a 12-month follow-up study  

PubMed Central

Few studies have examined the impact of educational interventions on participants’ long-term knowledge and use of folic acid for prevention of neural tube defects (NTD). Objective The objective of this pilot study was to evaluate changes in knowledge and behaviors in a sample of college women one year after such a program. Methods Female students of a residential college campus voluntarily attended the event, which was advertised to the campus community as a women’s health seminar. Participants completed a multiple-choice test assessing knowledge of folic acid and NTD and frequency of multivitamin use before and immediately after a 30-minute oral presentation. Following 3 reminder messages sent via email or mail, knowledge and multivitamin use were re-assessed 1-month and 12-months post-intervention. Results Thirty-two college women participated in the educational intervention; 27 (84%) completed the 12-month post-test. At 12 months, statistically significant increases in knowledge from baseline remained for questions pertaining to food high in folic acid (p=0.023); completion of spinal column (p=0.011); and 2 questions on NTD prevention (p=0.044). Increases in knowledge regarding recommended daily allowance of folic acid (p=0.817) and difficulty in receiving adequate folic acid from diet alone (p=0.617) were not statistically significant from baseline. Regular multivitamin use (?4 times per week) was not statistically significantly increased from baseline (p=0.592). Conclusions Although it was encouraging that the women retained much of the information learned during the program, it appears that the changes in multivitamin use seen at 1-month were not sustained at 12-months. Further study with larger groups of college women is recommended. PMID:24155825

Murphy, Bethany L.; DiPietro, Natalie A.

228

Folic acid-conjugated 4-amino-phenylboronate, a boron-containing compound designed for boron neutron capture therapy, is an unexpected agonist for human neutrophils and platelets.  

PubMed

Boron neutron capture therapy (BNCT) is an anticancer treatment based on the accumulation in the tumor cells of (10) B-containing molecules and subsequent irradiation with low-energy neutrons, which bring about the decay of (10) B to very toxic (7) Li(3+) and (4) He(2+) ions. The effectiveness of BNCT is limited by the low delivery and accumulation of the used (10) B-containing compounds. Here, we report the development of folic acid-conjugated 4-amino-phenylboronate as a novel possible compound for the selective delivery of (10) B in BNCT. An extensive analysis about its biocompatibility to mature blood cells and platelet progenitors revealed that the compound markedly supports platelet aggregation, neutrophil oxidative burst, and inhibition of megakaryocyte development, while it does not have any manifest effect on red blood cells. PMID:24666508

Achilli, Cesare; Jadhav, Sushilkumar A; Guidetti, Gianni F; Ciana, Annarita; Abbonante, Vittorio; Malara, Alessandro; Fagnoni, Maurizio; Torti, Mauro; Balduini, Alessandra; Balduini, Cesare; Minetti, Giampaolo

2014-05-01

229

Effect of Folic Acid and B-Vitamins on Risk of Cardiovascular Events and Total Mortality among Women at High Risk for Cardiovascular Disease: A Randomized Trial  

PubMed Central

Context Recent randomized trials among patients with pre-existing cardiovascular disease (CVD) have failed to support benefits of B-vitamin supplementation on cardiovascular risk. Observational data suggest benefits may be greater among women, who have been underrepresented in published randomized trials. Objective To test whether a combination of folic acid, vitamin B6, and vitamin B12 lowers risk of CVD among high-risk women with and without CVD. Design, Setting, and Participants Within an ongoing randomized trial of antioxidant vitamins, 5,442 female US health professionals 42 years of age or older, with either a history of CVD or three or more coronary risk factors were randomized to a combination pill containing folic acid, vitamin B6, and vitamin B12 or a matching placebo and were followed for 7.3 years from April, 1998 until July, 2006. Intervention 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg vitamin B12 Main Outcome Measures A composite outcome of myocardial infarction (MI), stroke, coronary revascularization, or CVD mortality. Results Compared to placebo, active treatment with the combination pill did not decrease the risk of the primary combined endpoint (226.9 per 10,000 person-years versus 219.2 per 10,000 person-years; relative risk =1.03; 95 percent confidence interval, 0.90–1.19, P=0.65), or any of the secondary outcomes including MI (34.5 per 10,000 person-years versus 39.5 per 10,000 person-years; relative risk =0.87; 95 percent confidence interval, 0.63–1.22), stroke (41.9 per 10,000 person-years versus 36.8 per 10,000 person-years in placebo; relative risk =1.14; 95 percent confidence interval, 0.82–1.57), and CVD mortality (50.3 per 10,000 person-years versus 49.6 per 10,000 person-years; relative risk =1.01; 95 percent confidence interval, 0.76–1.35). In a blood sub-study, geometric mean plasma homocysteine level was decreased by 18.5% (95% CI, 12.5–24.1; P<0.001) in the active arm (n=150) over that observed in the placebo arm (n=150) for a difference of 2.27 ?mol per liter (95% CI, 1.54 –2.96). CONCLUSION Over the longest follow-up recorded thus far, a combination of folic acid/vitamin B6/vitamin B12 did not reduce a combined endpoint of total cardiovascular events among high-risk women despite significant homocysteine lowering. Trial Registration clinicaltrials.gov Identifier: NCT00000541 PMID:18460663

Albert, Christine M.; Cook, Nancy R.; Gaziano, J. Michael; Zaharris, Elaine; MacFadyen, Jean; Danielson, Eleanor; Buring, Julie E.; Manson, JoAnn E.

2009-01-01

230

Long-term intermittent multiple micronutrient supplementation enhances hemoglobin and micronutrient status more than iron + folic acid supplementation in Bangladeshi rural adolescent girls with nutritional anemia.  

PubMed

Previous short-term supplementation studies showed no additional hematologic benefit of multiple micronutrients (MMN) compared with iron + folic acid (IFA) in adolescent girls. This study examines whether long-term once- or twice-weekly supplementation of MMN can improve hemoglobin (Hb) and micronutrient status more than twice-weekly IFA supplementation in anemic adolescent girls in Bangladesh. Anemic girls (n = 324) aged 11-17 y attending rural schools were given once- or twice-weekly MMN or twice-weekly IFA, containing 60 mg iron/dose in both supplements, for 52 wk in a randomized double-blind trial. Blood samples were collected at baseline and 26 and 52 wk. Intent to treat analysis showed no significant difference in the Hb concentration between treatments at either 26 or 52 wk. However, after excluding girls with hemoglobinopathy and adjustment for baseline Hb, a greater increase in Hb was observed with twice-weekly MMN at 26 wk (P = 0.045). Although all 3 treatments effectively reduced iron deficiency, once-weekly MMN produced significantly lower serum ferritin concentrations than the other treatments at both 26 and 52 wk. Both once- and twice-weekly MMN significantly improved riboflavin, vitamin A, and vitamin C status compared with IFA. Overall, once-weekly MMN was less efficacious than twice-weekly MMN in improving iron, riboflavin, RBC folic acid, and vitamin A levels. Micronutrient supplementation beyond 26 wk was likely important in sustaining improved micronutrient status. These findings highlight the potential usefulness of MMN intervention in this population and have implications for programming. PMID:20702745

Ahmed, Faruk; Khan, Moududur R; Akhtaruzzaman, Mohammad; Karim, Rezaul; Williams, Gail; Torlesse, Harriet; Darnton-Hill, Ian; Dalmiya, Nita; Banu, Cadi P; Nahar, Badrun

2010-10-01

231

Completeness of reporting of setting and health worker cadre among trials on antenatal iron and folic acid supplementation in pregnancy: an assessment based on two Cochrane reviews  

PubMed Central

Background Poor reporting of medical trials has triggered the development of trial reporting standards within the scientific community. In addition to a description of the proposed intervention, adequate information about the trial setting and the group of health workers (cadre) delivering the intervention would allow a better understanding of the generalizability of the trial findings, facilitate replication of trial interventions and assist with assessment of trials for inclusion in systematic reviews. This study aims to determine the completeness of reporting for trial setting and cadre among trials included in two Cochrane reviews on iron and folic acid supplementation for women during pregnancy. Methods From the 81 trials included in the two Cochrane reviews, we extracted data on the trial setting, including the facility type and geographic location, facility descriptors (i.e. level of care) and population descriptors (i.e. socioeconomic status); and the cadre, including professional qualifications, training and supervision. Results Almost all studies reported the facility type and location (96%). However, only 68% included this information in the “methods” section of the report. Facility descriptors and population descriptors were less commonly reported (26% and 54% respectively). For 34% of the trials, we found some account of the type of health worker that delivered the intervention. Only 4% of the trials reported any training procedures. Conclusions Currently, complete reporting of setting and health worker cadre in iron and folic acid supplementation in pregnancy trials remains far from ideal, limiting assessments of the applicability of the trial findings. Trialists and journals need to ensure that this information is included in trial reports by adhering to and improving current reporting standards and by not making assumptions regarding readers’ knowledge of the context and of the intervention delivery mechanism. PMID:23773404

2013-01-01

232

Use of short chain alkyl imidazolium ionic liquids for on-line stacking and sweeping of methotrexate, flinic acid and folic acid: their application to biological fluids.  

PubMed

Methotrexate (MTX) is widely used for the treatment of many types of cancer. Folinic acid (FNA) and folic acid (FA) were usually simultaneously supplemented with MTX to reduce the side effects of a folate deficiency. This study, for the first time, included on-line sample preconcentration by stacking and sweeping techniques under reduced or enhanced electric conductivity in the sample region using short chain alkyl imidazolium ionic liquids (ILs) as micelle forming agents for analyte focusing. Both analyte focusing by micelle collapse (AFMC) and sweeping-MEKC had been investigated for the comparison of their effectiveness to examine simultaneously MTX, FNA and FA in plasma and urine under physiological conditions. In sweeping-MEKC, the sample solution without micelles was hydrodynamically injected as a long plug into a fused-silica capillary pre-filled with phosphate buffer containing 3.0 mol/L of 1-butyl-3-methylimidazolium bromide (BMIMBr). Using AFMC, the analytes were prepared in BMIMBr micellar matrix and hydrodynamically injected into the phosphate buffer without IL micelles. The conductivity ratio between BGE and sample (?, BGE/sample) was optimized to be 3.0 in sweeping-MEKC and 0.33 in AFMC resulting the adequate separation of analytes within 4.0 min. To reduce the possibility of BMIMBr adsorption, an appropriate rinsing protocol was used. The limits of detection were calculated as 0.1 ng/mL MTX, 0.05 ng/mL FNA and 0.05 ng/mL FA by sweeping-MEKC and 0.5 ng/mL MTX, 0.3 ng/mL FNA and 0.3 ng/mL FA by AFMC. The accuracy was tested by recovery in plasma and urine matrices giving values ranging between 90 and 110%. Both stacking and sweeping by BMIMBr could be successfully used for the rapid, selective and sensitive determination of pharmaceuticals in complex matrices due to its fascinating properties, including high conductivity, good thermal stability and ability to form different types of interactions by electrostatic, hydrophobic, hydrogen bonding and ?-? interactions. In sweeping-MEKC, the using of BMIMBr enhanced the ? factor, k retention factor and the injected amount of sample. Consequently, this technique offers particular potential for higher sensitivity by giving 22- and 5-fold sensitivity enhancement factors (SEFs) of MTX compared to CZE and AFMC, respectively. PMID:24737623

Abd El-Hady, Deia; Albishri, Hassan M; Rengarajan, Rajesh; Wätzig, Hermann

2014-07-01

233

Folic Acid-Conjugated MnO Nanoparticles as a T1 Contrast Agent for Magnetic Resonance Imaging of Tiny Brain Gliomas.  

PubMed

Detection of brain gliomas at the earliest stage is of great importance to improve outcomes, but it remains a most challenging task. In this study, oleic acid capped manganese oxide (MnO) nanoparticles (NPs) were prepared by the thermal decomposition of manganese oleate precursors and then transformed to water-dispersible MnO NPs by replacing oleic acid with N-(trimethoxysilylpropyl) ethylene diamine triacetic acid (TETT) silane. The covalently bonded TETT silane offers MnO NPs colloidal stability and abundant carboxylic functional groups allowing the further conjugation of the glioma-specific moiety, folic acid (FA). Moreover, the thin layer of TETT silane ensures a short distance between external Mn ion and water proton, which endows the FA-conjugated, TETT modified MnO (MnO-TETT-FA) NPs a longitudinal relaxivity as high as 4.83 mM(-1) s(-1). Accordingly, the in vivo magnetic resonance (MR) images demonstrated that MnO-TETT-FA NPs could efficiently enhance the MRI contrast for tiny brain gliomas. More importantly, due to the specificity of FA, MnO-TETT-FA NPs led to a clearer margin of the tiny glioma. This together with the good biocompatibility discloses the great potential of MnO-TETT-FA NPs as effective MRI contrast agents for the early diagnosis of brain gliomas. PMID:25335117

Chen, Ning; Shao, Chen; Qu, Yanming; Li, Shuai; Gu, Wei; Zheng, Tingting; Ye, Ling; Yu, Chunjiang

2014-11-26

234

Discovery of a Novel Series of CRTH2 (DP2) Receptor Antagonists Devoid of Carboxylic Acids.  

PubMed

Antagonism of the CRTH2 receptor represents a very attractive target for a variety of allergic diseases. Most CRTH2 antagonists known to date possess a carboxylic acid moiety, which is essential for binding. However, potential acid metabolites O-acyl glucuronides might be linked to idiosynchratic toxicity in humans. In this communication, we describe a new series of compounds that lack the carboxylic acid moiety. Compounds with high affinity (K i < 10 nM) for the receptor have been identified. Subsequent optimization succeeded in reducing the high metabolic clearance of the first compounds in human and rat liver microsomes. At the same time, inhibition of the CYP isoforms was optimized, giving rise to stable compounds with an acceptable CYP inhibition profile (IC50 CYP2C9 and 2C19 > 1 ?M). Taken together, these data show that compounds devoid of carboxylic acid groups could represent an interesting alternative to current CRTH2 antagonists in development. PMID:24900284

Crosignani, Stefano; Jorand-Lebrun, Catherine; Campbell, Gordon; Prêtre, Adeline; Grippi-Vallotton, Tania; Quattropani, Anna; Bouscary-Desforges, Gwenaelle; Bombrun, Agnes; Missotten, Marc; Humbert, Yves; Frémaux, Christèle; Pâquet, Mikaël; El Harkani, Kamel; Bradshaw, Charles G; Cleva, Christophe; Abla, Nada; Daff, Hamina; Schott, Olivier; Pittet, Pierre-André; Arrighi, Jean-François; Gaudet, Marilène; Johnson, Zoë

2011-12-01

235

[Antagonistic properties of lactic acid bacteria isolated from apparently healthy and osteoporotic women].  

PubMed

Antagonistic activity of 74 cultures of lactic acid bacteria, isolated from healthy and osteoporotic women-patients aged 50-79 years, has been studied. It has been shown that the inhibitory effect of the strain studied was independent of the health of women (control group of women or patients with osteoporosis), but had strain specificity. Seventeen most active strains of lactobacilli, which showed the highest inhibitory activity against B. cereus, P. aeruginosa, P. vulgaris were selected. Only 6 strains of lactobacillus demonstrated specific antagonistic activity against the test-strains. PMID:23516836

Ohirchuk, K S; Poltavs'ka, O A; Kovalenko, N K

2013-01-01

236

Investigation of folic acid stability in fortified instant noodles by use of capillary electrophoresis and reversed-phase high performance liquid chromatography.  

PubMed

A single enzyme treatment with alpha-amylase, prior to the quantification of added folic acid (FA) in fortified instant fried Asian noodles with analysis performed by capillary zone electrophoresis (CZE) and reversed-phase high performance liquid chromatography (RP-HPLC) with UV detection, is described. The method was validated and optimized for capillary electrophoresis (CE) with separation achieved using a 8 mM phosphate-12 mM borate run buffer with 5% MeOH at pH 9.5. FA was well separated from matrix components with nicotinic acid (NA) employed as an internal standard. In a comparative study, separation of FA was performed using HPLC with a mobile phase consisting of 27% MeOH (v/v) in aqueous potassium phosphate buffer (3.5 mM KH(2)PO(4) and 3.2 mM K(2)HPO(4)), pH 8.5, and containing 5 mM tetrabutylammonium dihydrogen phosphate as an ion-pairing agent. For both methods, excellent results were obtained for various analytical parameters including linearity, accuracy and precision. The limit of detection was calculated to be 2.2 mg/L for CE without sample stacking and 0.10 mg/L with high performance liquid chromatography (HPLC). Sample extraction involved homogenization and enzymatic extraction with alpha-amylase. Results indicated that FA was stable during four main stages of instant fried noodle manufacturing (dough crumbs, cut sheets, steaming and frying). PMID:18930464

Hau Fung Cheung, Rodney; Morrison, Paul D; Small, Darryl M; Marriott, Philip J

2008-12-01

237

Novel Cyclic Phosphinic Acids as GABAC ? Receptor Antagonists: Design, Synthesis, and Pharmacology.  

PubMed

Understanding the role of GABAC receptors in the central nervous system is limited due to a lack of specific ligands. Novel ?-aminobutyric acid (GABA) analogues based on 3-(aminomethyl)-1-oxo-1-hydroxy-phospholane 17 and 3-(guanido)-1-oxo-1-hydroxy-phospholane 19 were investigated to obtain selective GABAC receptor antagonists. A compound of high potency (19, K B = 10 ?M) and selectivity (greater than 100 times at ?1 GABAC receptors as compared to ?1?2?2L GABAA and GABAB(1b,2) receptors) was obtained. The cyclic phosphinic acids (17 and 19) are novel lead agents for developing into more potent and selective GABAC receptor antagonists with increased lipophilicity for future in vivo studies. PMID:24900248

Gavande, Navnath; Yamamoto, Izumi; Salam, Noeris K; Ai, Tu-Hoa; Burden, Peter M; Johnston, Graham A R; Hanrahan, Jane R; Chebib, Mary

2011-01-13

238

A simple and efficient electrochemical sensor for folic acid determination in human blood plasma based on gold nanoparticles-modified carbon paste electrode.  

PubMed

Folic acid (FA) is a water soluble vitamin that exists in many natural species. The lack of FA causes some deficiencies in human body, so finding a simple and sensitive method for determining the FA is important. A new chemically modified electrode was fabricated for determination of FA in human blood plasma using gold nanoparticles (AuNPs) and carbon paste electrode (CPE). Gold nanoparticles-modified carbon paste electrode (AuNPs/CPE) was characterized by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The experimental parameters such as pH, scan rate (?) and amount of modifier were studied by cyclic voltammetry and the optimized values were chosen. The electrochemical parameters such as diffusion coefficient of FA (D(FA)), electrode surface area (A) and electron transfer coefficient (?) were calculated. Square wave voltammetry as an accurate technique was used for quantitative calculations. A good linear relation was observed between anodic peak current (ipa) and FA concentration (CFA) in the range of 6×10(-8) to 8×10(-5) mol L(-1), and the detection limit (LOD) achieved 2.7×10(-8) mol L(-1), that is comparable with recently studies. This paper demonstrated a novel, simple, selective and rapid sensor for determining the FA in the biological samples. PMID:23706236

Arvand, Majid; Dehsaraei, Mohammad

2013-08-01

239

Estimation of serum and erythrocyte folate concentrations in the New Zealand adult population within a background of voluntary folic acid fortification.  

PubMed

National data on the blood folate status of New Zealand adults is lacking. The objective of this study was to describe the blood folate status and examine the predictors of blood folate status in a national sample of adults from New Zealand, a country with voluntary folic acid fortification. The 2008/09 New Zealand Adult Nutrition Survey was a nationwide multistage systematic random cross-sectional survey. Serum and erythrocyte folate concentrations were measured by microbiologic assay. The survey included 4721 participants aged ?15 y, 3359 of whom provided a nonfasting blood sample. Biochemical folate status was measured in 3277 participants. The median serum and erythrocyte folate concentrations were 23 and 809 nmol/L, respectively. The prevalence of biochemical folate deficiency, defined as plasma folate <6.8 nmol/L or erythrocyte folate <305 nmol/L, was 2%. Having breakfast daily compared with never eating breakfast was associated with 53% higher serum and 25% higher erythrocyte folate concentrations; consumers of fortified yeast extract spread had 17% higher serum and 14% higher erythrocyte folate concentrations than nonconsumers; daily users of folate-containing supplements compared with nonusers had 48% higher serum and 28% higher erythrocyte folate concentrations. The prevalence of biochemical folate deficiency in New Zealand adults is low. Participants who ate breakfast more frequently, consumed folate-fortified yeast, or used a daily folate supplement had higher blood folate concentrations. PMID:24174623

Bradbury, Kathryn E; Williams, Sheila M; Mann, Jim I; Brown, Rachel C; Parnell, Winsome; Skeaff, C Murray

2014-01-01

240

Fabrication and characterization of a triple functionalization of graphene oxide with Fe3O4, folic acid and doxorubicin as dual-targeted drug nanocarrier.  

PubMed

A novel triple functionalized drug delivery system was synthesized by encapsulation of superparamagnetic graphene oxide (GO) and doxorubicin (DOX) with folic acid (FA) conjugated chitosan (CHI). The carrier exhibited a high loading efficiency (0.98 mg/mg), a high saturation magnetization (10.5 emu/g) and a prolonged release rate. A real-time monitoring method on the drug release from graphene oxide (GO) was reported using DOX as the model drug. The release mechanism of DOX at different pH was investigated via monitoring the time dependency of the accumulative drug release. Results show that the drug release of DOX was pH sensitive as observed at pH 5.3 and pH 7.4 PBS solutions, the lower pH values lead to weaker hydrogen bonds and degradation of CHI, and thus result in a higher release rate of DOX. Especially, this system could be applied as a dual-targeted drug nanocarrier by combined biological (active) and magnetical (passive) targeting capabilities. Our research suggests that a novel triple functionalized, pH-responsive nanocarrier for anticancer drug has been synthesized. PMID:23434692

Wang, Zonghua; Zhou, Chengfeng; Xia, Jianfei; Via, Brian; Xia, Yanzhi; Zhang, Feifei; Li, Yanhui; Xia, Linhua

2013-06-01

241

AS1411 aptamer and folic acid functionalized pH-responsive ATRP fabricated pPEGMA-PCL-pPEGMA polymeric nanoparticles for targeted drug delivery in cancer therapy.  

PubMed

Nonspecificity and cardiotoxicity are the primary limitations of current doxorubicin chemotherapy. To minimize side effects and to enhance bioavailability of doxorubicin to cancer cells, a dual-targeted pH-sensitive biocompatible polymeric nanosystem was designed and developed. An ATRP-based biodegradable triblock copolymer, poly(poly(ethylene glycol) methacrylate)-poly(caprolactone)-poly(poly(ethylene glycol) methacrylate) (pPEGMA-PCL-pPEGMA), conjugated with doxorubicin via an acid-labile hydrazone bond was synthesized and characterized. Dual targeting was achieved by attaching folic acid and the AS1411 aptamer through EDC-NHS coupling. Nanoparticles of the functionalized triblock copolymer were prepared using the nanoprecipitation method, resulting in an average particle size of ?140 nm. The biocompatibility of the nanoparticles was evaluated using MTT cytotoxicity assays, blood compatibility studies, and protein adsorption studies. In vitro drug release studies showed a higher cumulative doxorubicin release at pH 5.0 (?70%) compared to pH 7.4 (?25%) owing to the presence of the acid-sensitive hydrazone linkage. Dual targeting with folate and the AS1411 aptamer increased the cancer-targeting efficiency of the nanoparticles, resulting in enhanced cellular uptake (10- and 100-fold increase in uptake compared to single-targeted NPs and non-targeted NPs, respectively) and a higher payload of doxorubicin in epithelial cancer cell lines (MCF-7 and PANC-1), with subsequent higher apoptosis, whereas a normal (noncancerous) cell line (L929) was spared from the adverse effects of doxorubicin. The results indicate that the dual-targeted pH-sensitive biocompatible polymeric nanosystem can act as a potential drug delivery vehicle against various epithelial cancers such as those of the breast, ovary, pancreas, lung, and others. PMID:24689987

Lale, Shantanu V; R G, Aswathy; Aravind, Athulya; Kumar, D Sakthi; Koul, Veena

2014-05-12

242

Rapid determination of thiamine, riboflavin, niacinamide, pantothenic acid, pyridoxine, folic acid and ascorbic acid in Vitamins with Minerals Tablets by high-performance liquid chromatography with diode array detector.  

PubMed

A simple, isocratic, and stability-indicating high-performance liquid chromatography (HPLC) method has been developed for the rapid determination of thiamine (VB(1)), niacinamide (VB(3)), pyridoxine (VB(6)), ascorbic acid (VC), pantothenic acid (VB(5)), riboflavin (VB(2)) and folic acid (VB(9)) in Vitamins with Minerals Tablets (VMT). An Alltima C(18) column (250 mm × 4.6 mm i.d., 5 ?m) was used for the separation at ambient temperature, with 50mM ammonium dihydrogen phosphate (adjusting with phosphoric acid to pH 3.0) and acetonitrile as the mobile phase at the flow rate of 0.5 ml min(-1). VB(1), VB(3), VB(6), VC and VB(5) were extracted with a solution containing 0.05% phosphoric acid (v/v) and 0.3% sodium thiosulfate (w/v), and were then simultaneously analyzed by using the mobile phase of phosphate buffer-acetonitrile (95:5, v/v), while VB(2) and VB(9) were extracted with a solution containing 0.5% ammonium hydroxide solution (v/v), and were then simultaneously analyzed by using the mobile phase of phosphate buffer-acetonitrile (85:15, v/v). The detection wavelengths were 275 nm for VB(1), VB(3), VB(6), VC, 210 nm for VB(5), and 282 nm for VB(2) and VB(9). The method showed good system suitability, sensitivity, linearity, specificity, precision, stability and accuracy. All the seven water-soluble vitamins were well separated from other ingredients and degradation products. Method comparison indicated good concordance between the developed method and the USP method. The developed method was reliable and convenient for the rapid determination of VB(1), VB(3), VB(6), VC, VB(5), VB(2) and VB(9) in VMT. PMID:22785377

Jin, Pengfei; Xia, Lufeng; Li, Zheng; Che, Ning; Zou, Ding; Hu, Xin

2012-11-01

243

Differential Regulation of Hepatic Transcription Factors in the Wistar Rat Offspring Born to Dams Fed Folic Acid, Vitamin B12 Deficient Diets and Supplemented with Omega-3 Fatty Acids  

PubMed Central

Nutritional status of the mother is known to influence various metabolic adaptations required for optimal fetal development. These may be mediated by transcription factors like peroxisome proliferator activated receptors (PPARs), which are activated by long chain polyunsaturated fatty acids. The objective of the current study was to examine the expression of different hepatic transcription factors and the levels of global methylation in the liver of the offspring born to dams fed micronutrient deficient (folic acid and vitamin B12) diets and supplemented with omega-3 fatty acids. Female rats were divided into five groups (n?=?8/group) as follows; control, folic acid deficient (FD), vitamin B12 deficient (BD) and omega-3 fatty acid supplemented groups (FDO and BDO). Diets were given starting from pre-conception and continued throughout pregnancy and lactation. Pups were dissected at the end of lactation. Liver tissues were removed; snap frozen and stored at ?80°C. Maternal micronutrients deficiency resulted in lower (p<0.05) levels of pup liver docosahexaenoic acid (DHA) and arachidonic acid (ARA) as compared to the control group. Pup liver PPAR? and PPAR? expression was lower (p<0.05) in the BD group although there were no differences in the expression of SREBP-1c, LXR? and RXR? expression. Omega-3 fatty acids supplementation to this group normalized (p<0.05) levels of both PPAR? and PPAR? but reduced (p<0.05) SREBP-1c, LXR? and RXR? expression. There was no change in any of the transcription factors in the pup liver in the FD group. Omega-3 fatty acids supplementation to this group reduced (p<0.05) PPAR?, SREBP-1c and RXR? expression. Pup liver global methylation levels were higher (p<0.01) in both the micronutrients deficient groups and could be normalized (p<0.05) by omega-3 fatty acid supplementation. Our novel findings suggest a role for omega-3 fatty acids in the one carbon cycle in influencing the hepatic expression of transcription factors in the offspring. PMID:24587285

Meher, Akshaya; Joshi, Asmita; Joshi, Sadhana

2014-01-01

244

Folate and arsenic metabolism: a double-blind, placebo-controlled folic acid-supplementation trial in Bangladesh13  

Microsoft Academic Search

Background: Populations in South and East Asia and many other regions of the world are chronically exposed to arsenic- contaminated drinking water. To various degrees, ingested inor- ganic arsenic (InAs) is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via folate-dependent one- carbon metabolism; impaired methylation is associated with ad- verse health outcomes. Consequently, folate nutritional status may influence

Mary V Gamble; Xinhua Liu; Habibul Ahsan; J Richard Pilsner; Vesna Ilievski; Vesna Slavkovich; Faruque Parvez; Yu Chen; Diane Levy; Pam Factor-Litvak; Joseph H Graziano

245

Rapid Quantitation of Ascorbic and Folic Acids in SRM 3280 Multivitamin/Multielement Tablets using Flow-Injection Tandem Mass Spectrometry  

SciTech Connect

RATIONALE: Ascorbic acid (AA) and folic acid (FA) are water-soluble vitamins and are usually fortified in food and dietary supplements. For the safety of human health, proper intake of these vitamins is recommended. Improvement in the analysis time required for the quantitative determination of these vitamins in food and nutritional formulations is desired. METHODS: A simple and fast (~5 min) in-tube sample preparation was performed, independently for FA and AA, by mixing extraction solvent with a powdered sample aliquot followed by agitation, centrifugation, and filtration to recover an extract for analysis. Quantitative detection was achieved by flow-injection (1 L injection volume) electrospray ionization tandem mass spectrometry (ESI-MS/MS) in negative ion mode using the method of standard addition. RESULTS: Method of standard addition was employed for the quantitative estimation of each vitamin in a sample extract. At least 2 spiked and 1 non-spiked sample extract were injected in triplicate for each quantitative analysis. Given an injection-to-injection interval of approximately 2 min, about 18 min was required to complete the quantitative estimation of each vitamin. The concentration values obtained for the respective vitamins in the standard reference material (SRM) 3280 using this approach were within the statistical range of the certified values provided in the NIST Certificate of Analysis. The estimated limit of detections of FA and AA were 13 and 5.9 ng/g, respectively. CONCLUSIONS: Flow-injection ESI-MS/MS was successfully applied for the rapid quantitation of FA and AA in SRM 3280 multivitamin/multielement tablets.

Bhandari, Deepak [ORNL] [ORNL; Kertesz, Vilmos [ORNL] [ORNL; Van Berkel, Gary J [ORNL] [ORNL

2013-01-01

246

Naturally Occurring Eccentric Cleavage Products of Provitamin A ?-Carotene Function as Antagonists of Retinoic Acid Receptors*  

PubMed Central

?-Carotene is the major dietary source of provitamin A. Central cleavage of ?-carotene catalyzed by ?-carotene oxygenase 1 yields two molecules of retinaldehyde. Subsequent oxidation produces all-trans-retinoic acid (ATRA), which functions as a ligand for a family of nuclear transcription factors, the retinoic acid receptors (RARs). Eccentric cleavage of ?-carotene at non-central double bonds is catalyzed by other enzymes and can also occur non-enzymatically. The products of these reactions are ?-apocarotenals and ?-apocarotenones, whose biological functions in mammals are unknown. We used reporter gene assays to show that none of the ?-apocarotenoids significantly activated RARs. Importantly, however, ?-apo-14?-carotenal, ?-apo-14?-carotenoic acid, and ?-apo-13-carotenone antagonized ATRA-induced transactivation of RARs. Competitive radioligand binding assays demonstrated that these putative RAR antagonists compete directly with retinoic acid for high affinity binding to purified receptors. Molecular modeling studies confirmed that ?-apo-13-carotenone can interact directly with the ligand binding site of the retinoid receptors. ?-Apo-13-carotenone and the ?-apo-14?-carotenoids inhibited ATRA-induced expression of retinoid responsive genes in Hep G2 cells. Finally, we developed an LC/MS method and found 3–5 nm ?-apo-13-carotenone was present in human plasma. These findings suggest that ?-apocarotenoids function as naturally occurring retinoid antagonists. The antagonism of retinoid signaling by these metabolites may have implications for the activities of dietary ?-carotene as a provitamin A and as a modulator of risk for cardiovascular disease and cancer. PMID:22418437

Eroglu, Abdulkerim; Hruszkewycz, Damian P.; dela Sena, Carlo; Narayanasamy, Sureshbabu; Riedl, Ken M.; Kopec, Rachel E.; Schwartz, Steven J.; Curley, Robert W.; Harrison, Earl H.

2012-01-01

247

A turn-on highly selective and ultrasensitive determination of copper (II) in an aqueous medium using folic acid capped gold nanoparticles as the probe  

NASA Astrophysics Data System (ADS)

This paper describes a ‘turn-on’ fluorescent determination of Cu(II) in an aqueous medium using folic acid capped gold nanoparticles (FA-AuNPs) as the probe. The FA-AuNPs were synthesized by the wet chemical method and were characterized by UV-visible, fluorescence, HR-TEM, XRD, zeta potential, and DLS techniques. The FA-AuNPs show an absorption maximum at 510 nm and an emission maximum at 780 nm (?ex: 510 nm). On adding 10 ?M Cu(II), the wine-red color of FA-AuNPs changed to purple and the absorbance at 510 nm decreased. The observed changes were ascribed to the aggregation of AuNPs. This was confirmed by DLS and HR-TEM studies. Interestingly, the emission intensity of FA-AuNPs was enhanced even in the presence of a picomolar concentration of Cu(II). Based on the enhancement of the emission intensity, the concentration of Cu(II) was determined. The FA-AuNPs showed an extreme selectivity towards the determination of 10 nM Cu(II) in the presence of 10?000-fold higher concentration of interferences except EDTA and the carboxylate anion. A good linearity was observed from 10 × 10-9 to 1 × 10-12 M Cu(II), and the detection limit was found to be 50 fM l-1 (S/N = 3). The proposed method was successfully applied to determine Cu(II) in real samples. The results obtained were validated with ICP-AES.

Vasimalai, N.; Prabhakarn, A.; John, S. Abraham

2013-12-01

248

Multifunctional Core/Shell Nanoparticles Cross-linked Polyetherimide-folic Acid as Efficient Notch-1 siRNA Carrier for Targeted Killing of Breast Cancer.  

PubMed

In gene therapy, how genetic therapeutics can be efficiently and safely delivered into target tissues/cells remains a major obstacle to overcome. To address this issue, nanoparticles consisting of non-covalently coupled polyethyleneimine (PEI) and folic acid (FA) to the magnetic and fluorescent core/shell of Fe3O4@SiO2(FITC) was tested for their ability to deliver Notch-1 shRNA. Our results showed that Fe3O4@SiO2(FITC)/PEI-FA/Notch-1 shRNA nanoparticles are 64?nm in diameter with well dispersed and superparamagnetic. These nanoparticles with on significant cytotoxicity are capable of delivering Notch-1 shRNA into human breast cancer MDA-MB-231 cells with high efficiency while effectively protected shRNA from degradation by exogenous DNaseI and nucleases. Magnetic resonance (MR) imaging and fluorescence microscopy showed significant preferential uptake of Fe3O4@SiO2(FITC)/PEI-FA/Notch-1 shRNA nanocomplex by MDA-MB-231 cells. Transfected MDA-MB-231 cells exhibited significantly decreased expression of Notch-1, inhibited cell proliferation, and increased cell apoptosis, leading to the killing of MDA-MB-231 cells. In light of the magnetic targeting capabilities of Fe3O4@SiO2(FITC)/PEI-FA, our results show that by complexing with a second molecular targeting therapeutic, such as Notch-1 shRNA in this report, Fe3O4@SiO2(FITC)/PEI-FA can be exploited as a novel, non-viral, and concurrent targeting delivery system for targeted gene therapy as well as for MR imaging in cancer diagnosis. PMID:25400232

Yang, Hong; Li, Ying; Li, Tingting; Xu, Min; Chen, Yin; Wu, Chunhui; Dang, Xitong; Liu, Yiyao

2014-01-01

249

The effects of folic acid application on IL-1beta levels of human gingival fibroblasts stimulated by phenytoin and TNFalpha in vitro: a preliminary study.  

PubMed

Folic acid (FA), that is required for the integrity of gingival tissues, was found to decrease in patients using phenytoin (PHT). Interleukin-1 beta (IL-1beta) was reported to enhance the extracellular matrix synthesis in fibroblasts. The purpose of this study was to assess the role of FA supplementation on PHT-induced overgrowth by investigating its effect on IL-1beta production of human gingival fibroblasts induced by tumor necrosis factor alfa (TNFalpha) in cell culture. PHT (20 microg/ml), FA (20 or 40 ng/ml) + PHT, PHT + TNF (10 ng/ml), FA (20 or 40 ng/ml) + PHT + TNF, or only culture medium (control) was added to 24-well plates containing fibroblasts. After an incubation period of 72 h, culture medium and cells were harvested separately. Then, IL-1beta levels in cell lysate were measured using enzyme-linked immunosorbent assay. The cellular IL-1beta level in the PHT group was 1 pg/ml. In PHT + 20 or 40 ng/ml FA-added cultures, the results obtained respectively were 0.8 and 0.7 pg/ml, whereas the control group value was 0.7 pg/ml. IL-1beta level was 4 pg/ml in the cultures that PHT and TNFalpha were applied simultaneously (P < 0.05). When PHT and either 20 or 40 ng/ml FA were simultaneously added into TNFalpha-induced cultures, the IL-1beta levels were 1.8 and 1.3 pg/ml, respectively. IL-1beta level in gingival tissues might play a role in PHT-induced overgrowth by increasing in the gingival tissues, and FA application might play a role in decreasing gingival tissues. However, further studies are needed for a more complete understanding of PHT-induced gingival overgrowth at the cellular level. PMID:11848192

Do?an, A; Tunca, Y; Ozdemir, A; Sengül, A; Imirzalio?lu, N

2001-12-01

250

Multifunctional Core/Shell Nanoparticles Cross-linked Polyetherimide-folic Acid as Efficient Notch-1 siRNA Carrier for Targeted Killing of Breast Cancer  

PubMed Central

In gene therapy, how genetic therapeutics can be efficiently and safely delivered into target tissues/cells remains a major obstacle to overcome. To address this issue, nanoparticles consisting of non-covalently coupled polyethyleneimine (PEI) and folic acid (FA) to the magnetic and fluorescent core/shell of Fe3O4@SiO2(FITC) was tested for their ability to deliver Notch-1 shRNA. Our results showed that Fe3O4@SiO2(FITC)/PEI-FA/Notch-1 shRNA nanoparticles are 64?nm in diameter with well dispersed and superparamagnetic. These nanoparticles with on significant cytotoxicity are capable of delivering Notch-1 shRNA into human breast cancer MDA-MB-231 cells with high efficiency while effectively protected shRNA from degradation by exogenous DNaseI and nucleases. Magnetic resonance (MR) imaging and fluorescence microscopy showed significant preferential uptake of Fe3O4@SiO2(FITC)/PEI-FA/Notch-1 shRNA nanocomplex by MDA-MB-231 cells. Transfected MDA-MB-231 cells exhibited significantly decreased expression of Notch-1, inhibited cell proliferation, and increased cell apoptosis, leading to the killing of MDA-MB-231 cells. In light of the magnetic targeting capabilities of Fe3O4@SiO2(FITC)/PEI-FA, our results show that by complexing with a second molecular targeting therapeutic, such as Notch-1 shRNA in this report, Fe3O4@SiO2(FITC)/PEI-FA can be exploited as a novel, non-viral, and concurrent targeting delivery system for targeted gene therapy as well as for MR imaging in cancer diagnosis. PMID:25400232

Yang, Hong; Li, Ying; Li, Tingting; Xu, Min; Chen, Yin; Wu, Chunhui; Dang, Xitong; Liu, Yiyao

2014-01-01

251

Earlier Initiation and Use of a Greater Number of Iron-Folic Acid Supplements during Pregnancy Prevents Early Neonatal Deaths in Nepal and Pakistan  

PubMed Central

Introduction Early neonatal deaths account for 75% of neonatal deaths globally. Antenatal iron-folic acid (IFA) supplementation has significantly reduced the risk of early neonatal deaths in China and Indonesia. We investigated the impact of antenatal IFA supplements on the risk of early neonatal deaths in Nepal and Pakistan during the last decade. Methods Data from the most recent singleton live-births of 8,186 from two Nepal Demographic and Health Surveys (DHS) and 13,034 from two Pakistan DHS were selected for the current study. The primary outcome was early neonatal deaths and the main study variable was antenatal IFA supplementation. Analyses used multivariate Cox proportional regression, adjusted for the cluster sampling design and for 18 potential confounders. Findings The adjusted risk of early neonatal deaths was significantly reduced by 51% (aHR?=?0.49, 95% CI?=?0.32–0.75) in Nepal and 23% (aHR?=?0.77, 95% CI?=?0.59–0.99) in Pakistan with any use of IFA compared to none. When IFA supplementation started at or before the 5th month of pregnancy, the adjusted risk of early neonatal mortality was significantly reduced by 53% in Nepal, and 28% in Pakistan, compared to no IFA. When >90 IFA supplements were used and started at or before 5th months, the adjusted risk of early neonatal deaths was significantly reduced by 57% in Nepal, and 45% in Pakistan. In Nepal 4,600 and in Pakistan 75,000 early neonatal deaths could be prevented annually if all pregnant women used >90 IFA supplements and started at or before the 5th month of pregnancy. Conclusions Any use of IFA supplements was significantly associated with reduced risk of early neonatal deaths in Nepal and Pakistan. The greatest mortality sparing effect of IFA on early neonatal deaths in both countries was with early initiation and use of a greater number of supplements. PMID:25398011

Nisar, Yasir Bin; Dibley, Michael J.

2014-01-01

252

Adequate but not supplemental folic acid combined with soy isoflavones during early life improves bone health at adulthood in male mice.  

PubMed

Previous investigations from our laboratory have demonstrated that neonatal exposure to soy isoflavones (ISO) improves bone outcomes in CD-1 mice at adulthood with greater benefits in females than males. This study determined whether early-life exposure to supplemental folic acid (FA) - that may enhance DNA methylation of target genes - in combination with ISO provides greater benefits to male bone development than ISO alone. CD-1 dams were randomized to a low (0 mg/kg diet), adequate (2 mg/kg diet) or supplemental (8 mg/kg diet) level of FA during pregnancy and lactation. Offspring received corn oil or ISO (7 mg/kg of body weight per day) from postnatal day 1-10. From weaning, males were fed adequate FA and studied to age 4 months. Offspring exposed to adequate FA+ISO had multiple benefits to bone health: higher (P<.05) bone mineral density (BMD) and greater (P<.05) resistance to fracture at the femur and lumbar spine than mice exposed to adequate FA alone. Exposure to supplemental FA+ISO resulted in higher (P<.05) serum osteoprotegerin (OPG), and a higher ratio of OPG to receptor activator for nuclear factor ?? ligand (RANKL) but did not result in greater BMD or strength at the femur or lumbar spine than supplemental FA alone. In conclusion, early-life exposure to adequate FA+ISO provided functional benefits to male bone development, while improvements induced by supplemental FA+ISO were limited to a higher level of serum OPG. Mechanistic studies are needed to better understand how FA and ISO improve bone development in male offspring. PMID:23643520

Kaludjerovic, Jovana; Ward, Wendy E

2013-10-01

253

Folic Acid Protects against Lipopolysaccharide-Induced Preterm Delivery and Intrauterine Growth Restriction through Its Anti-Inflammatory Effect in Mice  

PubMed Central

Increasing evidence demonstrates that maternal folic acid (FA) supplementation during pregnancy reduces the risk of neural tube defects, but whether FA prevents preterm delivery and intrauterine growth restriction (IUGR) remains obscure. Previous studies showed that maternal lipopolysaccharide (LPS) exposure induces preterm delivery, fetal death and IUGR in rodent animals. The aim of this study was to investigate the effects of FA on LPS-induced preterm delivery, fetal death and IUGR in mice. Some pregnant mice were orally administered with FA (0.6, 3 or 15 mg/kg) 1 h before LPS injection. As expected, a high dose of LPS (300 ?g/kg, i.p.) on gestational day 15 (GD15) caused 100% of dams to deliver before GD18 and 89.3% of fetuses dead. A low dose of LPS (75 ?g/kg, i.p.) daily from GD15 to GD17 resulted in IUGR. Interestingly, pretreatment with FA prevented LPS-induced preterm delivery and fetal death. In addition, FA significantly attenuated LPS-induced IUGR. Further experiments showed that FA inhibited LPS-induced activation of nuclear factor kappa B (NF-?B) in mouse placentas. Moreover, FA suppressed LPS-induced NF-?B activation in human trophoblast cell line JEG-3. Correspondingly, FA significantly attenuated LPS-induced upregulation of cyclooxygenase (COX)-2 in mouse placentas. In addition, FA significantly reduced the levels of interleukin (IL)-6 and keratinocyte-derived cytokine (KC) in amniotic fluid of LPS-treated mice. Collectively, maternal FA supplementation during pregnancy protects against LPS-induced preterm delivery, fetal death and IUGR through its anti-inflammatory effects. PMID:24324824

Dong, Xu-Ting; Zhou, Jun; Chen, Xue; Wang, Hua; Wu, Shu-Xian; Xia, Mi-Zhen; Zhang, Cheng; Xu, De-Xiang

2013-01-01

254

Design of novel neurokinin 1 receptor antagonists based on conformationally constrained aromatic amino acids and discovery of a potent chimeric opioid agonist-neurokinin 1 receptor antagonist.  

PubMed

A screening of conformationally constrained aromatic amino acids as base cores for the preparation of new NK1 receptor antagonists resulted in the discovery of three new NK1 receptor antagonists, 19 [Ac-Aba-Gly-NH-3',5'-(CF(3))(2)-Bn], 20 [Ac-Aba-Gly-NMe-3',5'-(CF(3))(2)-Bn], and 23 [Ac-Tic-NMe-3',5'-(CF(3))(2)-Bn], which were able to counteract the agonist effect of substance P, the endogenous ligand of NK1R. The most active NK1 antagonist of the series, 20 [Ac-Aba-Gly-NMe-3',5'-(CF(3))(2)-Bn], was then used in the design of a novel, potent chimeric opioid agonist-NK1 receptor antagonist, 35 [Dmt-D-Arg-Aba-Gly-NMe-3',5'-(CF(3))(2)-Bn], which combines the N terminus of the established Dmt(1)-DALDA agonist opioid pharmacophore (H-Dmt-D-Arg-Phe-Lys-NH(2)) and 20, the NK1R ligand. The opioid component of the chimeric compound 35, that is, Dmt-D-Arg-Aba-Gly-NH(2) (36), also proved to be an extremely potent and balanced ? and ? opioid receptor agonist with subnanomolar binding and in vitro functional activity. PMID:21413804

Ballet, Steven; Feytens, Debby; Buysse, Koen; Chung, Nga N; Lemieux, Carole; Tumati, Suneeta; Keresztes, Attila; Van Duppen, Joost; Lai, Josephine; Varga, Eva; Porreca, Frank; Schiller, Peter W; Vanden Broeck, Jozef; Tourwé, Dirk

2011-04-14

255

Excitatory amino acid receptor antagonists and electroacupuncture synergetically inhibit carrageenan-induced behavioral hyperalgesia and spinal fos expression in rats  

Microsoft Academic Search

The interaction between electroacupuncture and an N-methyl-d-aspartic acid (NMDA) receptor antagonist, (DL-2-amino-5-phosphonopentanoic acid; AP5), or an (±)-?-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid\\/kainite (AMPA\\/KA) receptor antagonist, (6,7-dinitroquinoxaline-2,3 (1H,4H); DNQX) administered intrathecally on carrageenan-induced thermal hyperalgesia and spinal c-Fos expression was investigated. The latency of paw withdrawal (PWL) from a thermal stimulus was used as a measure of hyperalgesia in awake rats. Intrathecal (i.t.) injection of

Yu-Qiu Zhang; Guang-Chen Ji; Gen-Cheng Wu; Zhi-Qi Zhao

2002-01-01

256

Piperazine-2,3-dicarboxylic acid Derivatives as Dual Antagonists of NMDA and GluK1-Containing Kainate Receptors  

PubMed Central

Competitive N-methyl-D-aspartate receptor (NMDAR) antagonists bind to the GluN2 subunit, of which there are four types (GluN2A-D). We report that some N1-substituted derivatives of cis-piperazine-2,3-dicarboxylic acid display improved relative affinity for GluN2C and GluN2D versus GluN2A and GluN2B. These derivatives also display subtype-selectivity among the more distantly related kainate receptor family. Compounds 18i and (?)-4 were the most potent kainate receptor antagonists and 18i was selective for GluK1 versus GluK2, GluK3 and AMPA receptors. Modeling studies revealed structural features required for activity at GluK1 subunits and suggested that S674 was vital for antagonist activity. Consistent with this hypothesis, replacing the equivalent residue in GluK3 (alanine) with a serine imparts 18i antagonist activity. Antagonists with dual GluN2D and GluK1 antagonist activity may have beneficial effects in various neurological disorders. Consistent with this idea, antagonist 18i (30 mg/Kg i.p.) showed antinociceptive effects in an animal model of mild nerve injury. PMID:22111545

Irvine, Mark W.; Costa, Blaise M.; Dlaboga, Daniel; Culley, Georgia; Hulse, Richard; Scholefield, Caroline L.; Atlason, Palmi; Fang, Guangyu; Eaves, Richard; Morley, Richard; Mayo-Martin, Maria B.; Amici, Mascia; Bortolotto, Zuner A.; Donaldson, Lucy; Collingridge, Graham L.; Molnár, Elek; Monaghan, Daniel T.; Jane, David E.

2011-01-01

257

Hereditary folate malabsorption: A positively charged amino acid at position 113 of the proton-coupled folate transporter (PCFT/SLC46A1) is required for folic acid binding  

SciTech Connect

The proton-coupled folate transporter (PCFT/SLC46A1) mediates intestinal folate uptake at acidic pH. Some loss of folic acid (FA) transport mutations in PCFT from hereditary folate malabsorption (HFM) patients cluster in R113, thereby suggesting a functional role for this residue. Herein, unlike non-conservative substitutions, an R113H mutant displayed 80-fold increase in the FA transport Km while retaining parental Vmax, hence indicating a major fall in folate substrate affinity. Furthermore, consistent with the preservation of 9% of parental transport activity, R113H transfectants displayed a substantial decrease in the FA growth requirement relative to mock transfectants. Homology modeling based on the crystal structures of the Escherichia coli transporter homologues EmrD and glycerol-3-phosphate transporter revealed that the R113H rotamer properly protrudes into the cytoplasmic face of the minor cleft normally occupied by R113. These findings constitute the first demonstration that a basic amino acid at position 113 is required for folate substrate binding.

Lasry, Inbal; Berman, Bluma [The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel)] [The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel); Glaser, Fabian [Bioinformatics Knowledge Unit, The Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion, Haifa 32000 (Israel)] [Bioinformatics Knowledge Unit, The Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion, Haifa 32000 (Israel); Jansen, Gerrit [Department of Rheumatology, VU University Medical Center, Amsterdam (Netherlands)] [Department of Rheumatology, VU University Medical Center, Amsterdam (Netherlands); Assaraf, Yehuda G., E-mail: assaraf@tx.technion.ac.il [The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel)

2009-08-28

258

MACROCYTIC ANEMIA OF PREGNANCY REVIEW OF LITERATURE AND REPORT OF A CASE TREATED WITH FOLIC AcID*  

E-print Network

The association of anemia with pregnancy is well recognized. In this country the anemia is commonly due to iron deficiencies and is hypochromic. In the tropics a macrocytic, hyperchromic anemia of pregnancy has attracted attention and has been the subject of many recent investigations. Its counterpart in the temperate climates, the macrocytic or so-called pernicious anemia of pregnancy, has been considered a relatively rare dyscrasia.', The macrocytic anemia of pregnancy was first recognized over a century ago when Channing2 reported ten fatal cases. In 1919 Osler7 differentiated the so-called pernicious anemia of pregnancy from typical Addisonian anemia by pointing out that when recovery from the former disease took place it was permanent and the woman might escape it in subsequent pregnancies. In macrocytic anemia of pregnancy the peripheral blood picture may vgry from one identical with that of true pernicous anemia to one lacking all characteristic features of this anemia.1 13 On the other hand, examination of the bone marrow reveals pictures identical with those found in true Addisonian pernicious anemia and clearly indicates that macrocytic anemia of pregnancy has for its immediate cause arrested maturation of the megaloblasts. The two features which may be relied upon for the certain diagnosis of macrocytic anemia of pregnancy are the appearance of megaloblasts in the peripheral blood and the finding of a megaloblastic change in the bone marrow.1 If the peripheral blood picture is not diagnostic, bone marrow biopsy by means of sternal puncture is necessary or some cases will be missed. The following features serve to differentiate the macrocytic anemia of pregnancy from the true Addisonian pernicious anemia: the presence of free hydrochloric acid in gastric juice either without or after histamine injection, a lower frequency and the degree of macrocytosis and

Sidney E

259

Calcium Antagonists Inhibit Sustained Gibberellic Acid-Induced Growth of Avena (Oat) Stem Segments.  

PubMed Central

The elongation response of Avena sativa (oat) stem segments to gibberellic acid (GA3) is of large magnitude, with high hormonal sensitivity and specificity, but without cell division activity. This system is therefore an excellent model for mechanistic studies on higher plant cell elongation and the action of gibberellin. At millimolar concentrations, the calcium antagonists verapamil, D-600, nicardipine, diltiazem, bepridil, 8-(N,N,-diethylamino)-octyl-3,4,5-trimethoxybenzoate HCl, and lanthanum substantially inhibited the growth of GA3-treated segments but had no effect on the elongation of nonhormone-treated segments. Although verapamil reduced the maximum growth rate and caused premature cessation of growth, even preincubation of the segments with the drug prior to treatment with GA3 failed to inhibit the earliest measured stimulation of growth by the hormone. Inhibition by verapamil was not reversed by increased concentrations of GA3 or calcium. Neither the calcium ionophore A23187 nor agonist BAY K 8644 had any effect on growth. Light microscopic examination of epidermal peels from antagonist-treated internodal tissue revealed no obvious differences from the control except that the cells were not as elongated. Although these results may support a role for calcium ion movement in maintaining the GA3-induced growth of Avena stem segments, they do not support the involvement of calcium ion movement in the hormone-mediated initiation of growth. PMID:12231695

Montague, M. J.

1993-01-01

260

Inhibition of pathological retinal angiogenesis by the integrin ?v?3 antagonist tetraiodothyroacetic acid (tetrac)  

PubMed Central

Retinal angiogenesis is a major cause of blindness in ischemic retinopathies including diabetic retinopathy and retinopathy of prematurity. Integrin ?v?3 is a promising therapeutic target for ocular angiogenesis, modulating the pro-angiogenic actions of multiple growth factors. In this study, we sought to determine the effects of the integrin ?v?3 antagonist tetra-iodothyroacetic acid (tetrac) on the angiogenic actions of VEGF and erythropoietin (EPO) in cultured human retinal endothelial cells. In addition, we investigated the effect of tetrac and a nanoparticulate formulation of tetrac on retinal angiogenesis in vivo, in the mouse oxygen-induced retinopathy (OIR) model. Tetrac inhibitory activity was evaluated in human retinal endothelial cells treated with VEGF and/or EPO. Endothelial cell proliferation, migration, and tube formation were assessed, in addition to phosphorylation of ERK1/2. For the studies of the oxygen-induced retinopathy model, C57BL/6 mice were exposed to 75% oxygen from postnatal day (P)7 to P12, and then returned to room air. Tetrac and tetrac-nanoparticle (tetrac-NP) were administered at P12 and P15 by either intraperitoneal or intravitreal injection. Retinal neovascularization was quantitated at P18. Tetrac significantly inhibited pro-angiogenic effects of VEGF and/or EPO on retinal endothelial cells, indicating that the angiogenic effects of both growth factors are dependent on integrin ?v?3. Retinal neovascularization in the OIR model was significantly inhibited by both tetrac and tetrac-NP. These results indicate that the integrin ?v?3 antagonist, tetrac, is an effective inhibitor of retinal angiogenesis. The ability of tetrac to inhibit the pro-angiogenic effect of both VEGF and EPO on retinal endothelial cells suggests that tetrac (and antagonism of integrin ?v?3) is a viable therapeutic strategy for proliferative diabetic retinopathy. PMID:22123068

Yoshida, Takeshi; Gong, Junsong; Xu, Zhenhua; Wei, Yanhong; Duh, Elia J.

2011-01-01

261

The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14.  

PubMed

A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY(14) with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y(14) with a good pharmacokinetic profile. PMID:21507640

Gauthier, Jacques Yves; Belley, Michel; Deschênes, Denis; Fournier, Jean-François; Gagné, Sébastien; Gareau, Yves; Hamel, Martine; Hénault, Martin; Hyjazie, Huda; Kargman, Stacia; Lavallée, Geneviève; Levesque, Jean-François; Li, Lianhai; Mamane, Yaël; Mancini, Joseph; Morin, Nicolas; Mulrooney, Erin; Robichaud, Joël; Thérien, Michel; Tranmer, Geoffrey; Wang, Zhaoyin; Wu, Jin; Black, W Cameron

2011-05-15

262

Practice Parameter update: Management issues for women with epilepsy--Focus on pregnancy (an evidence-based review): Vitamin K, folic acid, blood levels, and breastfeeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society  

Microsoft Academic Search

Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy. Methods: A 20-member

C. L. Harden; P. B. Pennell; B. S. Koppel; C. A. Hovinga; B. Gidal; K. J. Meador; J. Hopp; T. Y. Ting; W. A. Hauser; D. Thurman; P. W. Kaplan; J. N. Robinson; J. A. French; S. Wiebe; A. N. Wilner; B. Vazquez; L. Holmes; A. Krumholz; R. Finnell; P. O. Shafer; C. Le Guen

2009-01-01

263

The prevalence of low serum vitamin B-12 status in the absence of anemia or macrocytosis did not increase among older U.S. adults after mandatory folic acid fortification.  

PubMed

Whether folic acid fortification and supplementation at the population level have led to a higher prevalence of vitamin B-12 deficiency in the absence of anemia remains to be examined among a nationally representative sample of older U.S. adults. We assessed the prevalence of low vitamin B-12 status in the absence of anemia or macrocytosis before and after fortification among adults aged >50 y using cross-sectional data from the NHANES 1991-1994 (prefortification) and 2001-2006 (postfortification). We compared the prefortification and postfortification prevalence of multiple outcomes, including serum vitamin B-12 deficiency (<148 pmol/L) and marginal deficiency (148-258 pmol/L) with and without anemia (hemoglobin <130 g/L for men, <120 g/L for women) and with and without macrocytosis (mean cell volume >100 fL) using multinomial logistic regression, adjusting for age, sex, ethnicity, body mass index, C-reactive protein, and vitamin B-12 supplement use. Prefortification and postfortification serum vitamin B-12 deficiency without anemia [4.0 vs. 3.9%; adjusted prevalence ratio (aPR) (95% CI): 0.98 (0.67, 1.44)] or without macrocytosis [4.2 vs. 4.1%; aPR (95% CI): 0.96 (0.65, 1.43)] remained unchanged. Marginal deficiency without anemia [25.1 vs. 20.7%; aPR (95% CI): 0.82 (0.72, 0.95)] or without macrocytosis [25.9 vs. 21.3%; aPR (95% CI): 0.82 (0.72, 0.94)] were both significantly lower after fortification. After fortification, higher folic acid intake was associated with a lower prevalence of low serum B-12 status in the absence of anemia or macrocytosis. Results suggest that the prevalence of low serum B-12 status in the absence of anemia or macrocytosis among older U.S. adults did not increase after fortification. Thus, at the population level, we found no evidence to support concerns that folic acid adversely affected the clinical presentation of vitamin B-12 deficiency among older adults. PMID:24306216

Qi, Yan Ping; Do, Ann N; Hamner, Heather C; Pfeiffer, Christine M; Berry, Robert J

2014-02-01

264

Practical synthesis of a chromene analog for use as a retinoic acid receptor alpha antagonist lead compound  

PubMed Central

Retinoic acid receptor alpha (RAR?) selective compounds may guide the design of drugs that can be used in conjunction with hormonal adjuvant therapy in the treatment of breast cancer. Herein we report a modified synthesis of a known RAR? antagonist, 2-fluoro-4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid and a synthesis of its unknown, desfluoro analog, 4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid. The modified route allows for facile reaction workups, increased yields, lower cost and incorporates a green alternative step. Structure–activity relationship studies determined through functional cell-based assays, demonstrated antagonism to RAR? for both compounds. Molecular modeling within the RAR? binding pocket was used to compare binding interactions of the desfluoro analog to a known RAR antagonist. PMID:23474897

Jetson, Rachael; Malik, Neha; Luniwal, Amarjit; Chari, Venkatesh; Ratnam, Manohar; Erhardt, Paul

2013-01-01

265

Designed abscisic acid analogs as antagonists of PYL-PP2C receptor interactions.  

PubMed

The plant stress hormone abscisic acid (ABA) is critical for several abiotic stress responses. ABA signaling is normally repressed by group-A protein phosphatases 2C (PP2Cs), but stress-induced ABA binds Arabidopsis PYR/PYL/RCAR (PYL) receptors, which then bind and inhibit PP2Cs. X-ray structures of several receptor-ABA complexes revealed a tunnel above ABA's 3' ring CH that opens at the PP2C binding interface. Here, ABA analogs with sufficiently long 3' alkyl chains were predicted to traverse this tunnel and block PYL-PP2C interactions. To test this, a series of 3'-alkylsulfanyl ABAs were synthesized with different alkyl chain lengths. Physiological, biochemical and structural analyses revealed that a six-carbon alkyl substitution produced a potent ABA antagonist that was sufficiently active to block multiple stress-induced ABA responses in vivo. This study provides a new approach for the design of ABA analogs, and the results validated structure-based design for this target class. PMID:24792952

Takeuchi, Jun; Okamoto, Masanori; Akiyama, Tomonori; Muto, Takuya; Yajima, Shunsuke; Sue, Masayuki; Seo, Mitsunori; Kanno, Yuri; Kamo, Tsunashi; Endo, Akira; Nambara, Eiji; Hirai, Nobuhiro; Ohnishi, Toshiyuki; Cutler, Sean R; Todoroki, Yasushi

2014-06-01

266

Effect of long-term intermittent supplementation with multiple micronutrients compared with iron-and-folic acid supplementation on Hb and micronutrient status of non-anaemic adolescent schoolgirls in rural Bangladesh.  

PubMed

The present study examined whether long-term supplementation with once- and twice-weekly multiple micronutrients (MMN-1 and MMN-2) can improve Hb and micronutrient status more than twice-weekly Fe-folic acid (IFA-2) supplementation in non-anaemic adolescent girls in Bangladesh. An equal number of 324 rural schoolgirls aged 11-17 years were given MMN-1 or MMN-2 or IFA-2 supplements for 52 weeks in a randomised, double-blind trial. Blood samples were collected at baseline, and at 26 and 52 weeks of supplementation. The girls receiving IFA-2 supplements were more likely to be anaemic than the girls receiving MMN-2 supplements for 26 weeks (OR 5·1, 95% CI 1·3, 19·5; P = 0·018). All three supplements reduced Fe deficiency effectively. Both the MMN-1 and MMN-2 groups showed significantly greater improvements in vitamins A, B(2) and C status than the girls in the IFA-2 group, as might be expected. Receiving a MMN-1 supplement was found to be less effective than MMN-2 supplement in improving Fe, vitamins A, B(2) and folic acid status. Receiving micronutrient supplements beyond 26 weeks showed little additional benefit in improving micronutrient status. In conclusion, given twice-weekly for 26 weeks, MMN supplements can improve micronutrient status effectively with no significant increase in Hb concentration compared with IFA supplements in non-anaemic Bangladeshi adolescent girls. However, it significantly reduces the risk of anaemia. Before any recommendations can be made, further research, including into cost-effectiveness, is needed to see whether MMN supplementation has any additional longer-term health benefits over that of IFA supplementation in this population. PMID:22244349

Ahmed, Faruk; Khan, Moududur R; Akhtaruzzaman, Mohammad; Karim, Rezaul; Williams, Gail; Banu, Cadi P; Nahar, Badrun; Darnton-Hill, Ian

2012-10-28

267

Antiepileptic effects of focal micro-injection of excitatory amino acid antagonists  

Microsoft Academic Search

Summary The role of excitatory synaptic activity at various brain regions in the development and spread of seizure activity has been investigated by the focal microinjection of 2-amino-7-phosphono-heptanoate (2-APH), a selective antagonist at the N-methyl-D-aspartate preferring receptor, or?-D-glutamylaminomethyl sulphonate (GAMS), a partially selective antagonist at the kainate receptor. In genetically epilepsy prone rats the seizure response to a loud sound

B. Meldrum; M. Millan; S. Patel; G. de Sarro

1988-01-01

268

Pomolic acid, triterpenoid isolated from Licania pittieri, as competitive antagonist of ADP-induced aggregation of human platelets.  

PubMed

Pomolic acid (PA), triterpenoid isolated from Licania pittieri, has previously shown a potent ability to inhibit adenosine diphosphate (ADP)- and epinephrine-induced human platelet aggregation. To investigate whether PA could be an antagonist of ADP-activated receptors of human platelets (P2Y(1) and P2Y(12)), pharmacological studies were conducted to examining its ability to modulate the platelet shape change induced by a selective P2Y(1) receptor agonist MRS2365 and also the nature of its possible interaction with ADP receptors by analyzing the characteristics of log concentration-response curves of ADP constructed in the absence and in the presence of fixed concentrations of PA, using in vitro platelet aggregation assays. PA did not interfere with the activation of P2Y(1) receptor by MRS2365 to induce platelet shape change and displayed a competitive antagonism of ADP-induced platelet aggregation, which most probably involves competition for a single binding site in platelets. The estimated equilibrium dissociate constant (K(b)) of PA as ADP receptor antagonist was 15.4±0.06nM. Together, these findings give indirect evidence for the idea that PA could be a potent competitive antagonist of P2Y(12) receptor, and open the possibility to consider it as new member of the non-nucleotide generation of antiplatelet drugs. PMID:22402243

Alvarado-Castillo, Claudia; Estrada, Omar; Carvajal, Edilmo

2012-04-15

269

The intrathecal administration of excitatory amino acid receptor antagonists selectively attenuated carrageenan-induced behavioral hyperalgesia in rats.  

PubMed

A single unilateral injection of carrageenan (4.5-6.0 mg in 0.15-0.20 ml saline) into the rat hindpaw induced behavioral hyperalgesia as evidenced by a significant reduction in hindpaw withdrawal latency to a noxious thermal stimulus. The involvement of N-methyl-D-aspartate (NMDA) receptors in this model of hyperalgesia was examined by intrathecal administration of the selective excitatory amino acid (EAA) receptor antagonists: (+/-)-2-amino-5-phosphonopentanoic acid (AP-5), (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), ketamine hydrochloride (ketamine), 7-chlorokynurenic acid (7-Cl kynurenic acid), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The effects of dizocilpine maleate (MK-801) were studied under the same conditions and published previously (Ren et al., 1992) and the data are presented for comparison. While the withdrawal latencies of the non-injected paws and of the paws of naive rats were not significantly affected by application of the EAA receptor antagonists at doses tested, the paw withdrawal latencies of the carrageenan-injected paws were elevated dose dependently. The rank order of potency of these agents to reduce hyperalgesia was: MK-801 greater than or equal to AP-5 greater than or equal to CPP = 7-Cl kynurenic acid = ketamine much greater than CNQX greater than 0. In contrast, intrathecal injection of the opioid receptor agonists, [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO, mu-selective) and [D-Pen2,D-Pen5] enkephalin (DPDPE, delta-selective), produced antinociception in both injected and non-injected paws. DAMGO was much more potent, while DPDPE was less potent, than MK-801.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1358641

Ren, K; Williams, G M; Hylden, J L; Ruda, M A; Dubner, R

1992-08-25

270

Actions of excitatory amino acid agonists and antagonists on the primary afferents of the vestibular system of the axolotl (Ambystoma mexicanum)  

Microsoft Academic Search

In order to determine the nature of the transmitter in the synapse between hair cells and primary afferent fibers, both resting and evoked spike activity of vestibular system afferents were recorded. Excitatory amino acid agonists and antagonists were applied by mi- cro perfusion. Excitatory amino acid agonists consistently increased the firing rate of these afferents. The rank order in potencies

Enrique Soto; Rosario Vega

1988-01-01

271

On-line solid-phase enrichment coupled to packed reactor flow injection analysis in a green analytical procedure to determine low levels of folic acid using fluorescence detection  

PubMed Central

Background Analysis of folic acid (FA) is not an easy task because of its presence in lower concentrations, its lower stability under acidic conditions, and its sensitiveness against light and high temperature. The present study is concerned with the development and validation of an automated environmentally friendly pre-column derivatization combined by solid-phase enrichment (SPEn) to determine low levels of FA. Results Cerium (IV) trihydroxyhydroperoxide (CTH) as a packed oxidant reactor has been used for oxidative cleavage of FA into highly fluorescent product, 2-amino-4-hydroxypteridine-6-carboxylic acid. FA was injected into a carrier stream of 0.04 M phosphate buffer, pH 3.4 at a flow-rate of 0.25 mL/min. The sample zone containing the analyte was passed through the CTH reactor thermostated at 40°C, and the fluorescent product was trapped and enriched on a head of small ODS column (10 mm x 4.6 mm i.d., 5 ?m particle size). The enriched product was then back-flush eluted by column-switching from the small ODS column to the detector with a greener mobile phase consisting of ethanol and phosphate buffer (0.04M, pH 3.4) in the ratio of 5:95 (v/v). The eluent was monitored fluorimetrically at emission and excitation wavelengths of 463 and 367 nm, respectively. The calibration graph was linear over concentrations of FA in the range of 1.25-50 ng/mL, with a detection limit of 0.49 ng/mL. Conclusion A new simple and sensitive green analytical procedure including on-line pre-column derivatization combined by SPEn has been developed for the routine quality control and dosage form assay of FA at very low concentration level. The method was a powerful analytical technique that had excellent sensitivity, sufficient accuracy and required relatively simple and inexpensive instrumentation. PMID:23234331

2012-01-01

272

Discovery of novel agonists and antagonists of the free fatty acid receptor one (FFAR1) using virtual screening  

PubMed Central

The G protein-coupled receptor free fatty acid receptor 1 (FFAR1), previously named GPR40, is a possible novel target for the treatment of type 2 diabetes. In an attempt to identify new ligands for this receptor, we performed virtual screening (VS) based on 2D-similarity, 3D-pharmacophore searches and docking studies, using the structure of known agonists and our model of the ligand binding site, which was validated by mutagenesis. VS of a database of 2.6 million compounds followed by extraction of structural neighbors of functionally-confirmed hits resulted in identification of 15 compounds active at FFAR1 either as full agonists, partial agonists, or pure antagonists. Site-directed mutagenesis and docking studies revealed different patterns of ligand-receptor interactions, and provided important information on the role of specific amino acids in binding and activation of FFAR1. PMID:18193825

Tikhonova, Irina G.; Sum, Chi Shing; Neumann, Susanne; Engel, Stanislav; Raaka, Bruce M.; Costanzi, Stefano; Gershengorn, Marvin C.

2013-01-01

273

Simultaneous Determination of Gallic Acid, Ellagic Acid, and Eugenol in Syzygium aromaticum and Verification of Chemical Antagonistic Effect by the Combination with Curcuma aromatica Using Regression Analysis  

PubMed Central

This study was designed to perform simultaneous determination of three reference compounds in Syzygium aromaticum (SA), gallic acid, ellagic acid, and eugenol, and to investigate the chemical antagonistic effect when combining Curcuma aromatica (CA) with SA, based on chromatographic analysis. The values of LODs and LOQs were 0.01–0.11??g/mL and 0.03–0.36??g/mL, respectively. The intraday and interday precisions were <3.0 of RSD values, and the recovery was in the range of 92.19–103.24%, with RSD values <3.0%. Repeatability and stability were 0.38–0.73% and 0.49–2.24%, respectively. Compared with the content of reference and relative peaks in SA and SA combined with CA (SAC), the amounts of gallic acid and eugenol were increased, while that of ellagic acid was decreased in SAC (compared with SA), and most of peak areas in SA were reduced in SAC. Regression analysis of the relative peak areas between SA and SAC showed r2 values >0.87, indicating a linear relationship between SA and SAC. These results demonstrate that the components contained in CA could affect the extraction of components of SA mainly in a decreasing manner. The antagonistic effect of CA on SA was verified by chemical analysis. PMID:23878761

Seo, Chang-Seob; Kim, Seong-Sil; Ha, Hyekyung

2013-01-01

274

Chitinase Expression Due to Reduction in Fusaric Acid Level in an Antagonistic Trichoderma harzianum S17TH.  

PubMed

To study the effect of reduction in phytotoxin level on fungal chitinases, antagonistic Trichoderma spp. were screened for their ability to reduce the level of fusaric acid (FA), the phytotoxin produced by Fusarium spp. A T. harzianum isolate S17TH was able to tolerate high levels of FA (up to 500 ppm) but was unable to reduce the toxin to a significant level (non-toxic) added to minimal synthetic broth (MSB). However, the isolate was able to reduce 400 ppm FA in the liquid medium after 7 days to a non-toxic level and displayed similar level of antagonism over the control (without FA). In studies of the effect of the reduction in FA (400 ppm) level on chitinase gene expression in PCR assays, nag1 was significantly repressed but ech42 expression was only slightly repressed. Chitinase activity was either reduced or absent in the extracellular proteins of MSB supplemented with 400 ppm FA, which could be attributed to the effect of residual FA or its breakdown products through unknown mechanisms. Selection of S17TH as a toxin insensitive isolate that could commensurate the negative effect on chitinase activity makes it a potential antagonist against Fusarium spp. PMID:24426111

Sharma, Vivek; Bhandari, Pamita; Singh, Bikram; Bhatacharya, Amita; Shanmugam, Veerubommu

2013-06-01

275

[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C?T polymorphism of methylenetetrahydrofolate reductase  

PubMed Central

Background and purpose: 5,10-Methylenetetrahydrofolate reductase (MTHFR) is responsible for the synthesis of 5-methyltetrahydrofolate (5-MTHF). The 677C?T mutation of MTHFR reduces the activity of this enzyme. The aim of this study was, first, to compare pharmacokinetic parameters of [6S]-5-MTHF and folic acid (FA) in women with the homozygous (TT) and wild-type (CC) 677C?T mutation, and second, to explore genotype differences. The metabolism of [6S]-5-MTHF and FA was evaluated by measuring plasma folate derivatives. Experimental approach: Healthy females (TT, n= 16; CC, n= 8) received a single oral dose of FA (400 µg) and [6S]-5-MTHF (416 µg) in a randomized crossover design. Plasma folate was measured up to 8 h after supplementation. Concentration-time-profile [area under the curve of the plasma folate concentration vs. time (AUC)], maximum concentration (Cmax) and time-to-reach-maximum (tmax) were calculated. Key results: AUC and Cmax were significantly higher, and tmax significantly shorter for [6S]-5-MTHF compared with FA in both genotypes. A significant difference between the genotypes was observed for tmax after FA only (P < 0.05). Plasma folate consisted essentially of 5-MTHF irrespective of the folate form given. Unmetabolized FA in plasma occurs regularly following FA supplementation, but rarely with [6S]-5-MTHF. Conclusions and implications: These data suggest that [6S]-5-MTHF increases plasma folate more effectively than FA irrespective of the 677C?T mutation of the MTHFR. This natural form of folate could be an alternative to FA supplementation or fortification. PMID:19917061

Prinz-Langenohl, R; Brämswig, S; Tobolski, O; Smulders, YM; Smith, DEC; Finglas, PM; Pietrzik, K

2009-01-01

276

An acidic fibroblast growth factor protein generated by alternate splicing acts like an antagonist  

PubMed Central

Polymerase chain reaction amplification of cDNA for acidic fibroblast growth factor in several lines of cultured human cells revealed two forms of mRNA. The novel smaller mRNA lacks the entire second coding exon of the acidic fibroblast growth factor gene, whereas the previously identified mRNA consists of three coding exons. The truncated variant of acidic fibroblast growth factor (aFGF') is only 60 amino acids long with an apparent molecular mass of 6.7 kD on sodium dodecyl sulfate gels in contrast to 18 kD for the full-length acidic fibroblast growth factor. aFGF' elicits only minimal fibroblast proliferation and antagonizes the effects of acidic fibroblast growth factor when added exogenously to or when coexpressed with aFGF in BALB/c/3T3 fibroblasts. Thus, the truncated variant of acidic fibroblast growth factor may provide fibroblasts with a unique mechanism for endogenous regulation of their responses to acidic fibroblast growth factor. PMID:1372643

1992-01-01

277

Differential effects of transient receptor vanilloid one (TRPV1) antagonists in acid-induced excitation of esophageal vagal afferent fibers of rats  

Microsoft Academic Search

Gastro-esophageal acid reflux can stimulate esophageal vagal sensory afferents by activating proton-sensitive ion channel transient receptor vanilloid one (TRPV1). The objective of this study was to investigate the response characteristics of vagal afferent fibers of rats to acid (0.1 N HCl) and capsaicin (CAP) following esophagitis and differential effects of two classes of TRPV1 antagonists on responses of vagal afferent

S. Peles; B. K. Medda; Zhihong Zhang; B. Banerjee; A. Lehmann; R. Shaker; J. N. Sengupta

2009-01-01

278

Glutamate-evoked release of endogenous brain dopamine: inhibition by an excitatory amino acid antagonist and an enkephalin analogue.  

PubMed Central

The present study examined the effect of a selective delta-opioid receptor agonist [D-Ala2-D-Leu5] enkephalin (DADL) on the spontaneous and the L-glutamic acid (L-Glu)-evoked release of endogenous dopamine from superfused slices of rat caudate-putamen. The amount of dopamine in slice superfusates was measured by a sensitive method employing high-performance liquid chromatography with electrochemical detection (h.p.l.c.-e.d.) after a two-step separation procedure. The spontaneous release of endogenous dopamine was partially dependent on Ca2+, enhanced in Mg2+-free superfusion medium, partially reduced by tetrodotoxin (TTX, 0.3 microM), partially reduced by the putative excitatory amino acid receptor antagonist DL-2-amino-7-phosphonoheptanoic acid (DL-APH, 1 mM), and increased 10 fold by the dopamine uptake blocker, nomifensine (10 microM). DADL (5 and 50 nM) did not significantly affect spontaneous dopamine release. L-Glu (0.1-10 mM) produced a concentration-dependent release of endogenous dopamine from slices of caudate-putamen. This effect was Ca2+-dependent, strongly inhibited by 1.2 mM Mg2+, attenuated by DL-APH (1 mM), attenuated by TTX (0.3 microM), and enhanced by nomifensine (10 microM). In the presence of nomifensine DADL (50 nM) reduced significantly the L-Glu-evoked release of endogenous dopamine by 20%. The inhibitory effect of DADL was blocked by 10 microM naloxone. These results indicate that L-Glu stimulates the Ca2+-dependent release of endogenous dopamine in the caudate-putamen by activation of N-methy-D-aspartate-type of excitatory amino acid receptors. This release can be selectively modified by the delta-opioid agonist DADL in a naloxone-sensitive manner. PMID:2884003

Jhamandas, K.; Marien, M.

1987-01-01

279

Differential and antagonistic effects of 9- cis -retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro  

PubMed Central

Retinoids and vitamin D are known to exert important anti-tumour effects in a variety of cell types. In this study the effects of 9- cis -retinoic acid (9cRA) the vitamin D analogues EB1089 and CB1093 on three pancreatic adenocarcinoma cell lines were investigated. All compounds caused inhibition of in vitro growth but the vitamin D analogues were generally the more potent growth inhibitors. They were also more effective on their own than in combination with 9cRA. Growth arrest correlated with an increased proportion of cells in the G0/G1 phase. Apoptosis was induced in the three cell lines by 9cRA, whereas neither EB1089 nor CB1093 had this effect. Furthermore, addition of EB1089 or CB1093 together with 9cRA resulted in significantly reduced apoptosis. Our results show that retinoic acids as well as vitamin D analogues have inhibitory effects on pancreatic tumour cells but different and antagonistic mechanisms seem to be employed. © 2000 Cancer Research Campaign PMID:10901377

Pettersson, F; Colston, K W; Dalgleish, A G

2000-01-01

280

Differential effects of transient receptor vanilloid one (TRPV1) antagonists in acid-induced excitation of esophageal vagal afferent fibers of rats.  

PubMed

Gastro-esophageal acid reflux can stimulate esophageal vagal sensory afferents by activating proton-sensitive ion channel transient receptor vanilloid one (TRPV1). The objective of this study was to investigate the response characteristics of vagal afferent fibers of rats to acid (0.1 N HCl) and capsaicin (CAP) following esophagitis and differential effects of two classes of TRPV1 antagonists on responses of vagal afferent fibers. The chronic reflux was induced by ligating the fundus of the stomach and partial constriction of pylorus. Extracellular single fiber recordings were made from the cervical vagal afferent fibers from naive control and fundus-ligated (FL) esophagitis rats. Innervations of fibers were identified to esophageal distension (ED) and subsequently tested to CAP and acid before and after injection of TRPV1 antagonist JYL1421 or AMG9810 (10 micromol/kg i.v.). Seventy-five vagal afferent fibers from 70 rats were identified to ED. Intra-esophageal CAP (0.1 ml of 1 mg/ml) excited 39.5% (17/43, 5/22 from naive and 12/21 from FL rats) fibers. In contrast, i.v. injection of CAP (0.03-0.3 micromol/kg) dose-dependently excited 72% (42/58) fibers. Responses to CAP were significantly greater for fibers from FL rats (n=32) than naive rats (n=25). TRPV1 antagonists JYL1421 and AMG9810 (10 micromol/kg) significantly blocked response to CAP. Intra-esophageal acid infusion stimulated 5/17 (29.4%) fibers from naive rats and 12/28 (42%) from FL rats. Effect of acid was significantly blocked by AMG9810, but not by JYL1421. Results indicate that following esophagitis the number of fibers responsive to CAP and acid is greater than noninflamed esophagus, which may contribute to esophageal hypersensitivity. Acid-induced excitation of vagal sensory afferents can be differentially attenuated by different classes of TRPV1 antagonists. Therefore, TRPV1 antagonists play a key role in attenuation of hypersensitivity following reflux-induced esophagitis. The use of TRPV1 antagonists could be an alternative to the traditional symptoms-based treatment of chronic acid reflux and esophageal hypersensitivity. PMID:19324074

Peles, S; Medda, B K; Zhang, Zhihong; Banerjee, B; Lehmann, A; Shaker, R; Sengupta, J N

2009-06-30

281

Polyamine spider toxins are potent un-competitive antagonists of rat cortex excitatory amino acid receptors.  

PubMed

We examined the effect of argiopine and argiopinine 3, low molecular weight polyamine venom components of the spider Argiope lobata, on rat cortical excitatory amino acid (EAA) receptors expressed in Xenopus oocytes. Responses to 100 microM N-methyl-D-aspartate (NMDA) with 10 microM glycine were blocked by both of the polyamine toxins in a dose-dependent manner. Both compounds had similar potencies against 100 microM kainate or 50 microM (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (L-AMPA). Oscillatory responses to 2 microM quisqualate were unaffected by either polyamine toxin. Increasing concentrations of either NMDA, kainate or AMPA were unable to overcome the antagonism by either spider toxin. We were able to demonstrate a use-dependent phenomenon similar to that of phencyclidine; neither polyamine toxin affected the NMDA, kainate or AMPA response without the presence of the respective agonist. PMID:1385187

Davies, M S; Baganoff, M P; Grishin, E V; Lanthorn, T H; Volkova, T M; Watson, G B; Wiegand, R C

1992-09-01

282

Cis-acting DNA Elements Responsive to Gibberellin and Its Antagonist Abscisic Acid  

Microsoft Academic Search

We have used a transient expression assay in aleurone protoplasts of barley to delineate hormone response elements of the abscisic acid (ABA)-responsive rice gene Rab-16A and of the gibberellin A_3 (GA_3)-responsive barley alpha-amylase gene Amy 1\\/6-4. Our approach used transcriptional fusions between their 5' upstream sequences and a bacterial chloramphenicol acetyltransferase reporter gene. A chimeric promoter containing six copies of

Karen Skriver; Finn Lok Olsen; John C. Rogers; John Mundy

1991-01-01

283

A Lower Degree of PBMC L1 Methylation in Women with Lower Folate Status May Explain the MTHFR C677T Polymorphism Associated Higher Risk of CIN in the US Post Folic Acid Fortification Era  

PubMed Central

Background Studies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk. Methods The study included 457 US women diagnosed with either CIN 2+ (cases) or ? CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN. Results The 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR?=?2.41, P?=?0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR?=?0.28, P?=?0.017). Conclusions This study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation. PMID:25302494

Badiga, Suguna; Johanning, Gary L.; Macaluso, Maurizio; Azuero, Andres; Chambers, Michelle M.; Siddiqui, Nuzhat R.; Piyathilake, Chandrika J.

2014-01-01

284

Stapling Mimics Noncovalent Interactions of ?-Carboxyglutamates in Conantokins, Peptidic Antagonists of N-Methyl-d-Aspartic Acid Receptors*  

PubMed Central

Conantokins are short peptides derived from the venoms of marine cone snails that act as antagonists of the N-methyl-d-aspartate (NMDA) receptor family of excitatory glutamate receptors. These peptides contain ?-carboxyglutamic acid residues typically spaced at i,i+4 and/or i,i+7 intervals, which by chelating divalent cations induce and stabilize helical conformation of the peptide. Introduction of a dicarba bridge (or a staple) can covalently stabilize peptide helicity and improve its pharmacological properties. To test the hypothesis that stapling can effectively replace ?-carboxyglutamic acid residues in stabilizing the helical conformation of conantokins, we designed, synthesized, and characterized several stapled analogs of conantokin G (conG), with varying connectivities in terms of staple length and location along the face of the ?-helix. NMR studies confirmed that the ring-closing metathesis reaction yielded a single product with the Z configuration of the olefinic bond. Based on circular dichroism and molecular modeling, the stapled analogs exhibited significantly enhanced helicity compared with the native peptide in a metal-free environment. Stapling i,i+4 was benign with respect to effects on in vitro and in vivo pharmacological properties. One analog, namely conG[11–15,Si,i+4S(8)], blocked NR2B-containing NMDA receptors with IC50 = 0.7 ?m and provided significant protection in the 6-Hz psychomotor model of pharmacoresistant epilepsy in mice. Remarkably, unlike native conG, conG[11–15,Si,i+4S(8)] produced no behavioral motor toxicity. Our results extend the applications of peptide stapling to helical peptides with extracellular targets and provide a means for engineering conantokins with improved pharmacological properties. PMID:22518838

Platt, Randall J.; Han, Tiffany S.; Green, Brad R.; Smith, Misty D.; Skalicky, Jack; Gruszczynski, Pawel; White, H. Steve; Olivera, Baldomero; Bulaj, Grzegorz; Gajewiak, Joanna

2012-01-01

285

LXR-? antagonist meso-dihydroguaiaretic acid attenuates high-fat diet-induced nonalcoholic fatty liver.  

PubMed

Collaborative regulation of liver X receptor (LXR) and sterol regulatory element binding protein (SREBP)-1 are main determinants in hepatic steatosis, as shown in both animal models and human patients. Recent studies indicate that selective intervention of overly functional LXR? in the liver shows promise in treatment of fatty liver disease. In the present study, we evaluated the effects of meso-dihydroguaiaretic acid (MDGA) on LXR? activation and its ability to attenuate fatty liver in mice. MDGA inhibited activation of the LXR? ligand-binding domain by competitively binding to the pocket for agonist T0901317 and decreased the luciferase activity in LXRE-tk-Luc-transfected cells. MDGA significantly attenuated hepatic neutral lipid accumulation in T0901317- and high fat diet (HFD)-induced fatty liver. The effect of MDGA was so potent that treatment with 1mg/kg for 2 weeks completely reversed the lipid accumulation induced by HFD feeding. MDGA reduced the expression of LXR? co-activator protein RIP140 and LXR? target gene products associated with lipogenesis in HFD-fed mice. These results demonstrate that MDGA has the potential to attenuate nonalcoholic steatosis mediated by selective inhibition of LXR? in the liver in mice. PMID:24955981

Sim, Woo-Cheol; Park, Sora; Lee, Kang-Yo; Je, Young-Tae; Yin, Hu-Quan; Choi, You-Jin; Sung, Sang Hyun; Park, So-Jung; Park, Hyun-Ju; Shin, Kye Jung; Lee, Byung-Hoon

2014-08-15

286

Mercaptoacetate and fatty acids exert direct and antagonistic effects on nodose neurons via GPR40 fatty acid receptors.  

PubMed

?-mercaptoacetate (MA) is a drug known to block mitochondrial oxidation of medium- and long-chain fatty acids (FAs) and to stimulate feeding. Because MA-induced feeding is vagally dependent, it has been assumed that the feeding response is mediated by MA's antimetabolic action at a peripheral, vagally innervated site. However, MA's site of action has not yet been identified. Therefore, we used fluorescent calcium measurements in isolated neurons from rat nodose ganglia to determine whether MA has direct effects on vagal sensory neurons. We found that MA alone did not alter cytosolic calcium concentrations in nodose neurons. However, MA (60 ?M to 6 mM) significantly decreased calcium responses to both linoleic acid (LA; 10 ?M) and caprylic acid (C8; 10 ?M) in all neurons responsive to LA and C8. GW9508 (40 ?M), an agonist of the FA receptor, G protein-coupled receptor 40 (GPR40), also increased calcium levels almost exclusively in FA-responsive neurons. MA significantly inhibited this response to GW9508. MA did not inhibit calcium responses to serotonin, high K(+), or capsaicin, which do not utilize GPRs, or to CCK, which acts on a different GPR. GPR40 was detected in nodose ganglia by RT-PCR. Results suggest that FAs directly activate vagal sensory neurons via GPR40 and that MA antagonizes this effect. Thus, we propose that MA's nonmetabolic actions on GPR40 membrane receptors, expressed by multiple peripheral tissues in addition to the vagus nerve, may contribute to or mediate MA-induced stimulation of feeding. PMID:24760994

Darling, Rebecca A; Zhao, Huan; Kinch, Dallas; Li, Ai-Jun; Simasko, Steven M; Ritter, Sue

2014-07-01

287

Designing hypothesis of some 2,4 -disubstituted-phenoxy acetic acid derivatives as a Crth2 receptor antagonist: A QSAR approach  

Microsoft Academic Search

In pursuit of better CRTh2 receptor antagonist agents, 2D-QSAR, 3D- QSAR studies were performed on a series of 2,4-disubstituted-phenoxy acetic acid derivatives. The best QSAR model was selected, having correlation coefficient R = 0.904, standard error of estimation SEE = 0.456 and cross validated squared correlation coefficient Q2 = 0.739. The predictive ability of the selected model was also confirmed

Abhishek Jain; R. K. Agrawal

2009-01-01

288

A Placebo-Controlled Randomized Crossover Trial of the N-Methyl-d-Aspartic Acid Receptor Antagonist, Memantine, in Patients with Chronic Phantom Limb Pain  

Microsoft Academic Search

In the present study we investigated the effect of the N-methyl-d-aspartic acid (NMDA) receptor antagonist memantine (30 mg\\/d) on the intensity of chronic phan- tom limb pain (PLP) and cortical reorganization. In 8 patients with chronic PLP, memantine was tested in a placebo-controlled double-blinded crossover trial of 4 wk duration per trial. The intensity of PLP was rated hourly by

Katja Wiech; Ralph-Thomas Kiefer; Hubert Preissl; Christoph Braun; Klaus Unertl; Herta Flor; Niels Birbaumer

2004-01-01

289

Spina Bifida and Folic Acid Awareness  

ERIC Educational Resources Information Center

Spina bifida is the most common, permanently disabling birth defect in the United States. It is a birth defect that involves incomplete formation of the spine during the first month of pregnancy--often before a woman even knows she is pregnant. Everyday, an average of eight babies are born with spina bifida or a similar birth defect of the brain…

Exceptional Parent, 2007

2007-01-01

290

Cyclopentane-1,3-dione: A Novel Isostere for the Carboxylic Acid Functional Group. Application to the Design of Potent Thromboxane (A2)-Receptor Antagonists  

PubMed Central

Cyclopentane-1,3-diones are known to exhibit pKa values typically in the range of carboxylic acids. To explore the potential of the cyclopentane-1,3-dione unit as a carboxylic acid isostere, the physical-chemical properties of representative congeners were examined and compared with similar derivatives bearing carboxylic acid or tetrazole residues. These studies suggested that cyclopentane-1,3-diones may effectively substitute for the carboxylic acid functional group. To demonstrate the use of the cyclopentane-1,3-dione isostere in drug-design, derivatives of a known thromboxane-A2 prostanoid (TP) receptor antagonist, 3-(3-(2-(4-chlorophenylsulfonamido)ethyl)-phenyl)propanoic acid (12), were synthesized and evaluated in both functional and radioligand-binding assays. A series of mono- and di-substituted cyclopentane-1,3-dione derivatives (41–45) were identified that exhibit nM IC50 and Kd values similar to 12. Collectively, these studies demonstrate that the cyclopentane-1,3-dione moiety comprises a novel isostere of the carboxylic acid functional group. Given the combination of the relatively strong acidity, tunable lipophilicity, and versatility of the structure, the cyclopentane-1,3-dione moiety may constitute a valuable addition to the palette of carboxylic acid isosteres. PMID:21863799

Ballatore, Carlo; Soper, James; Piscitelli, Francesco; James, Michael; Huang, Longchuan; Atasoylu, Onur; Huryn, Donna M.; Trojanowski, John Q.; Lee, Virginia M.-Y.; Brunden, Kurt R.; Smith, Amos B.

2011-01-01

291

Anti-Diabetic Efficacy and Impact on Amino Acid Metabolism of GRA1, a Novel Small-Molecule Glucagon Receptor Antagonist  

PubMed Central

Hyperglucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the glucagon receptor (GCGR) thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small-molecule GCGR antagonist that blocks glucagon binding to the human GCGR (hGCGR) and antagonizes glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma glucagon and glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism. PMID:23185367

Mu, James; Qureshi, Sajjad A.; Brady, Edward J.; Muise, Eric S.; Candelore, Mari Rios; Jiang, Guoqiang; Li, Zhihua; Wu, Margaret S.; Yang, Xiaodong; Dallas-Yang, Qing; Miller, Corey; Xiong, Yusheng; Langdon, Ronald B.; Parmee, Emma R.; Zhang, Bei B.

2012-01-01

292

D and L -N-[(1-benzyl-1H-imidazol-5-yl)-alkyl]-amino acids as angiotensin II AT1 antagonists  

Microsoft Academic Search

A series of D and L-N-[(1-benzyl-1H-imidazol-5-yl)-alkyl]-aromatic amino acids (2 to 9) and several achiral analogs (1,10,11) were found to be potent AII antagonists (nM range). Among chiral pairs the D isomer had the highest affinity for the binding site. A D-phenylalanine analog, 3, was the most potent (IC50 3.8 nM) and had activity in vivo similar to SK&F 108566 when

David T. Hill; Gerald R. Girard; Joseph Weinstock; Richard M. Edwards; Edwin F. Weidley; Eliot Ohlstein; Catherine E. Peishoff; Elayne Baker; Nambi Aiyar

1995-01-01

293

Pharmacological characterization of LY233053: A structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action  

SciTech Connect

This study reports the activity of a structurally novel excitatory amino acid receptor antagonist, LY233053 (cis-(+-)-4-((2H-tetrazol-5-yl)methyl)piperidine-2-carboxylic acid), the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of (3H) CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in (3H)alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or (3H)kainate binding assays was observed (IC50 values greater than 10,000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats, LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons, LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However, a dose of 160 mg/kg, i.m., was required to produce phencyclidine-like catalepsy in pigeons. In mice, LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary, the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity.

Schoepp, D.D.; Ornstein, P.L.; Leander, J.D.; Lodge, D.; Salhoff, C.R.; Zeman, S.; Zimmerman, D.M. (Eli Lilly and Company, Indianapolis, IN (USA))

1990-12-01

294

Associations of erythrocyte membrane fatty acids with the concentrations of C-reactive protein, interleukin 1 receptor antagonist and adiponectin in 1373 men.  

PubMed

Dietary and endogenous fatty acids could play a role in low-grade inflammation. In this cross-sectional study the proportions of erythrocyte membrane fatty acids (EMFA) and the concentrations of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra) and adiponectin were measured and their confounder-adjusted associations examined in 1373 randomly selected Finnish men aged 45-70 years participating in the population based Metsim study in Eastern Finland. The sum of n-6 EMFAs, without linoleic acid (LA), was positively associated with concentrations of CRP and IL-1Ra (rpartial=0.139 and rpartial=0.115, P<0.001). These associations were especially strong among lean men (waist circumference <94cm; rpartial=0.156 and rpartial=0.189, P<0.001). Total n-3 EMFAs correlated inversely with concentrations of CRP (rpartial=-0.098, P<0.001). Palmitoleic acid (16:1n-7) correlated positively with CRP (rpartial=0.096, P<0.001). Cis-vaccenic acid (18:1n-7) was associated with high concentrations of adiponectin (rpartial=0.139, P<0.001). In conclusion, n-6 EMFAs, except for LA, correlated positively with the inflammatory markers. Palmitoleic acid was associated with CRP, whereas, interestingly, its elongation product, cis-vaccenic acid, associated with anti-inflammatory adiponectin. PMID:25087591

Takkunen, M J; de Mello, V D F; Schwab, U S; Agren, J J; Kuusisto, J; Uusitupa, M I J

2014-10-01

295

Glucocorticoid antagonist RU38486 fails to block acid-induced muscle wasting in vivo or in vitro  

Microsoft Academic Search

Background. Increased protein degradation during metabolic acidosis contributes to muscle wasting in uraemia. Adrenalectomy experiments in severely acidotic rats (arterial pH ? 7.15) have shown that this is preventedin the absence of glucocorticoid . It shouldtherefore be possible to block such muscle wasting with glucocorticoidreceptor antagonist 11 - (4-dimethylaminophenyl)-17-hydroxy,-17a-(prop-1-ynyl)- estra-4,9-dien-3-one (RU38486). Methods. The effect of oral RU38486 (50 mg\\/kg body

Warren P. Pickering; Frease E. Baker; Jeremy Brown; Heather L. Butler; Sheena Govindji; Julie M. Parsons; Izabella Z. A. Pawluczyk

296

An Amino Acid Substitution Inhibits Specialist Herbivore Production of an Antagonist Effector and Recovers Insect-Induced Plant Defenses1[W][OA  

PubMed Central

Plants respond to insect herbivory through the production of biochemicals that function as either direct defenses or indirect defenses via the attraction of natural enemies. While attack by closely related insect pests can result in distinctive levels of induced plant defenses, precise biochemical mechanisms responsible for differing responses remain largely unknown. Cowpea (Vigna unguiculata) responds to Fall armyworm (Spodoptera frugiperda) herbivory through the detection of fragments of chloroplastic ATP synthase ?-subunit proteins, termed inceptin-related peptides, present in larval oral secretions (OS). In contrast to generalists like Fall armyworm, OS of the legume-specializing velvetbean caterpillar (VBC; Anticarsia gemmatalis) do not elicit ethylene production and demonstrate significantly lower induced volatile emission in direct herbivory comparisons. Unlike all other Lepidoptera OS examined, which preferentially contain inceptin (Vu-In; +ICDINGVCVDA?), VBC OS contain predominantly a C-terminal truncated peptide, Vu-In?A (+ICDINGVCVD?). Vu-In?A is both inactive and functions as a potent naturally occurring antagonist of Vu-In-induced responses. To block antagonist production, amino acid substitutions at the C terminus were screened for differences in VBC gut proteolysis. A valine-substituted peptide (Vu-In?V; +ICDINGVCVDV?) retaining full elicitor activity was found to accumulate in VBC OS. Compared with the native polypeptide, VBC that previously ingested 500 pmol of the valine-modified chloroplastic ATP synthase ?-subunit precursor elicited significantly stronger plant responses in herbivory assays. We demonstrate that a specialist herbivore minimizes the activation of defenses by converting an elicitor into an antagonist effector and identify an amino acid substitution that recovers these induced plant defenses to a level observed with generalist herbivores. PMID:23008466

Schmelz, Eric A.; Huffaker, Alisa; Carroll, Mark J.; Alborn, Hans T.; Ali, Jared G.; Teal, Peter E.A.

2012-01-01

297

The calpain inhibitor MDL-28170 and the AMPA/KA receptor antagonist CNQX inhibit neurofilament degradation and enhance neuronal survival in kainic acid-treated hippocampal slice cultures.  

PubMed

The cytoskeleton controls the architecture and survival of the central nervous system neurons by maintaining the stability of axons, dendrites and cellular architecture, and any disturbance in this genuine structure could compromise cell survival. The developmentally regulated intracellular intermediate filament protein neurofilament (NF), composed of the light (NF-L), medium (NF-M) and high (NF-H) molecular weight isoforms, is expressed abundantly in nerve cells but its significance in nerve cell survival in stress situations in the brain is unknown. We have used Western blotting, immunocytochemistry, and Fluoro-Jade B and thionine stainings to clarify the effect of kainic acid (KA) treatment on NF protein stability, and its importance for neuronal survival in hippocampal slice cultures. The contribution of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/KA glutamate receptor subtypes, calpain proteases and L-type Ca2+-channels to these processes were also assessed. Our results indicated that KA-induced degradation of NF was a fast process, similarly affecting all three NF proteins. It was effectively inhibited by the AMPA/KA receptor antagonist CNQX and the calpain inhibitor MDL-28170, whereas the Ca2+-channel blocker nifedipine and the NMDA receptor antagonist MK-801 had no significant effect. Moreover, KA-induced neuronal damage was effectively decreased in cultures treated with CNQX and MDL-28170. Our results suggest that the stability of NF proteins is an important factor contributing to neuronal survival after excitotoxic injury, and that both AMPA/KA receptor antagonists and calpain inhibitors might serve as neuroprotectants against this type of insult in the immature hippocampus. PMID:16817871

Lopez-Picon, Francisco R; Kukko-Lukjanov, Tiina-Kaisa; Holopainen, Irma E

2006-05-01

298

Screening of surface properties and antagonistic substances production by lactic acid bacteria isolated from the mammary gland of healthy and mastitic cows.  

PubMed

Bovine mastitis (BM) is a costly disease in dairy cattle production. The prevention and treatment of mastitis is performed by applying antimicrobial products that negatively affect milk quality. In the last years, the use of probiotic microorganisms to prevent infections in humans and animals has being aggressively studied. Samples from teat canal and milk (foremilk and stripping) were taken from healthy and mastitic mammary quarters. A screening of the surface properties and antagonistic substances production of lactic acid bacteria (LAB) isolated from the mammary gland was performed to select potential probiotic strains to prevent mastitis. Somatic cell count, physico-chemical and microbiological studies were carried out. Pre-selected microorganisms were genetically identified. Compared with stripping milk, foremilk showed lower levels of fat and higher levels of pH, density, microorganism numbers, lower percentage of strains with mean and high hydrophobicity and mean autoaggregation and higher number of strains able to produce hydrogen peroxide and bacteriocins. The other parameters analyzed were not statistically significant. One hundred and two LAB strains were isolated. Most of them had low degrees of hydrophobicity and autoaggregation. No correlation between these properties was found. Antagonistic metabolites were mainly produced by strains isolated from healthy quarters. Most of the pre-selected strains were identified as Streptococcus bovis and Weissella paramesenteroides. Three bacteriocin-producers were found and their products partially characterized. The results of this work are the basis for the further design of a specie-specific probiotic product able to prevent BM. PMID:19041199

Espeche, Maria Carolina; Otero, Maria Claudia; Sesma, Fernando; Nader-Macias, Maria Elena Fatima

2009-03-30

299

?-aminobutyric acid(C) (GABAC) selective antagonists derived from the bioisosteric modification of 4-aminocyclopent-1-enecarboxylic acid: amides and hydroxamates.  

PubMed

Series of compounds were generated via the bioisosteric replacement of the carboxylate of 4-ACPCA (2) with hydroxamate or amide groups. All compounds from this study exhibited increased selectivity for GABAC, the most potent being 4-ACPHA (10a, IC50 = 13 ?M) and 4-ACPAM (11a, IC50 = 10 ?M). This provides evidence that a zwitterionic structure is not essential for GABAC antagonists, rather the emphasis lies in appropriate heteroatoms to participate in hydrogen bonding. PMID:23755849

Locock, Katherine E S; Yamamoto, Izumi; Tran, Priscilla; Hanrahan, Jane R; Chebib, Mary; Johnston, Graham A R; Allan, Robin D

2013-07-11

300

Discovery of potent, selective, and orally bioavailable alkynylphenoxyacetic acid CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.  

PubMed

New phenoxyacetic acid antagonists of CRTH2 are described. Following the discovery of a hit compound by a focused screening, high protein binding was identified as its main weakness. Optimization aimed at reducing serum protein binding led to the identification of several compounds that showed not only excellent affinities for the receptor (41 compounds with K(i) < 10 nM) but also excellent potencies in a human whole blood assay (IC(50) < 100 nM; PGD2-induced eosinophil shape change). Additional optimization of the PK characteristics led to the identification of several compounds suitable for in vivo testing. Of these, 19k and 19s were tested in two different pharmacological models (acute FITC-mediated contact hypersensitivity and ovalbumin-induced eosinophilia models) and found to be active after oral dosing (10 and 30 mg/kg). PMID:21916510

Crosignani, Stefano; Prêtre, Adeline; Jorand-Lebrun, Catherine; Fraboulet, Gaële; Seenisamy, Jeyaprakashnarayanan; Augustine, John Kallikat; Missotten, Marc; Humbert, Yves; Cleva, Christophe; Abla, Nada; Daff, Hamina; Schott, Olivier; Schneider, Manfred; Burgat-Charvillon, Fabienne; Rivron, Delphine; Hamernig, Ingrid; Arrighi, Jean-François; Gaudet, Marilène; Zimmerli, Simone C; Juillard, Pierre; Johnson, Zoe

2011-10-27

301

Antagonistic properties of a natural product – Bicuculline with the gamma-aminobutyric acid receptor: Studied through electrostatic potential mapping, electronic and vibrational spectra using ab initio and density functional theory  

Microsoft Academic Search

(+)-Bicuculline (hereinafter referred to as bicuculline), a phthalide isoquinoline alkaloid is of current interest as an antagonist of gamma-aminobutyric acid (GABA). Its inhibitor properties have been studied through molecular electrostatic potential (MEP) mapping of this molecule and GABA receptor. The hot site on the potential surface of bicuculline, which is also isosteric with GABA receptor, has been used to interpret

Anubha Srivastava; Poonam Tandon; Sudha Jain; B. P. Asthana

2011-01-01

302

Dual orexin receptor antagonists show distinct effects on locomotor performance, ethanol interaction and sleep architecture relative to gamma-aminobutyric acid-A receptor modulators  

PubMed Central

Dual orexin receptor antagonists (DORAs) are a potential treatment for insomnia that function by blocking both the orexin 1 and orexin 2 receptors. The objective of the current study was to further confirm the impact of therapeutic mechanisms targeting insomnia on locomotor coordination and ethanol interaction using DORAs and gamma-aminobutyric acid (GABA)-A receptor modulators of distinct chemical structure and pharmacological properties in the context of sleep-promoting potential. The current study compared rat motor co-ordination after administration of DORAs, DORA-12 and almorexant, and GABA-A receptor modulators, zolpidem, eszopiclone, and diazepam, alone or each in combination with ethanol. Motor performance was assessed by measuring time spent walking on a rotarod apparatus. Zolpidem, eszopiclone and diazepam [0.3–30 mg/kg administered orally (PO)] impaired rotarod performance in a dose-dependent manner. Furthermore, all three GABA-A receptor modulators potentiated ethanol- (0.25–1.5 g/kg) induced impairment on the rotarod. By contrast, neither DORA-12 (10–100 mg/kg, PO) nor almorexant (30–300 mg/kg, PO) impaired motor performance alone or in combination with ethanol. In addition, distinct differences in sleep architecture were observed between ethanol, GABA-A receptor modulators (zolpidem, eszopiclone, and diazepam) and DORA-12 in electroencephalogram studies in rats. These findings provide further evidence that orexin receptor antagonists have an improved motor side-effect profile compared with currently available sleep-promoting agents based on preclinical data and strengthen the rationale for further evaluation of these agents in clinical development. PMID:24399926

Ramirez, Andres D.; Gotter, Anthony L.; Fox, Steven V.; Tannenbaum, Pamela L.; Yao, Lihang; Tye, Spencer J.; McDonald, Terrence; Brunner, Joseph; Garson, Susan L.; Reiss, Duane R.; Kuduk, Scott D.; Coleman, Paul J.; Uslaner, Jason M.; Hodgson, Robert; Browne, Susan E.; Renger, John J.; Winrow, Christopher J.

2013-01-01

303

Neuronal Activity Controls the Antagonistic Balance Between Peroxisome Proliferator-Activated Receptor-? Coactivator-1? and Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptors in Regulating Antioxidant Defenses  

PubMed Central

Abstract Transcriptional coactivators and corepressors often have multiple targets and can have opposing actions on transcription and downstream physiological events. The coactivator peroxisome proliferator-activated receptor-? coactivator (PGC)-1? is under-expressed in Huntington's disease and is a regulator of antioxidant defenses and mitochondrial biogenesis. We show that in primary cortical neurons, expression of PGC-1? strongly promotes resistance to excitotoxic and oxidative stress in a cell autonomous manner, whereas knockdown increases sensitivity. In contrast, the transcriptional corepressor silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) specifically antagonizes PGC-1?-mediated antioxidant effects. The antagonistic balance between PGC-1? and SMRT is upset in favor of PGC-1? by synaptic activity. Synaptic activity triggers nuclear export of SMRT reliant on multiple regions of the protein. Concommitantly, synaptic activity post-translationally enhances the transactivating potential of PGC-1? in a p38-dependent manner, as well as upregulating cyclic-AMP response element binding protein-dependent PGC-1? transcription. Activity-dependent targeting of PGC-1? results in enhanced gene expression mediated by the thyroid hormone receptor, a prototypical transcription factor coactivated by PGC-1? and repressed by SMRT. As a consequence of these events, SMRT is unable to antagonize PGC-1?-mediated resistance to oxidative stress in synaptically active neurons. Thus, PGC-1? and SMRT are antagonistic regulators of neuronal vulnerability to oxidative stress. Further, this coactivator–corepressor antagonism is regulated by the activity status of the cell, with implications for neuronal viability. Antioxid. Redox Signal. 14, 1425–1436. PMID:20849372

Soriano, Francesc X.; Leveille, Frederic; Papadia, Sofia; Bell, Karen F.S.; Puddifoot, Clare

2011-01-01

304

Identification of endogenous gibberellins in Petunia flowers. Identification of anthocyanin biosynthetic gene expression and antagonistic effect of abscisic acid  

Microsoft Academic Search

~~~~~ ~ ~ ~ The elongation and pigmentation of corollas of Petunia hybrida requires the presence of anthers. The ability of exogenous gibberel- lic acid (CA,) to substitute for the anthers suggests a role for endogenous CAs. Here we report the identification of endogenous CAs in corollas and in anthers and show that both tissues contain detectable levels of CAI,

David Weiss; Arnold van der Luit; Erik Knegt; Evert Vermeer; J. N. M. Mol; Jan M. Kooter

1995-01-01

305

Differential and antagonistic effects of 9-cis-retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro  

Microsoft Academic Search

Retinoids and vitamin D are known to exert important anti-tumour effects in a variety of cell types. In this study the effects of 9-cis-retinoic acid (9cRA) the vitamin D analogues EB1089 and CB1093 on three pancreatic adenocarcinoma cell lines were investigated. All compounds caused inhibition of in vitro growth but the vitamin D analogues were generally the more potent growth

F Pettersson; K W Colston; A G Dalgleish

2000-01-01

306

Molecular Basis Determining Inhibition/Activation of Nociceptive Receptor TRPA1 Protein: A SINGLE AMINO ACID DICTATES SPECIES-SPECIFIC ACTIONS OF THE MOST POTENT MAMMALIAN TRPA1 ANTAGONIST.  

PubMed

The transient receptor potential ankyrin 1 (TRPA1) is a Ca(2+)-permeable, nonselective cation channel mainly expressed in a subset of nociceptive neurons. TRPA1 functions as a cellular sensor detecting mechanical, chemical, and thermal stimuli. Because TRPA1 is considered to be a key player in nociception and inflammatory pain, TRPA1 antagonists have been developed as analgesic agents. Recently, by utilizing species differences, we identified the molecular basis of the antagonistic action of A967079, one of the most potent mammalian TRPA1 antagonists. Here, we show a unique effect of A967079 on TRPA1 from diverse vertebrate species, i.e. it acts as an agonist but not as an antagonist for chicken and frog TRPA1s. By characterizing chimeric channels of human and chicken TRPA1s, as well as point mutants, we found that a single specific amino acid residue located within the putative fifth transmembrane domain was involved in not only the stimulatory but also the inhibitory actions of A967079. AP18, structurally related to A967079, exerted similar pharmacological properties to A967079. Our findings and previous reports on species differences in the sensitivity to TRPA1 antagonists supply useful information in the search for novel analgesic medicines targeting TRPA1. PMID:25271161

Banzawa, Nagako; Saito, Shigeru; Imagawa, Toshiaki; Kashio, Makiko; Takahashi, Kenji; Tominaga, Makoto; Ohta, Toshio

2014-11-14

307

A SHATTERPROOF-like gene controls ripening in non-climacteric strawberries, and auxin and abscisic acid antagonistically affect its expression  

PubMed Central

Strawberries (Fragaria×ananassa) are false fruits the ripening of which follows the non-climacteric pathway. The role played by a C-type MADS-box gene [SHATTERPROOF-like (FaSHP)] in the ripening of strawberries has been studied by transiently modifying gene expression through either over-expression or RNA-interference-mediated down-regulation. The altered expression of the FaSHP gene caused a change in the time taken by the over-expressing and the down- regulated fruits to attain the pink stage, which was slightly shorter and much longer, respectively, compared to controls. In parallel with the modified ripening times, the metabolome components and the expression of ripening-related genes also appeared different in the transiently modified fruits. Differences in the response time of the analysed genes suggest that FaSHP can control the expression of ripening genes either directly or indirectly through other transcription factor-encoding genes. Because fleshy strawberries are false fruits these results indicate that C-type MADS-box genes like SHATTERPROOF may act as modulators of ripening in fleshy fruit-like structures independently of their anatomical origin. Treatment of strawberries with either auxin or abscisic acid had antagonistic impacts on both the expression of FaSHP and the expression of ripening-related genes and metabolome components. PMID:23888065

Casadoro, Giorgio

2013-01-01

308

Using an experimental medicine model to understand the antidepressant potential of the N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine  

PubMed Central

There is growing interest in the role of the glutamatergic system both in depression and as a novel target for treatments. Preclinical studies suggested that the non-competitive N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine might have antidepressant properties, but a randomised controlled trial failed to support this. A healthy volunteer model of emotional processing was used to assess the neuropsychological profile of action of memantine. Healthy volunteers (n=32) were randomised to receive a single dose of memantine (10 mg) or placebo, and subsequently completed a battery of tasks measuring emotional processing, including facial expression recognition, emotional memory, dot-probe and emotion-potentiated startle tasks, as well as working and verbal memory. Memantine treated volunteers showed an increased emotion-potentiated startle, and a reduced bias for negative items in emotional recognition memory. There were no effects of the drug on any other aspect of emotional or non-emotional information processing. These results suggest that a single dose of memantine produces an early anxiogenic response in the emotion-potentiated startle similar to that seen following a single dose of the selective serotonin reuptake inhibitor, citalopram. However, the overall profile of effects is more limited than that which might be expected in response to a conventional antidepressant. PMID:22596208

Parsons, E; Cowen, LG; McTavish, SF; Cowen, PJ; Harmer, CJ

2012-01-01

309

Antagonistic roles of abscisic acid and cytokinin during response to nitrogen depletion in oleaginous microalga Nannochloropsis oceanica expand the evolutionary breadth of phytohormone function.  

PubMed

The origin of phytohormones is poorly understood, and their physiological roles in microalgae remain elusive. Genome comparison of photosynthetic autotrophic eukaryotes has revealed that the biosynthetic pathways of abscisic acid (ABA) and cytokinins (CKs) emerged in unicellular algae. While ABA and CK degradation mechanisms emerged broadly in algal lineages, complete vascular plant-type conjugation pathways emerged prior to the rise of Streptophyta. In microalgae, a complete set of proteins from the canonical ABA and CK sensing and signaling pathways is not essential, but individual components are present, suggesting stepwise recruitment of phytohormone signaling components. In the oleaginous eustigmatophyte Nannochloropsis oceanica IMET1, UHPLC-MS/MS detected a wide array of plant hormones, despite a phytohormone profile that is very distinct from that of flowering plants. Time-series transcriptional analysis during nitrogen depletion revealed activation of the ABA biosynthetic pathway and antagonistic transcription of CK biosynthetic genes. Correspondingly, the ABA level increases while the dominant bioactive CK forms decrease. Moreover, exogenous CKs stimulate cell-cycle progression while exogenous ABA acts as both an algal growth repressor and a positive regulator in response to stresses. The presence of such functional flowering plant-like phytohormone signaling systems in Nannochloropsis sp. suggests a much earlier origin of phytohormone biosynthesis and degradation than previously believed, and supports the presence in microalgae of as yet unknown conjugation and sensing/signaling systems that may be exploited for microalgal feedstock development. PMID:25041627

Lu, Yandu; Tarkowská, Danuše; Ture?ková, Veronika; Luo, Tingwei; Xin, Yi; Li, Jing; Wang, Qintao; Jiao, Nianzhi; Strnad, Miroslav; Xu, Jian

2014-10-01

310

Salvianolic acid B inhibits platelets as a P2Y12 antagonist and PDE inhibitor: Evidence from clinic to laboratory.  

PubMed

Salviae miltiorrhiza (Danshen) has been used for thousands of years in China and some other Asian countries to treat atherothrombotic diseases. Salvianolate which consists of three water-soluble ingredients purified from Salviae miltiorrhiza, has been approved by Chinese SFDA to treat coronary artery disease. So far, there is no evidence clearly showing the clinical efficiency of salvianolate and the underlying mechanism. This study is to evaluate the effects of salvianolate on platelets in patients with acute coronary syndrome and explore the underlying mechanism. We evaluated the effects of salvianolate on platelets in patients with acute coronary syndrome by measuring ADP-induced PAC-1 binding and P-selectin expression on platelets. Salvianolate significantly potentiated the antiplatelet effects of standard dual antiplatelet therapy. We also investigated the antiplatelet effects of salvianolatic acid B (Sal-B), the major component which composes 85% of salvianolate. Sal-B inhibits human platelet activation induced by multiple agonists in vitro by inhibiting phosphodiesterase (PDE) and antagonizing P2Y12 receptor. For the first time, we show the antiplatelet efficiency of salvianolate in ACS patients undergoing treatment with clopidogrel plus aspirin, and demonstrate that Sal-B, the major component of salvianolate inhibits human platelet activation via PDE inhibition and P2Y12 antagonism which may account for the clinical antiplatelet effects of salvianolate. Our results suggest that Sal-B may substitute salvianolate for clinical use. PMID:25077998

Liu, Lei; Li, Jian; Zhang, Yan; Zhang, Shenghui; Ye, Jianqin; Wen, Zhichao; Ding, Jianping; Kunapuli, Satya P; Luo, Xinping; Ding, Zhongren

2014-10-01

311

Evolution of the Bifunctional Lead ? Agonist/? Antagonist Containing the 2?,6?-Dimethyl-l-tyrosine-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid (Dmt-Tic) Opioid Pharmacophore  

PubMed Central

Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead ? agonist/? antagonist, H-Dmt-Tic-Gly-NH-Bzl (Dmt = 2?,6?-dimethyl-l-tyrosine, Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, Bzl = benzyl). Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (?Cl, ?CH3, partially ?NO2, inactive ?NH2) was found to give a more potent ? agonist/antagonist effect associated with a relatively unmodified ? antagonist activity (pA2 = 8.28?9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the ? agonist and ? antagonist activities of the lead compound. Finally and quite unexpectedly d-Tic2, considered as a wrong opioid message now, inserted into the reference compound in lieu of l-Tic provided a ? agonist/? agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph; Ph = phenyl) and was endowed with the same pharmacological profile. PMID:20352071

2009-01-01

312

Chimeric antagonist anth1  

US Patent & Trademark Office Database

A recombinant chimeric antagonist formed by a 60 amino acid fragment of the N-terminal region of human interleukin 2 (IL-2) fused to the N-terminal of the extracellular region of the alpha subunit of the gamma IFN (IFN .gamma.) receptor. In vitro this protein has a T cell growth stimulating activity, it inhibits the growth stimulating activity of IL-2 in T cells, it inhibits the induction of HLA-DR by IFN .gamma. and it inhibits the antiproliferative activity of .gamma. IFN. This invention can be applied in the field of medicine for the treatment of several pathologies such as autoimmune diseases, graft rejections, chronic inflammations, sepsis, ischemia and reperfusion syndrome and atherosclerosis.

2008-09-30

313

Prodrugs of 3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039): A potent and orally active group II mGluR antagonist with antidepressant-like potential  

Microsoft Academic Search

3-(3,4-Dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 5 (MGS0039) is a highly selective and potent group II metabotropic glutamate receptor (mGluR) antagonist (antagonist activities for mGluR2; IC50=20.0nM, mGluR3; IC50=24.0nM) and is detected in both plasma (492ng\\/mL) and brain (13.2ng\\/g) at oral administration of 10ng\\/mL [J. Med. Chem.2004, 47, 4750], but the oral bioavailability of 5 was 10.9%. In order to improve the oral bioavailability of

Akito Yasuhara; Masato Nakamura; Kazunari Sakagami; Toshiharu Shimazaki; Ryoko Yoshikawa; Shigeyuki Chaki; Hiroshi Ohta; Atsuro Nakazato

2006-01-01

314

Original article Folate deficiency and congenital malformations  

E-print Network

malforma- tions and the decrease of folic acid in rat mothers and embryos, a folic acid antagonist to women less than 3 months pregnant (Thiersch, 1952) induced fetal death followed by abortion (10/12 cases

Paris-Sud XI, Université de

315

Folates and Folic Acid: From Fundamental Research Toward Sustainable Health  

Microsoft Academic Search

Folates are of paramount importance in one-carbon metabolism of most organisms. Plants and microorganisms are able to synthesize folates de novo, making them the main dietary source for humans and animals, which are dependent on food or feed supplies for folates. Folate deficiency is an increasing problem in the developing, as well as in the developed regions of the world,

Dieter Blancquaert; Sergei Storozhenko; Karen Loizeau; Hans De Steur; Veerle De Brouwer; Jacques Viaene; Stéphane Ravanel; Fabrice Rébeillé; Willy Lambert; Dominique Van Der Straeten

2010-01-01

316

Rational discovery of novel nuclear hormone receptor antagonists  

NASA Astrophysics Data System (ADS)

Nuclear hormone receptors (NRs) are potential targets for therapeutic approaches to many clinical conditions, including cancer, diabetes, and neurological diseases. The crystal structure of the ligand binding domain of agonist-bound NRs enables the design of compounds with agonist activity. However, with the exception of the human estrogen receptor-, the lack of antagonist-bound "inactive" receptor structures hinders the rational design of receptor antagonists. In this study, we present a strategy for designing such antagonists. We constructed a model of the inactive conformation of human retinoic acid receptor- by using information derived from antagonist-bound estrogen receptor-? and applied a computer-based virtual screening algorithm to identify retinoic acid receptor antagonists. Thus, the currently available crystal structures of NRs may be used for the rational design of antagonists, which could lead to the development of novel drugs for a variety of diseases.

Schapira, Matthieu; Raaka, Bruce M.; Samuels, Herbert H.; Abagyan, Ruben

2000-02-01

317

Arabidopsis Class I and Class II TCP Transcription Factors Regulate Jasmonic Acid Metabolism and Leaf Development Antagonistically1[C][W  

PubMed Central

TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR1 (TCP) transcription factors control developmental processes in plants. The 24 TCP transcription factors encoded in the Arabidopsis (Arabidopsis thaliana) genome are divided into two classes, class I and class II TCPs, which are proposed to act antagonistically. We performed a detailed phenotypic analysis of the class I tcp20 mutant, showing an increase in leaf pavement cell sizes in 10-d-old seedlings. Subsequently, a glucocorticoid receptor induction assay was performed, aiming to identify potential target genes of the TCP20 protein during leaf development. The LIPOXYGENASE2 (LOX2) and class I TCP9 genes were identified as TCP20 targets, and binding of TCP20 to their regulatory sequences could be confirmed by chromatin immunoprecipitation analyses. LOX2 encodes for a jasmonate biosynthesis gene, which is also targeted by class II TCP proteins that are under the control of the microRNA JAGGED AND WAVY (JAW), although in an antagonistic manner. Mutation of TCP9, the second identified TCP20 target, resulted in increased pavement cell sizes during early leaf developmental stages. Analysis of senescence in the single tcp9 and tcp20 mutants and the tcp9tcp20 double mutants showed an earlier onset of this process in comparison with wild-type control plants in the double mutant only. Both the cell size and senescence phenotypes are opposite to the known class II TCP mutant phenotype in JAW plants. Altogether, these results point to an antagonistic function of class I and class II TCP proteins in the control of leaf development via the jasmonate signaling pathway. PMID:22718775

Danisman, Selahattin; van der Wal, Froukje; Dhondt, Stijn; Waites, Richard; de Folter, Stefan; Bimbo, Andrea; van Dijk, Aalt DJ; Muino, Jose M.; Cutri, Lucas; Dornelas, Marcelo C.; Angenent, Gerco C.; Immink, Richard G.H.

2012-01-01

318

[Calcium antagonists: current and future applications based on new evidence. The mechanisms on lowering serum uric acid level by calcium channel blockers].  

PubMed

In hypertensive subjects, their serum uric acid levels tend to be higher because of decreasing urinary secretion or overproduction of uric acid. Among calcium channel blockers (CCBs) , long acting nifedipine and cilnidipine reveal serum uric acid lowering action. They decrease the production of uric acid precursor in skeletal muscles under anaerobic condition induced by hypertension or insulin resistance. Hyperuricemia is considered to be a risk factor of not only gout but also renal and cardiovascular diseases, thus, it is important to use CCBs without adverse effect on uric acid metabolisms. PMID:20048433

Mizuta, Einosuke; Hamada, Toshihiro; Igawa, Osamu; Shigemasa, Chiaki; Hisatome, Ichiro

2010-01-01

319

The antagonistic strain Bacillus subtilis?UMAF6639 also confers protection to melon plants against cucurbit powdery mildew by activation of jasmonate- and salicylic acid-dependent defence responses.  

PubMed

Biological control of plant diseases has gained acceptance in recent years. Bacillus subtilis?UMAF6639 is an antagonistic strain specifically selected for the efficient control of the cucurbit powdery mildew fungus Podosphaera fusca, which is a major threat to cucurbits worldwide. The antagonistic activity relies on the production of the antifungal compounds iturin and fengycin. In a previous study, we found that UMAF6639 was able to induce systemic resistance (ISR) in melon and provide additional protection against powdery mildew. In the present work, we further investigated in detail this second mechanism of biocontrol by UMAF6639. First, we examined the signalling pathways elicited by UMAF6639 in melon plants, as well as the defence mechanisms activated in response to P.?fusca. Second, we analysed the role of the lipopeptides produced by UMAF6639 as potential determinants for ISR activation. Our results demonstrated that UMAF6639 confers protection against cucurbit powdery mildew by activation of jasmonate- and salicylic acid-dependent defence responses, which include the production of reactive oxygen species and cell wall reinforcement. We also showed that surfactin lipopeptide is a major determinant for stimulation of the immune response. These results reinforce the biotechnological potential of UMAF6639 as a biological control agent. PMID:23302493

García-Gutiérrez, Laura; Zeriouh, Houda; Romero, Diego; Cubero, Jaime; de Vicente, Antonio; Pérez-García, Alejandro

2013-05-01

320

Vitamin B12 and pteroylglutamic acid studies in the domestic fowl  

E-print Network

? ration of vitamin B, p on the B-. P content of egg yolks........................... 5 Chapter 3. Factors affecting the in vitro conversion of folic acid (PGA) to the citrovorum factor (CF)............................ 29 Chapter 4. Effect of vitamin... of vitamin B^2 several workers (Doctor et al., '53; Drysdale et al., *51) have reported that the vitamin is implicated in utilization of pteroylglutamic acid (folic acid). Soon after the discovery of the citrovorum factor (OF, folinic acid...

Reid, Bobby Leroy

2013-10-04

321

Synergistic and antagonistic effects between halide ions and carboxymethyl cellulose for the corrosion inhibition of mild steel in sulphuric acid solution  

Microsoft Academic Search

The corrosion and corrosion inhibition effect of carboxymethyl cellulose (CMC) for mild steel in sulphuric acid medium was\\u000a investigated using chemical (weight loss and hydrogen evolution) techniques at 30–60 °C. The effect of addition of halide\\u000a ions (Cl?, Br?, and I?) was also studied. It was found that CMC functions as an inhibitor for acid induced corrosion for mild steel. Inhibition

S. A. Umoren; M. M. Solomon; I. I. Udosoro; A. P. Udoh

2010-01-01

322

Tannins as Gibberellin Antagonists 1  

PubMed Central

Fourteen chemically defined hydrolyzable tannins and six impure mixtures of either condensed or hydrolyzable tannins were found to inhibit the gibberellin-induced growth of light-grown dwarf pea seedlings. The highest ratio of tannins to gibberellic acid tested (1000: 1 by weight) inhibited from 80 to 95% of the induced growth for all tannins tested except for two monogalloyl glucose tannins which inhibited only 50% of the induced growth. The lowest ratio tested (10: 1) inhibited the induced growth by less than 25% except for the case of terchebin where 50% inhibition was found. The inhibition of gibberellin-induced growth was found to be completely reversed by increasing the amount of gibberellin in three cases tested. Tannins alone did not inhibit endogenous growth of either dwarf or nondwarf pea seedlings. Eight compounds related to tannins, including coumarin, trans-cinnamic acid, and a number of phenolic compounds were also tested as gibberellin antagonists. Most of these compounds showed some inhibition of gibberellin-induced growth, but less than that of the tannins. At the highest ratio (1000: 1) the greatest inhibition was 55%; at the lowest ratio (10: 1) no more than 17% was observed. These compounds did not inhibit endogenous growth, and the inhibition of gibberellin-induced growth could be reversed by increasing the amount of gibberellin in two cases tested. Six chemically defined tannins were found to inhibit hypocotyl growth induced by gibberellic acid in cucumber seedlings. Growth induced by indoleacetic acid in the same test was not inhibited. The highest ratio of tannin to promotor tested gave strong inhibition of gibberellic acid-induced growth, but actually enhanced the growth induced by indoleacetic acid. This difference in action suggests a specificity between the tannins and gibberellic acid. PMID:16657953

Corcoran, Mary Ritzel; Geissman, T. A.; Phinney, Bernard O.

1972-01-01

323

3-amino-4-(3-hexylphenylamino)-4-oxobutyl phosphonic acid (W146), a Selective Antagonist of Sphingosine-1-phospahte Receptor Subtype 1, Enhances AMD3100-stimulated Mobilization of Hematopoietic Stem Progenitor Cells in Animals  

PubMed Central

Sphingosine-1-phosphate (S1P), a serum-borne bioactive lipid, regulates various physiological functions. We observed that the S1P receptor subtype 1 (S1P1), a high affinity G-protein coupled receptor of S1P, is the major S1P receptor expressed in the Kit+/Sca-1+/Lin? (KSL) hematopoietic stem progenitor cells (HSPCs, KSL-HSPCs). In this study, we investigate function of S1P1 receptors in the regulation of HSPC mobilization in animals. Treatment with SEW2871, a specific agonist of S1P1, had no effect on KSL-HSPC mobilization. In addition, mice pretreated with SEW2871 followed by AMD3100, a well-known activator of KSL-HSPC mobilization by antagonizing the stromal-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling axis, did not enhance the AMD3100-induced KSL-HSPC mobilization. In contrast, pretreatment of (R)-3-amino-4-(3-hexylphenylamino)-4-oxobutyl phosphonic acid (W146), a selective antagonist of S1P1, significantly augments AMD3100-induced KSL-HSPC mobilization into peripheral blood. The inactive enantiomer W140 was incapable of enhancing the AMD3100-induced KSL-HSPC mobilization. Moreover, treatment with selective antagonists for S1P2 and S1P3 had no effects on AMD3100-mediated KSL-HSPC mobilization. Collectively, our data suggest that S1P/S1P1 signaling regulates the SDF-1/CXCR4-mediated retention of KSL-HSPCs in bone marrow microenvironment. PMID:25383272

Liu, Jingjing; Zhao, Jiawei; Lee, Jen-Fu; Gartung, Allison; Jawadi, Hiba; Zhang, Wenliang; Lominadze, David; Lee, Menq-Jer

2013-01-01

324

Opioid Antagonist Impedes Exposure.  

ERIC Educational Resources Information Center

Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

Merluzzi, Thomas V.; And Others

1991-01-01

325

N-Methyl-D-aspartate receptor antagonist d-AP5 prevents pertussis toxin-induced alterations in rat spinal cords by inhibiting increase in concentrations of spinal CSF excitatory amino acids and downregulation of glutamate transporters.  

PubMed

Recently, we found that intrathecal (i.t.) pertussis toxin (PTX) injection produces thermal hyperalgesia and is associated with increasing concentrations of excitatory amino acids (EAAs) in spinal cerebrospinal fluid (CSF) dialysates; a reduction in the antinociceptive effects of morphine and glutamate transporters (GTs) was also observed. The reduction in the morphine-induced analgesic effects is directly related to increased extracellular EAA levels, which are maintained by GTs at physiological levels. In this study, we aimed to examine the role of GT isoforms in thermal hyperalgesia, determine the EAA concentrations in CSF dialysates, and elucidate the role of N-methyl-d-aspartate (NMDA) receptors in PTX-induced reduction in the antinociceptive effects of morphine. Two i.t. catheters and one microdialysis probe were inserted into male Wistar rats: one catheter was used for PTX (1 microg) and morphine (10 microg) injection and the other was connected to an osmotic pump for NMDA receptor antagonist d-2-amino-5-phosphonopentanoic acid (d-AP5; 2 microg/h for 4 days) continuous infusion. The microdialysis probe was used to collect CSF dialysates for EAA measurements by high-performance liquid chromatography. Intrathecal morphine failed to produce antinociceptive effects in PTX-treated rats, and d-AP5 coinfusion prevented the PTX-induced reduction in the antinociceptive effect and associated downregulation of the GTs. We conclude that NMDA receptor suppression inhibits EAA excitation and reduces the morphine-induced antinociception in PTX-treated rats. PMID:19463918

Wong, Chih-Shung; Wu, Gong-Jhe; Chen, Wu-Fu; Jean, Yen-Hsuan; Hung, Ching-Hsien; Lin, Chan-Shing; Huang, Shi-Ying; Wen, Zhi-Hong

2009-08-28

326

Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid: an orally active, selective very late antigen-4 antagonist.  

PubMed

We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events. PMID:19891440

Muro, Fumihito; Iimura, Shin; Sugimoto, Yuuichi; Yoneda, Yoshiyuki; Chiba, Jun; Watanabe, Toshiyuki; Setoguchi, Masaki; Iigou, Yutaka; Matsumoto, Keiko; Satoh, Atsushi; Takayama, Gensuke; Taira, Tomoe; Yokoyama, Mika; Takashi, Tohru; Nakayama, Atsushi; Machinaga, Nobuo

2009-12-24

327

Xanthines as Adenosine Receptor Antagonists  

PubMed Central

The natural plant alkaloids caffeine and theophylline were the first adenosine receptor (AR) antagonists described in the literature. They exhibit micromolar affinities and are non-selective. A large number of derivatives and analogs have subsequently been synthesized and evaluated as AR antagonists. Very potent antagonists have thus been developed with selectivity for each of the four AR subtypes. PMID:20859796

Jacobson, Kenneth A.

2013-01-01

328

Acid-induced sweetness of neoculin is ascribed to its pH-dependent agonistic-antagonistic interaction with human sweet taste receptor  

Microsoft Academic Search

Neoculin (NCL) is a sweet protein that also has taste-modifying activity to convert sourness to sweetness. However, it has been unclear how NCL induces this unique sensation. Here we quantitatively evaluated the pH-dependent acid-induced sweetness of NCL using a cell-based assay system. The human sweet taste receptor, hT1R2-hT1R3, was functionally ex- pressed in HEK293T cells together with G protein. When

Ken-ichiro Nakajima; Yuji Morita; Ayako Koizumi; Tomiko Asakura; Tohru Terada; Keisuke Ito; Akiko Shimizu-Ibuka; Jun-ichi Maruyama; Katsuhiko Kitamoto; Takumi Misaka; Keiko Abe

2008-01-01

329

Lipopeptide antagonists of growth hormone-releasing hormone with improved antitumor activities  

Microsoft Academic Search

Antagonists of growth hormone-releasing hormone (GHRH) synthesized previously inhibit proliferation of various human cancers, but derivatisation with fatty acids could enhance their clinical efficacy. We synthesized a series of antagonists of GHRH(1-29)NH2 acylated at the N terminus with monocarboxylic or ,-dicarboxylic acids containing six to sixteen carbon atoms. These peptides are analogs of prior potent antagonists JV-1-36, JV-1-38, and JV-1-65

Marta Zarandi; Jozsef L. Varga; Andrew V. Schally; Judit E. Horvath; Gabor L. Toller; Magdolna Kovacs; Markus Letsch; Kate Groot; Patricia Armatis; Gabor Halmos

2006-01-01

330

Effect of 3-cyclopropyl-1-enlyl-propanoic acid sodium salt, a novel water soluble antagonist of ethylene action, on plant responses to ethylene  

Microsoft Academic Search

A novel water soluble inhibitor of ethylene action, 3-cyclopropyl-1-enyl-propanoic acid sodium salt [(CPAS) Patent Application\\u000a number: PCT\\/IL2008\\/000995, US Application number 61\\/144758, International publication number: WO 2009\\/010981 AI] was synthesized\\u000a in a highly purified form, and its effect to retard various exogenous or endogenous ethylene-mediated processes was tested.\\u000a The inhibitor was applied by loading, dipping or spraying. CPAS retarded some ripening

Raphael Goren; Moshe Huberman; Joseph Riov; Eliezer E. Goldschmidt; Edward C. Sisler; Akiva Apelbaum

331

Effect of BN 52021, a specific antagonist of platelet activating factor (PAF-acether), on calcium movements and phosphatidic acid production induced by PAF-acether in human platelets  

SciTech Connect

/sup 32/P-labelled human platelets loaded with quin 2 and pretreated with aspirin were stimulated with 1-100 nM platelet activating factor (PAF-acether or 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine) in a medium containing the ADP-scavenging system creatine phosphate/creatine phosphokinase. Under these conditions, PAF-acether evoked a characteristic fluorescence change allowing to quantify elevations in cytoplasmic free Ca/sup 2 +/ from internal stores (Ca/sup 2 +/ mobilization) or from external medium (Ca/sup 2 +/ influx), as well as an increased production of phosphatidic acid, reflecting phospholipase C activation. These effects, which can be attributed to PAF-acether only and not to released products such as ADP or thromboxane A2, were strongly inhibited in a dose-dependent manner by BN 52021, a specific antagonist of PAF-acether isolated from Ginkgo biloba. As the drug remained inactive against the same effects elicited by thrombin, it is concluded that BN 52021 does not interfere directly with the mechanism of transmembrane signalling involving inositol-phospholipids or (and) some putative receptor-operated channels, but rather acts on the binding of PAF-acether to its presumed membrane receptor.

Simon, M.F.; Chap, H.; Braquet, P.; Douste-Blazy, L.

1987-02-15

332

A comparative assessment of ?-lipoic acid N-phenylamides as non-steroidal androgen receptor antagonists both on and off gold nanoparticles.  

PubMed

A group of ?-lipoic acid N-phenylamides were synthesized employing a variety of amide coupling protocols utilizing electron deficient anilines. These compounds were then assessed for their ability to block androgen-stimulated proliferation of a human prostate cancer cell line, LNCaP. These structurally simple compounds displayed anti-proliferative activities at, typically, 5-20 ?M concentrations and were comparable to a commonly used anti-androgen Bicalutamide®. The inclusion of a disulfide (RS-SR) moiety, serving as an anchor to several metal nanoparticle systems (Au, Ag, Fe(2)O(3), etc.), does not impede any biological activity. Conjugation of these compounds to a gold nanoparticle surface resulted in a high degree of cellular toxicity, attributed to the absence of a biocompatible group such as PEG within the organic scaffold. PMID:22196975

Henderson, Luke C; Altimari, Jarrad M; Dyson, Gail; Servinis, Linden; Niranjan, Birunthi; Risbridger, Gail P

2012-02-01

333

The Ras antagonist, farnesylthiosalicylic acid (FTS), decreases fibrosis and improves muscle strength in dy/dy mouse model of muscular dystrophy.  

PubMed

The Ras superfamily of guanosine-triphosphate (GTP)-binding proteins regulates a diverse spectrum of intracellular processes involved in inflammation and fibrosis. Farnesythiosalicylic acid (FTS) is a unique and potent Ras inhibitor which decreased inflammation and fibrosis in experimentally induced liver cirrhosis and ameliorated inflammatory processes in systemic lupus erythematosus, neuritis and nephritis animal models. FTS effect on Ras expression and activity, muscle strength and fibrosis was evaluated in the dy(2J)/dy(2J) mouse model of merosin deficient congenital muscular dystrophy. The dy(2J)/dy(2J) mice had significantly increased RAS expression and activity compared with the wild type mice. FTS treatment significantly decreased RAS expression and activity. In addition, phosphorylation of ERK, a Ras downstream protein, was significantly decreased following FTS treatment in the dy(2J)/dy(2J) mice. Clinically, FTS treated mice showed significant improvement in hind limb muscle strength measured by electronic grip strength meter. Significant reduction of fibrosis was demonstrated in the treated group by quantitative Sirius Red staining and lower muscle collagen content. FTS effect was associated with significantly inhibition of both MMP-2 and MMP-9 activities. We conclude that active RAS inhibition by FTS was associated with attenuated fibrosis and improved muscle strength in the dy(2J)/dy(2J) mouse model of congenital muscular dystrophy. PMID:21445359

Nevo, Yoram; Aga-Mizrachi, Shlomit; Elmakayes, Edva; Yanay, Nurit; Ettinger, Keren; Elbaz, Moran; Brunschwig, Zivia; Dadush, Oshrat; Elad-Sfadia, Galit; Haklai, Roni; Kloog, Yoel; Chapman, Joab; Reif, Shimon

2011-01-01

334

Prostaglandin EP4 antagonists.  

PubMed

Prostaglandin antagonists, with their pharmacological effects, are well-known drugs capable of treating widely diffused illnesses, including pain and inflammation disorders. In recent years, a major research focus has been devoted to the identification of agents able to selectively antagonize each receptor with which prostaglandins interact. This review attempts to give a broad overview of molecules capable of selectively blocking the prostaglandin PGE2 EP4 receptor. Further therapeutic applications and uses have also been disccussed, including the first drug candidate to have reached clinical trials within the last few years. PMID:24237064

Borriello, Manuela; Stasi, Luigi Piero

2013-05-01

335

7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex.  

PubMed Central

Glycine markedly potentiates N-methyl-D-aspartate (N-Me-D-Asp) responses in mammalian neurons by an action at a modulatory site on the N-Me-D-Asp receptor-ionophore complex. Here we present evidence that 7-chlorokynurenic acid (7-Cl KYNA) inhibits N-Me-D-Asp responses by a selective antagonism of glycine at this modulatory site. In rat cortical slices 7-Cl KYNA (10-100 microM) noncompetitively inhibited N-Me-D-Asp responses, and this effect could be reversed by the addition of glycine (100 microM) or D-serine (100 microM). Radioligand binding experiments showed that 7-Cl KYNA had a much higher affinity for the strychnine-insensitive [3H]glycine binding site (IC50 = 0.56 microM) than for the N-Me-D-Asp (IC50 169 microM), quisqualate (IC50 = 153 microM), or kainate (IC50 greater than 1000 microM) recognition sites. In whole-cell patch-clamp recordings from rat cortical neurones in culture, the inhibitory effects of 7-Cl KYNA on N-Me-D-Asp-induced currents could not be overcome by increasing the N-Me-D-Asp concentration but could be reversed by increasing the glycine concentration. 7-Cl KYNA could completely abolish N-Me-D-Asp responses, including basal responses in the absence of added glycine, suggesting that it may possess negative modulatory effects at the glycine site. These findings indicate that the glycine modulatory site is functional in intact adult tissue and that 7-Cl KYNA should prove to be a selective tool for elucidating the involvement of this site in physiological and pathological events mediated by N-Me-D-Asp receptors. PMID:2842779

Kemp, J A; Foster, A C; Leeson, P D; Priestley, T; Tridgett, R; Iversen, L L; Woodruff, G N

1988-01-01

336

LXR antagonists induce ABCD2 expression.  

PubMed

X-linked adrenoleukodystrophy (X-ALD) is a rare neurodegenerative disorder characterized by the accumulation of very-long-chain fatty acids resulting from a beta-oxidation defect. Oxidative stress and inflammation are also key components of the pathogenesis. X-ALD is caused by mutations in the ABCDI gene, which encodes for a peroxisomal half ABC transporter predicted to participate in the entry of VLCFA-CoA into the peroxisome, the unique site of their beta-oxidation. Two homologous peroxisomal ABC transporters, ABCD2 and ABCD3 have been proven to compensate for ABCD1 deficiency when overexpressed. Pharmacological induction of these target genes could therefore represent an alternative therapy for X-ALD patients. Since LXR activation was shown to repress ABCD2 expression, we investigated the effects of LXR antagonists in different cell lines. Cells were treated with GSK(17) (a LXR antagonist recently discovered from the GlaxoSmithKline compound collection), 22(S)-hydroxycholesterol (22S-HC, another LXR antagonist) and 22R-HC (an endogenous LXR agonist). We observed up-regulation of ABCD2,ABCD3 and CTNNB1 (the gene encoding for beta-catenin, which was recently demonstrated to induce ABCD2 expression) in human HepG2 hepatoma cells and in X-ALD skin fibroblasts treated with LXR antagonists. Interestingly, induction in X-ALD fibroblasts was concomitant with a decrease in oxidative stress. Rats treated with 22S-HC showed hepatic induction of the 3 genes of interest. In human, we show by multiple tissue expression array that expression of ABCD2 appears to be inversely correlated with NR1H3 (LXRalpha) expression. Altogether, antagonists of LXR that are currently developed in the context of dyslipidemia may find another indication with X-ALD. PMID:24239766

Gondcaille, Catherine; Genin, Emmanuelle C; Lopez, Tatiana E; Dias, Alexandre M M; Geillon, Flore; Andreoletti, Pierre; Cherkaoui-Malki, Mustapha; Nury, Thomas; Lizard, Gérard; Weinhofer, Isabelle; Berger, Johannes; Kase, Eili T; Trompier, Doriane; Savary, Stéphane

2014-02-01

337

Effects of the Competitive N-Methyl-D-aspartate Receptor Antagonist, LY235959 [(-)-6-Phosphonomethyl-deca-hydroisoquinoline-3-carboxylic Acid], on Responding for Cocaine under Both Fixed and Progressive Ratio Schedules of Reinforcement  

Microsoft Academic Search

It is difficult to determine the precise role of the N-methyl-D- aspartate (NMDA) receptor system in the reinforcing effects of cocaine since uncompetitive NMDA receptor antagonists alter cocaine self-administration in different ways, depending on the antagonist examined and the behavior being measured. To increase understanding of the role of the NMDA system in cocaine's reinforcing effects, this study measured the

Richard M. Allen; Regina M. Carelli; Linda A. Dykstra; Therese L. Suchey; Carson V. Everett

2005-01-01

338

Tachykinin NK 2 Receptor Antagonists  

Microsoft Academic Search

\\u000a The tachykinin NK2 receptor is widel y distributed in the peripheral and central nervou s system. It mediates numerous pharmacological effects\\u000a of neurokinin A, suggesting that the tachykinin NK2 receptor may be possible target for new therapeutics. Many effor ts to identify and cha racterize selective antagonists of\\u000a this receptor have been undertaken and several antagonists of both peptide and

X. Emonds-Alt

339

Isolation of Bacterial Antagonists of Aspergillus flavus from Almonds  

Microsoft Academic Search

Bacteria were isolated from California almond orchard samples to evaluate their potential antifungal activity against aflatoxin-producing Aspergillus flavus. Fungal populations from the same samples were examined to determine the incidence of aflatoxigenic Aspergillus species. Antagonistic activities of the isolated bacterial strains were screened against a nonaflatoxigenic nor mutant of A. flavus, which accumulates the pigmented aflatoxin precursor norsolorinic acid (NOR)

Jeffrey D. Palumbo; James L. Baker; Noreen E. Mahoney

2006-01-01

340

The H2-receptor antagonist era in duodenal ulcer disease.  

PubMed Central

This paper reviews the remarkable impact of H2-receptor antagonists on duodenal ulcer management. The development and the scientific rationale of these agents are presented, and efficacy and safety aspects in the short- and long-term treatment of duodenal ulcer disease discussed. Attention is focused on the possible role of "acid rebound" in ulcer relapse following the withdrawal of therapy and on the clinical relevance of prolonged suppression of acid secretion in patients on long-term therapy. PMID:1364125

Marks, I. N.

1992-01-01

341

Increased efficacy of ?-opioid agonist-induced antinociception by metabotropic glutamate receptor antagonists in C57BL\\/6 mice: comparison with (?)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959)  

Microsoft Academic Search

Rationale  Recent experimental data suggest that metabotropic glutamate receptor (mGluR) antagonists with selectivity for mGluR1 and\\u000a mGluR2\\/3 enhance morphine-induced antinociception.\\u000a \\u000a \\u000a \\u000a \\u000a Objectives  The present study addressed the hypothesis that mGluR antagonists enhance opioid antinociception by increasing opioid efficacy.\\u000a \\u000a \\u000a \\u000a Materials and methods  The antinociceptive effects of the partial ?-opioid receptor agonists buprenorphine and dezocine were first assessed in a\\u000a hot-plate procedure under conditions of low

Bradford D. Fischer; Laurence L. Miller; Fredrick E. Henry; Mitchell J. Picker; Linda A. Dykstra

2008-01-01

342

Lipopeptide antagonists of growth hormone-releasing hormone with improved antitumor activities.  

PubMed

Antagonists of growth hormone-releasing hormone (GHRH) synthesized previously inhibit proliferation of various human cancers, but derivatisation with fatty acids could enhance their clinical efficacy. We synthesized a series of antagonists of GHRH(1-29)NH(2) acylated at the N terminus with monocarboxylic or alpha,omega-dicarboxylic acids containing six to sixteen carbon atoms. These peptides are analogs of prior potent antagonists JV-1-36, JV-1-38, and JV-1-65 with phenylacetyl group at their N terminus. Several new analogs, including MZ-J-7-46 and MZ-J-7-30, more effectively inhibited GHRH-induced GH release in vitro in a superfused rat pituitary system than their parent compound JV-1-36 and had increased binding affinities to rat pituitary GHRH receptors, but they showed weaker inhibition of GH release in vivo than JV-1-36. All antagonists acylated with fatty acids containing 8-14 carbon atoms inhibited the proliferation of MiaPaCa-2 human pancreatic cancer cells in vitro better than JV-1-36 or JV-1-65. GHRH antagonist MZ-J-7-114 (5 mug/day) significantly suppressed the growth of PC-3 human androgen-independent prostate cancers xenografted into nude mice and reduced serum IGF-I levels, whereas antagonist JV-1-38 had no effect at the dose of 10 mug/day. GHRH antagonists including MZ-J-7-46 and MZ-J-7-114 acylated with octanoic acid and MZ-J-7-30 and MZ-J-7-110 acylated with 1,12-dodecanedicarboxylic acid represent relevant improvements over earlier antagonists. These and previous results suggest that this class of GHRH antagonists might be effective in the treatment of various cancers. PMID:16537407

Zarandi, Marta; Varga, Jozsef L; Schally, Andrew V; Horvath, Judit E; Toller, Gabor L; Kovacs, Magdolna; Letsch, Markus; Groot, Kate; Armatis, Patricia; Halmos, Gabor

2006-03-21

343

A comparison of the relative activities of a number of GABAB antagonists in the isolated vas deferens of the rat.  

PubMed Central

1. A series of GABAB receptor antagonists were tested against (+/-)-baclofen for activity on the presynaptic GABAB receptor in the rat vas deferens. 2. All the antagonists tested caused a rightward shift in the concentration-response curve to (+/-)-baclofen. 3. pA2 values calculated from full Schild analysis were as follows: phaclofen, pA2 = 4.3; delta-amino valeric acid, pA2 = 4.4; 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348), pA2 = 5.0; 3-amino-propyl(n-hexyl)phosphinic acid (3-APHPA), pA2 = 4.5. 4. These results show that none of the above compounds possess potent antagonist activity at the GABAB receptor (i.e. pA2 > 6) in this peripheral tissue. In addition, the more recently available phosphinic acid antagonists, appear to offer no great advance over the GABAB antagonists previously available. PMID:1364830

Hills, J. M.; Larkin, M. M.; Howson, W.

1991-01-01

344

Two Cases of H2-Receptor Antagonist Hypersensitivity and Cross-Reactivity  

PubMed Central

H2-receptor antagonists, such as cimetidine, ranitidine and famotidine, are some of the most commonly prescribed medications for gastric acid-related disorders. These compounds are generally well-tolerated and anaphylactic reactions to them are rare. Here, we report two cases of H2-receptor antagonist-induced anaphylactic reactions: the first presented with sudden dyspnea, sneezing, urticaria, and swelling of the eyelids after ranitidine intake. The second presented with sudden severe urticaria, facial swelling, chest discomfort, dizziness, and hypotension. Possible cross-reactivity with other H2-receptor antagonists was assessed by oral challenge and skin tests. To date, only a few reports addressing cross-reactivity among H2-receptor antagonists have been published. We review the literature and summarize the data available on drug cross-reactivity in H2-receptor antagonist hypersensitivity. PMID:21461253

Song, Woo-Jung; Kim, Min-Hye; Lee, Sang-Min; Kwon, Yong-Eun; Kim, Sae-Hoon; Cho, Sang-Heon; Min, Kyung-Up; Kim, You-Young

2011-01-01

345

Percolation on Dependent Antagonistic Networks  

E-print Network

Percolation analysis on interdependent networks has shown the existence of first order phase transitions. In this article we show that for a system consisting of antagonistic and dependent interactions between two networks, the phase transition is continuous. By antagonistic dependent interactions, we mean that a proportion of functional nodes in a network cause failure of nodes in the other, while failure of nodes in the other results in failure of links in the first. Surprisingly, we observe a region in the parameter space where the giant connected components of both networks start oscillating, whereas outside this region both networks are stable. For Erdos-Renyi and scale free networks this happens only when the dependency and antagonism between them is very high.

Kotnis, Bhushan

2014-01-01

346

Opioid antagonists and alcoholism treatment.  

PubMed

The increasing evidence for a neurobiologic basis for alcoholism has spurred the search for pharmacologic agents to treat alcohol abuse. The complex set of symptoms and behaviors that characterizes alcoholism has been linked to dopaminergic and opioid neurotransmitter systems, suggesting that opioid antagonists, such as naltrexone, may alter the positive reinforcement effects and craving involved in alcoholism. Laboratory and clinical investigations of naltrexone have demonstrated the potential for this agent to reduce craving, increase the aversive effects of alcohol, decrease drinking days, and increase abstinence. While naltrexone and other opioid antagonists, such as nalmefene, may be effective components of an alcohol-treatment program, they should only be used in combination with psychosocial interventions, such as support groups and psychotherapy. PMID:18296998

Swift, R M

2000-02-01

347

Membrane Antioxidant Effects of the Charged Dihydropyridine Calcium Antagonist Amlodipine  

Microsoft Academic Search

The effect of the highly lipophilic calcium channel antagonist (CCA) amlodipine on membrane oxyradical damage was examined and compared to that of other CCA analogs and a sulfhydryl-containing ACE inhibitor in isolated membrane vesicles enriched with polyunsaturated fatty acids (PUFA). Under physiological-like conditions, the dihydropyridine CCA amlodipine significantly (P102?m) at concentrations as low as 10.0 nm. Under identical conditions, inhibition

R. Preston Mason; Mary F. Walter; Mark W. Trumbore; Edwin G. Olmstead Jr; Pamela E. Mason

1999-01-01

348

Opioid antagonists for smoking cessation  

PubMed Central

Background The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking. Objectives To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone. Search methods We searched the Cochrane Tobacco Addiction Group Specialised Register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using ’Narcotic antagonists’ and smoking terms in April 2013. We also contacted investigators, when possible, for information on unpublished studies. Selection criteria We considered randomised controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence. Data collection and analysis We extracted data in duplicate on the study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. Abstinence at end of treatment was a secondary outcome. We extracted cotinine- or carbon monoxide-verified abstinence where available. Where appropriate, we performed meta-analysis, pooling risk ratios using a Mantel-Haenszel fixed-effect model. Main results Eight trials of naltrexone met inclusion criteria for meta-analysis of long-term cessation. One trial used a factorial design so five trials compared naltrexone versus placebo and four trials compared naltrexone plus nicotine replacement therapy (NRT) versus placebo plus NRT. Results from 250 participants in one long-term trial remain unpublished. No significant difference was detected between naltrexone and placebo (risk ratio (RR) 1.00; 95% confidence interval (CI) 0.66 to 1.51, 445 participants), or between naltrexone and placebo as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30, 768 participants). The estimate was similar when all eight trials were pooled (RR 0.97; 95% CI 0.76 to 1.24, 1213 participants). In a secondary analysis of abstinence at end of treatment, there was also no evidence of any early treatment effect, (RR 1.03; 95% CI 0.88 to 1.22, 1213 participants). No trials of naloxone or buprenorphine reported abstinence outcomes. Authors’ conclusions Based on data from eight trials and over 1200 individuals, there was no evidence of an effect of naltrexone alone or as an adjunct to NRT on long-term smoking abstinence, with a point estimate strongly suggesting no effect and confidence intervals that make a clinically important effect of treatment unlikely. Although further trials might narrow the confidence intervals they are unlikely to be a good use of resources. PMID:23744347

David, Sean P; Lancaster, Tim; Stead, Lindsay F; Evins, A. Eden; Prochaska, Judith J

2014-01-01

349

Guiding principles applied in the design of GPCR-selective hypothalamic hormone agonists and antagonists  

Microsoft Academic Search

Strategies for the design of peptide agonists and antagonists of gonadotropin releasing hormone (GnRH, one ligand and one\\u000a receptor) and of receptor-selective agonists and antagonists of somatostatin (SRIF, three ligands and five receptors) and\\u000a corticotropin releasing factor (CRF, three ligands and two receptors) are described. These strategies include the use of unusual\\u000a amino acids, a versatile scaffold based on aminoglycine

J. Rivier; J. Gulyas; J. Erchegyi; S. C. Koerber; C. R. R. Grace; R. Riek; M. DiGruccio; M. Perrin; C. Rivier; V. Eltschinger; B. Waser; R. Cescato; J. C. Reubi; W. Vale

350

Potentiation of morphine-induced antinociception in acute spinal rats by the NMDA antagonist dextrorphan  

Microsoft Academic Search

Neurophysiologic and behavioral evidence indicates that excitatory amino acid (EAA) antagonists may provide a new class of selective analgesics for opiate resistant, neuropathic pain syndromes. Therapeutic applications have been limited because of unacceptable side effects of most EAA blockers. However, dextrorphan, a metabolite of the antitussive drug, dextromethorphan, is a non-competitive antagonist of theN-methyl-d-aspartate (NMDA) subtype of EAA receptor with

C. Advokat; F. Q. Rhein

1995-01-01

351

NMDA antagonists for refractory seizures.  

PubMed

Refractory status epilepticus (RSE) poses significant challenge, with a variety of novel therapeutics employed. Our goal was to evaluate the effectiveness of N-methyl D-aspartate (NMDA) receptor antagonists in the control of RSE. We performed a systematic review of all the literature, with all articles pulled from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to September 2013), reference lists of relevant articles, and gray literature. Two reviewers independently identified all manuscripts pertaining to the administration of NMDA receptor antagonists in humans for the purpose of controlling refractory seizures. Secondary outcome of adverse NMDA antagonist effects and patient outcome was assessed. Two reviewers independently extracted data including population characteristics, treatment characteristics, and outcomes. The strength of evidence was adjudicated using both the Oxford and GRADE methodology. Our search strategy produced a total of 759 citations. Twenty-three articles, 16 manuscripts, and seven meeting proceedings, were considered for the review with all utilizing ketamine for seizure control. Only three studies were prospective studies. Fifteen and nine studies pertained to adults and pediatrics, respectively. Across all studies, of the 110 adult patients described, ketamine was attributed to electroencephalogram seizure response in 56.5 %, with a 63.5 % response in the 52 pediatric patients described. Adverse events related to ketamine were rare. Outcomes were poorly documented in the majority of the studies. There currently exists Oxford level 4, GRADE C evidence to support the use of ketamine for refractory seizures in the adult and pediatric populations. Further prospective study of early ketamine administration is warranted. PMID:24519081

Zeiler, F A; Teitelbaum, J; Gillman, L M; West, M

2014-06-01

352

Mineralcorticoid antagonists in heart failure.  

PubMed

Mineralocorticoid receptor antagonists (MRAs) have become mandated therapy in patients with reduced ejection fraction (systolic) heart failure (HF) across all symptom classes. These agents should also be prescribed in the early post-myocardial infarction setting in those with reduced ejection fraction and either HF symptoms or diabetes. This article explores the pathophysiological role of aldosterone, an endogenous ligand for the mineralcorticoid receptor (MR), and summarizes the clinical data supporting guideline recommendations for these agents in systolic HF. The use of MRAs in novel areas beyond systolic HF ejection is also explored. Finally, the current status of newer agents will be examined. PMID:25217431

D'Elia, Emilia; Krum, Henry

2014-10-01

353

Interactions between plants and antagonistic streptomycetes.  

E-print Network

??This work explores a variety of mechanisms through which plants impact associated streptomycete communities. Streptomycete antibiotic-mediated antagonistic activity is a particular focus. Plant host species… (more)

Bakker, Matthew Gene

2011-01-01

354

Synthetic peptide antagonists of glucagon  

SciTech Connect

Several glucagon analogs were synthesized in an effort to find derivatives that would bind with high affinity to the glucagon receptor of rat liver membranes but would not activate membrane-bound adenylate cyclase and, therefore, would serve as antagonists of the hormone. Measurements on a series of glucagon/secretin hybrids indicated that replacement of Asp/sup 9/ in glucagon by Glu/sup 9/, found in secretin, was the important sequence difference in the N terminus of the two hormones. Further deletion of His/sup 1/ and introduction of a C-terminal amide resulted in des-His/sup 1/-(Glu/sup 9/)glucagon amide, which had a 40% binding affinity relative to that of native glucagon but caused no detectable adenylate cyclase activation in the rat liver membrane. This antagonist completely inhibited the effect of a concentration of glucagon that alone gave a full agonist response. It had an inhibition index of 12. The pA/sub 2/ was 7.2. An attempt was made to relate conformation with receptor binding. The peptides were synthesized by solid-phase methods and purified to homogeneity by reverse-phase high-performance liquid chromatography on C/sub 18/-silica columns.

Unson, C.G.; Andreu, D.; Gurzenda, E.M.; Merrifield, R.B.

1987-06-01

355

In utero physiology: role of folic acid in nutrient delivery and fetal development.  

PubMed

Despite the isolation of placental folate receptors 25 y ago and progress in defining the mechanism of folate delivery, considerable gaps remain in the literature for each level of the maternal-placental-fetal unit. Although a critical role of placental folate receptors in maternal-to-fetal folate transport was shown by use of the isolated perfused-placental cotyledon model a decade ago, in vivo confirmation is still needed. Knockout of folate receptors in mice, and knock-down of folate receptors by delivery of antisense oligonucleotides at gestation day 8 or antibodies to folate receptor, results in profound developmental abnormalities in the fetus, ranging from neural tube defects to neurocristopathies such as cleft-lip and cleft-palate, cardiac septal defects, and eye defects. These abnormalities can be prevented by ensuring the entry of folate into cells via alternative pathways. Controlled dietary folate restriction studies also identified adverse effects on reproductive performance, implantation, and fetal growth and other subtler (microscopic) defects in murine fetal development. Longitudinal follow-up showed that gestational folate deficiency results in behavioral changes-an anxiety phenotype-during adulthood in these mice, which supports the Barker hypothesis. The extent to which these findings are relevant to humans is unclear, however. Nevertheless, the high incidence of neural tube defects among North Indian women, who chronically subsist on one-third to one-half of the optimum folate needed to prevent birth defects, underscores the magnitude of the public health problem and emphasizes the urgent challenge to define the most efficient way to ensure adequate dietary folate for hundreds of millions of such women at risk in developing countries. PMID:17284762

Antony, Asok C

2007-02-01

356

Preclinical Evaluation to Specifically Target Ovarian Cancer with Folic Acid-Conjugated Nanoceria.  

National Technical Information Service (NTIS)

Despite the fact that there have been significant developments in anti-cancer technology, ovarian cancer still remains one of the leading causes of gynecological cancer deaths in the United States. To contribute towards novel approaches with minimal toxic...

R. Rattan

2012-01-01

357

Controlled release of folic acid through liquid-crystalline folate nanoparticles.  

PubMed

The present study explores folate nanoparticles as nano-carriers for controlled drug delivery. Cross-linked nanoparticles of liquid crystalline folates are composed of ordered stacks. This paper shows that the folate nanoparticles can be made with less than 5% loss in folate ions. In addition, this study shows that folate nanoparticles can disintegrate in a controlled fashion resulting in controlled release of the folate ions. Release can be controlled by the size of nanoparticles, the extent of cross-linking and the choice of cross-linking cation. The effect of different factors like agitation, pH, and temperature on folate release was also studied. Studies were also carried out to show the effect of release medium and role of ions in the release medium on disruption of folate assembly. PMID:25280715

Misra, Rahul; Katyal, Henna; Mohanty, Sanat

2014-11-01

358

Hyperhomocysteinemia in chronic alcoholism: relations to folic acid and vitamins b 6 and b 12 status  

Microsoft Academic Search

The objective of this review is to present and discuss the current perspectives of homocysteine and one carbon metabolism in chronic alcoholism. Chronic alcoholics frequently suffer from specific micronutrient deficiencies, including vitamins involved in one carbon metabolism, i.e., folate, vitamin B6 and vitamin B12. The possible link between homocysteine and alcoholism stems from the fact that homocysteine metabolism is closely

Mar??lia L Cravo; Maria E Camilo

2000-01-01

359

5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia  

Microsoft Academic Search

Background—Impaired nitric oxide (NO) activity is an early event in the pathogenesis of cardiovascular disease, resulting from either reduced NO formation or increased NO degradation. Administration of tetrahydrobiopterin (BH4), an essential cofactor for NO production, could restore NO activity in familial hypercholesterolemia (FH). Because folates have been suggested to stimulate endogenous BH4 regeneration, we hypothesized that administration of 5-methyltetrahydrofolate (5-MTHF,

Marianne C. Verhaar; Robert M. F. Wever; John J. P. Kastelein; Thea van Dam; Hein A. Koomans; Ton J. Rabelink

1998-01-01

360

AMPHOTERICIN B- AND FOLIC ACID-INDUCED NEPHROPATHIES IN DEVELOPING RATS  

EPA Science Inventory

The kidneys of newborn rats, which are both morphologically and physiologically immature, have been shown to be relatively insensitive to the nephrotoxic effects of several chemicals. To examine the specificity of these age-related differences, pups received either 20 mg/kg of Am...

361

Configurationally Restricted Bismacrocyclic CXCR4 Receptor Antagonists  

E-print Network

Configurationally Restricted Bismacrocyclic CXCR4 Receptor Antagonists Gina C. Valks, Graeme Mc configurationally restricted analogue of bismacrocyclic cyclam-type CXCR4 chemokine receptor antagonists has been,4,8,11-tetraazacyclotetradecane)), Figure 1c, is a drug that interacts with a cell surface protein (CXCR4) via hydrogen bonding

Hubin, Tim

362

A new alcohol antagonist: Phaclofen  

SciTech Connect

The ability of the GABA{sub B} receptor antagonist, phaclofen to alter behavioral effects of ethanol was evaluated by loss of righting reflex (sleep time), motor incoordination (bar holding), spontaneous locomotion (open field activity) and hypothermia. Pretreatment with phaclofen significantly decreased the effects of ethanol on motor incoordination, locomotor activity and hypothermia. However, phaclofen had no effect on either pentobarbital- or diazepam-induced motor incoordination. Phaclofen slightly increased the ED{sub 50} for loss of the righting reflex but did not alter either the duration of reflex loss produced by ethanol or blood ethanol levels at awakening. Our results suggest phaclofen is rapidly inactivated resulting in difficulty in observing antagonism of long duration ethanol effects. These findings suggest that the GABA{sub B} system may play a role in mediating several important actions of ethanol.

Allan, A.M. (Washington Univ. School of Medicine, Saint Louis, MO (USA)); Harris, R.A. (Univ. of Colorado School of Medicine, Denver (USA))

1989-01-01

363

Dietary Intake of Natural Sources of Docosahexaenoic Acid and Folate in Pregnant Women of Three European Cohorts  

Microsoft Academic Search

Background: Folic acid plays a fundamental role in cell division and differentiation. Docosahexaenoic acid (DHA) has been associated with infantile neurological and cognitive development. Thus, optimal intrauterine development and growth requires adequate supply of these nutrients during pregnancy. Methods: Healthy pregnant women, aged 18–41 years, were recruited in Granada (Spain; n = 62), Munich (Germany; n = 97) and Pécs

C. Franke; S. Verwied-Jorky; C. Campoy; M. Trak-Fellermeier; T. Decsi; V. Dolz; B. Koletzko

2008-01-01

364

PXR antagonists and implication in drug metabolism  

PubMed Central

Adopted orphan nuclear receptor (NR), pregnane X receptor (PXR), plays a central role in the regulation of xeno- and endobiotic metabolism. Since the discovery of the functional role of PXR in 1998, there is evolving evidence for the role of PXR agonists in abrogating metabolic pathophysiology (e.g., cholestasis, hypercholesterolemia, and inflammation). However, more recently, it is clear that PXR is also an important mediator of adverse xeno- (e.g., enhances acetaminophen toxicity) and endobiotic (e.g., hepatic steatosis) metabolic phenotypes. Moreover, in cancer therapeutics, PXR activation can induce drug resistance, and there is growing evidence for tissue-specific enhancement of the malignant phenotype. Thus, in these instances, there may be a role for PXR antagonists. However, as opposed to the discovery efforts for PXR agonists, there are only a few antagonists described. The mode of action of these antagonists (e.g., sulforaphane) remains less clear. Our laboratory efforts have focused on this question. Since the original discovery of azoles analogs as PXR antagonists, we have preliminarily defined an important PXR antagonist pharmacophore and developed less-toxic PXR antagonists. In this review, we describe our published and unpublished findings on recent structure-function studies involving the azole chemical scaffold. Further work in the future is needed to fully define potent, more-selective PXR antagonists that may be useful in clinical application. PMID:23330542

Mani, Sridhar; Dou, Wei; Redinbo, Matthew R.

2013-01-01

365

Sulfamethoxazole/Trimethoprim (Bactrim or Septra) and Pregnancy  

MedlinePLUS

... Reprod Toxicol 15:637-646. Czeizel AE, et al. 2004. Possible association between different congenital abnormalities and use of different sulfonamides during pregnancy. Congenital Abnormalities 44:79-86. Folic ... 8/31/11. Hernandez S, et al. 2000. Folic acid antagonists during pregnancy and the ...

366

[Significance of aldosterone antagonist therapy].  

PubMed

Since the introduction of ACE-inhibitors into clinical practice, the diuretic treatment with the classical aldosterone antagonist spironolactone has disappeared. It was generally believed that chronic treatment with ACE-inhibitors significantly reduces aldosterone secretion via reduction of angiotensin II-dependent aldosterone formation. However, aldosterone "escape" occurs: Even during chronic treatment with ACE-inhibitors, plasma levels of aldosterone rise again, which is associated with increased cardiovascular risk. Furthermore, extrarenal actions of aldosterone have been demonstrated, which detrimentally affect coagulation, autonomic activity, inflammatory signalling, hemodynamics, and fibrosis, subsequently leading to cardiovascular damage. Recently published studies (RALES, EPHESUS) convincingly support the concept of detrimental cardiovascular aldosterone actions even during chronic ACE-inhibition. In addition to those cardiovascular effects, aldosterone antagonism has beneficial impacts on ascites, chronic renal disease, renal volume regulation, and hypokalemia induced by diuretics. Of note, aldosterone dependent mechanisms are believed to be even involved in essential hypertension, and the value of aldosterone antagonism is currently tested in those patients. In conclusion, an old-fashioned, previously abandoned treatment strategy is currently celebrating its revival. PMID:14997312

Christ, M; Grimm, W; Maisch, B

2004-03-01

367

Antagonistic competition moderates virulence in Bacillus thuringiensis  

E-print Network

LETTER Antagonistic competition moderates virulence in Bacillus thuringiensis Jennie Garbutt,1 infections led to improved suppression of competitors in the bacterial insect pathogen Bacillus thuringiensis Antagonism, Bacillus thuringiensis, evolution of virulence, interference competition, mixed infection, social

Obbard, Darren

368

Gastric acid secretion in the chicken: effect of histamine H2 antagonists and H+/K(+)-ATPase inhibitors on gastro-intestinal pH and of sexual maturity calcium carbonate level and particle size on proventricular H+/K+ ATPase activity.  

PubMed

1. Cimetidine was more potent 4 hr after a single injection of 25 or 100 mg/kg body wt in increasing gastric pH than other H2 receptor antagonists, ranitidine and famotidine but was less efficient than H+/K(+)-ATPase inhibitors. Omeprazole rose proventricular and gizzard pH at a lower dose than SCH 28080 and Ro 18-5364 (30, 50 and 200 mg/kg body wt, respectively). 2. Proventricular and gizzard pH values were maximal 1 and 4 hr after a single injection of 7.5 mumol/kg body wt omeprazole. Inhibition of acid secretion was maintained for 24 hr after an injection of 100 mumol/kg. 3. H+/K(+)-ATPase activity in vitro was 10 mumol Pi/hr/mg protein in the microsomal fractions of the proventriculus. It was doubled by nigericine and inhibited by SCH 28080. However, western blots by high specific H+/K(+)-ATPase monoclonal antibody 95-A3 and 95-111 recognized a 42 kDa band but hardly exhibited the specific 95 kDa band recognition. 4. Chickens and immature pullets showed a higher H+/K(+)-ATPase activity than laying hens. Calcium level of the diet did not affect the enzyme activity but coarse particles of calcium fed to pullets or laying hens enhanced the H+/K(+)-ATPase activity when compared with ground particles. PMID:7902802

Guinotte, F; Gautron, J; Soumarmon, A; Robert, J C; Peranzi, G; Nys, Y

1993-10-01

369

Design, Synthesis, and Pharmacological Evaluation of Novel 2-(4-substituted piperazin-1-yl)1, 8 Naphthyridine 3-Carboxylic Acids as 5-HT3 Receptor Antagonists for the Management of Depression.  

PubMed

1, 8-naphthyridine-3-carboxylic acid analogs were synthesized and found to possess potential 5-HT3 receptor antagonism as well as antidepressant-like activity. Initially, 5-HT3 receptor antagonism of all the compounds was determined in the form of pA2 value against agonist 2-methyl 5-HT in longitudinal muscle-myenteric plexus preparation from guinea-pig ileum. Among all the compounds tested, compound 7a demonstrated most promising pA2 value of 7.6. Subsequently, all the compounds were evaluated for antidepressant activity using forced swim test and tail suspension test in mice. Compounds 7a, 7d, 7f, 7h, and 7i exhibited significant (p < 0.05) antidepressant-like activity as compound to vehicle-treated group. Importantly, none of the tested compound affected locomotor activity of mice at tested dose levels. PMID:24903617

Dhar, Arghya K; Mahesh, Radhakrishnan; Jindal, Ankur; Devadoss, Thangaraj; Bhatt, Shvetank

2014-12-01

370

[Fermentation of Bacillus subtilis ge25 strain and preliminary study on its antagonistic substances].  

PubMed

Panax ginseng is one of the most important traditional Chinese herbal medicine, soil borne diseases influenced the yield and quality severely. In our previous work, endophytic Bacillus subtilis ge25 strain was isolated from ginseng root, and which showed significant antagonistic activity against several most destructive ginseng phytopathogens. In the present work, crude protein and lipopeptid extracts were prepared from LB and Landy supernate by salting out, acid precipitation methods respectively. The antagonistic activity of crude extracts and stability to temperature and protease digestion were examined by ginseng phytopathogen Alternaria panax. Results showed that, the antagonistic activity of crude protein extracts from LB culture was complete and partially lost when treated by high temperature and proteinase K. However, crude lipopeptid from Landy culture showed significant stabile antagonistic activity to them. Acid-hydrolyzation and TLC-bioautography analysis showed, that the crude lipopeptide contained at least one cyclic lipopeptide. In consideration of the stability and perfect antagonistic activity of ge25, further researches will promote the biocontrol of ginseng diseases in the field. PMID:25272485

Hu, Chen-Yun; Li, Yong; Liu, Min; Ding, Wan-Long; Qin, Min-Jian

2014-07-01

371

Effect of Prostaglandin and Leukotriene Antagonists in Acute Mesenteric Artery Occlusion  

Microsoft Academic Search

Superior mesenteric artery occlusion leads to mesenteric ischemia, activation of arachidonic acid metabolism and release of endotoxins into the systemic circulation. The effect of leukotriene and prostaglandin antagonists on hemodynamic response and survival of rats after superior mesenteric artery (SMA) occlusion was investigated. The animals were divided into five groups: in group 1 (n = 105) the SMA was clamped

J. Ben-Dahan; D. Gross; H. Abu-Dalu; B. Klin; E. H. Landau; A. Nyska; M. M. Krausz

1988-01-01

372

Modeling the Effects of the NMDA Receptor Antagonist MK-801 on Timing in Rats  

E-print Network

when animals are tested with the differential rein- forcement of low rate of responding (DRL) schedule influence timing comes from investigations of NMDA antagonists in a differential reinforcement of low rate- noic acid (AP5) decreases efficiency (the number of reinforce- ments delivered relative to the total

Liu, Taosheng

373

Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot  

Microsoft Academic Search

We have identified mouse and human cDNAs encoding a novel secreted BMP inhibitor, which we have named ectodin. It is most homologous (?37% amino acid identity) to sclerostin that is a secreted BMP antagonist. Recombinant ectodin protein produced in cultured cells was efficiently secreted as a antagonist. Ectodin inhibited the activity of BMP2, BMP4, BMP6, and BMP7 for mouse preosteoblastic

Johanna Laurikkala; Yoshiaki Kassai; Leila Pakkasjärvi; Irma Thesleff; Nobuyuki Itoh

2003-01-01

374

Antinociceptive effects of NMDA and non-NMDA receptor antagonists in the tail flick test in mice  

Microsoft Academic Search

Inhibition of spinal glutamate receptors induces antinociceptive effects in numerous animal models of pain. The present study compares the effects of intrathecally administered N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptor antagonists on nociceptive responses in the tail flick test. Potency of antagonists at NMDA and ?-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors was first measured by electrical assays in Xenopus oocytes expressing rat cerebral

Kabirullah Lutfy; Sui Xiong Cai; Richard M Woodward; Eckard Weber

1997-01-01

375

Synthesis and Biological Activities of Highly Potent Antagonists of Growth Hormone-Releasing Hormone  

Microsoft Academic Search

In the search for antagonists of human growth hormone-releasing hormone (hGHRH) with high activity, 22 analogs were synthesized by solid-phase methods, purified, and tested biologically. Within the N-terminal sequence of 28 or 29 amino acids of hGHRH, all the analogs contained D-Arg^2, Phe(4-Cl)^6 (para-chlorophenylalanine), Abu15 (alpha-aminobutyric acid), and Nle27 and most of them had Agm29 (agmatine) substituents. All the peptides,

M. Zarandi; J. E. Horvath; G. Halmos; J. Pinski; A. Nagy; K. Groot; Z. Rekasi; A. V. Schally

1994-01-01

376

Therapeutic efficacy of dimercaptosuccinic acid and thiamine/ascorbic acid on lead intoxication in rats  

SciTech Connect

Thiamine, folic acid, pyridoxine and ascorbic acid either individually or in combination have been proven to be effective in reducing the toxic manifestations of lead and in enhancing the antidotal efficacy of CaNa{sub 2}EDTA. In a recent report from the authors' laboratory, it was observed that given combination of thiamine and ascorbic acid with thiol chelators improved the ability of the animals to excrete lead thereby reducing body lead burden. In view of the beneficial effect of these two vitamins, it was considered of interest to evaluate their potential to modify the prophylactic action of DMS in lead intoxication in rat after repeated administration.

Tandon, S.K.; Flora, S.J.S. (Industrial Toxicology Research Centre, Lucknow (India))

1989-11-01

377

Plant-dependent genotypic and phenotypic diversity of antagonistic rhizobacteria isolated from different Verticillium host plants.  

PubMed

To study the effect of plant species on the abundance and diversity of bacterial antagonists, the abundance, the phenotypic diversity, and the genotypic diversity of rhizobacteria isolated from potato, oilseed rape, and strawberry and from bulk soil which showed antagonistic activity towards the soilborne pathogen Verticillium dahliae Kleb. were analyzed. Rhizosphere and soil samples were taken five times over two growing seasons in 1998 and 1999 from a randomized field trial. Bacterial isolates were obtained after plating on R2A (Difco, Detroit, Mich.) or enrichment in microtiter plates containing high-molecular-weight substrates followed by plating on R2A. A total of 5,854 bacteria isolated from the rhizosphere of strawberry, potato, or oilseed rape or bulk soil from fallow were screened by dual testing for in vitro antagonism towards VERTICILLIUM: The proportion of isolates with antagonistic activity was highest for strawberry rhizosphere (9.5%), followed by oilseed rape (6.3%), potato (3.7%), and soil (3.3%). The 331 Verticillium antagonists were identified by their fatty acid methyl ester profiles. They were characterized by testing their in vitro antagonism against other pathogenic fungi; their glucanolytic, chitinolytic, and proteolytic activities; and their BOX-PCR fingerprints. The abundance and composition of Verticillium antagonists was plant species dependent. A rather high proportion of antagonists from the strawberry rhizosphere was identified as Pseudomonas putida B (69%), while antagonists belonging to the Enterobacteriaceae (Serratia spp., Pantoea agglomerans) were mainly isolated from the rhizosphere of oilseed rape. For P. putida A and B plant-specific genotypes were observed, suggesting that these bacteria were specifically enriched in each rhizosphere. PMID:12089011

Berg, Gabriele; Roskot, Nicolle; Steidle, Anette; Eberl, Leo; Zock, Angela; Smalla, Kornelia

2002-07-01

378

Temperature dependence of calcium antagonist action.  

PubMed

Calcium-tolerant ventricular myocytes from adult rats were electrically stimulated. The maximal contraction frequency (fm) was determined at different temperatures. In drug-free Tyrode solution, fm follows the Arrhenius equation from 7 to 39.5 degrees C. However, all investigated calcium antagonist drugs (verapamil, nifedipine, diltiazem, fendiline) introduce a discontinuity between 27 and 30 degrees C into the Arrhenius plots of fm. Above this transition temperature calcium antagonists lower fm more pronouncedly than below. Below, 10- or 100 fold higher concentrations are needed for the same relative effect as at 37 degrees C. It is argued that these findings might be important in cardiac surgery when calcium antagonists are used for cardioplegia at deep hypothermia. PMID:4074403

Piper, H M; Hütter, J F; Spieckermann, P G

1985-01-01

379

Detecting sexually antagonistic coevolution with population crosses.  

PubMed Central

The result of population crosses on traits such as mating rate, oviposition rate and survivorship are increasingly used to distinguish between modes of coevolution between the sexes. Two key hypotheses, erected from a verbal theory of sexually antagonistic coevolution, have been the subject of several recent tests. First, statistical interactions arising in population crosses are suggested to be indicative of a complex signal/receiver system. In the case of oviposition rates, an interaction between populations (x, y and z) would be indicated by the rank order of female oviposition rates achieved by x, y and z males changing depending upon the female (x, y or z) with which they mated. Second, under sexually antagonistic coevolution females will do 'best' when mated with their own males, where best is defined by the weakest response to the signal and the highest fitness. We test these hypotheses by crossing strains generated from a formal model of sexually antagonistic coevolution. Strains differ in the strength of natural selection acting on male and female traits. In our model, we assume sexually antagonistic coevolution of a single male signal and female receptor. The female receptor is treated as a preference function where both the slope and intercept of the function can evolve. Our results suggest that neither prediction is consistently supported. Interactions are not diagnostic of complex signal-receiver systems, and even under sexually antagonistic coevolution, females may do better mating with males of strains other than their own. These results suggest a reinterpretation of several recent experiments and have important implications for developing theories of speciation when sexually antagonistic coevolution is involved. PMID:14561288

Rowe, Locke; Cameron, Erin; Day, Troy

2003-01-01

380

Development of novel EDG3 antagonists using a 3D database search and their structure-activity relationships.  

PubMed

Sphingosine-1-phosphate (S1P) is an intracellular second messenger and an extracellular mediator through endothelial differentiation gene (EDG) receptors, which are a novel class of G-protein-coupled receptors. Although EDG has attracted much attention because of its various roles, no selective agonists or antagonists have yet been developed. This could account for the delay in clarifying the physiological roles of members of the EDG family. Because precise structural information on EDG receptors is not yet available, pharmacophore models were generated based on structural information for S1P using the rational drug design software Catalyst. Novel antagonists, 2-alkylthiazolidine-4-carboxylic acids, were retrieved from a three-dimensional database search using the pharmacophore models, and these showed activity for EDG3. On the basis of their nonphosphoric acid structure, more potent antagonists, 2-(m- or p-heptylphenyl)thiazolidine-4-carboxylic acid, were developed. PMID:12361389

Koide, Yuuki; Hasegawa, Takeshi; Takahashi, Atsuo; Endo, Akira; Mochizuki, Naoki; Nakagawa, Masako; Nishida, Atsushi

2002-10-10