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Folic Acid  


Folic acid is used to treat or prevent folic acid deficiency. It is a B-complex vitamin needed by ... Folic acid comes in tablets. It usually is taken once a day. Follow the directions on your prescription label ...


Folic Acid  


Folic acid is a B vitamin. It helps the body make healthy new cells. Everyone needs folic acid. For women who may get pregnant, it is really important. Getting enough folic acid before and during pregnancy can prevent major birth ...


Folic Acid  


... acid Description Folic acid, or folate, is a B vitamin found in many beans, grains, fortified breakfast cereals, ... for use? Folic acid, or folate, is a B vitamin. It is promoted mainly as part of a ...


Folic acid - test  


Folic acid is a type of B vitamin. This article discusses the test to measure the amount of folic acid in the blood. ... that may interfere with test results, including folic acid supplements. Drugs that can decrease folic acid measurements ...


Folic Acid and Pregnancy  


... What to Expect Ebola: What to Know Folic Acid and Pregnancy KidsHealth > Parents > Pregnancy & Newborn Center > Your ... before conception and during early pregnancy . About Folic Acid Folic acid, sometimes called folate, is a B ...


Folate Nutrigenetics: A Convergence of Dietary Folate Metabolism, Folic Acid Supplementation, and Folate Antagonist Pharmacogenetics  

Microsoft Academic Search

Folate (Vitamin B9, Folic acid, folinic acid, folacin, pteroyglutamic acid) is essential for life-sustaining proc- esses of DNA synthesis, replication, and repair which are naturally present in common foods such as peas, oranges, broc- coli, and whole-wheat products. Folate levels have been associated with birth defects, cardiovascular disease, and many other important healthcare issues, which has resulted in government-mandated food

Brian Meshkin; Kenneth Blum



Facts about Folic Acid  


... For... Media Policy Makers Facts About Folic Acid Language: English Español (Spanish) Share Compartir CDC urges women to ... Blood Disorders & Disabilities Information For... Media Policy Makers Language: English Español (Spanish) File Formats Help: How do I ...


Folic Acid: Data and Statistics  


... . Folic Acid Share Compartir Data and Statistics On this Page In the United States Hispanic/ ... Questions & Answers Cereals with Folic Acid Data and Statistics Research Birth Defects COUNT Articles & Key Findings Recommendations ...


Homocysteine, Folic Acid and Cardiovascular Disease  


... t recommend widespread use of folic acid and B vitamin supplements to reduce the risk of heart disease ... been established. How do folic acid and other B vitamins affect homocysteine levels? Folic acid and other B ...


Folic acid: a biopharmaceutical evaluation.  


Abstract The aqueous solubility and drug product dissolution are important factors that determine the rate and extent of drug absorption from immediate release solid oral dosage forms. The aim of this article was to perform a folic acid biopharmaceutical study to evaluate the biowaiver of new products containing folic acid. We studied the solubility of its raw material and the dissolution profile of two commercially available products. Three different buffers (pH 1.2, 4.5 and 6.8) were used as the media of the solubility and dissolution tests (apparatus II, at 50?rpm and 900?mL of medium volume). We found that folic acid solubility and its release from tablets are pH dependent. The dissolution profiles of both tablets were compared by dissolution efficiency (%), using t-test or variance analysis (ANOVA). The dissolution profiles obtained for the two products at pH 1.2 medium were similar (p?>?0.05), but they were dissimilar at pH 4.5 and 6.8 (p?folic acid for each product at three different dissolution media used. The results showed that physicochemical characteristics of folic acid affect its dissolution and absorption making it difficult to take a decision on their biowaiver based on BCS. PMID:24867254

Bellavinha, Karime Resende; Silva-Barcellos, Neila Márcia; Souza, Janine Braga; Leite, Jaqueline Costa; Souza, Jacqueline de



Folic acid and birth defect prevention  


Prevention of birth defects with folic acid (folate) ... There is good evidence that taking folic acid before and during pregnancy can reduce the risk of certain birth defects ( spina bifida , anencephaly , and some heart defects). Experts recommend taking 400 ...


Photosensitized degradation of folic acid  

NASA Astrophysics Data System (ADS)

We demonstrate the key role of singlet oxygen in photodegradation of folic acid on exposure to UVA radiation and with photosensitizing treatment. We propose possible uses for photosensitized degradation of folates to enhance the efficacy of photodynamic therapy and for development of a high-sensitivity photochemical method for determining folates in biological systems.

Vorobei, A. V.; Vorobei, P. A.



Folic acid in diet  


... certain types of anemias . Folate works along with vitamin B12 and vitamin C to help the body break ... Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. National Academy Press, ...


Folic Acid Helps Prevent Neural Tube Defects  


... What's this? Submit Button CDC Features Folic Acid Helps Prevent Neural Tube Defects Language: English Español (Spanish) ... Submit Button Language: English Español (Spanish) File Formats Help: How do I view different file formats (PDF, ...


Effect of maternal and postweaning folic acid supplementation on colorectal cancer risk in the offspring  

Technology Transfer Automated Retrieval System (TEKTRAN)

Intrauterine and early life exposure to folic acid has significantly increased in North America owing to folic acid fortification, widespread supplemental use and periconceptional folic acid supplementation. The effect of maternal and postweaning folic acid supplementation on colorectal cancer risk ...


21 CFR 172.345 - Folic acid (folacin).  

Code of Federal Regulations, 2014 CFR

...glutamic acid. (b) Folic acid meets the accordance with 5 U.S.C. 552(a) and 1...chapter. (f) Folic acid may be added to a medical...Orphan Drug Act (21 U.S.C. 360ee(b)(3...formulated. (g) Folic acid may be added to food...



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...



21 CFR 862.1295 - Folic acid test system.  

Code of Federal Regulations, 2011 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...



Neural tube defects, folic acid and methylation.  


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



Neural Tube Defects, Folic Acid and Methylation  

PubMed Central

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.



Contemporary Issues Surrounding Folic Acid Fortification Initiatives  

PubMed Central

The impact of folate on health and disease, particularly pregnancy complications and congenital malformations, has been extensively studied. Mandatory folic acid fortification therefore has been implemented in multiple countries, resulting in a reduction in the occurrence of neural tube defects. However, emerging evidence suggests increased folate intake may also be associated with unexpected adverse effects. This literature review focuses on contemporary issues of concern, and possible underlying mechanisms as well as giving consideration the future direction of mandatory folic acid fortification. Folate fortification has been associated with the presence of unmetabolized folic acid (PteGlu) in blood, masking of vitamin B12 deficiency, increased dosage for anti-cancer medication, photo-catalysis of PteGlu leading to potential genotoxicity, and a role in the pathoaetiology of colorectal cancer. Increased folate intake has also been associated with twin birth and insulin resistance in offspring, and altered epigenetic mechanisms of inheritance. Although limited data exists to elucidate potential mechanisms underlying these issues, elevated blood folate level due to the excess use of PteGlu without consideration of an individual’s specific phenotypic traits (e.g. genetic background and undiagnosed disease) may be relevant. Additionally, the accumulation of unmetabolized PteGlu may lead to inhibition of dihydrofolate reductase and other enzymes. Concerns notwithstanding, folic acid fortification has achieved enormous advances in public health. It therefore seems prudent to target and carefully monitor high risk groups, and to conduct well focused further research to better understand and to minimize any risk of mandatory folic acid fortification. PMID:25580388

Choi, Jeong-Hwa; Yates, Zoe; Veysey, Martin; Heo, Young-Ran; Lucock, Mark



Contemporary issues surrounding folic Acid fortification initiatives.  


The impact of folate on health and disease, particularly pregnancy complications and congenital malformations, has been extensively studied. Mandatory folic acid fortification therefore has been implemented in multiple countries, resulting in a reduction in the occurrence of neural tube defects. However, emerging evidence suggests increased folate intake may also be associated with unexpected adverse effects. This literature review focuses on contemporary issues of concern, and possible underlying mechanisms as well as giving consideration the future direction of mandatory folic acid fortification. Folate fortification has been associated with the presence of unmetabolized folic acid (PteGlu) in blood, masking of vitamin B12 deficiency, increased dosage for anti-cancer medication, photo-catalysis of PteGlu leading to potential genotoxicity, and a role in the pathoaetiology of colorectal cancer. Increased folate intake has also been associated with twin birth and insulin resistance in offspring, and altered epigenetic mechanisms of inheritance. Although limited data exists to elucidate potential mechanisms underlying these issues, elevated blood folate level due to the excess use of PteGlu without consideration of an individual's specific phenotypic traits (e.g. genetic background and undiagnosed disease) may be relevant. Additionally, the accumulation of unmetabolized PteGlu may lead to inhibition of dihydrofolate reductase and other enzymes. Concerns notwithstanding, folic acid fortification has achieved enormous advances in public health. It therefore seems prudent to target and carefully monitor high risk groups, and to conduct well focused further research to better understand and to minimize any risk of mandatory folic acid fortification. PMID:25580388

Choi, Jeong-Hwa; Yates, Zoe; Veysey, Martin; Heo, Young-Ran; Lucock, Mark



Hydroperoxide-dependent folic acid degradation by cytochrome c.  


Folic acid is degraded by cytochrome c in the presence of hydrogen peroxide/tert-butyl hydroperoxide at the C9-N10 bond. The degradation is increased with increasing temperature. When guanidine HCl or benzoate are included in the reaction medium, the amount of folic acid degradation is enhanced. Catalase, formate, and thiourea inhibited hydrogen peroxide-dependent folic acid degradation only, and not tert-butyl hydroperoxide dependent degradation. Cyanide and azide markedly inhibited both the hydroperoxide-dependent degradations. Superoxide dismutase, EDTA, ethanol, mannitol, and dimethyl sulfoxide did not inhibit the degradation. The mechanism of cytochrome c-catalyzed folic acid degradation is discussed. PMID:2828540

Taher, M M; Lakshmaiah, N



The action spectrum for folic acid photodegradation in aqueous solutions.  


Folate is essential for cell division and growth. Deficiency is linked to birth defects, magaloblastic anaemia, cardiovascular disease, etc. Folic acid is a synthetic form of folate and is used to fortify food and in supplements. In aqueous solutions, in blood and even in human skin, folic acid may be degraded by ultraviolet radiation. Consequently, photodegradation of folic acid in human blood may lead to folate deficiency. However, the degree and the health consequences of such photodegradation are unknown. It is not clear which spectral region plays the most important role in the photodegradation of folic acid. In this study the photodegradation of folic acid in aqueous solution under different wavelengths of ultraviolet radiation (260-400nm) was investigated by fluorescence spectroscopy. The photodegradation rate of folic acid was dependent on wavelength. Action spectrum for 1?M folic acid photodegradation was determined. Its action spectrum is not identical to its absorption or fluorescence excitation spectra. The action spectrum demonstrated that UVB and UVA degrade folic acid. Protecting skin against UVB and UVA radiation by sunscreens may help to protect folic acid in human blood under intense solar radiation. PMID:23892004

Juzeniene, Asta; Thu Tam, Tran Thi; Iani, Vladimir; Moan, Johan



Fluorescence spectroscopic behaviour of folic acid  

NASA Astrophysics Data System (ADS)

The fluorescence spectroscopic behaviour of folic acid (FA) in 4 M HCl (dominant bi-cationic form), 0.1 M HCl (bi-cationic and cationic form), citric acid-NaOH pH 6 buffer (neutral form), 0.1 M and 4 M KOH (anionic form), and trifluoroacetic acid is studied. The thermal stability is investigated. Absolute absorption cross-section spectra are determined and compared with fluorescence excitation spectra. Intrinsic fluorescence quantum distributions and fluorescence quantum yields are extracted from fluorescence spectra measurements. The temporal fluorescence decay after picosecond pulse excitation is studied. The fluorescence quenching mechanisms for the different ionic forms of FA are discussed: excited-state proton release for bi-cationic FA, photo-physical non-radiative relaxation for cationic FA, and photo-induced intra-molecular electron transfer for neutral and anionic FA. Aerobic FA in 4 M KOH at elevated temperature dehydrated to 9,10-dehydro-folic acid. Its photo-dynamics was governed by twisted intra-molecular charge transfer and photo-isomerisation.

Tyagi, A.; Penzkofer, A.



Folic acid in the monkey brain: an immunocytochemical study.  


The present report describes the first visualization of folic acid-immunoreactive fibers in the mammalian central nervous system using a highly specific antiserum directed against this vitamin. The distribution of folic acid-immunoreactive structures was studied in the brainstem and thalamus of the monkey using an indirect immunoperoxidase technique. We observed fibers containing folic acid, but no folic acid-immunoreactive cell bodies were found. In the brainstem, no immunoreactive structures were visualized in the medulla oblongata, pons, or in the medial-caudal mesencephalon, since at this location immunoreactive fibers containing folic acid were only found at the rostral level in the dorsolateral mesencephalon (in the mesencephalic-diencephalic junction). In the thalamus, the distribution of folic acid-immunoreactive structures was more widespread. Thus, we found immunoreactive fibers in the midline, in nuclei close to the midline (dorsomedial nucleus, centrum medianum/parafascicular complex), in the ventral region of the thalamus (ventral posteroinferior nucleus, ventral posteromedial nucleus), in the ventrolateral thalamus (medial geniculate nucleus, lateral geniculate nucleus, inferior pulvinar nucleus) and in the dorsolateral thalamus (lateral posterior nucleus, pulvinar nucleus). The highest density of fibers containing folic acid was observed in the dorsolateral mesencephalon and in the pulvinar nucleus. The distribution of folic acid-immunoreactive structures in the monkey brain suggests that this vitamin could be involved in several mechanisms, such as visual, auditory, motor and somatosensorial functions. PMID:15158027

Mangas, A; Coveñas, R; Geffard, K; Geffard, M; Marcos, P; Insausti, R; Dabadie, M P



Folic acid complexes with human and bovine serum albumins.  


The interaction of folic acid with human serum (HSA) and bovine serum albumins (BSA) at physiological conditions, using constant protein concentration and various folic acid contents was investigated. FTIR, UV-visible and fluorescence spectroscopic methods as well as molecular modelling were used to analyse folic acid binding sites, the binding constant and the effect on HSA and BSA stability and conformations. Structural analysis showed that folic acid binds HSA and BSA via both hydrophilic and hydrophobic contacts with overall binding constants of Kfolic acid-HSA=8.1 (±0.5)×10(4)M(-1) and Kfolic acid-BSA=1.0 (±0.3)×10(5)M(-1). The number of bound acid molecules per protein was 1.7 (±0.4) for HSA and 1.5 (±0.3) for BSA complexes. Molecular modelling showed participation of several amino acids in folic acid-protein complexes stabilised by hydrogen bonding network. Folic acid complexation altered protein secondary structure by major reduction of ?-helix from 59% (free HSA) to 35% (acid-complex) and 62% (free BSA) to 25% (acid-complex) with an increase in random coil, turn and ?-sheet structures indicating protein unfolding. The results suggest that serum albumins might act as carrier proteins for folic acid in delivering it to target molecules. PMID:25212350

Bourassa, P; Hasni, I; Tajmir-Riahi, H A



Knowledge about folic acid and use of multivitamins containing folic acid among reproductive-aged women--Georgia, 1995.  


Neural tube defects (NTDs) are serious birth defects that affect an estimated 4000 pregnancies each year in the United States. However, women can substantially decrease the risk for this birth defect by consuming 400 micrograms (0.4 mg) of folic acid per day before conception and during early pregnancy. In September 1992, the Public Health Service (PHS) recommended that all women of childbearing age who are capable of becoming pregnant consume 400 micrograms of folic acid daily. To characterize knowledge about the benefits of folic acid and use of multivitamins containing folic acid among Georgia women, the Division of Public Health, Georgia Department of Human Resources (GDHR), analyzed data from the 1995 Georgia Women's Health Survey (GWHS)--a comprehensive study of women's health that included questions about folic acid. This report summarizes the survey findings regarding knowledge and use of folic acid, which indicate that only 20% of Georgia women aged 15-44 years consumed a multivitamin containing > or = 400 micrograms of folic acid per day, and 71% did not know that folic acid can prevent some birth defects. PMID:8926994



Folate during reproduction: the Canadian experience with folic acid fortification  

PubMed Central

Folate has received international attention regarding its role in the risk-reduction of birth defects, specifically neural tube defects (NTDs). In 1998, health officials in Canada, like the United States, mandated the addition of folic acid to white flour and select grain products to increase the folate intake of reproductive-aged women. Subsequent to this initiative there has been an increase in blood folate concentrations in Canada and a 50% reduction in NTDs. Many countries, including Korea, have not mandated folic acid fortification of their food supply. Reasons vary but often include concern over the masking of vitamin B12 deficiency, a belief that folate intakes among womenare adequate, low priority relative to other domestic issues, and the philosophy that individuals have the right not to consume supplemental folic acid if they so choose. Prior to folic acid fortification of the food supply in Canada, the folate intakes of women were low, and their blood folate concentrations while not sufficiently low to produce overt signs of folate deficiency (eg. anemia) were inconsistent with a level known to reduce the risk of an NTD-affected pregnancy. The purpose of this article is to describe the role of folate during the periconceptional period, pregnancy, and during lactation. The rationale for, and history of recommending folic acid-containing supplements during the periconceptional period and pregnancy is described as is folic acid fortification of the food supply. The impact of folic acid fortification in Canada is discussed, and unresolved issues associated with this policy described. While the incidence of NTDs in Canada pre-folic acid fortification were seemingly higherthan that of Korea today, blood folate levels of Korean women are strikingly similar. We will briefly explore these parallels in an attempt to understand whether folic acid fortification of the food supply in Korea might be worth consideration PMID:20368933

Lindzon, Gillian



The neurology of folic acid deficiency.  


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



21 CFR 862.1295 - Folic acid test system.  

Code of Federal Regulations, 2013 CFR




[Folic acid use by pregnant women in Israel for preventing neural tube defects].  


Spina bifida and anencephaly are the most common, serious malformations in neural tube defects (NTD). Randomized trials in the last 2 decades have demonstrated that folic acid, 0.4 mg/d, reduces the incidence of NTD by more than 50%. We investigated the use of folic acid and multivitamins containing folic acid in childbearing women. Of 221 women interviewed, 67 (30%) regularly took pills containing 0.4 mg folic acid. Women with higher educational levels were more likely to take multivitamins with folic acid than were the less educated (p = 0.05). Of the women who took folic acid, only 5 (7.5%) used separate folic acid tablets, before and during their pregnancy. The rest used multivitamins containing folic acid. The 5 women who took folic acid separately were college-educated and nonreligious, and they took multivitamins in addition (p > 0.05). Of the women interviewed, 58 (26.2%) were Bedouin of the Negev. 24 (41.4%) of them took pills containing folic acid on a regular basis. This percentage is higher than that in the Jewish women in the study who took folic acid for prevention of NTD (17%; p = 0.038). Most of the women took folic acid after the first trimester. Only a minority took daily periconceptional folic acid. Multivitamins containing 0.4 mg of folic acid were more popular than folic acid tablets alone. This study emphasizes the need for continuing efforts to increase consumption of folic acid and awareness of its benefits among women of childbearing age. PMID:11341184

Gil, Z; Aran, A; Friedman, O; Beni-Adani, L; Constantini, S



Folic acid and mental symptoms in children with epilepsy.  

PubMed Central

312 children resident at a hospital school received a neuropsychiatric examination and information was provided on their IQ status. Children with a fall in their IQ were identified. Serum and red cell folate values were estimated and the relationship between neuropsychiatric disturbances and folate disturbances explored. Patients with a fall in IQ, neurotic disturbance and depression all had significantly lower serum folic acid levels than the rest of the population, and the children with neurotic disturbances and depression had significantly lower red cell folate values. The relationship between folic acid metabolism and the neuropsychiatric disturbances is discussed in the light of these findings. PMID:7441279

Trimble, M R; Corbett, J A; Donaldson, D



Locating the binding sites of folic acid with milk ?- and ?-caseins.  


We located the binding sites of folic acid with milk ?- and ?-caseins at physiological conditions, using constant protein concentration and various folic acid contents. FTIR, UV-visible, and fluorescence spectroscopic methods as well as molecular modeling were used to analyze folic acid binding sites, the binding constant, and the effect of folic acid interaction on the stability and conformation of caseins. Structural analysis showed that folic acid binds caseins via both hydrophilic and hydrophobic contacts with overall binding constants of K(folic acid-?-caseins) = 4.8 (±0.6) × 10(4) M(-1) and K(folic acid-?-caseins) = 7.0 (±0.9) × 10(4) M(-1). The number of bound acid molecules per protein was 1.5 (±0.4) for ?-casein and 1.4 (±0.3) for ?-casein complexes. Molecular modeling showed different binding sites for folic acid on ?- and ?-caseins. The participation of several amino acids in folic acid-protein complexes was observed, which was stabilized by hydrogen bonding network and the free binding energy of -7.7 kcal/mol (acid-?-casein) and -8.1 kcal/mol (acid-?-casein). Folic acid complexation altered protein secondary structure by the reduction of ?-helix from 35% (free ?-casein) to 33% (acid-complex) and 32% (free ?-casein) to 26% (acid-complex) indicating a partial protein destabilization. Caseins might act as carriers for transportation of folic acid to target molecules. PMID:22103859

Bourassa, P; Tajmir-Riahi, H A



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

E-print Network

citrovorum factor (rep rin t )....................................................................... Conversion of folic acid to citrovorum factor by avian liver homogenates. I . Influence of reducing agents and anaerobiosis................................................................... 7 Manometric studies on oxidation of choline by avian liver homogenates (rep rin t )............. Chapter 5* Conversion of folic acid to citrovorum factor by avian liver homogenates, I I . Influence of dietary vitamin B a n d folic a c id...

Doctor, Vasant Manilal



Folic acid-Functionalized Nanoparticles for Enhanced Oral Drug Delivery  

PubMed Central

The oral absorption of drugs that have poor bioavailability can be enhanced by encapsulation in polymeric nanoparticles. Transcellular transport of nanoparticle-encapsulated drug, possibly through transcytosis, is likely the major mechanism through which nanoparticles improve drug absorption. We hypothesized that the cellular uptake and transport of nanoparticles can be further increased by targeting the folate receptors expressed on the intestinal epithelial cells. The objective of this research was to study the effect of folic acid functionalization on transcellular transport of nanoparticle-encapsulated paclitaxel, a chemotherapeutic with poor oral bioavailability. Surface-functionalized poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles loaded with paclitaxel were prepared by the interfacial activity assisted surface functionalization technique. Transport of paclitaxel-loaded nanoparticles was investigated using Caco-2 cell monolayers as an in vitro model. Caco-2 cells were found to express folate receptor and the drug efflux protein, p-glycoprotein, to high levels. Encapsulation of paclitaxel in PLGA nanoparticles resulted in a 5-fold increase in apparent permeability (Papp) across Caco-2 cells. Functionalization of nanoparticles with folic acid further increased the transport (8-fold higher transport compared to free paclitaxel). Confocal microscopic studies showed that folic acid-functionalized nanoparticles were internalized by the cells and that nanoparticles did not have any gross effects on tight junction integrity. In conclusion, our studies indicate that folic acid functionalized nanoparticles have the potential to enhance the oral absorption of drugs with poor oral bioavailability. PMID:22670575

Roger, Emilie; Kalscheuer, Stephen; Kirtane, Ameya; Guru, Bharath Raja; Grill, Alex E.; Whittum-Hudson, Judith; Panyam, Jayanth



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.



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



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



Knowledge and use of folic acid in women of reproductive age.  


Folic acid reduces the risk of neural tube defects. As approximately 50% of pregnancies are unintended, women of reproductive age should be aware of the importance of folic acid. We reviewed the existing literature on these women's knowledge of folic acid and neural tube defects. Databases searched were PubMed, CINAHL, and Health Reference Center Academic. We used terms such as "folic acid knowledge" and "folic acid awareness" to search articles published from 1998 to 2010. Awareness of the benefits of folic acid before conception and during pregnancy was low, although knowledge levels were associated with education and household income. Women who were already knowledgeable about folic acid cited health care professionals, magazines and newspapers, and radio and television as common sources of information. Effective knowledge translation is needed to ensure that women are informed about the benefits of folic acid during the reproductive years. This knowledge will allow them to make informed decisions about folic acid consumption. Health care professionals play an influential role in promoting folic acid knowledge among women of childbearing age. Lower levels of knowledge among women with lower levels of education and/or household income must be addressed. PMID:22146120

Fehr, Kelly R S; Fehr, Kelsey D H; Protudjer, Jennifer Lisa Penner



Preventive effects of folic acid supplementation on adverse maternal and fetal outcomes.  


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



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



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.



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


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



Folic acid in early pregnancy: a public health success story  

PubMed Central

Folate is a water-soluble B vitamin that must be obtained in the diet or through supplementation. For >50 yr, it has been known that folate plays an integral role in embryonic development. In mice, inactivation of genes in the folate pathway results in malformations of the neural tube, heart, and craniofacial structures. It has been shown that diets and blood levels of women who had a fetus with a neural tube defect are low for several micronutrients, particularly folate. Periconceptional use of folic acid containing supplements decreased recurrent neural tube defects in the offspring of women with a previously affected child and the occurrence of a neural tube defect and possibly other birth defects in the offspring of women with no prior history. Based on these findings, the U.S. Public Health Service recommended that all women at risk take folic acid supplements, but many did not. Mandatory food fortification programs were introduced in numerous countries, including the United States, to improve folate nutritional status and have resulted in a major decrease in neural tube defect prevalence. The success story of folate represents the cooperation of embryologists, experimentalists, epidemiologists, public health scientists, and policymakers.—Obi?an, S. G., Finnell, R. H., Mills, J. L., Shaw, G. M., Scialli, A. R. Folic acid in early pregnancy: a public health success story. PMID:20631328

Obi?an, Sarah G.; Finnell, Richard H.; Mills, James L.; Shaw, Gary M.; Scialli, Anthony R.



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))



Studies on the absorption and metabolism of folic acid  

PubMed Central

Folic acid absorption was studied in anesthetized dogs by determining the amount and chemical nature of folate in venous blood emerging from isolated intestinal segments containing free folic acid and/or pteroylpolyglutamates of a known chain length. Chromatographically pure test materials placed in the lumen were prepared by unambiguous solid phase synthetic methods. This synthetic procedure not only yields compounds of known structure, it also provides a means by which glutamic acid residues at any given position in the gamma glutamyl chain can be made radioactive. For example, teropterin (pteroyltriglutamate) was synthesized in such a way that 14C was present only in the middle glutamic acid unit. Suitable placement of label permitted assessment of the extent of peptide cleavage. The action of plasma conjugase was inhibited by copper chloride. Plasma samples were analyzed by Lactobacillus casei and Streptococcus faecalis assay, by column chromatography, and by quantitative measurement of pteridine-bound radioactivity. It was observed that biologically active folate appeared in the mesenteric vein with either pteroylmono-, di-, tri-, penta-, or heptaglutamate in the lumen. Generally speaking the absorption rate appeared to be inversely related to the length of the gamma glutamyl side chain. Roughly twice as much folic acid appeared in the circulation from 3H-labeled pteroylmonoglutamate as from 14C-labeled pteroylpentaglutamate when equimolar amounts of each were placed simultaneously in a single intestinal segment. Pteroylmonoglutamate appeared to be the predominant form entering the blood from each of the precursors tested. However, evidence was obtained that pteroyldiglutamate may enter the mesenteric vein soon after placing pteroyldi-, or triglutamate in the lumen, but not with the higher polyglutamates. Comparison of radioactivity and biological activity patterns suggests little conversion, if any, to reduced or methylated forms during the first 30 min of passage through the intestinal mucosa. We conclude that both pteroylmonoglutamates and pteroyldiglutamates may across the intestinal mucosa of the dog, and that reduction and methylation are not essential to the absorption process. PMID:5000560

Baugh, C. M.; Krumdieck, C. L.; Baker, H. J.; Butterworth, C. E.



Folic Acid for the Prevention of Infant Neural Tube Defects: U.S. Preventive Services Task Force Recommendation  


Folic Acid for the Prevention of Infant Neural Tube Defects: U.S. Preventive Services Task Force Recommendation Summaries for Patients ... modern medicine. The full reports are titled “Folic Acid for the Prevention of Neural Tube Defects: U.S. ...


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



Folic acid facilitates in vitro maturation of mouse and Xenopus laevis oocytes.  


The water-soluble B vitamins, folate and folic acid, play an important role in reproductive health, but little is known about the effects of folic acid on infertility. The present study tested the hypothesis that folic acid affects oocyte maturation, a possible cause of female infertility. We have studied the in vitro maturation of mouse and Xenopus oocytes. Hypoxanthine (Hx) was used as an inhibitor of mouse oocyte maturation to mimic in vivo conditions by maintaining high levels of cyclic-AMP. The frequency of first polar body (PB1) formation and germinal vesicle breakdown (GVBD) in mouse oocytes was decreased by Hx. This effect was counteracted by folic acid added to the medium. PB1 extrusion and GVBD percentages rose to 27·7 and 40·0% from 12·8 and 19·9%, respectively, by exposure to 500 ?M-folic acid. Folic acid also restored the spindle configuration, which had been elongated by Hx, as well as normalising the distribution of cortical granules (CG). In folic acid-treated Xenopus eggs, extracellular signal-regulated kinase 1 was phosphorylated, cyclin B2 and Mos were up-regulated and the frequency of GVBD was accelerated. Taken together, the findings suggest that folic acid facilitates oocyte maturation by altering the expression and phosphorylation of proteins involved in M-phase-promoting factor and mitogen-activated protein kinase pathways, as well as causing changes in spindle configuration and CG migration. PMID:22932126

Huang, Xiaoli; Gao, Shu; Xia, Wei; Hou, Shaoying; Wu, Kun



Effect of combined folic acid, Vitamin B6, and Vitamin B12 on colorectal adenoma  

Technology Transfer Automated Retrieval System (TEKTRAN)

Folic acid, vitamin B(6), and vitamin B(12) act in concert in the one-carbon metabolism and may protect against colorectal neoplasia. We examined the effect of combined B-vitamin treatment on the occurrence of colorectal adenoma. The Women's Antioxidant and Folic Acid Cardiovascular Study was a rand...


Multivitamins, Folic Acid and Birth Defects: Knowledge, Beliefs and Behaviors of Hispanic Women in North Carolina  

ERIC Educational Resources Information Center

Background: Consumption of folic acid prior to conception can prevent up to 70% of neural tube defect (NTD)-affected pregnancies. In 1992, the U.S. Public Health Service (USPHS) issued a recommendation that all women of childbearing age capable of becoming pregnant consume 400 [mu]g of folic acid daily to reduce their risk for a NTD-affected…

deRosset, Leslie; Mullenix, Amy; Zhang, Lei



Chemiluminescence determination of folic acid by a flow injection analysis assembly.  


A flow injection (FI) method is reported for the determination of folic acid by chemiluminescence method. This method is based on the reaction of folic acid with Ru(bipy)(3)(2+) and Ce(IV) to produce chemiluminescence. The calibration curve was linear over the range of 2.5×10(-5)-3.1×10(-7) mol/L with a detection limit of 2.3×10(-8) mol/L (S/N=3). The relative standard deviation of 1.0×10(-6) mol/L folic acid was found 3.5% (n=11). The influences of potential interfering substances were studied. The recovery was higher than 95.3%. The method was accurate, sensitive, and effective for assay of folic acid. This CL method was successfully applied to the determination of folic acid in pharmaceutical preparations. The mechanism of CL reaction was also studied. PMID:23334502

Wabaidur, Saikh Mohammad; Alam, Seikh Mafiz; Lee, Sang Hak; Alothman, Zeid Abdullah; Eldesoky, Gaber E



Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance among American seniors  

Technology Transfer Automated Retrieval System (TEKTRAN)

Folate deficiency has serious consequences for the fetus. Folic acid fortification of food addresses this problem. However, clinical consequences of vitamin B-12 deficiency may be worsened by high folic acid intakes, perhaps as a direct result of unmetabolized folic acid, which does not occur natura...


Soy protein/soy polysaccharide complex nanogels: folic acid loading, protection, and controlled delivery.  


In this study, we developed a facile approach to produce nanogels via self-assembly of folic acid, soy protein, and soy polysaccharide. High-pressure homogenization was introduced to break down the original aggregates of soy protein, which benefits the binding of soy protein with soy polysaccharide and folic acid at pH 4.0. After a heat treatment that causes the soy protein denaturation and gelation, folic acid-loaded soy protein/soy polysaccharide complex nanogels were fabricated. The nanogels have a polysaccharide surface that makes the nanogels dispersible in acidic conditions where folic acid is insoluble and soy protein forms precipitates after heating. More importantly, the protein and polysaccharide can inhibit the reactions between dissolved oxygen and folic acid during UV irradiation. After the preparation and storage of the nanogels in the presence of heat, oxygen, and light in acidic conditions, most of the folic acid molecules in the nanogels remain in their natural structure and can be released rapidly at neutral pH, that is, in the intestine. Because most food and beverages are acidic, the nanogels are a suitable delivery system of folic acid in food and beverages. PMID:23758109

Ding, Xuzhe; Yao, Ping




Technology Transfer Automated Retrieval System (TEKTRAN)

The hyperhomocysteinemia found in most hemodialysis patients is refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid (FA). We evaluated whether a high-dose L-folinic acid- based regimen provided improved total homocysteine (tHcy)-lowering efficacy in...


Knowledge, attitude and practice regarding folic acid deficiency; A hidden hunger  

PubMed Central

Objectives: To find the Knowledge Attitude and Practice regarding Folic Acid Deficiency among Women of Child Bearing Age (WPCBA). To find out the Association of Education Level with Practice of Folic Acid in WPCBA. Methods: A Descriptive cross sectional study (Knowledge Practice and Attitude) was conducted at Military Hospital and Combined Hospital Rawalpindi from September 2012 to February 2013. About 400 married females of age group 21-42 years were included by convenient sampling technique. After taking informed verbal consent, a closed ended interviewer administered questionnaire was filled. Data was entered and analyzed using SPSS version 20. Results: Mean age of the respondents was 30.31 + 5.280 years. Illiterate and literate were 165 (41.25%) and 235 (58.75%) respectively. The knowledge regarding folic acid need was 172 (43%). Only 161 (40.25%) thought that folic acid deficiency in pregnant women results in abnormality in newborn. In pregnancy, 205 (51.25%) had received folic acid supplementation. Association between education level and practice of folic acid was significant (p= 0.009) at 95% confidence level. Conclusion: Knowledge regarding folic acid deficiency among WOCBA was low along with the poor attitude. Practice was also not satisfactory. Education status plays important role in preventing micronutrient deficiency. PMID:24948984

Hisam, Aliya; Rahman, Mahmood Ur; Mashhadi, Syed Fawad



Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage.  


Key research findings relative to the question of whether maternal use of folic acid before and during pregnancy reduces the chance that offspring will be born with a congenital heart defect or an orofacial cleft are reviewed in this paper. Observational studies in general support an association between maternal use of multivitamins containing folic acid and a reduction in the occurrence of congenital heart defects and orofacial clefts. Results from one randomized controlled trial (RCT) provide the strongest evidence that multivitamins prevent congenital heart defects, but this RCT did not provide evidence that multivitamins prevent orofacial clefts. In addition, most observational and interventional studies are not designed to detect an independent effect from folic acid. Early studies suggested that periconceptional multivitamin use was associated with an increased occurrence of both miscarriages and multiple births, which has resulted in a great deal of controversy about the safety of folic acid use during pregnancy. We also review reports that were designed to answer these questions with more definitive data. When more substantial evidence about the effect of periconceptional folic acid on the occurrence of congenital heart defects and orofacial clefts is reported, we will have additional support for promoting folic acid intervention programs. All women capable of becoming pregnant should continue to consume 400 mug/d of folic acid in addition to a healthy diet as advised. PMID:15883454

Bailey, Lynn B; Berry, Robert J



Assessment of Folic Acid and DNA Damage in Cleft Lip and Cleft Palate  

PubMed Central

Studies have identified the risk factors like folic acid deficiency during gestational period, family history for orofacial clefts, drugs like antiepileptic, vitamin A. But, the data regarding the folic acid status in children with cleft lip/palate is hardly evaluated in depth. Here, an assessment of folic acid and DNA damage were carried out in children with orofacial anomalies. Folic acid level and DNA damage were evaluated by folic acid assay (direct chemiluminescent technology) and single cell gel electrophoresis or comet assay method respectively. The mean value of plasma folic acid by direct chemiluminescent technology was 6.5±3.6 nmol/L and the normal value in children ranges from 11.3 to 47.6 nmol/L. The amount of damaged DNA, measured as the tail length of the comet in cases, was 19.4±8.9 ?m and the mean percentage of DNA in tail was 16.5±3.7. Folic acid deficiency could be the reason for DNA damage. PMID:24847430

Brooklyin, Sivakumar; Jana, Rashmoni; Aravinthan, Singaravelu; Adhisivam, Bethou; Chand, Parkash



Mechanism of photooxidation of folic acid sensitized by unconjugated pterins.  


Folic acid, or pteroyl-l-glutamic acid (PteGlu), is a precursor of coenzymes involved in the metabolism of nucleotides and amino acids. PteGlu is composed of three moieties: a 6-methylpterin (Mep) residue, a p-aminobenzoic acid (PABA) residue, and a glutamic acid (Glu) residue. Accumulated evidence indicates that photolysis of PteGlu leads to increased risk of several pathologies. Thus, a study of PteGlu photodegradation can have significant ramifications. When an air-equilibrated aqueous solution of PteGlu is exposed to UV-A radiation, the rate of the degradation increases with irradiation time. The mechanism involved in this "auto-photo-catalytic" effect was investigated in aqueous solutions using a variety of tools. Whereas PteGlu is photostable under anaerobic conditions, it is converted into 6-formylpterin (Fop) and p-aminobenzoyl-l-glutamic acid (PABA-Glu) in the presence of oxygen. As the reaction proceeds and enough Fop accumulates in the solution, a photosensitized electron-transfer process starts, where Fop photoinduces the oxidation of PteGlu to Fop, and H(2)O(2) is formed. This process also takes place with other pterins as photosensitizers. The results are discussed with the context of previous mechanisms for processes photosensitized by pterins, and their biological implications are evaluated. PMID:20922252

Dántola, M Laura; Denofrio, M Paula; Zurbano, Beatriz; Gimenez, Carlos S; Ogilby, Peter R; Lorente, Carolina; Thomas, Andrés H



Severe thrombocytopenia associated with acute folic acid deficiency and severe hemorrhage in two patients.  

PubMed Central

Severe thrombocytopenia associated with acute folic acid deficiency in two inpatients is described. Both patients had severe hemorrhagic manifestations. A similar syndrome has previously been described in patients who have undergone extensive surgery or dialysis or both. The present cases show that acute folic acid deficiency can occur in other circumstances and may go unrecognized because other signs in the peripheral blood of a megaloblastic process may be minimal. A good response was obtained with folic acid therapy. Images FIG. 2 FIG. 3 PMID:6607097

Easton, D. J.



Folic acid supplementation attenuates hyperhomocysteinemia-induced preeclampsia-like symptoms in rats?  

PubMed Central

Folic acid participates in the metabolism of homocysteine and lowers plasma homocysteine levels directly or indirectly. To establish a hyperhomocysteinemic pregnant rat model, 2 mL of DL-homocysteine was administered daily by intraperitoneal injection at a dose of 200 mg/kg from day 10 to day 19 of gestation. Folic acid was administered by intragastric administration at a dose of 20 mg/kg during the period of preeclampsia induction. Results showed that systolic blood pressure, proteinuria/creatinine ratio, and plasma homocysteine levels in the hyperhomocysteinemic pregnant rats increased significantly, and that body weight and brain weight of rat pups significantly decreased. Folic acid supplementation markedly reversed the above-mentioned abnormal changes of hyperhomocysteinemic pregnant rats and rat pups. These findings suggest that folic acid can alleviate the symptoms of hyperhomocysteinemia- induced preeclampsia in pregnant rats without influencing brain development of rat pups.

Wang, Jun; Cui, Yan; Ge, Jing; Ma, Meijing



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



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



Development of electrochemical folic acid sensor based on hydroxyapatite nanoparticles  

NASA Astrophysics Data System (ADS)

We report the synthesis of hydroxyapatite (HA) nanoparticles (NPs) by a simple microwave irradiation method and its application as sensing element for the precise determination of folic acid (FA) by electrochemical method. The structure and composition of the HA NPs characterized using XRD, FTIR, Raman and XPS. SEM and EDX studies confirmed the formation of elongated spherical shaped HA NPs with an average particle size of about 34 nm. The HA NPs thin film on glassy carbon electrode (GCE) were deposited by drop casting method. Electrocatalytic behavior of FA in the physiological pH 7.0 was investigated by cyclic voltammetry (CV), linear sweep voltammetry (LSV) and chronoamperometry. The fabricated HA/GCE exhibited a linear calibration plot over a wide FA concentration ranging from 1.0 × 10-7 to 3.5 × 10-4 M with the detection limit of 75 nM. In addition, the HA NPs modified GCE showed good selectivity toward the determination of FA even in the presence of a 100-fold excess of ascorbic acid (AA) and 1000-fold excess of other common interferents. The fabricated biosensor exhibits good sensitivity and stability, and was successfully applied for the determination of FA in pharmaceutical samples.

Kanchana, P.; Sekar, C.



Development of electrochemical folic acid sensor based on hydroxyapatite nanoparticles.  


We report the synthesis of hydroxyapatite (HA) nanoparticles (NPs) by a simple microwave irradiation method and its application as sensing element for the precise determination of folic acid (FA) by electrochemical method. The structure and composition of the HA NPs characterized using XRD, FTIR, Raman and XPS. SEM and EDX studies confirmed the formation of elongated spherical shaped HA NPs with an average particle size of about 34nm. The HA NPs thin film on glassy carbon electrode (GCE) were deposited by drop casting method. Electrocatalytic behavior of FA in the physiological pH 7.0 was investigated by cyclic voltammetry (CV), linear sweep voltammetry (LSV) and chronoamperometry. The fabricated HA/GCE exhibited a linear calibration plot over a wide FA concentration ranging from 1.0×10(-7) to 3.5×10(-4)M with the detection limit of 75nM. In addition, the HA NPs modified GCE showed good selectivity toward the determination of FA even in the presence of a 100-fold excess of ascorbic acid (AA) and 1000-fold excess of other common interferents. The fabricated biosensor exhibits good sensitivity and stability, and was successfully applied for the determination of FA in pharmaceutical samples. PMID:25194322

Kanchana, P; Sekar, C



Cancer risk with folic acid supplements: a systematic review and meta-analysis  

PubMed Central

Objective To explore if there is an increased cancer risk associated with folic acid supplements given orally. Design Systematic review and meta-analysis of controlled studies of folic acid supplementation in humans reporting cancer incidence and/or cancer mortality. Studies on folic acid fortification of foods were not included. Data sources Cochrane Library, Medline, Embase and Centre of Reviews and Dissemination, clinical trial registries and hand-searching of key journals. Results From 4104 potential references, 19 studies contributed data to our meta-analyses, including 12 randomised controlled trials (RCTs). Meta-analysis of the 10 RCTs reporting overall cancer incidence (N=38?233) gave an RR of developing cancer in patients randomised to folic acid supplements of 1.07 (95% CI 1.00 to 1.14) compared to controls. Overall cancer incidence was not reported in the seven observational studies. Meta-analyses of six RCTs reporting prostate cancer incidence showed an RR of prostate cancer of 1.24 (95% CI 1.03 to 1.49) for the men receiving folic acid compared to controls. No significant difference in cancer incidence was shown between groups receiving folic acid and placebo/control group, for any other cancer type. Total cancer mortality was reported in six RCTs, and a meta-analysis of these did not show any significant difference in cancer mortality in folic acid supplemented groups compared to controls (RR 1.09, 95% CI 0.90 to 1.30). None of the observational studies addressed mortality. Conclusions A meta-analysis of 10 RCTs showed a borderline significant increase in frequency of overall cancer in the folic acid group compared to controls. Overall cancer incidence was not reported in the seven observational studies. Prostate cancer was the only cancer type found to be increased after folic acid supplementation (meta-analyses of six RCTs). Prospective studies of cancer development in populations where food is fortified with folic acid could indicate whether fortification similar to supplementation moderately increases prostate cancer risk. PMID:22240654

Wien, Tale Norbye; Pike, Eva; Wisløff, Torbjørn; Staff, Annetine; Smeland, Sigbjørn



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



Determination of folic acid by capillary electrophoresis with chemiluminescence detection.  


A rapid and simple method is presented for the determination of folic acid (FA) by capillary electrophoresis (CE) with chemiluminescence (CL) detection. This method was based on enhance effect of FA on the CL reaction between luminol and BrO(-) in alkaline aqueous solution. Optimal separation and determination was obtained with an electrophoretic buffer of 35 mM sodium borate (pH 9.4) containing 0.8 mM luminol, and an oxidizer solution of 1.6 mM NaBrO in 100 mM NaCO(3) buffer solution (pH 12.0). Under the optimal conditions, the determination of FA was achieved in less than 20 min, and the detection limit was 2.0 x 10(-8) M (S/N=3). The relative standard deviations (RSDs) on peak area and migration time were in the 1.5 and 1.1%, respectively. The present CE-CL method was applied to the determination of FA in commercial pharmaceutical tablets, apple juices and human urine. PMID:16413558

Zhao, Shulin; Yuan, Hongyan; Xie, Chao; Xiao, Dan



A food industry perspective on folic acid fortification.  


The U.S. Public Health Service (PHS) has recommended that all women of childbearing years, capable of becoming pregnant, consume 400 micrograms folic acid/d to reduce their risk of having a neural tube defect (NTD)-affected pregnancy. The U.S. Food and Drug Administration subsequently proposed a folate fortification scheme for cereal grains, which also allowed the continued fortification of breakfast cereals at 0.1 mg per serving. To determine the contribution of ready-to-eat breakfast cereals (RTEC) to folate intakes in women of childbearing years, data were analyzed from the U.S. Department of Agriculture's 1989-1991 Continuing Survey of Food Intakes by Individuals and 1987-1988 Nationwide Food Consumption Survey. Women consuming RTEC have higher intakes of folate than women reporting no RTEC consumption. Recent reports indicate that most women are unaware of the PHS recommendation to consume more folate, and many health professionals are not advising women of the need to consume adequate folate during childbearing years. The food industry has been an effective communicator of health and nutrition messages and should be encouraged to raise awareness about the role of folate in NTDs. Better analysis also needs to be conducted to identify women at risk of low folate intakes, so that targeted education efforts can be made and appropriate vehicles identified for delivering folate to these women. PMID:8598562

Schaller, D R; Olson, B H



Evidence that folic acid deficiency is a major determinant of hyperhomocysteinemia in Parkinson's disease.  


In the present work we measured blood levels of total homocysteine ((t)Hcy), vitamin B(12) and folic acid in patients with Parkinson s disease (PD) and in age-matched controls and searched for possible associations between these levels with smoking, alcohol consumption, L-DOPA treatment and disease duration in PD patients. We initially observed that plasma (t)Hcy levels were increased by around 30 % in patients affected by PD compared to controls. Linear correlation, multiple regression and comparative analyses revealed that the major determinant of the increased plasma concentrations of (t)Hcy in PD patients was folic acid deficiency, whereas in controls (t)Hcy levels were mainly determined by plasma vitamin B(12) concentrations. We also observed that alcohol consumption, gender and L-DOPA treatment did not significantly alter plasma (t)Hcy, folic acid and vitamin B(12) levels in parkinsonians. Furthermore, disease duration was positively associated with (t)Hcy levels and smoking was linked with a deficit of folic acid in PD patients. Considering the potential synergistic deleterious effects of Hcy increase and folate deficiency on the central nervous system, we postulate that folic acid should be supplemented to patients affected by PD in order to normalize blood Hcy and folate levels, therefore potentially avoiding these risk factors for neurologic deterioration in this disorder. PMID:19294496

dos Santos, Eliseu Felippe; Busanello, Estela Natacha Brandt; Miglioranza, Anelise; Zanatta, Angela; Barchak, Alethea Gatto; Vargas, Carmen Regla; Saute, Jonas; Rosa, Charles; Carrion, Maria Júlia; Camargo, Daiane; Dalbem, André; da Costa, Jaderson Costa; de Sousa Miguel, Sandro René Pinto; de Mello Rieder, Carlos Roberto; Wajner, Moacir



Neuroprotective effects of folic acid on experimental diabetic peripheral neuropathy.  


Diabetic peripheral neuropathy (DPN) is widely considered as a degenerative complication of diabetic patients. The clinical effectiveness of folic acid (FA) on DPN is uncertain. The objective of the present study was to determine the effect of FA in DPN using electromyography (EMG), histopathological examination, immunohistochemistry, inclined plane test, and malondialdehyde (MDA) levels as a marker for lipid peroxidation in experimental diabetic rats. A total of 21 Sprague Dawley rats were randomly divided into 3 groups: control group, diabetes group, and FA-treated group. In EMG, compound muscle action potential (CMAP) amplitude in the sciatic nerve was lower in the diabetes group compared with the control group. CMAP amplitude in the sciatic nerve was higher in the FA-treated group when compared with the diabetes group. Distal latency and CMAP duration in the sciatic nerve were lower in the FA-treated group when compared with the diabetes group. In histopathological examination of the sciatic nerve, peripheral fibrosis was present in the diabetic group; the fibrosis was lower in the FA-treated group. In comparison with the diabetes group, the expression of nerve growth factor (NGF) was higher in the FA-treated group. The scores for the inclined plane test were lower in the diabetes group and higher in the FA-treated group than the control group. The MDA levels were significantly lower in the FA-treated group when compared with the diabetes group.The study suggests that FA can protect diabetic rats against DPN and that the underlying mechanism for this may be related to improvement of the expression of NGF and lower MDA levels. PMID:24311627

Yilmaz, Mustafa; Aktug, Huseyin; Oltulu, Fatih; Erbas, Oytun



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


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



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.



Computational and experimental studies of the interaction between single-walled carbon nanotubes and folic acid  

NASA Astrophysics Data System (ADS)

This Letter involved the preparation of a conjugate between single-walled carbon nanotubes and folic acid that was obtained without covalent chemical functionalization using a simple 'one pot' synthesis method. Subsequently, the conjugate was investigated by a computational hybrid method: our own N-layered Integrated Molecular Orbital and Molecular Mechanics (B3LYP(6-31G(d):UFF)). The results confirmed that the interaction occurred via hydrogen bonding between protons of the glutamic moiety from folic acid and ? electrons from the carbon nanotubes. The single-walled carbon nanotube-folic acid conjugate presented herein is believed to lead the way to new potential applications as carbon nanotube-based drug delivery systems.

Castillo, John J.; Rozo, Ciro E.; Castillo-León, Jaime; Rindzevicius, Tomas; Svendsen, Winnie E.; Rozlosnik, Noemi; Boisen, Anja; Martínez, Fernando



Effect of Baking Process on Added Folic Acid and Endogenous Folates Stability in Wheat and Rye Breads  

Microsoft Academic Search

In Poland bread as a staple food both made from wheat and rye flour can be a potential product for future fortification with folic acid. The objective of the study was to examine the effect of fermentation and baking on added folic acid and some endogenous folates stability during breadmaking of rye and wheat breads. Breads were produced using the

El?bieta Gujska; Katarzyna Majewska



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



The administration of folic acid reduces intravascular oxidative stress in diabetic rabbits.  


There is evidence that plasma homocysteine augments angiopathy in patients with diabetes mellitus. Although lowering homocysteine with folic acid improves endothelial function, the precise mechanisms underlying this effect are unknown. To study this area further, the effect of administration of folic acid to diabetic rabbits on intraaortic oxidative stress was studied by assessing the formation of superoxide (O(2)(-)), 8-isoprostane F(2alpha) (8-IPF(2alpha)), and prostacyclin (as 6-keto-PGF(1alpha)) as well as acetylcholine-stimulated relaxation and gp47(phox) content. Nonketotic diabetes mellitus was induced in New Zealand rabbits with alloxan, and low- and high-dose folic acid was administered daily for 1 month. Rabbits were killed, aortae were excised, and rings were prepared. Rings were mounted in an organ bath, and relaxation was elicited with acetylcholine. The O(2)(-) release was measured spectrophotometrically; the gp47(phox) expression, by Western blotting; and the 8-IPF(2alpha) and 6-keto-PGF(1alpha) formation, by enzyme-linked immunosorbent assay. Blood was collected for measurement of homocysteine, red blood cell folate, and glucose. In aortae from the diabetic rabbits, acetylcholine-induced relaxation was significantly impaired compared with that in untreated controls. The O(2)(-) release, p47(phox) expression, and 8-IPF(2alpha) formation were all enhanced and 6-keto-PGF(1alpha) formation was reduced compared with controls. All these effects were reversed by both low- and high-dose folic acid. Plasma total homocysteine was reduced by high-dose, but not low-dose, folic acid. Red blood cell folate was elevated in both groups. The improvement of endothelial function in patients receiving folic acid may be due to inhibition of nicotinamide adenine nucleotide phosphate oxidase (NADPH) oxidase expression and therefore conservation of nitric oxide and prostacyclin bioavailability, 2 vasculoprotective factors. PMID:18502259

Shukla, Nilima; Angelini, Gianni D; Jeremy, Jamie Y



Effects of Intraperitoneally Administered Folic Acid on the Healing of Repaired Tibial Nerves in Rats.  


Background?Complete nerve regeneration and clinical healing remain a challenge despite considerable advances in the treatment of peripheral nerve injuries. To improve nerve regeneration, several experimental molecular procedures have been attempted. This study aimed to investigate the effects of folic acid on peripheral nerve healing after transection and end-to-end suture repair of the tibial nerve in rats. Methods?In this study, 20 adult male Wistar Albino rats weighing 225 to 250?g were used. The right tibial nerves of 20 rats were explored, transected, and sutured using the end-to-end technique. The rats were randomly allocated to either the intraperitoneally administered folic acid group (test group) or the control group. Preoperative and 6-week postoperative neurophysiological studies were performed by the same researcher. Myelin-sheathed axons were counted. Results?The results demonstrated that the folic acid-treated group exhibited improved electromyographic results compared with the control group. Histological evaluation revealed that the axons were well preserved and that the axon quantity and density were increased in the test group compared with the control group. Quantitative results also increased in the test group compared with the control group (p?=?0.001). Conclusion?In this study, 6-week intraperitoneal administration of 80 µg/kg of folic acid significantly improved peripheral nerve healing. Histological analysis of the group that received folic acid revealed increased axon myelination with little granular tissue or fibrosis. We propose that folic acid supplementation may be an effective component of peripheral nerve injury treatment. PMID:25423028

Harma, Ahmet; Sahin, Mehmet Sukru; Zorludemir, Suzan



A history of the isolation and identification of folic acid (folate).  


In the 1930s, Lucy Wills identified a 'new hemopoietic factor' in yeast and liver which cured tropical macrocytic anemia in humans and experimental anemia in monkeys. Janet Watson and William B. Castle named the unknown substance, which would ultimately become a form of folate, 'Wills' factor'. Further studies with this unknown substance showed that it was active against nutritional pancytopenia in monkeys and experimental anemia in chicks, leading to various designations such as vitamin M (monkey) and vitamin B(c) (chick). Other factors with growth-promoting activity for microorganisms such as Lactobacillus casei were given the interim names including folic acid - in recognition of extracts from leafy greens. Competing pharmaceutical research groups headed by Robert Stokstad at Lederle Laboratories and Joseph John Pfiffner at Parke-Davis Research Laboratory independently isolated factors bearing the biological properties of Wills' factor and other unknown related factors including folic acid, Lederle Laboratories from a bacterial culture and Parke-Davis Laboratory from yeast and liver as a conjugate of folate. The new vitamin then was crystallized, chemically identified, and synthesized as pteroylglutamic acid and named folic acid between 1943 and 1945. Further studies of the monoglutamic folic acid and the yeast isolate polyglutamyl folate followed through the 1950s and to the present. PMID:23183294

Rosenberg, Irwin H



Folic acid and pantothenic acid protection against valproic acid-induced neural tube defects in CD-1 mice  

SciTech Connect

In utero exposure to valproic acid (VPA) during pregnancy is associated with an increased risk of neural tube defects (NTDs). Although the mechanism by which VPA mediates these effects is unknown, VPA-initiated changes in embryonic protein levels have been implicated. The objectives of this study were to investigate the effect of in utero VPA exposure on embryonic protein levels of p53, NF-{kappa}B, Pim-1, c-Myb, Bax, and Bcl-2 in the CD-1 mouse. We also evaluated the protective effects of folic acid and pantothenic acid on VPA-induced NTDs and VPA-induced embryonic protein changes in this model. Pregnant CD-1 mice were administered a teratogenic dose of VPA prior to neural tube closure and embryonic protein levels were analyzed. In our study, VPA (400 mg/kg)-induced NTDs (24%) and VPA-exposed embryos with an NTD showed a 2-fold increase in p53, and 4-fold decreases in NF-{kappa}B, Pim-1, and c-Myb protein levels compared to their phenotypically normal littermates (P < 0.05). Additionally, VPA increased the ratio of embryonic Bax/Bcl-2 protein levels (P < 0.05). Pretreatment of pregnant dams with either folic acid or pantothenic acid prior to VPA significantly protected against VPA-induced NTDs (P < 0.05). Folic acid also reduced VPA-induced alterations in p53, NF-{kappa}B, Pim-1, c-Myb, and Bax/Bcl-2 protein levels, while pantothenic acid prevented VPA-induced alterations in NF-{kappa}B, Pim-1, and c-Myb. We hypothesize that folic acid and pantothenic acid protect CD-1 embryos from VPA-induced NTDs by independent, but not mutually exclusive mechanisms, both of which may be mediated by the prevention of VPA-induced alterations in proteins involved in neurulation.

Dawson, Jennifer E. [Department of Pharmacology and Toxicology and School of Environmental Studies, Queen's University, Kingston, Ontario, K7L 3N6 (Canada); Raymond, Angela M. [Department of Pharmacology and Toxicology and School of Environmental Studies, Queen's University, Kingston, Ontario, K7L 3N6 (Canada); Winn, Louise M. [Department of Pharmacology and Toxicology and School of Environmental Studies, Queen's University, Kingston, Ontario, K7L 3N6 (Canada)]. E-mail:



The adaptive transport of folic acid in the intestine of laying hens with increased supplementation of dietary folic acid.  


Different aspects of folic acid (FA) transport in the intestine of the laying hen have been characterized. Less is known about the adaptive response of this process to a dietary challenge. To this end, a study was conducted to evaluate the effect of increased dietary FA supplementation on the rate of intestinal FA transport and the expression of the intestinal folate transporter genes, the proton-coupled folate transporters (PCFT) and the reduced folate carrier (RFC), in the laying hen. Twenty-four Shaver White hens at 34 wk of age were randomly assigned to receive 1 of 3 dietary treatments: 1) basal diet with no supplemental folate (n = 8), 2) basal diet + 10 mg/kg of crystalline FA (n = 8), and 3) basal diet + 100 mg/kg of crystalline FA (n = 8). A completely randomized design with 3 dietary treatments was used. Production performance was not affected by FA supplementation; however, egg and plasma folate concentrations increased (P < 0.001), whereas plasma homocysteine concentrations decreased (P < 0.011) in birds fed 10 or 100 mg of FA/kg of diet, relative to controls. Mucosal to serosal uptake of FA in the duodenum was decreased (P < 0.002), but the mRNA levels of the duodenal PCFT and RFC genes were not affected when birds were fed 10 or 100 mg of FA/kg of diet. In the jejunum, the mucosal to serosal uptake of FA, as well as the mRNA levels of the PCFT and RFC genes, were not influenced by increased FA supplementation. Overall, increased dietary levels of FA resulted in decreased transport of FA in the duodenum but not in the jejunum of laying hens. This decrease was not associated with decreased mRNA expression of the duodenal PCFT and RFC genes. Therefore, a posttranscriptional or translational adaptation of the intestinal folate transporters may be involved in the much lower transport of FA in the duodenum of laying hens during increased dietary supplementation of FA. PMID:22184437

Tactacan, G B; Rodriguez-Lecompte, J C; O, K; House, J D



Development and application of nanoparticles synthesized with folic acid-conjugated soy protein  

Technology Transfer Automated Retrieval System (TEKTRAN)

In this study, soy protein isolate (SPI) was conjugated with folic acid (FA) to prepare nanoparticles for target-specific drug delivery. Successful conjugation was evidenced by UV spectrophotometry and primary amino group analysis. An increase in count rate by at least 142% was observed in FA-conjug...


Knowledge and use of folic acid by women of childbearing age--United States, 1997.  


Each year in the United States, approximately 4000 pregnancies are affected by spina bifida and anencephaly. Babies born with spina bifida usually survive, often with serious disability, but anencephaly is invariably fatal. The B vitamin folic acid can reduce the occurrence of spina bifida and anencephaly by at least 50% when consumed daily before conception and during early pregnancy. In 1992, the Public Health Service (PHS) recommended that all women of childbearing age who are capable of becoming pregnant consume 400 microg of folic acid daily. Folic acid can be obtained from multivitamins or certain other supplements and from some fortified breakfast cereals. It is found naturally in orange juice, green leafy vegetables, and beans; however, it is difficult to obtain the recommended 400 microg daily through diet alone. This report summarizes findings from a survey conducted during January and February 1997 that indicate modest increases since 1995 in knowledge about and consumption of folic acid among U.S. women aged 18-45 years and highlights the need for additional public health efforts to take full advantage of this prevention opportunity. PMID:9262072



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.



[Spectroscopic study on binding of folic acid to human serum albumin].  


The interaction of human serum albumin and folic acid was studied using fluorescence spectroscopy, UV absorption and synchronous fluorescence spectroscopy in the pH 7.4 Tris-HCl buffer system at different temperatures. The research shows that these interactions result in the endogenous fluorescence quenching of HSA, which belongs to a static quenching mechanism. The quenching rate constants, the binding constants and the binding sites of the static quenching were calculated. The distance between the body (HSA) and receptor (folic acid) and the efficiency of energy transfer were obtained to be 1.77 nm and 0. 052 65 respectively, based on the theory of Forster nonradiative energy transfer. And according to the thermodynamic parameters calculated the binding of HSA and folic acid is mainly attributed to the hydrophobic interaction, partly static force. Further more the synchronous fluorescence spectrum was utilized to investigate the conformational transformation; The decline result of the hydrophobic nature around Trp demonstrates that the folic acid is in the hydrophobic cavity of HSA. PMID:19798971

Liu, Hui-Juan; Li, Peng; Zhang, Ya-Dong; Guo, Cao; Deng, Jun-Yuan; Cai, Jian-Wei; Liu, Bo-Li



Folic Acid Supplements and Risk of Facial Clefts: National Population Based Case-Control Study  

Microsoft Academic Search

Objective To explore the role of folic acid supplements, dietary folates, and multivitamins in the prevention of facial clefts. Design National population based case-control study. Setting Infants born 1996-2001 in Norway. Participants 377 infants with cleft lip with or without cleft palate; 196 infants with cleft palate alone; 763 controls. Main outcome measures Association of facial clefts with maternal intake

Allen J. Wilcox; Rolv Terje Lie; Kari Solvoll; Jack Taylor; D Robert McConnaughey; Hallvard Vindenes; Stein Emil Vollset; Christian A. Drevon




Technology Transfer Automated Retrieval System (TEKTRAN)

Sixty-four samples of fortified bread collected from bakeries from Santiago, Chile were assayed for their folic acid (FA) content using high performance liquid chromatography-mass spectrometry (LC-MS). A 13C-labeled analogue of FA was spiked into each sample as an internal standard and the analyte ...



EPA Science Inventory

The study was conducted jointly between CDC and Chinese health officials in 1998 to determine folic acid's effectiveness in reducing rates of neural tube defects (NTDs) in two areas of China. In summary, this study showed that in northern China, which has a high incidence of NTDs...


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

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.


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

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.


Serum folic acid and RFC A80G polymorphism in Alzheimer's disease and vascular dementia.  


Low level of vitamin B12 and folic acid has been reported to play an important role in the pathogenesis of Alzheimer's disease (AD) and vascular dementia (VaD). Serum folic acid and vitamin B12 were assayed in 80 AD and 50 VaD cases and in 120 healthy controls. The reduced folate carrier (RFC1) gene, rs1051266, which encodes the RFC 1, protein was analyzed for polymorphism by polymerase chain reaction-restriction fragment length polymorphism. It was observed that the patients having folic acid <8.45 ng/mL had 2.4 (95% confidence interval [CI]: 1.4-4.5) times higher odds of having AD and 2.1 (95% CI: 1.1-4.2) times higher odds of having VaD than patients having folic acid ?8.45 ng/mL. Serum vitamin B12 level did not show any such statistically significant effect in altering the odds. No direct association was found between variant (G) allele or genotype of rs1051266 with AD and VaD cases. On serum folate level no association was observed with gene polymorphism. PMID:24554143

Mansoori, Nasim; Tripathi, Manjari; Alam, Rizwan; Luthra, Kalpana; Sharma, Sumit; Lakshmy, Ramakrishnan; Kalaivani, Mani; Mukhopadhyay, Asok K



Dietary Supplements of Folic Acid During Lactation: Effects on the Performance of Dairy Cows1  

Microsoft Academic Search

The present experiment was undertaken to deter- mine the effects of dietary supplements of folic acid administered from 4 wk prepartum to 305 d of lacta- tion on lactational performance. Sixty-three Holstein cows were assigned to 22 blocks of 3 cows according to lactation number, milk production, and body weight (BW). Within each block, cows received 0, 2, or 4

C. L. Girard; J. J. Matte



Folic acid fortification and cancer risk: plea for objective evaluation of the evidence  

Technology Transfer Automated Retrieval System (TEKTRAN)

The letter from Bayston and colleagues,1 representing the Association for Spina Bifida and Hydrocephalus, dismisses concerns raised by two recent studies2, 3 of a possible increase in colorectal cancer (CRC) risk following a high intake of folic acid. In relation to the postulated link between forti...


Moderately high intake of folic acid has a negative impact on mouse embryonic development  

Technology Transfer Automated Retrieval System (TEKTRAN)

The incidence of neural tube defects has diminished considerably since the implementation of food fortification with folic acid (FA). However, the impact of excess FA intake, particularly during pregnancy, requires investigation. In a recent study, we reported that a diet supplemented with 20-fold h...


Introduction of biotin or folic acid into polypyrrole magnetite core-shell nanoparticles  

SciTech Connect

In order to contribute to the trend in contemporary research to develop magnetic core shell nanoparticles with better properties (reduced toxicity, high colloidal and chemical stability, wide scope of application) in straightforward and reproducible methods new core shell magnetic nanoparticles were developed based on polypyrrole shells functionalized with biotin and folic acid. Magnetite nanoparticles stabilized by sebacic acid were used as magnetic cores. The morphology of magnetite was determined by transmission electron microscopy TEM, while the chemical structure investigated by FT-IR.

Nan, Alexandrina; Turcu, Rodica [National Institute of Research and Development for Isotopic and Molecular Technologies, Donath 65-103, Cluj-Napoca (Romania)] [National Institute of Research and Development for Isotopic and Molecular Technologies, Donath 65-103, Cluj-Napoca (Romania); Liebscher, Jürgen [National Institute of Research and Development for Isotopic and Molecular Technologies, Donath 65-103, Cluj-Napoca, Romania and Institute of Chemistry, Humboldt-University Berlin, Brook-Taylor 2, D-12489 Berlin (Germany)] [National Institute of Research and Development for Isotopic and Molecular Technologies, Donath 65-103, Cluj-Napoca, Romania and Institute of Chemistry, Humboldt-University Berlin, Brook-Taylor 2, D-12489 Berlin (Germany)



HPLC Determination of Stability and Distribution of Added Folic Acid and Some Endogenous Folates During Breadmaking 1  

Microsoft Academic Search

Cereal Chem. 78(4):375-378 Bread flour was spiked with folic acid (1.40 mg\\/lb or 3.08 µg\\/g of flour) and processed into bread by the sponge and dough method. Changes that occurred to added folic acid and endogenous folate contents through different processing stages, including sponge formation, proofing, and baking, were assessed by reversed-phase ion-pair HPLC combined with UV and fluorometric detection.

Elolo S. Osseyi; Randy L. Wehling; Julie A. Albrecht



Effect of folic acid and vitamin B12 on pemetrexed antifolate chemotherapy in nutrient lung cancer cells.  


Pemetrexed (MTA) is a multitargeted antifolate drug approved for lung cancer therapy. Clinically, supplementation with high doses of folic acid (FA) and vitamin B12 (VB12) lowers MTA cytotoxicities. An antagonistic effect of FA/VB12 on MTA efficacy has been proposed. However, patients who receive FA/VB12 show better tolerance to MTA with improved survival. The aims of this study are to investigate the modulation of FA and VB12 on MTA drug efficacy in human nonsmall cell lung cancer (NSCLC) cell lines. The sensitivities of cells, apoptosis, and MTA-regulated proteins were characterized to determine the possible effects of high doses of FA and VB12 on MTA efficacy. MTA has the lowest efficacy under 10% serum conditions. However, supplementation with FA and VB12 individually and additively reversed the insensitivity of NSCLC cells to MTA treatment with 10% serum. The enhanced sensitivities of cells following FA/VB12 treatment were correlated with increasing apoptosis and were specific to MTA but not to 5-fluorouracil (5-FU). Enhanced sensitivity was also associated with p21(WAF1/Cip1) expression level. Our results revealed no antagonistic effect of high doses of FA/VB12 on MTA efficacy in cancer cells grown in nutrient medium. Furthermore, these data may partially explain why supplementation of FA and VB12 resulted in better survival in MTA-treated patients. PMID:23984356

Yang, Tsung-Ying; Chang, Gee-Chen; Hsu, Shih-Lan; Huang, Yi-Rou; Chiu, Ling-Yen; Sheu, Gwo-Tarng



Arnold Chiari Malformation with Spina Bifida: A Lost Opportunity of Folic Acid Supplementation  

PubMed Central

In Arnold Chiari (kee-AHR-ee) II malformation elongated cerebellar tonsils are displaced inferiorly through the Foramen Magnum into the upper cervical spinal canal. It is a complex anomaly with skull, dura, brain, spine and cord manifestations. Meningomyelocele is seen in all cases. We present a case of type II Arnold Chiari Malformation diagnosed in utero in a pregnant lady .There was no periconceptional folic acid supplementation. As the role of the Methylene Tetra Hydro Folate Reductase gene polymorphism in neural tube defects is becoming evident, a simple opportunity as folic acid supplementation should not be missed. Folate supplementation as fortification of cereal grains will also prevent other conditions like congenital heart defects, urinary tract anomalies, orofacial defects, limb defects and pyloric stenosis.

Sagayaraj, Benjamin M; Barua, Ravi Kumar; Sharma, Nidhi; Ranga, Upasana



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



A sandwich substrate for ultrasensitive and label-free SERS spectroscopic detection of folic acid / methotrexate.  


A highly sensitive surface enhanced Raman scattering (SERS) substrate with particle-film sandwich geometry has been developed for the label free detection of folic acid (FA) and methotrexate (MTX). In this sandwich structure, the bottom layer is composed of a copper foil decorated with silver nanoparticles synthesized by the galvanic displacement reaction, and top layer is constituted by silver nanoparticles. The FA and MTX molecules are sandwiched between the silver nanoparticles decorated copper film and the silver nanoparticles. The plasmonic coupling between the two layers of the sandwich structure greatly enhances the SERS spectra of FA and MTX. SERS activity of the substrate was studied and optimized by adjusting the time of galvanic displacement reaction. The SERS spectra of the FA and MTX showed the minimum detection concentration of 100 pM. The identification of methotrexate and folic acid analogs was also carried out by SERS spectra analysis. PMID:24850231

Yang, Jing; Tan, Xuebin; Shih, Wei-Chuan; Cheng, Mark Ming-Cheng



Folic acid supplementation before and during pregnancy in the Newborn Epigenetics STudy (NEST)  

Microsoft Academic Search

BACKGROUND: Folic acid (FA) added to foods during fortification is 70-85% bioavailable compared to 50% of folate occurring naturally in foods. Thus, if FA supplements also are taken during pregnancy, both mother and fetus can be exposed to FA exceeding the Institute of Medicine's recommended tolerable upper limit (TUL) of 1,000 micrograms per day (?g\\/d) for adult pregnant women. The

Cathrine Hoyo; Amy P Murtha; Joellen M Schildkraut; Michele R Forman; Brian Calingaert; Wendy Demark-Wahnefried; Joanne Kurtzberg; Randy L Jirtle; Susan K Murphy



Is adequate and balanced nutrition during pregnancy more effective than iron and folic acid supplements?  

Microsoft Academic Search

To provide instruction for pregnant women regarding adequate and balanced nutrition and determine whether iron and folic acid\\u000a supplementation is essential. The research was an experimental clinical intervention. The study was conducted between March\\u000a 2004 and May 2005 with 80 pregnant volunteers. The study participants were in their 16th to 24th weeks of pregnancy; all participants\\u000a were healthy, carried only

Funda Elmacioglu; Bulent Surucu; Tayfun Alper; Aliye Ozenoglu; Serdal Ugurlu



The role of folic acid fortification in neural tube defects: a review.  


The worldwide prevalence of neural tube defects (NTDs) has fallen noticeably during the past 30 years, but the specific etiology and causative mechanism of NTDs remain unknown. Since introduction of mandatory fortification of grains with folic acid, a further decrease in NTD prevalence has been reported in North America and other countries with large variations among ethnic subgroups. However, a significant portion of NTDs still persists. Population data suggest that women of childbearing age may not yet be adequately targeted, while the general population may be overfortified with folic acid. While an excessive folate intake may be associated with adverse effects, there remains uncertainty about the minimum effective folate intake and status required for NTD prevention, and the safe upper folate level. Besides folate, several other lifestyle and environmental factors as well as genetic variations may influence NTD development, possibly by affecting one-carbon metabolism and thus epigenetic events. In conclusion, mandatory folic acid fortification plays a significant part in the reduction of NTD prevalence, but possibly at a cost and with a portion of NTDs remaining. More effective preventive strategies require better understanding of the etiology of this group of birth defects. PMID:24007422

Osterhues, Anja; Ali, Nyima S; Michels, Karin B



Effect of Folic Acid on Hematological Changes in Methionine-Induced Hyperhomocysteinemia in Rats  

PubMed Central

The present study was designed to investigate the effect of folic acid on homocysteine, lipid profile and hematological changes in methionine-induced hyperhomocysteinemic rats. Hyperhomocysteinemia was induced by methionine (1 g/kg, p.o.) administration for 30 days. Biochemical and hematological observations were further substantiated with histopathological examination. The increase in homocysteine, total cholesterol, low density lipoprotein-cholesterol, very low density lipoprotein-cholesterol and triglycerides levels with reduction in the levels of high density lipoprotein in serum were the salient features observed in methionine treated toxicologic control rats (i.e. group II). Hematological observations of the peripheral blood smears of toxicologic rats also showed crenation of red blood cells membrane and significant (P<0.01) increase in total leukocyte count, differential leukocyte count and platelet counts with significant (P<0.01) decrease in the mean hemoglobin levels, as compared to vehicle control rats. Administration of folic acid (100 mg/kg, p.o.) for 30 days to methionine- induced hyperhomocysteinemic rats produced a significant (P< 0.01) decrease in the levels of homocysteine, total cholesterol, low density lipoprotein-cholesterol, very low density lipoprotein-cholesterol and triglycerides with significant (P< 0.01) increase in high density lipoprotein-cholesterol levels in serum when compared with toxicologic control rats. The present study, for the first time, investigates the effect of folic acid treatment on hematological changes in rats with methionine-induced hyperhomocysteinemia. PMID:20490293

Ansari, M. N.; Nigam, G. K.; Bhandari, Uma



PHARMACOLOGY AND CELL METABOLISM Lipid Metabolism in Ethanol-Treated Rat Pups and Adults: Effects of Folic Acid  

E-print Network

Abstract — Aims: In this study we determined whether a folic acid-supplemented diet could change hyperlipaemia provoked by chronic ethanol intake in adult and pup rats. Methods: Animals were randomized into eight groups (four adults and four pups): control groups, water and basic diet; alcohol groups, 20 % ethanol and basic diet; alcohol folic acid groups, 20 % ethanol and diet supplemented with folic acid; control folic acid groups, water and folic acid-supplemented diet. We determined serum and liver total cholesterol (Chol), HDL, triglycerides (TG), phospholipids (PL) and bile acids (BA) levels in all of the groups. Hydroxymethylglutaryl-CoA (HMG-CoA) reductase activity was also measured in the livers. Results: Ethanol-fed rats have higher serum HDL and PL levels in pups and higher serum LDL, TG and PL levels in adults than controls and supplemented animals with or without alcohol ingestion. Ethanol provokes an increase in hepatic Chol and BA, and a decrease in hepatic TG and PL in pups; in adults it also provokes an increase in hepatic Chol and BA and a significant increase in HMG-CoA reductase activity. Alcohol intake plus folic acid supplementation has no effects on these values except BA levels that were significantly higher, in both pups and adult rats, than in the control group. Conclusion: Despite the fact that alcohol intake provokes different lipid alterations in adults and in pups whose mothers drank ethanol, folic acid contributes to the alleviation of these adverse effects reducing HMG-CoA reductase activity in adult rats and, except BA levels, to normalizing lipids

M A Luisa Ojeda; M A Jesús Delgado-villa; Ruth Llopis; M A Luisa Murillo; Olimpia Carreras



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



Folic acid and melatonin ameliorate carbon tetrachloride-induced hepatic injury, oxidative stress and inflammation in rats  

PubMed Central

This study investigated the protective effects of melatonin and folic acid against carbon tetrachloride (CCl4)-induced hepatic injury in rats. Oxidative stress, liver function, liver histopathology and serum lipid levels were evaluated. The levels of protein kinase B (Akt1), interferon gamma (IFN-?), programmed cell death-receptor (Fas) and Tumor necrosis factor-alpha (TNF-?) mRNA expression were analyzed. CCl4 significantly elevated the levels of lipid peroxidation (MDA), cholesterol, LDL, triglycerides, bilirubin and urea. In addition, CCl4 was found to significantly suppress the activity of both catalase and glutathione (GSH) and decrease the levels of serum total protein and HDL-cholesterol. All of these parameters were restored to their normal levels by treatment with melatonin, folic acid or their combination. An improvement of the general hepatic architecture was observed in rats that were treated with the combination of melatonin and folic acid along with CCl4. Furthermore, the CCl4-induced upregulation of TNF-? and Fas mRNA expression was significantly restored by the three treatments. Melatonin, folic acid or their combination also restored the baseline levels of IFN-? and Akt1 mRNA expression. The combination of melatonin and folic acid exhibited ability to reduce the markers of liver injury induced by CCl4 and restore the oxidative stability, the level of inflammatory cytokines, the lipid profile and the cell survival Akt1 signals. PMID:23374533



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



Folic acid supplementation on homocysteine levels in children taking antiepileptic drugs: A randomized controlled trial  

PubMed Central

Objectives: To assess the level of homocysteine (tHcy) in children taking AEDs and to study whether daily oral supplementation of folic acid for 1 month will reduce the tHcy level. Materials and Methods: This was a double-blinded, randomized control trial conducted in Institute of Maternal and Child Health, Kozhikode, India. Totally 60 children were recruited and of them, 48 were enrolled. Of these children, 32 were assigned to the experimental group and 16 to the control group. Baseline data collection and tHcy estimation were done. One mg folic acid tablets were given to the experimental group and placebo tablets to the control group for 30 days. tHcy levels were re-estimated after 1 month follow-up. Statistical significance was tested by ?2 test, and paired and unpaired t-tests, as appropriate. Correlation was tested by Pearson correlation test and P value less than 0.05 was taken as the cut-off for statistical significance. Results: Baseline plasma tHcy concentrations in both groups were comparable [11.90 (6.3) and 13.02 (2.4) ?mol/l, respectively]. During the follow-up period, no increase in seizure episodes or no serious adverse reactions were noticed in either group. The reduction of tHcy in the experimental group was 1.92 ?mol/l (P = 0.04) and in the control group, there was an increase of 1.05 ?mol/l (P = 0.16). Conclusions: In children on AED treatment, folic acid supplementation may reduce tHcy level and thus reduce CVD risk. PMID:24799812

Jeeja, Mathummal Cherumanalil; Jayakrishnan, Thayyil; Narayanan, Puthiya Veettil; Kumar, Mathur Sreedharan Vinod; Thejus, Thayyil; Anilakumari, Vadakay Purayil



The Chilean Flour Folic Acid Fortification Program Reduces Serum Homocysteine Levels and Masks Vitamin B12 Deficiency in Elderly People1  

Microsoft Academic Search

Hyperhomocysteinemia is considered a risk factor for cardiovascular disease and is prevalent in the elderly. Supplementation with folic acid, vitamin B-6 and B-12 lowers homocysteine levels. In January 2000, the Chil- ean government initiated a flour folic acid fortification pro- gram to decrease the occurrence of neural tube defects. The aim of this study was to evaluate the effect of

Sandra Hirsch; Pia de la Maza; Gladys Barrera; Vivian Gattas; Margarita Petermann; Daniel Bunout


First report for voltammetric determination of methyldopa in the presence of folic acid and glycine.  


In this study, a carbon paste electrode modified with TiO2 nanoparticles and ferrocene monocarboxylic acid (FM) was used to prepare a novel electrochemical sensor. The objective of this novel electrode modification was to seek new electrochemical performances for the detection of methyldopa in the presence of folic acid and glycine. The peak potentials recorded in a phosphate buffer solution (PBS) of pH7.0 were 325, 750 and 880 mV vs. Ag/AgCl/KCl (3.0M) for methyldopa, folic acid and glycine, respectively. Under the optimum pH of 7.0, the oxidation of methyldopa occurred at a potential about 160 mV less positive than that of the unmodified carbon paste electrode (CPE). The response of catalytic current with methyldopa concentration showed a linear relation in the range from 2.0×10(-7) to 1.0×10(-4)M with a detection limit of 8.0 (± 0.2)×10(-8)M. PMID:24433900

Molaakbari, Elahe; Mostafavi, Ali; Beitollahi, Hadi



Prenatal multivitamins containing folic acid do not decrease prevalence of depression among pregnant women.  


Several studies have reported an association between depression and folic acid deficiency. We investigated whether intake of prenatal multivitamins containing folic acid (MVandFA) was associated with decreased rates of depression among pregnant women. A questionnaire was given to 1,314 low-risk pregnant women. Of them, 1,277 (97.2%) women completed the questionnaire. The overall prevalence of depression was 8.1%. Of 652 participants who did not take MVandFA, 9.4% had depression, whereas 6.9% of 624 women who had MVandFA had depression (p = 0.11). In a multivariate logistic regression analysis, family history of depression (adjusted OR 3.7; 95% CI 1.9-7.3) and premenstrual syndrome (adjusted OR 3.0, 95% CI 1.8-4.8) were identified as risk factors for depression during pregnancy. In conclusion, intake of MVandFA was not associated with lower rates of depression during pregnancy whereas family history of depression and personal history of premenstrual syndrome were significant risk factors. PMID:18850419

Cho, Y J; Han, J Y; Choi, J S; Ahn, H K; Ryu, H M; Kim, M Y; Yang, J H; Nava-Ocampo, A A; Koren, G



Adaptive transport of folic acid across renal epithelia in folate-deficient rats.  


Folate (vitamin B(9)) is an essential vitamin for a wide spectrum of biochemical reactions; however, unlike bacteria and plants, mammals are devoid of folate biosynthesis and thus must obtain this cofactor from exogenous sources. The activities of folate transporters on the kidneys play an important role in conserving folate excretion and reabsorption across the apical membrane of the renal proximal tubules. The different transport system activities may become identifiable in response to external stimuli, such as folate availability and exposure to chemotherapeutic agents. We have explored the effect of folate deficiency on the activity and expression of folate transporters in rat kidneys. Wistar rats were fed a folate-containing diet (2 mg folic acid kg(-1) diet) or a folic acid-free diet over a 3-month period, and mechanisms of folate transport were studied in renal brush border membrane vesicles and basolateral membrane vesicles. The renal folate uptake process is saturable and pH dependent, and it involves the folate receptor and reduced folate carrier (RFC) systems and possibly the proton coupled folate transporter (PCFT) system. We found that folate deficiency increased the renal brush border membrane and basolateral folate uptake by increasing the number of transporter molecules. The observed up-regulation of mRNA expression was also associated with a significant increase in RFC and PCFT expression at the protein level. PMID:22865158

Wani, Nissar Ahmad; Kaur, Jyotdeep



Small molecule-folic acid modification on nanopatterned PDMS and investigation on its surface property.  


Folic acid (or folate, FA) has attracted considerable attention for cancer therapy. As one small molecule, its receptor (folate receptor, FR) is significantly overexpressed on the surface of many human tumor cells compared with normal cells. In this work, physical and chemical coupled modification method, that is the combination of nanoimprinting technique and graft polymerization, was adopted to modify FA on nanopatterned polydimethylsiloxane (PDMS) surface for possible application in micro-nanofluidic cytology. The surface property of differently treated PDMS was characterized by FTIR, AFM and contact angle measurement. AO/PI double staining, cell counting and MTT method were performed to examine the potential influence of FA modified nanopatterned PDMS on human cervical carcinoma (HeLa) cell behavior. Both FA modification and nanostructure have positive effect on the growth and viability of HeLa cells. It is the first time that the small molecule-folic acid was used to immobilize on the surface of PDMS in order to improve its surface property. PMID:24627217

Hu, Yuanyuan; Ma, Binjie; Zhang, Yingying; Wang, Min



Polygenic Association with Total Homocysteine in the Post Folic Acid Fortification Era: the CARDIA Study  

PubMed Central

Elevated plasma concentration of total homocysteine (tHcy) has been linked with many diseases. tHcy is associated with a variety of factors, including polymorphisms in genes involved in homocysteine metabolism. It is not clear whether US-mandated fortification of grain products with folic acid has affected the association of genetic variants with tHcy levels. We determined tHcy concentrations in sera from 997 Caucasians and 692 African Americans participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study before and after folic acid fortification. DNA was genotyped for variants present in four genes involved in homocysteine metabolism: cystathionine ?-synthase (CBS) 844ins68, methionine synthase (MS) 2756A>G; methionine synthase reductase (MTRR) 66A>G, and methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C. A greater number of African Americans were homozygous for the MS 2756GG, MTRR 66GG and CBS 844ins68 genotypes compared to Caucasians, while prevalence of MTHFR 677TT and 1298CC genotypes was substantially lower in African Americans compared to Caucasians. The overall variance in tHcy levels at y 0, 7, and 15 that can be explained by the combined presence of all five variants increased slightly over time in Caucasians (17%, y 0; 21%, y 7 and 26%, y 15) and in African Americans (13%, y 0; 17% y 7; 18% y 15) largely due to decrease in tHcy variance. PMID:19577940

Tsai, Michael Y.; Loria, Catherine M.; Cao, Jing; Kim, Yongin; Siscovick, David S.; Schreiner, Pamela J.; Hanson, Naomi Q.



Polygenic association with total homocysteine in the post-folic acid fortification era: the CARDIA study.  


Elevated plasma concentration of total homocysteine (tHcy) has been linked with many diseases. tHcy is associated with a variety of factors, including polymorphisms in genes involved in homocysteine metabolism. It is not clear whether US-mandated fortification of grain products with folic acid has affected the association of genetic variants with tHcy levels. We determined tHcy concentrations in sera from 997 Caucasians and 692 African Americans participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study before and after folic acid fortification. DNA was genotyped for variants present in four genes involved in homocysteine metabolism: cystathionine beta-synthase (CBS) 844ins68, methionine synthase (MS) 2756A>G; methionine synthase reductase (MTRR) 66A>G and methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C. A greater number of African Americans were homozygous for the MS 2756GG, MTRR 66GG and CBS 844ins68 genotypes compared to Caucasians, while prevalence of MTHFR 677TT and 1298CC genotypes was substantially lower in African Americans compared to Caucasians. The overall variance in tHcy levels at y 0, 7 and 15 that can be explained by the combined presence of all five variants increased slightly over time in Caucasians (17%, y 0; 21%, y 7; and 26%, y 15) and in African Americans (13%, y 0; 17% y 7; and 18% y 15) largely due to decrease in tHcy variance. PMID:19577940

Tsai, Michael Y; Loria, Catherine M; Cao, Jing; Kim, Yongin; Siscovick, David S; Schreiner, Pamela J; Hanson, Naomi Q



Effect of baking process on added folic acid and endogenous folates stability in wheat and rye breads.  


In Poland bread as a staple food both made from wheat and rye flour can be a potential product for future fortification with folic acid. The objective of the study was to examine the effect of fermentation and baking on added folic acid and some endogenous folates stability during breadmaking of rye and wheat breads. Breads were produced using the formulation containing enriched flour with 0.2 mg folic acid/100 g product, baker's yeast and additionally ascorbic acid for wheat bread and lactic acid for rye bread. Folates were extracted with Hepes/Ches buffer (pH = 7.85) followed by destruction of matrix by amylase and protease and deconjugation with rat serum conjugase. Affinity chromatography (FBP bovine milk) was used to purify and concentrate samples. The folates were separated by HPLC with C18 column and with a combination of fluorescence and UV detection. For both rye and wheat breads there was a decrease of folic acid from flour to bread stage. The total losses depend on baking process and ranged from 12 to 21%. Some changes in the level of different native folate forms during the stage of baking process were also observed. PMID:16021829

Gujska, Elzbieta; Majewska, Katarzyna



Improved stability and antidiabetic potential of insulin containing folic acid functionalized polymer stabilized multilayered liposomes following oral administration.  


The present study reports the folic acid (FA) functionalized insulin loaded stable liposomes with improved bioavailability following oral administration. Liposomes were stabilized by alternating coating of negatively charged poly(acrylic acid) (PAA) and positively charged poly(allyl amine) hydrochloride (PAH) over liposomes. Furthermore, folic acid was appended as targeting ligand by synthesizing folic acid-poly(allyl amine) hydrochloride conjugate. The insulin entrapped within the freeze-dried formulation was found stable both chemically as well as conformationally and developed formulation exhibited excellent stability in simulated biological fluids. Caco-2 cell and ex vivo intestinal uptake studies revealed higher uptake of folic acid functionalized layersomes in comparison with their plain counterparts. In vivo pharmacodynamic and pharmacokinetic studies further revealed almost double hypoglycemia and approximately 20% relative bioavailability in comparison with subcutaneously administered standard insulin solution. Overall the proposed strategy is expected to contribute significantly in the field of designing ligand-anchored, polyelectrolyte-based stable systems in drug delivery. PMID:24283460

Agrawal, Ashish Kumar; Harde, Harshad; Thanki, Kaushik; Jain, Sanyog



Folic Acid  

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Effects of supplementation with folic acid and antioxidant vitamins on homocysteine levels and LDL oxidation in coronary patients  

Microsoft Academic Search

Hyperhomocysteinemia is an important cardiovascular risk factor. Serum homocysteine levels are specially dependent on folate nutritional status. In addition, the oxidative modification of low-density lipoproteins (LDLs) in the endothelial microenvironment is a damaging factor that can be modified with fat-soluble antioxidant vitamins. The present study was done to assess the effect of a supplementation of folic acid and antioxidant vitamins

Daniel Bunout; Argelia Garrido; Myriam Suazo; Ronald Kauffman; Paz Venegas; Pia de la Maza; Margarita Petermann; Sandra Hirsch



The Interactions between L-Tyrosine Based Nanoparticles Decorated with Folic Acid and Cervical Cancer Cells Under Physiological Flow  

PubMed Central

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 dynes/cm2. 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 non-decorated (plain) nanoparticles and drug alone against HeLa cells. Thus, targeted nanoparticles are a promising delivery platform for developing anticancer therapies that over-express the folate receptors (FRs). PMID:22957928

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



Development and validation of a high performance liquid chromatography method for the simultaneous determination of aspirin and folic acid from nano-particulate systems  

PubMed Central

Attention has shifted from the treatment of colorectal cancer (CRC) to chemoprevention using aspirin and folic acid as agents capable of preventing the onset of colon cancer. However, no sensitive analytical method exists to simultaneously quantify the two drugs when released from polymer-based nanoparticles. Thus, a rapid, highly sensitive method of high performance liquid chromatography (HPLC) analysis to simultaneously detect low quantities of aspirin (hydrolyzed to salicylic acid, the active moiety) and folic acid released from biodegradable polylactide-co-glycolide (PLGA) copolymer nanoparticles was developed. Analysis was done on a reversed phase C18 column using a photodiode array (PDA) detector at wavelengths of 233 nm (salicylic acid) and 277 nm (folic acid). The mobile phase consisted of acetonitrile ? 0.1% trifluoroacetic acid mixture programmed for a 30 min gradient elution analysis. In the range of 0.1 – 100 ?g/mL, the assay showed good linearity for salicylic acid (R2 = 0.9996) and folic acid (R2 = 0.9998). The method demonstrated good reproducibility, intra- and inter-day precision and accuracy (99.67, 100.1%) and low values of detection (0.03, 0.01 ?g/mL) and quantitation (0.1 and 0.05 ?g/mL) for salicylic acid and folic acid, respectively. The suitability of the method was demonstrated by simultaneously determining salicylic acid and folic acid released from PLGA nanoparticles. PMID:20033881

Chaudhary, Abhishek; Wang, Jeffrey



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 NCT00789490 PMID:19635145

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



Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition.  


Prenatal nutritional constraint is associated with increased risk of metabolic dysregulation in adulthood contingent on adult diet. In rats, folic acid supplementation of a protein-restricted (PR) diet during pregnancy prevents altered phenotype and epigenotype in the offspring induced by the PR diet. We hypothesized that increasing folic acid intake during the juvenile-pubertal (JP) period would reverse the effects of a maternal PR diet on the offspring. Rats were fed a control (C) or PR diet during pregnancy and AIN93G during lactation. Offspring were weaned on d 28 onto diets containing 1 mg [adequate folate (AF)] or 5 mg [folic acid-supplemented (FS)] folic acid/kg feed. After 28 d, all offspring were fed a high-fat (18% wt:wt) diet and killed on d 84. As expected, offspring of PR dams fed the AF diet had increased fasting plasma triglyceride (TAG) and beta-hydroxybutyrate (betaHB) concentrations. The FS diet induced increased weight gain, a lower plasma betaHB concentration, and increased hepatic and plasma TAG concentration compared with AF offspring irrespective of maternal diet. PPARalpha and glucocorticoid receptor promoter methylation increased in liver and insulin receptor promoter methylation decreased in liver and adipose tissue in FS compared with AF offspring, with reciprocal changes in mRNA expression irrespective of maternal diet. These findings show that increased folic acid intake during the JP period did not simply reverse the phenotype induced by the maternal diet. This may represent a period of plasticity when specific nutrient intakes may alter the phenotype of the offspring through epigenetic changes in specific genes. PMID:19339705

Burdge, Graham C; Lillycrop, Karen A; Phillips, Emma S; Slater-Jefferies, Joanne L; Jackson, Alan A; Hanson, Mark A



Updated estimates of neural tube defects prevented by mandatory folic Acid fortification - United States, 1995-2011.  


In 1992, the U.S. Public Health Service recommended that all women capable of becoming pregnant consume 400 µg of folic acid daily to prevent neural tube defects (NTDs). NTDs are major birth defects of the brain and spine that occur early in pregnancy as a result of improper closure of the embryonic neural tube, which can lead to death or varying degrees of disability. The two most common NTDs are anencephaly and spina bifida. Beginning in 1998, the United States mandated fortification of enriched cereal grain products with 140 µg of folic acid per 100 g. Immediately after mandatory fortification, the birth prevalence of NTD cases declined. Fortification was estimated to avert approximately 1,000 NTD-affected pregnancies annually. To provide updated estimates of the birth prevalence of NTDs in the period after introduction of mandatory folic acid fortification (i.e., the post-fortification period), data from 19 population-based birth defects surveillance programs in the United States, covering the years 1999-2011, were examined. After the initial decrease, NTD birth prevalence during the post-fortification period has remained relatively stable. The number of births occurring annually without NTDs that would otherwise have been affected is approximately 1,326 (95% confidence interval = 1,122-1,531). Mandatory folic acid fortification remains an effective public health intervention. There remain opportunities for prevention among women with lower folic acid intakes, especially among Hispanic women, to further reduce the prevalence of NTDs in the United States. PMID:25590678

Williams, Jennifer; Mai, Cara T; Mulinare, Joe; Isenburg, Jennifer; Flood, Timothy J; Ethen, Mary; Frohnert, Barbara; Kirby, Russell S



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


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



Folic acid attenuates cognitive dysfunction in streptozotocin-induced diabetic rats  

PubMed Central

Diabetic cognitive dysfunction is common in patients with diabetes but its pathogenesis is not clear. The aim of the present study is to investigate the role of 5’, 10’ methylene tetrahydrofolate reductase (MTHFR) in the development of diabetic cognitive impairment and test whether folic acid (FA) supplementation prevents cognitive dysfunction in diabetic rats. In the current study, three months after streptozotocin-induced diabetes onset, rats showed cognitive dysfunction including the prolonged escape latency, the decreased time spent in the target quadrant and the declined number of crossing the platform in Morris water maze test. Diabetic rats also presented elevated plasma homocysteine level and downregulation of MTHFR in hippocampus revealed by Western blotting. The diabetic cognitive dysfunction was attenuated by 30-day dietary FA treatment with a significantly decreased homocysteine level. In conclusion, these results suggest that MTHFR plays a crucial role in diabetic cognitive dysfunction and folate fortification might become a potent therapeutic strategy against diabetic cognitive impairment.

Yang, Rui; Chen, Rong-Ping; Chen, Hong; Zhang, Hua; Cai, De-Hong



Modified Carbon Nanotube Paste Electrode for Voltammetric Determination of Carbidopa, Folic Acid, and Tryptophan  

PubMed Central

A simple and convenient method is described for voltammetric determination of carbidopa (CD), based on its electrochemical oxidation at a modified multiwall carbon nanotube paste electrode. Under optimized conditions, the proposed method exhibited acceptable analytical performances in terms of linearity (over the concentration range from 0.1 to 700.0??M), detection limit (65.0?nM), and reproducibility (RSD = 2.5%) for a solution containing CD. Also, square wave voltammetry (SWV) was used for simultaneous determination of CD, folic acid (FA), and tryptophan (TRP) at the modified electrode. To further validate its possible application, the method was used for the quantification of CD, FA, and TRP in urine samples. PMID:22666634

Esfandiari Baghbamidi, Sakineh; Beitollahi, Hadi; Karimi-Maleh, Hassan; Soltani-Nejad, Somayeh; Soltani-Nejad, Vahhab; Roodsaz, Sara



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


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



Improved mechanical and electronic properties of co-assembled folic acid gel with aniline and polyaniline.  


Co-assembled folic acid (F) gel with aniline (ANI) (ANI:F = 1:2, w/w) is produced at 2% (w/v) concentration in water/DMSO (1:1, v/v) mixture. The gel is rigid and on polymerization of the gel pieces in aqueous ammonium persulfate solution co-assembled folic acid - polyaniline (F-PANI) gel is formed. Both the co-assembled F-ANI and F-PANI gels have fibrillar network morphology, the fiber diameter and its degree of branching increase significantly from those of F gel. WAXS pattern indicates co-assembled structure with the F fiber at the core and ANI/PANI at its outer surface and the co-assembly is occurring in both F-ANI and F-PANI systems through noncovalent interaction of H-bonding and ? stacking processes between the components. FTIR and UV-vis spectra characterize the doped PANI formation and the MALDI mass spectrometry indicates the degree of polymerization of polyaniline in the range 24-653. The rheological experiments support the signature of gel formation in the co-assembled state and the storage (G') and loss (G?) modulii increase in the order F gel< F-ANI gel < F-PANI gel, showing the highest increase in G' ? 1100% for the F-PANI gel. The stress at break, elasticity, and stiffness also increase in the same order. The dc-conductivity of F-ANI and F-PANI xerogels is 2 and 7 orders higher than that of F xerogel. Besides, the current (I)-voltage (V) curves indicate that the F-xerogel is insulator, but F-ANI xerogel is semiconductor showing both electronic memory and rectification; on the other hand, the F-PANI xerogel exhibits a negative differential resistance (NDR) property with a NDR ratio of 3.0. PMID:24495072

Chakraborty, Priyadarshi; Bairi, Partha; Roy, Bappaditya; Nandi, Arun K



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

E-print Network

) reported that the temporary diabetes induced in humans by injections of ACTH was attended by a rise in uric acid and a fall in blood glutathione. Conn (36) again found that the hormone increased endogenous purine catabolism, that the islet, cells vere... 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



Nitration and chlorination of folic acid by peroxynitrite and hypochlorous acid, and the selective binding of 10-nitro-folate to folate receptor beta.  


The aim of this work was to characterize folates modified by ONOO(-) and HOCl and to evaluate the binding capacity of folates modified by ONOO(-) to folate receptor alpha and beta. For the modification of folate by ONOO(-), folic acid was reacted with the combination of PMA activated PMN and PAPA NONOate or chemically synthesized ONOO(-). For the modification of folate by HOCl, folic acid was reacted with the combination of MPO and H(2)O(2) or NaOCl. The structures of products were determined by 1H-NMR and MALDI-TOF mass. Nitrated folate species were identified as 10-nitro-folate and 12-nitro-folate, and chlorinated folate was identified as 12-chloro-folate. The 10-nitro-folate showed the selective binding to FR-beta, compared to folic acid. PMID:12372420

Nakamura, Motoyuki; Nagayoshi, Ryusaku; Ijiri, Kosei; Nakashima-Matsushita, Noriko; Takeuchi, Toru; Matsuyama, Takami



Bioavailability of iron, zinc, folic acid, and vitamin A from fortified maize.  


Several strategies appear suitable to improve iron and zinc bioavailability from fortified maize, and fortification per se will increase the intake of bioavailable iron and zinc. Corn masa flour or whole maize should be fortified with sodium iron ethylenediaminetetraacetate (NaFeEDTA), ferrous fumarate, or ferrous sulfate, and degermed corn flour should be fortified with ferrous sulfate or ferrous fumarate. The choice of zinc fortificant appears to have a limited impact on zinc bioavailability. Phytic acid is a major inhibitor of both iron and zinc absorption. Degermination at the mill will reduce phytic acid content, and degermed maize appears to be a suitable vehicle for iron and zinc fortification. Enzymatic phytate degradation may be a suitable home-based technique to enhance the bioavailability of iron and zinc from fortified maize. Bioavailability experiments with low phytic acid-containing maize varieties have suggested an improved zinc bioavailability compared to wild-type counterparts. The bioavailability of folic acid from maize porridge was reported to be slightly higher than from baked wheat bread. The bioavailability of vitamin A provided as encapsulated retinyl esters is generally high and is typically not strongly influenced by the food matrix, but has not been fully investigated in maize. PMID:24329552

Moretti, Diego; Biebinger, Ralf; Bruins, Maaike J; Hoeft, Birgit; Kraemer, Klaus



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


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. PMID:25257620

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



Reduction of homocysteine levels in coronary artery disease by low-dose folic acid combined with vitamins B 6 and B 12  

Microsoft Academic Search

An increased plasma homocysteine concentration is a risk factor for atherosclerosis. Folic acid lowers homocysteine but the optimal dose in patients with coronary artery disease (CAD) is unclear. This placebo-controlled, single-blind, dose-ranging study evaluates the effect of low-dose folic acid on homocysteine levels in 95 patients aged 61 ± 11 years (mean ± SD) with documented CAD. Patients in each

Arlene Lobo; Arabi Naso; Kristopher Arheart; Warren D Kruger; Tariq Abou-Ghazala; Fadi Alsous; Maher Nahlawi; Anjan Gupta; Ali Moustapha; Frederick van Lente; Donald W Jacobsen; Killian Robinson



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

NASA Astrophysics Data System (ADS)

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.

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



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



Folic acid supplement decreases the homocysteine increasing effect of filtered coffee. A randomised placebo-controlled study  

Microsoft Academic Search

Objective: Elevated levels of plasma total homocysteine (tHcy) are identified as independent risk factors for coronary heart disease and for fetal neural tube defects. tHcy levels are negatively associated with folic acid, pyridoxine and cobalamine, and positively associated with coffee consumption and smoking. A total of 600 ml of filtered coffee results in a tHcy increase that 200 ?g of

E Strandhagen; S Landaas; D S Thelle



In vitro evaluation of folic acid modified carboxymethyl chitosan nanoparticles loaded with doxorubicin for targeted delivery  

Microsoft Academic Search

The development of smart targeted nanoparticle that can deliver drugs to direct cancer cells, introduces better efficacy and\\u000a lower toxicity for treatment. We report the development and characterizations of pH-sensitive carboxymethyl chitosan modified\\u000a folic acid nanoparticles and manifest their feasibility as an effective targeted drug delivery vehicle. The nanoparticles\\u000a have been synthesized from carboxymethyl chitosan with covalently bonded bifunctional 2,2?-(ethylenedioxy)-bis-(ethylamine)

Sumanta K. Sahu; Sanjay K. Mallick; Susmita Santra; Tapas K. Maiti; Sudip K. Ghosh; Panchanan Pramanik



Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia: a randomized placebo-controlled trial  

Microsoft Academic Search

Background—Folates have been suggested to be of benefit in reducing cardiovascular risk. The present study was designed to examine whether oral folic acid supplementation could improve endothelial function as an intermediate end point for cardiovascular risk in patients with increased risk of atherosclerosis due to familial hypercholesterolemia (FH). Methods and Results—In a prospective, randomized, double-blind, placebo-controlled study with crossover design,

Marianne C. Verhaar; Robert M. F. Wever; John J. P. Kastelein; Douwe van Loon; S. Milstein; H. A. Koomans; T. J. Rabelink



Comparative analysis of serum homocysteine, folic acid and Vitamin B 12 levels in patients with noise-induced hearing loss  

Microsoft Academic Search

Objective: The aim of the present study was to determine the levels of homocysteine, folic acid, and Vitamin B12 in subjects with noise-induced hearing loss. Furthermore, possible links between these parameters and noise-induced hearing loss were aimed to be evaluated. Methods: In the present study, blood samples were obtained from all subjects after overnight fasting for biochemical analysis. We examined

Uzeyir Gok; Ihsan Halifeoglu; Halit Canatan; Mucahit Yildiz; M. Ferit Gursu; Biray Gur



Tamoxifen loaded folic acid armed PEGylated magnetic nanoparticles for targeted imaging and therapy of cancer.  


Magnetic nanoparticles (MNPs) have been widely used as drug delivery nanosystems and contrast agent for imaging and detection. To engineer multifunctional nanomedicines for simultaneous imaging and therapy of cancer cells, in the current study, we synthesized tamoxifen (TMX) loaded folic acid (FA) armed MNPs to target the folate receptor (FR) positive cancer cells. To this end, Fe3O4 nanoparticles (NPs) were synthesized through thermal decomposition of Fe(acac)3. Polyethylene glycol (PEG) was treated with excess bromoacetyl chloride (BrAc) and then with 3-aminopropyltriethoxysilane (APS) to synthesize bromoacetyl-terminal polyethylene glycol silane (APS-PEG-BrAc). The latter complex was treated with protected ethylene diamine to form a bifunctional PEG compound containing triethoxysilane at one end and amino group at the other end (APS-PEG-NH2). The Fe3O4-APS-PEG-NH2 NPs were prepared through self-assembly of APS-PEG-NH2 on MNPs, while the amino groups at the end of Fe3O4-APS-PEG-NH2 were conjugated with folic acid (FA), then loaded with TMX (Fe3O4-APS-PEG-FA-TMX). The average size of "Fe3O4-APS-PEG-FA-TMX" NPs was approximately 40 nm. The engineered MNPs were further characterized and examined in the human breast cancer MCF-7 cells that express FR. The TMX loaded MNPs (with loading efficiency of 49.1%) showed sustained liberation of TMX molecules (with 90% release in 72 h). Fluorescence microcopy and flow cytometry analyses revealed substantial interaction of Fe3O4-APS-PEG-FA-TMX NPs with the FR-positive MCF-7 cells. Cytotoxicity analysis resulted in significant growth inhibition in MCF-7 cells treated with Fe3O4-APS-PEG-FA-TMX NPs. Based on these findings, the TMX-loaded FA-armed PEGylated MNPs as a novel multifunctional nanomedicine/theranostic for concurrent targeting, imaging and therapy of the FR-positive cancer cells. PMID:23434700

Heidari Majd, Mostafa; Asgari, Davoud; Barar, Jaleh; Valizadeh, Hadi; Kafil, Vala; Abadpour, Alaleh; Moumivand, Efat; Mojarrad, Javid Shahbazi; Rashidi, Mohammad Reza; Coukos, George; Omidi, Yadollah



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



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



The Chilean flour folic acid fortification program reduces serum homocysteine levels and masks vitamin B-12 deficiency in elderly people.  


Hyperhomocysteinemia is considered a risk factor for cardiovascular disease and is prevalent in the elderly. Supplementation with folic acid, vitamin B-6 and B-12 lowers homocysteine levels. In January 2000, the Chilean government initiated a flour folic acid fortification program to decrease the occurrence of neural tube defects. The aim of this study was to evaluate the effect of this program on serum homocysteine and folate levels in elderly subjects after 6 mo. A total of 108 elderly people were studied. We measured serum folate, homocysteine and vitamin B-12 levels before the fortification started and 6 mo later. At baseline, folate deficiency (<6.8 nmol/L) was present in 1.8%, vitamin B-12 deficiency (<165 pmol/L) in 27.6% and hyperhomocysteinemia (>14 micromol/L) in 31% of the sample. Six months later, serum folate levels increased from 16.2 +/- 6.2 to 32.7 +/- 7.1 nmol/L (P < 0.001), homocysteine levels decreased from 12.95 +/- 3.7 to 11.43 +/- 3.6 micromol/L (P < 0.001) and vitamin B-12 levels were unchanged. Flour fortification with folic acid had a moderate lowering effect on homocysteine levels. Given that vitamin B-12 deficiency was more common than folate deficiency, it may be more appropriate to add vitamin B-12 to food, at least in foods for this age group. PMID:11823592

Hirsch, Sandra; de la Maza, Pía; Barrera, Gladys; Gattás, Vivian; Petermann, Margarita; Bunout, Daniel



Neuroprotective Effects of Glutamate Antagonists and Extracellular Acidity  

NASA Astrophysics Data System (ADS)

Glutamate antagonists protect neurons from hypoxic injury both in vivo and in vitro, but in vitro studies have not been done under the acidic conditions typical of hypoxia-ischemia in vivo. Consistent with glutamate receptor antagonism, extracellular acidity reduced neuronal death in murine cortical cultures that were deprived of oxygen and glucose. Under these acid conditions, N-methyl-D-aspartate and ?-amino-3-hydroxy-5-methyl-4-isox-azolepropionate-kainate antagonists further reduced neuronal death, such that some neurons tolerated prolonged oxygen and glucose deprivation almost as well as did astrocytes. Neuroprotection induced by this combination exceeded that induced by glutamate antagonists alone, suggesting that extracellular acidity has beneficial effects beyond the attenuation of ionotropic glutamate receptor activation.

Kaku, David A.; Giffard, Rona G.; Choi, Dennis W.



Neither folic acid supplementation nor pregnancy affects the distribution of folate forms in the red blood cells of women.  


It is not known whether folate metabolism is altered during pregnancy to support increased DNA and RNA biosynthesis. By using a state-of-the-art LC tandem mass spectrometry technique, the aim of this study was to investigate differences in RBC folate forms between pregnant and nonpregnant women and between nonpregnant women consuming different concentrations of supplemental folic acid. Forms of folate in RBCs were used to explore potential shifts in folate metabolism during early erythropoiesis. Total RBC folate and folate forms [tetrahydrofolate; 5-methyltetrahydrofolate (5-methyl-THF); 4?-hydroxy-5-methyl-tetrahydrofolate (an oxidation product of 5-methyl-THF); 5-formyl-tetrahydrofolate; and 5,10-methenyl-tetrahydrofolate] were measured in 4 groups of women (n = 26): pregnant women (PW) (30-36 wk of gestation) consuming 1 mg/d of folic acid, and nonpregnant women consuming 0 mg/d (NPW-0), 1 mg/d (NPW-1), and 5 mg/d (NPW-5) folic acid. The mean ± SD RBC folate concentration of the NPW-0 group (890 ± 530 nmol/L) was lower than the NPW-1 (1660 ± 350 nmol/L) and NPW-5 (1980 ± 570 nmol/L) groups as assessed by microbiologic assay (n = 26, P < 0.0022). No difference was found between the NPW-1 and NPW-5 groups. We detected 5-methyl-THF [limit of detection (LOD) = 0.06 nmol/L] in all groups and tetrahydrofolate (LOD = 0.2 nmol/L) in most women regardless of methylenetetrahydrofolate reductase genotype. Most women consuming folic acid supplements had detectable concentrations of 5,10-methenyl-tetrahydrofolate (LOD = 0.31 nmol/L). However, there was no difference in the relative distribution of 5-methyl-THF (83-84%), sum of non-methyl folates (0.6-3%), or individual non-methyl folate forms in RBCs across groups. We conclude that although folic acid supplementation in nonpregnant women increases RBC total folate and the concentration of individual folate forms, it does not alter the relative distribution of folate forms. Similarly, distribution of RBC folate forms did not differ between pregnant and nonpregnant women. This trial was registered at as NCT01741077. PMID:24991041

Hartman, Brenda A; Fazili, Zia; Pfeiffer, Christine M; O'Connor, Deborah L



High fidelity information processing in folic acid chemotaxis of Dictyostelium amoebae.  


Living cells depend upon the detection of chemical signals for their existence. Eukaryotic cells can sense a concentration difference as low as a few per cent across their bodies. This process was previously suggested to be limited by the receptor-ligand binding fluctuations. Here, we first determine the chemotaxis response of Dictyostelium cells to static folic acid gradients and show that they can significantly exceed this sensitivity, responding to gradients as shallow as 0.2% across the cell body. Second, using a previously developed information theory framework, we compare the total information gained about the gradient (based on the cell response) to its upper limit: the information gained at the receptor-ligand binding step. We find that the model originally applied to cAMP sensing fails as demonstrated by the violation of the data processing inequality, i.e. the total information exceeds the information at the receptor-ligand binding step. We propose an extended model with multiple known receptor types and with cells allowed to perform several independent measurements of receptor occupancy. This does not violate the data processing inequality and implies the receptor-ligand binding noise dominates both for low- and high-chemoattractant concentrations. We also speculate that the interplay between exploration and exploitation is used as a strategy for accurate sensing of otherwise unmeasurable levels of a chemoattractant. PMID:24026470

Segota, Igor; Mong, Surin; Neidich, Eitan; Rachakonda, Archana; Lussenhop, Catherine J; Franck, Carl



Estimation of dietary folic acid intake in three generations of females in Southern Spain.  


An adequate folic acid intake has been related to female fertility. The recommended intake of this vitamin was recently increased to 400?g/day, with an additional 200?g/day during pregnancy. The Mediterranean Diet includes sources of folate such as pulses, green-leaf vegetables, fruit, cereals, and dried fruits; other foods of interest are liver and blue fish. The objectives were to determine the foods that contribute most to folate intake and analyze the factors that influence their consumption by three generations in a female population (n=898; age, 10-75yrs) from Southern Spain: 230 adolescents (10-16yrs), 296 healthy pregnant women (19-45yrs), and 372 menopausal women (>45yrs). Participants completed a previously validated semi-quantitative food frequency questionnaire. Over 90% of their folate intake was supplied by cereals, fruit, natural juice, pulses, and cooked and raw vegetables. The mean (SD) daily intake of folate was 288.27(63.64) ?g. A higher Mediterranean Diet Score (MDS) was significantly related to a greater folate intake. The daily folate intake was not significantly influenced by educational level, number of children, or place of residence (rural vs. urban). In logistic regression analysis, the factors related to an adequate folate intake (>2/3 of recommendations) were higher age, higher MDS, and lower BMI. PMID:23587520

Monteagudo, C; Mariscal-Arcas, M; Palacin, A; Lopez, M; Lorenzo, M L; Olea-Serrano, F



High fidelity information processing in folic acid chemotaxis of Dictyostelium amoebae  

PubMed Central

Living cells depend upon the detection of chemical signals for their existence. Eukaryotic cells can sense a concentration difference as low as a few per cent across their bodies. This process was previously suggested to be limited by the receptor–ligand binding fluctuations. Here, we first determine the chemotaxis response of Dictyostelium cells to static folic acid gradients and show that they can significantly exceed this sensitivity, responding to gradients as shallow as 0.2% across the cell body. Second, using a previously developed information theory framework, we compare the total information gained about the gradient (based on the cell response) to its upper limit: the information gained at the receptor–ligand binding step. We find that the model originally applied to cAMP sensing fails as demonstrated by the violation of the data processing inequality, i.e. the total information exceeds the information at the receptor–ligand binding step. We propose an extended model with multiple known receptor types and with cells allowed to perform several independent measurements of receptor occupancy. This does not violate the data processing inequality and implies the receptor–ligand binding noise dominates both for low- and high-chemoattractant concentrations. We also speculate that the interplay between exploration and exploitation is used as a strategy for accurate sensing of otherwise unmeasurable levels of a chemoattractant. PMID:24026470

Segota, Igor; Mong, Surin; Neidich, Eitan; Rachakonda, Archana; Lussenhop, Catherine J.; Franck, Carl



Pharmacodynamics of long-acting folic acid-receptor targeted ritonavir-boosted atazanavir nanoformulations.  


Long-acting nanoformulated antiretroviral therapy (nanoART) that targets monocyte-macrophages could improve the drug's half-life and protein-binding capacities while facilitating cell and tissue depots. To this end, ART nanoparticles that target the folic acid (FA) receptor and permit cell-based drug depots were examined using pharmacokinetic and pharmacodynamic (PD) tests. FA receptor-targeted poloxamer 407 nanocrystals, containing ritonavir-boosted atazanavir (ATV/r), significantly increased drug bioavailability and PD by five and 100 times, respectively. Drug particles administered to human peripheral blood lymphocyte reconstituted NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ mice and infected with HIV-1ADA led to ATV/r drug concentrations that paralleled FA receptor beta staining in both the macrophage-rich parafollicular areas of spleen and lymph nodes. Drug levels were higher in these tissues than what could be achieved by either native drug or untargeted nanoART particles. The data also mirrored potent reductions in viral loads, tissue viral RNA and numbers of HIV-1p24+ cells in infected and treated animals. We conclude that FA-P407 coating of ART nanoparticles readily facilitates drug carriage and antiretroviral responses. PMID:25522973

Puligujja, Pavan; Balkundi, Shantanu S; Kendrick, Lindsey M; Baldridge, Hannah M; Hilaire, James R; Bade, Aditya N; Dash, Prasanta K; Zhang, Gang; Poluektova, Larisa Y; Gorantla, Santhi; Liu, Xin-Ming; Ying, Tianlei; Feng, Yang; Wang, Yanping; Dimitrov, Dimiter S; McMillan, JoEllyn M; Gendelman, Howard E



Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T genotype: Results from a crossover trial  

PubMed Central

Scope By increasing blood folate concentrations, folic acid supplementation reduces risk for neural tube defect-affected pregnancies, and lowers homocysteine concentrations. We assessed response of red blood cell (RBC) and serum folate to folic acid supplementation, and examined association of response with the genetic polymorphism C677T of the methylenetetrahydrofolate NAD(P)H (MTHFR) gene. Methods and Results Randomized, controlled, crossover trial with two folic acid supplement treatment periods and a 30-week washout period. The primary outcome is blood folate (serum and RBC) concentrations. Volunteers (n=142) aged 18-69 were randomized to two of three doses (0, 200, and 400 ?g) of folic acid for twelve weeks. Serum folate response depended on treatment period with significant responses to 200 ?g seen only in the second treatment periods (4.4 ng/mL or 3.4 ng/mL). Additionally, serum folate increased as folic acid dose increased to 400 ?g (p< 0.01) and response was greater after the washout period (8.7 ng/mL), than after a 6-week run-in (2.3 ng/mL). The differential change attributable to a daily supplement of 400 ?g compared to 200 ?g was 96.8 ng/mL; while the change attributable to 400 ?g compared to 0 ?g was 121.4. Increases in RBC folate concentrations with 400 ?g occurred within MTHFR gene mutation (C677T); and in the African American group. Conclusions Serum folate concentration is responsive to modest increases in folic acid intake. Red blood cell folate increases only with higher additional doses of folic acid supplementation, and this is true for each MTHFR C677T genotype. PMID:23456769

Anderson, Cheryl A.M.; Beresford, Shirley A. A.; McLerran, Dale; Lampe, Johanna W.; Deeb, Samir; Feng, Ziding; Motulsky, Arno G.



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


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



Spectrophotometric determination of folic acid in pharmaceutical preparations by coupling reactions with iminodibenzyl or 3-aminophenol or sodium molybdate-pyrocatechol.  


Novel coupling reagents are used for the simple and sensitive spectrophotometric determination of folic acid either in pure form or in its pharmaceutical preparations. The methods are based on the probable diazotization of the p-aminobenzoylglutamic acid obtained after reductive clevage of folic acid, followed by either coupling with iminodibenzyl to give a violet product with lambda(max) of 580nm or coupling with 3-aminophenol to produce an orange yellow-colored product with lambda(max) of 460nm. Sodium molybdate and pyrocatechol are used in the third method and the pale red-colored product formed has a lambda(max) of 490nm. The methods are highly reproducible and have been applied to the determination of folic acid in tablets and the results compare favorably with the official method. Common excipients used as additives in pharmaceutical preparations do not interfere in the proposed methods. PMID:12202249

Nagaraja, Padmarajaiah; Vasantha, Ramanathapura A; Yathirajan, Hemmige S



Pharmacokinetics, Biodistribution, and Toxicity of Folic Acid-Coated Antiretroviral Nanoformulations  

PubMed Central

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.



Nanoparticles of deoxycholic acid, polyethylene glycol and folic acid-modified chitosan for targeted delivery of doxorubicin.  


Chitosan (CS) was first modified hydrophobically with deoxycholic acid (DCA) and then with polyethylene glycol (PEG) to obtain a novel amphiphilic polymer (CS-DCA-PEG). This was covalently bound to folic acid (FA) to develop nanoparticles (CS-DCA-PEG-FA) with tumor cell targeting property. The structure of the conjugates was characterised using Fourier transform infrared and (1)H nuclear magnetic resonance spectroscopy and X-ray diffraction. Based on self-aggregation, the conjugates formed nanoparticles with a low critical aggregation concentration of 0.035 mg/ml. The anti-cancer drug doxorubicin (DOX) was encapsulated into the nanoparticles with a drug-loading capacity of 30.2 wt%. The mean diameter of the DOX-loaded nanoparticles was about 200 nm, with a narrow size distribution. Transmission electron microscopy images showed that the DOX-loaded nanoparticles were spherical. The drug release was studied under different conditions. Furthermore, the cytotoxic activities of DOX in CS-DCA-PEG-FA nanoparticles against folate receptor (FR)-positive HeLa cells and FR-negative fibroblast 3T3 cells were evaluated. These results suggested that the CS-DCA-PEG-FA nanoparticles may be a promising vehicle for the targeting anticancer drug to tumor cells. PMID:24327111

Shi, Zhonggen; Guo, Rui; Li, Weichang; Zhang, Yi; Xue, Wei; Tang, Yu; Zhang, Yuanming



Targeted delivery of 5-fluorouracil to HT-29 cells using high efficient folic acid-conjugated nanoparticles.  


Abstract The incorporation of a high percentage of targeting molecules into drug delivery system is one of the important methods for improving efficacy of targeting therapeutic drugs to cancer cells. PLGA-based drug delivery carriers with folic acid (FA) as targeting molecule have a low targeting efficiency due to a low FA conjugation ratio. In this work, we fabricated a FA-conjugated PLGA system using a crosslinker 1, 3-diaminopropane and have achieved a high conjugation ratio of 46.7% (mol/mol). The as-prepared PLGA-based biomaterial was used to encapsulate therapeutic drug 5-fluorouracil (5-FU) into nanoparticles. In the in vitro experiments, an IC50 of 5.69?µg/mL has been achieved for 5-FU loaded PLGA-1, 3-diaminopropane-folic acid nanoparticles on HT-29 cancer cells and is significantly lower than that of 5-FU and 5-FU loaded PLGA nanoparticles which only have an IC50 of 22.9 and 14.17?µg/mL, respectively. The fluorescent microscopy images showed that nanoparticles with FA are largely taken up by HT-29 cancer cells and the targeting nanoparticles have more affinity to cancer cells than the pure drugs and untreated nanoparticles. Therefore, the 1, 3-diaminopropane can facilitate the conjugation of FA to PLGA to form a novel polymer and 5-FU loaded PLGA-1, 3-diaminopropane-folic acid nanoparticles can be a highly efficient system for specific delivery of drugs to cancer cells. PMID:24437926

Wang, Yichao; Li, Puwang; Chen, Lijue; Gao, Weimin; Zeng, Fanbo; Kong, Ling Xue



Effects of folic acid and vitamin B12 supplementation on culling rate, diseases, and reproduction in commercial dairy herds.  


This study was undertaken to determine the effect of a combined folic acid and vitamin B12 supplement given in early lactation on culling rate, metabolic disorders and other diseases, and reproduction in commercial dairy herds. A total of 805 cows (271 primiparous and 534 multiparous cows) in 15 commercial dairy herds were involved. Every 2mo from February to December 2010 and within each herd, cows were assigned according to parity, previous 305-d milk production, and calving interval to 5mL of either (1) saline 0.9% NaCl (control group) or (2) 320mg of folic acid + 10mg of vitamin B12 (vitamin group). Treatments were administered weekly by intramuscular injections starting 3wk before the expected calving date until 8wk after parturition. A total of 221 cows were culled before the next dry period. Culling rate was not affected by treatment and was 27.5%; culling rate was greater for multiparous (32.2%) than for primiparous cows (18.8%). Within the first 60d in milk (DIM), 47 cows were culled, representing 21.3% of total culling, and no treatment effect was noted. Ketosis incidence based on a threshold ?100µmol/L of ?-hydroxybutyrate in milk was 38.3±2.9% for the vitamin group and 41.8±3.0% for the control group and was not affected by treatment. The combined supplement of folic acid and vitamin B12 did not decrease incidence of retained placenta, displaced abomasum, milk fever, metritis, or mastitis. However, the incidence of dystocia decreased by 50% in multiparous cows receiving the vitamin supplement, although no effect was observed in primiparous cows. The first breeding postpartum for multiparous cows occurred 3.8d earlier with the vitamin supplement compared with controls, whereas no treatment effect was seen for primiparous cows. Days open, first- and second-breeding conception rates, number of breedings per conception, and percentage of cows pregnant at 150 DIM were not affected by treatment. The reduced percentage of dystocia combined with the earlier DIM at first breeding for multiparous cows receiving the combined supplementation in folic acid and vitamin B12 indicates that the vitamin supplement had a positive effect in older cows. PMID:24485680

Duplessis, M; Girard, C L; Santschi, D E; Laforest, J-P; Durocher, J; Pellerin, D



Preparation of folic acid-conjugated, doxorubicin-loaded, magnetic bovine serum albumin nanospheres and their antitumor effects in vitro and in vivo  

PubMed Central

Background This study aimed to generate targeted folic acid-conjugated, doxorubicin-loaded, magnetic iron oxide bovine serum albumin nanospheres (FA-DOX-BSA MNPs) that lower the side effects and improve the therapeutic effect of antitumor drugs when combined with hyperthermia and targeting therapy. A new nanodrug using magnetic nanospheres for heating and addition of the folate receptor with cancer cell specificity was prepared. The characteristics of these nanospheres and their antitumor effects in nasopharyngeal carcinoma were explored. Methods FA-DOX-BSA MNPs comprising encapsulated magnetic iron oxide nanoparticles were prepared using a desolvation cross-linking method. Activated folic acid (N-hydroxysuccinimide ester of folic acid) was conjugated to the surface of albumin nanospheres via amino groups. Results Folic acid was successfully expressed on the surface of the nanospheres. Electron microscopy revealed that the FA-DOX-BSA MNPs were nearly spherical and uniform in size, with an average diameter of 180 nm. The nanomaterial could deliver doxorubicin at clinically relevant doses with an entrapment efficiency of 80%. An increasing temperature test revealed that incorporation of magnetic iron oxide into nanospheres could achieve a satisfactory heat treatment temperature at a significantly lower dose when placed in a high-frequency alternating magnetic field. FA-DOX-BSA MNPs showed greater inhibition of tumors than in the absence of folic acid in vitro and in vivo. Compared with chemotherapy alone, hyperthermia combined with chemotherapy was more effective against tumor cells. Conclusion Folic acid-conjugated bovine serum albumin nanospheres composed of mixed doxorubicin and magnetic iron oxide cores can enable controlled and targeted delivery of anticancer drugs and may offer a promising alternative to targeted doxorubicin therapy for nasopharyngeal carcinoma. PMID:25228802

Yang, Rui; An, YanLi; Miao, FengQin; Li, MengFei; Liu, PeiDang; Tang, QiuSha



High-dose folic acid supplementation effects on endothelial function and blood pressure in hypertensive patients: a meta-analysis of randomized controlled clinical trials  

PubMed Central

Abstract Objective Folic acid supplementation has been shown to be an effective agent for improving endothelial function, a prognostic factor for cardiovascular disease; but its effects on systolic and diastolic blood pressure in hypertensive individuals has been met with mixed results. Therefore, the purpose of this study was to provide a comprehensive meta-analysis of randomized controlled trials to investigate the effect of high-dose folic acid supplementation on blood pressure and endothelial function in hypertensive patients. Methods Twelve randomized controlled trials published between 1970 and December 2007 were identified using Medline and a manual search. All 12 studies used hypertensive subjects who were supplemented with at least 5000 ?g/d of folic acid for between 2 and 16 weeks. Three separate meta-analyses were carried out using a random-effects model, and the overall effect sizes were calculated for changes in systolic and diastolic blood pressures and for changes in endothelial function as measured through the percentage of change in flow-mediated dilation. Results The pooled estimate of effect of folic acid supplementation on systolic and diastolic blood pressure was ?2.03 mm Hg (95% confidence interval [CI], ?3.63 to ?0.43; P = .04) and 0.01 mm Hg (95% CI, ?1.12 to 1.13; not significant), respectively. The pooled estimate of effect of folic acid supplementation on change in flow-mediated dilation was 1.61% (95% CI, 1.27 to 1.96; P = .000). Conclusion Based upon the studies used in this meta-analysis, supplementation with at least 5000 ?g/d of folic acid, for a minimum of 6 weeks, can lower systolic blood pressure slightly; but the real clinical benefit is achieved through improved endothelial function. PMID:19646382

McRae, Marc P.



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


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



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))



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.



Effects of supplementation with folic acid and antioxidant vitamins on homocysteine levels and LDL oxidation in coronary patients.  


Hyperhomocysteinemia is an important cardiovascular risk factor. Serum homocysteine levels are specially dependent on folate nutritional status. In addition, the oxidative modification of low-density lipoproteins (LDLs) in the endothelial microenvironment is a damaging factor that can be modified with fat-soluble antioxidant vitamins. The present study was done to assess the effect of a supplementation of folic acid and antioxidant vitamins on homocysteine levels and in vitro LDL oxidation in patients with coronary artery disease. Twenty-three patients with angiographically proven coronary artery disease were given supplements for 15 d consisting of one capsule twice a day of a multivitamin preparation containing 0.65 mg folic acid, 150 mg alpha-tocopherol, 150 mg ascorbic acid, 12.5 mg beta-carotene, and 0.4 microgram vitamin B12. Serum lipids, vitamin and homocysteine levels, and in vitro LDL oxidation were measured before and after the supplementation period. During the supplementation period, serum folate levels increased from 5.0 +/- 1.5 to 10.8 +/- 3.8 ng/mL (P < 0.001), vitamin B12 increased from 317.4 +/- 130.4 to 334.5 +/- 123.8 pg/mL (P < 0.05), and alpha-tocopherol increased from 8.2 +/- 5.1 to 13.7 +/- 7.9 mg/L (P < 0.001). Serum homocysteine levels decreased from 8.7 +/- 4.3 to 6.3 +/- 2.2 mumol/L (P < 0.001). In vitro LDL oxidation decreased from 2.6 +/- 1.1 to 1.6 +/- 1.1 nmol malondialdehyde/mg protein (P < 0.001). In comparing patients with healthy controls, basal levels of folate were lower in the patients, whereas vitamin B12, alpha-tocopherol, and homocysteine levels were similar. No changes in serum lipid levels or body weight were observed. In conclusion, a short-term supplementation with folic acid and antioxidant vitamins can reduce serum homocysteine levels and in vitro LDL oxidation in patients with coronary artery disease. PMID:10696633

Bunout, D; Garrido, A; Suazo, M; Kauffman, R; Venegas, P; de la Maza, P; Petermann, M; Hirsch, S



Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification  

Technology Transfer Automated Retrieval System (TEKTRAN)

Historic data on folic acid treatment of pernicious anemia suggested that high-level fortification would delay diagnosis or exacerbate effects of vitamin B12 deficiency, which affects many seniors. This idea is controversial, however, because observational data are few and inconclusive and experime...


Effect of niacin and folic acid in feed rations on growth and live weights of Green catfish (Mystus nemurus Valenciennes 1840).  


This study aims to justify effects of niacin and folic acid in feed rations on growth and survival rate of the fish under in vitro conditions. A Completely Randomized Design (CRD) with four replications for Experiment I and three replications for Experiment II was used. Niacin (0, 5, 10, 20 and 40 mg kg(-1)) and folic acid (0, 2, 4, 6 and 8 mg kg(-1)) were used for Experiments I, and II, respectively. The cement tanks were used for Experiment I and fibre tanks for Experiment II. A static water system was used. Water temperature was maintained at a range from 26 to 30 degrees C with pH values from 7.4 to 7.9. The results showed that niacin at a rate of 10 mg kg(-1) feed ration gave significant differences on weight gained %, survival %, protein efficiency ratio, specific growth rate % and feed conversion ratio with mean values of 99.92, 100, 1.18, 5.77 and 1.35, respectively. Folic acid at a rate of 2 mg kg(-1) gave significant differences on weight gained %, survival %, protein efficiency ratio, specific growth rate % and feed conversion ratio with mean values of 108.88, 100, 1.22, 6.13 and 1.43, respectively. Niacin at a rate of 10 and 2 mg kg(-1) of folic acid were the best rates for in vitro culture of Green catfish. PMID:21913500

Hien, D V; Doolgindachbaporn, S



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


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



A Temporal Association between Folic Acid Fortification and a Rise in Colorectal Cancer Rates May be Illuminating Important Biological Principles: a Hypothesis  

Technology Transfer Automated Retrieval System (TEKTRAN)

Nationwide fortification of enriched uncooked cereal grains with folic acid began in the U.S. and Canada in 1996 and 1997, respectively, and became mandatory in 1998. The rationale was to reduce the number of births complicated by neural tube defects. Concurrently, the U.S. and Canada experienced ab...


Paclitaxel-Loaded, Folic-Acid-Targeted and TAT-Peptide-Conjugated Polymeric Liposomes: In Vitro and In Vivo Evaluation  

Microsoft Academic Search

Objective  Folic acid and TAT peptide were conjugated on the octadecyl-quaternized, lysine-modified chitosan-cholesterol polymeric liposomes\\u000a (FA-TATp-PLs) to investigate their potential feasibility for tumor-targeted drug delivery.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  FA-TATp-PLs encapsulating paclitaxel or calcein were synthesized and characterized. Cellular uptake of PLs, FA-PLs, TATp-PLs\\u000a and FA-TATp-PLs was studied by confocal laser scanning microscopy (CLSM) in folate receptor (FR)-positive KB nasopharyngeal\\u000a epidermal carcinoma cells and FR-deficient

Peiqi Zhao; Hanjie Wang; Man Yu; Shuzhen Cao; Fei Zhang; Jin Chang; Ruifang Niu



Dual responsive dysprosium-doped hydroxyapatite particles and toxicity reduction after functionalization with folic and glucuronic acids.  


The development of probes for biomedical applications demands materials with low toxicity levels besides fluorescence or magnetic properties to be detected by confocal microscopes or MRI resonators. Several drug delivery systems or other biomedical materials prepared with hydroxyapatite have been proposed, however, toxicity effects might arise when the size of particles is nanometric. In this study, hydroxyapatite functionalized with glucuronic or folic acids presented lower oxidative stress, measured from lipoperoxides and nitric oxide indicators in rats than pure hydroxyapatite. In separated experiments, hydroxyapatite was doped with dysprosium cations by coprecipitation producing a single crystal phase with fluorescent properties easily visualized by confocal microscopy when excited at 488nm. These particles also presented the ability to modify the proton relaxation time in T1 maps collected by magnetic resonance imaging. These modified hydroxyapatite nanoparticles could be candidates to design bimodal probes with low toxicity. PMID:25579955

Sánchez Lafarga, Ana Karen; Pacheco Moisés, Fermín P; Gurinov, Andrey; Ortiz, Genaro Gabriel; Carbajal Arízaga, Gregorio Guadalupe



Bioaccessibility of vitamin A, vitamin C and folic acid from dietary supplements, fortified food and infant formula.  


In the Netherlands, vitamin intake occurs mainly via food and for some vitamins also via fortified food. In addition, some people take dietary supplements. Information on the bioavailability of vitamins is important for a good estimation of the actual exposure to vitamins. Furthermore, for a reliable intake estimation, it is important to know the accurateness of the claimed vitamin concentration on the product label. In the current study, the amount of vitamin A, vitamin C, and folic acid in different products and their maximum bioavailability (bioaccessibility) were investigated. In about half of the products, the amount of vitamins significantly deviated from the declared amounts. The vitamin bioaccessibility ranged from <1% to 100%. When assessing the dietary intake exposure of vitamins, it is important to take into account both the possible deviation from the declared level and (the variability of) the bioaccessibility of the vitamin in the products. PMID:24625000

Brandon, E F A; Bakker, M I; Kramer, E; Bouwmeester, H; Zuidema, T; Alewijn, M



Photodynamic therapy effect of zinc monoamino phthalocyanine-folic acid conjugate adsorbed on single walled carbon nanotubes on melanoma cells  

NASA Astrophysics Data System (ADS)

This work reports on the photodynamic therapy effect of zinc monoamino phthalocyanine linked to folic acid represented as ZnMAPc-FA, which was further immobilized onto single walled carbon nanotube represented as ZnMAPc-FA-SWCNT on melanoma A375 cell line, the effect of SWCNT-FA (without ZnMAPc) was also examined. All the compounds were non-toxic to the melanoma A375 cell line in the absence of light. Upon irradiation of the melanoma A375 cell line with a 676 nm diode laser at a power density of 98 mW/cm2 at 5 J/cm2 about 60% and 63% cell death was observed in the presence of ZnMAPc-FA and ZnMAPc-FA-SWCNT respectively. SWCNT-FA had no significant photodynamic therapy or photothermal effect to the cell, only 23% of cell death was observed after irradiation.

Ogbodu, Racheal O.; Ndhundhuma, Ivy; Karsten, Aletta; Nyokong, Tebello



[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].  


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



The Restrained Expression of NF-kB in Renal Tissue Ameliorates Folic Acid Induced Acute Kidney Injury in Mice  

PubMed Central

The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) represent family of structurally-related eukaryotic transcription factors which regulate diverse array of cellular processes including immunological responses, inflammation, apoptosis, growth & development. Increased expression of NF-kB has often been seen in many diverse diseases, suggesting the importance of genomic deregulation to disease pathophysiology. In the present study we focused on acute kidney injury (AKI), which remains one of the major risk factor showing a high rate of mortality and morbidity. The pathology associated with it, however, remains incompletely known though inflammation has been reported to be one of the major risk factor in the disease pathophysiology. The role of NF-kB thus seemed pertinent. In the present study we show that high dose of folic acid (FA) induced acute kidney injury (AKI) characterized by elevation in levels of blood urea nitrogen & serum creatinine together with extensive tubular necrosis, loss of brush border and marked reduction in mitochondria. One of the salient observations of this study was a coupled increase in the expression of renal, relA, NF-kB2, and p53 genes and proteins during folic acid induced AKI (FA AKI). Treatment of mice with NF-kB inhibitor, pyrrolidine dithio-carbamate ammonium (PDTC) lowered the expression of these transcription factors and ameliorated the aberrant renal function by decreasing serum creatinine levels. In conclusion, our results suggested that NF-kB plays a pivotal role in maintaining renal function that also involved regulating p53 levels during FA AKI. PMID:25559736

Kumar, Dev; Singla, Surinder K.; Puri, Veena; Puri, Sanjeev



Use of multivitamins, folic acid and herbal supplements among breast cancer survivors: the black women's health study  

PubMed Central

Background Complementary and alternative medicine (CAM) use, including herbals and multivitamin supplements, is quite common in the U.S., and has been shown to be highest in breast cancer survivors. However, limited data are currently available for CAM usage among African Americans. Thus, we sought to determine the prevalence of multivitamins, folic acid and herbal supplement usage in African American breast cancer survivors, and to compare the characteristics of users and nonusers. Methods A cohort study of breast cancer survivors, who completed the 1999 Black Women's Health Study questionnaire and self-reported having been diagnosed with breast cancer between 1995 and 1999, comprised the study population. In this study, the intake of natural herbs, multivitamins and folic acid at least three days per week within the past two years was used as a proxy for typical usage of this complimentary alternative medicine (CAM) modality. Results A total of 998 breast cancer survivors were identified. Overall, 68.2% had used either herbals or multivitamin supplements or both. The three most frequently used herbals were garlic (21.2%), gingko (12.0%), and echinacea (9.4%). The multivariate analysis determined that single marital status (OR = 1.58; 95%CI: 1.04-2.41), and alcohol consumption of 1-3 drinks per week (OR = 1.86, 95%CI: 1.28-2.68) were significantly associated with increased herbal use. Multivitamin use was significantly lower among obese women (OR = 0.66, 95%CI: 0.46-0.94) and current smokers (OR = 0.53, 95%CI: 0.34-0.82). Conclusions A significant number of African American breast cancer survivors are using herbals and multivitamins as CAM modality. Additional research is needed to understand the impact of herbals and multivitamins in African American breast cancer survivors. PMID:21496245



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



Pharmacological Activity of Retinoic Acid Receptor Alpha-Selective Antagonists in Vitro and in Vivo  

PubMed Central

Oral administration of a retinoic acid receptor (RAR) pan-antagonist reversibly inhibits spermatogenesis. Given the importance of RAR? in regulating spermatogenesis, we identified two RAR?-selective antagonists by transactivation and transactivation competition assays and asked whether they effectively inhibit spermatogenesis. Although these two antagonists were potent in vitro, they displayed poor in vivo activity in mice when administered orally. Testicular weights were normal, and morphological analysis revealed normal spermatid alignment and sperm release. In vitro drug property analyses were performed with one of these antagonists and compared with the pan-antagonist. We showed that the discrepancies may be explained by several factors, including high plasma protein binding, faster hepatic metabolism relative to the pan-antagonist, and only moderate permeability. The conclusion of poor oral bioavailability was supported by more pronounced defects in mice when the antagonist was administered intravenously versus intraperitoneally. These results are crucial for designing new RAR?-selective antagonists for pharmaceutical application. PMID:24040487



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



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



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


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



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


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



U.S. provider reported folic acid or multivitamin ordering for non-pregnant women of childbearing age: NAMCS and NHAMCS, 2005-2006.  


Folic acid use started prior to pregnancy confers a decreased risk of neural tube defects, and yet 20-50% of pregnancies are unplanned. We sought to determine whether medical providers order folic acid (FA) or folic acid-containing multivitamins (MVI) for their non-pregnant female patients of childbearing age. This is a cross-sectional study using data from the CDC's National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) (2005 and 2006). Among non-pregnant, female patients of childbearing age (15-44), the proportion of preventive visits during which a provider ordered FA/MVI supplements was determined and compared to pregnant patients. Next, the rates of FA/MVI orders were examined according to race/ethnicity, age, insurance status, region of the country, provider type, contraceptive care, income and education. Analyses were conducted using SAS-callable Sudaan to account for survey design and to obtain population estimates. There were 4,634 preventive visits for non-pregnant women of childbearing age, representing 32.1 million visits nationally. Of these visits, 7.2% included provider-ordered FA/MVI. Multivariable logistic regression analyses revealed that provider-ordered FA/MVI was most common for women ages 30-34, who receive Medicaid, and whose race/ethnicity was other than White, Black or Hispanic. Preventive care visits represent an important venue for counseling regarding the benefits of FA for women of childbearing age, but appear to be under-utilized in all women. Our findings suggest that annually there may be over 29 million missed opportunities to recommend folic acid to non-pregnant women seeking preventive care. PMID:20204479

Burris, Heather H; Werler, Martha M



Supramolecular gel from folic acid with multiple responsiveness, rapid self-recovery and orthogonal self-assemblies.  


Through a good/poor solvent strategy, native folic acid (FA) which behaves as a super-gelator in DMSO-water system can be successfully employed to construct supramolecular gels. The system exhibited morphological evolution with the increase of FA concentration; various phases such as vesicles, fiber/vesicles, fiber/nanoparticles, nanoparticles were probed. In the self-assembly process, l-glutamic acid moiety induced the formation of helical 1-dimensional (1-D) fibers which further self-assembled into a gel. Stimuli like heat, stress, pH and light which affect the molecular structure of FA or solubility in the mixed solvents had a pronounced influence on the properties of the gels, such as mechanical properties or bulk phases. A time-dependent oscillatory stress scan indicated that the supramolecular gel had a self-healing property. Without tedious modification routes and addition of alkali metal ions, native FA which served as an efficient building block and super-gelator to build up multi-responsive and self-recovery material was investigated for the first time. PMID:24658366

Xing, Pengyao; Chu, Xiaoxiao; Ma, Mingfang; Li, Shangyang; Hao, Aiyou



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



Folic acid conjugated cross-linked acrylic polymer (FA-CLAP) hydrogel for site specific delivery of hydrophobic drugs to cancer cells  

PubMed Central

Background The hydrogel based system is found to be rarely reported for the delivery of hydrophobic drug due to the incompatibility of hydrophilicity of the polymer network and the hydrophobicity of drug. This problem can be solved by preparing semi-interpenetrating network of cross-linked polymer for tuning the hydrophilicity so as to entrap the hydrophobic drugs. The current study is to develop a folic acid conjugated cross-linked pH sensitive, biocompatible polymeric hydrogel to achieve a site specific drug delivery. For that, we have synthesized a folic acid conjugated PEG cross-linked acrylic polymer (FA-CLAP) hydrogel and investigated its loading and release of curcumin. The formed polymer hydrogel was then conjugated with folic acid for the site specific delivery of curcumin to cancer cells and then further characterized and conducted the cell uptake and cytotoxicity studies on human cervical cancer cell lines (HeLa). Results In this study, we synthesized folic acid conjugated cross-linked acrylic hydrogel for the delivery of hydrophobic drugs to the cancer site. Poly (ethyleneglycol) (PEG) diacrylate cross-linked acrylic polymer (PAA) was prepared via inverse emulsion polymerization technique and later conjugated it with folic acid (FA-CLAP). Hydrophobic drug curcumin is entrapped into it and investigated the entrapment efficiency. Characterization of synthesized hydogel was done by using Fourier Transform-Infrared spectroscopy (FT-IR), Transmission Electron Microscopy (TEM), Differential Scanning Calorimetry (DSC). Polymerization and folate conjugation was confirmed by FT-IR spectroscopy. The release kinetics of drug from the entrapped form was studied which showed initial burst release followed by sustained release due to swelling and increased cross-linking. In vitro cytotoxicity and cell uptake studies were conducted in human cervical cancer (HeLa) cell lines. Conclusions Results showed that curcumin entrapped folate conjugated cross-linked acrylic polymer (FA-CLAP) hydrogel showed higher cellular uptake than the non folate conjugated form. So this can be suggested as a better delivery system for site specific release of hydrophobic cancer drugs. PMID:25026938



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


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



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


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



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

NASA Astrophysics Data System (ADS)

In this research, folic acid functionalized silver nanoparticles (FA-AgNPs) were selected as a colorimetric and a ‘turn on’ fluorescent sensor for detecting Hg2+. After being added into Hg2+, 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 Hg2+ ions. Thus, we developed a simple, sensitive analytical method to detect Hg2+ based on the colorimetric and fluorescence enhancement of FA-AgNPs. The sensor exhibits two linear response ranges between absorbance and fluorescence intensity with Hg2+ concentration, respectively. Meanwhile, a detection limit of 1 nM is estimated based on the linear relationship between responses with a concentration of Hg2+. The high specificity of Hg2+ with FA-AgNPs interactions provided the excellent selectivity towards detecting Hg2+ over other metal ions (Pb2+, Mg2+, Zn2+, Ni2+, Cu2+, Co2+, Ca2+, Mn2+, Fe2+, Cd2+, Ba2+, Cr6+ and Cr3+). This will provide a simple, effective and multifunctional colorimetric and fluorescent sensor for on-site and real-time Hg2+ ion detection. The proposed method can be applied to the analysis of trace Hg2+ in lake water. Additionally, the FA-AgNPs can be used as efficient catalyst for the reduction of 4-nitrophenol and potassium hexacyanoferrate (III).

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



Single-base resolution of mouse offspring brain methylome reveals epigenome modifications caused by gestational folic acid  

PubMed Central

Background Epigenetic modifications, such as cytosine methylation in CpG-rich regions, regulate multiple functions in mammalian development. Maternal nutrients affecting one-carbon metabolism during gestation can exert long-term effects on the health of the progeny. Using C57BL/6 J mice, we investigated whether the amount of ingested maternal folic acid (FA) during gestation impacted DNA methylation in the offspring’s cerebral hemispheres. Reduced representation bisulfite sequencing at single-base resolution was performed to analyze genome-wide DNA methylation profiles. Results We identified widespread differences in the methylation patterns of CpG and non-CpG sites of key developmental genes, including imprinted and candidate autism susceptibility genes (P <0.05). Such differential methylation of the CpG and non-CpG sites may use different mechanisms to alter gene expressions. Quantitative real time reverse transcription-polymerase chain reaction confirmed altered expression of several genes. Conclusions These finding demonstrate that high maternal FA during gestation induces substantial alteration in methylation pattern and gene expression of several genes in the cerebral hemispheres of the offspring, and such changes may influence the overall development. Our findings provide a foundation for future studies to explore the influence of gestational FA on genetic/epigenetic susceptibility to altered development and disease in offspring. PMID:24484737



Effects of the storage time on the folic acid added to ready-to-eat meat products manufactured by irradiation  

NASA Astrophysics Data System (ADS)

Three different meat products enriched with folic acid (FA) (2.4 mg/100 g) were manufactured: hamburgers, cooked and dry fermented sausages. They were prepared as ready-to-eat (RTE) products using E-beam radiation (2 and 3 kGy) to ensure their safety. The stability of FA and sensory properties of the irradiated meat products were studied during three months of storage under freezing conditions for hamburgers and refrigeration conditions for cooked and dry fermented sausages. FA content was stable in non-irradiated and irradiated hamburgers and cooked sausages over the storage period, whereas it decreased 20% in non-irradiated dry fermented sausages and 12-8% in irradiated samples at 2 and 3 kGy, respectively. Nevertheless, the final amount remained sufficient to provide the recommended daily intake. Panelists rated the sensory properties of the hamburger as satisfactory even after irradiation and 90 days of storage. The overall acceptability of RTE cooked and dry fermented sausages improved slightly with storage (P>0.05).

Galán, I.; García, M. L.; Selgas, M. D.



Excitatory amino acid antagonists alleviate convulsive and toxic properties of lindane in mice.  


Pesticides acting at GABAA receptors may induce convulsions in man and animals, but the mechanisms responsible for their convulsant activity are not fully explained. The following excitatory amino acid antagonists were studied for their protective action in mice intoxicated with chlorinated hydrocarbon insecticide lindane (gamma-hexachlorocyclohexane): the competitive NMDA antagonist: 3-(2-carboxypiperazine-4-yl)propenyl-1- phosphonic acid (D-CPPene, 20 mg/kg), the non-competitive NMDA antagonist: dizocilpine (MK-801, 0.4 mg/kg), the glycine site antagonist of NMDA receptor: 2-phenyl-1,3-propane-diol dicarbamate (felbamate, 400 mg/kg) and the competitive AMPA antagonist: 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX, 100 mg/kg). Systemic administration of an antagonist prior to lindane resulted in a strong anticonvulsant effect. D-CPPene, MK-801 and NBQX produced a marked increase of CD50 values of lindane for clonic convulsions. All the antagonists protected animals against tonic convulsions. Toxicity of lindane was potently reduced, as assessed 2, 24 and 120 hr after administration of the pesticide. Our results demonstrate that excitatory amino acid antagonists reduce convulsant properties and toxicity of lindane, suggesting that excitatory amino acid neurotransmission may be involved in its central action. PMID:9553992

Blaszczak, P; Turski, W A



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



Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism.  


Nutritional imbalance is emerging as a causative factor of hearing loss. Epidemiologic studies have linked hearing loss to elevated plasma total homocysteine (tHcy) and folate deficiency, and have shown that folate supplementation lowers tHcy levels potentially ameliorating age-related hearing loss. The purpose of this study was to address the impact of folate deficiency on hearing loss and to examine the underlying mechanisms. For this purpose, 2-mo-old C57BL/6J mice (Animalia Chordata Mus musculus) were randomly divided into 2 groups (n = 65 each) that were fed folate-deficient (FD) or standard diets for 8 wk. HPLC analysis demonstrated a 7-fold decline in serum folate and a 3-fold increase in tHcy levels. FD mice exhibited severe hearing loss measured by auditory brainstem recordings and TUNEL-positive-apoptotic cochlear cells. RT-quantitative PCR and Western blotting showed reduced levels of enzymes catalyzing homocysteine (Hcy) production and recycling, together with a 30% increase in protein homocysteinylation. Redox stress was demonstrated by decreased expression of catalase, glutathione peroxidase 4, and glutathione synthetase genes, increased levels of manganese superoxide dismutase, and NADPH oxidase-complex adaptor cytochrome b-245, ?-polypeptide (p22phox) proteins, and elevated concentrations of glutathione species. Altogether, our findings demonstrate, for the first time, that the relationship between hyperhomocysteinemia induced by folate deficiency and premature hearing loss involves impairment of cochlear Hcy metabolism and associated oxidative stress. -Martínez-Vega, R., Garrido, F., Partearroyo, T., Cediel, R., Zeisel, S. H., Martínez-Álvarez, C., Varela-Moreiras, G., Varela-Nieto, I., and Pajares, M. A. Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism. PMID:25384423

Martínez-Vega, Raquel; Garrido, Francisco; Partearroyo, Teresa; Cediel, Rafael; Zeisel, Steven H; Martínez-Álvarez, Concepción; Varela-Moreiras, Gregorio; Varela-Nieto, Isabel; Pajares, María A



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.



Folic acid pathway single nucleotide polymorphisms associated with methotrexate significant adverse events in United States veterans with rheumatoid arthritis  

PubMed Central

Objective Methotrexate (MTX) is the cornerstone medication in the treatment of rheumatoid arthritis (RA). We examined whether single nucleotide polymorphisms (SNPs) in enzymes of the folic acid pathway (folylpoly-gamma-glutamate synthetase [FPGS], gamma-glutamyl hydrolase [GGH], and methylenetetrahydrofolate reductase [MTHFR]) associate with significant adverse events (SigAE). Methods Patients (n=319) enrolled in the Veterans Affairs RA (VARA) registry taking MTX were genotyped for HLA-DRB1-SE and the following SNPs: FPGS (rs7033913, rs10760503, rs10106), GGH (12548933, rs7010484, rs4617146, rs719235, rs11988534), MTHFR (rs1801131, rs1801133). AE were abstracted from the medical record using a structured instrument. SigAE were defined as an AE leading to MTX discontinuation. Covariates included: age, gender, race, RA antibody status, tobacco, RA disease duration between diagnosis and MTX course, Charlson-Deyo comorbidity index, glucocorticoids, use of prior RA medications, and mean 4-variable disease activity score. Cox regression was performed to determine factors associated with time-to-SigAE. A p-value ?0.005 established significance in the final model. Results The presence of ?1 copy of the minor allele in MTHFR rs1801131 was associated with an increased hazard ratio (HR) of SigAE (HR 3.05, 95% CI 1.48–6.29, p-value 0.003 and HR 3.88, 95% CI 1.62–9.28, p-value 0.002 for heterozygotes and homozygotes for the minor allele, respectively). An interaction term, between FPGS rs7033913 heterozygotes and GGH rs11988534 homozygotes for the minor allele, had a p-value <0.0001. Conclusion RA subjects taking MTX may have decreased time-to-SigAE with ? 1 copy of the minor allele in MTHFR rs1801131. Further investigation is warranted, as these SNPs may indicate susceptibility to MTX toxicity. PMID:24447348

Davis, Lisa A.; Polk, Brooke; Mann, Alyse; Wolff, Roger K.; Kerr, Gail S.; Reimold, Andreas M.; Cannon, Grant W.; Mikuls, Ted R.; Caplan, Liron



Biocompatible multi-walled carbon nanotube-chitosan-folic acid nanoparticle hybrids as GFP gene delivery materials.  


Carbon nanotube (CNT) is one of the inorganic delivery systems that show great potential for optimal biomolecule transporting. Concerning the preparation of CNT-based delivery vectors, it is very important to understand the internal relations of physical properties and surface functionalization of CNTs with the transfection efficiency and cytotoxicity. In this paper, the multi-walled CNTs (MWCNTs) of different length were functionalized with chitosan-folic acid nanoparticles (CS-FA NPs) by ionotropic gelation process. The micromorphologies, surface functional groups, and zeta potential of the MWCNT-CS-FA NPs were characterized. The effects of nanotube length and surface functionalization with CS-FA NPs on the gene transfection efficiency and cytotoxicity were investigated in detail. The non-functionalized MWCNTs and MWCNT-CS-FA NPs all can deliver the plasmid DNA of enhanced green fluorescent protein (pEGFP-N1) into HeLa and MCF-7 cells and the exogenous GFP gene has been expressed. The nanotube length shows a compromise influence on the transfection and cytotoxicity properties of MWCNTs. Having greater gene transfection ability, however, the shorter MWCNTs exhibit larger cytotoxicity than the longer ones. Moreover, the surface functionalization of MWCNTs with CS-FA NPs improves the transfection efficiency and decreases the cytotoxicity as well. Under optimal conditions, the pEGFP-N1 transfection efficiency of MWCNT-CS-FA NPs is about 4.1%, being 1.5 times as large as that of the non-functionalized MWCNTs. The MWCNT-CS-FA NPs show little effect on the cellular viability when the concentration is up to 250 ?g mL(-1). By optimal length control and surface functionalization, MWCNTs should have good applications in gene delivery vectors. PMID:23831590

Liu, Xiahui; Zhang, Yingying; Ma, Dongmei; Tang, Hao; Tan, Liang; Xie, Qingji; Yao, Shouzhuo



Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring.  


Environmental constraints during early life result in phenotypic changes that can be associated with increased disease risk in later life. This suggests persistent alteration of gene transcription. DNA methylation, which is largely established in utero, provides a causal mechanism by which unbalanced prenatal nutrition results in such altered gene expression. We investigated the effect of unbalanced maternal nutrition on the methylation status and expression of the glucocorticoid receptor (GR) and peroxisomal proliferator-activated receptor (PPAR) genes in rat offspring after weaning. Dams were fed a control protein (C; 180 g/kg protein plus 1 mg/kg folic acid), restricted protein (R; 90 g/kg casein plus 1 mg/kg folic acid), or restricted protein plus 5 mg/kg folic acid (RF) diet throughout pregnancy. Pups were killed 6 d after weaning (n = 10 per group). Gene methylation was determined by methylation-sensitive PCR and mRNA expression by semiquantitative RT-PCR. PPARalpha gene methylation was 20.6% lower (P < 0.001) and expression 10.5-fold higher in R compared with C pups. GR gene methylation was 22.8% lower (P < 0.05) and expression 200% higher (P < 0.01) in R pups than in C pups. The RF diet prevented these changes. PPARgamma methylation status and expression did not differ among the groups. Acyl-CoA oxidase expression followed that of PPARalpha. These results show that unbalanced prenatal nutrition induces persistent, gene-specific epigenetic changes that alter mRNA expression. Epigenetic regulation of gene transcription provides a strong candidate mechanism for fetal programming. PMID:15930441

Lillycrop, Karen A; Phillips, Emma S; Jackson, Alan A; Hanson, Mark A; Burdge, Graham C



Pregnancy-induced changes in the long-term pharmacokinetics of 1.1?mg vs. 5?mg folic acid: A randomized clinical trial.  


The objective of this randomized clinical trial was to compare steady-state gestational RBC and plasma folate concentrations in pregnant women supplementing daily with 1.1?mg (regular dose) vs. 5?mg (high dose) folic acid. Thirty-seven pregnant women, who were not previously taking folic acid, were enrolled in this open-label, 2-arm, randomized clinical trial after informed consent. Participants were randomly assigned either 1.1 or 5?mg of folic acid-containing prenatals until gestational age (g.a.) 30 weeks. Plasma and RBC folate concentrations were measured at baseline, g.a.6 weeks, g.a.12 weeks, and g.a.30 weeks using a chemiluminescent immunoassay. Results showed sustained significant increase in RBC folate in the 5?mg group between g.a.6 weeks and g.a.30 weeks (P?

Shere, Mahvash; Nguyen, Patricia; Tam, Carolyn; Stern, Seth; Kapur, Bhushan; O'Connor, Deborah L; Koren, Gideon



Expression of Genes Encoding Enzymes Involved in the One Carbon Cycle in Rat Placenta is Determined by Maternal Micronutrients (Folic Acid, Vitamin B12) and Omega-3 Fatty Acids  

PubMed Central

We have reported that folic acid, vitamin B12, and omega-3 fatty acids are interlinked in the one carbon cycle and have implications for fetal programming. Our earlier studies demonstrate that an imbalance in maternal micronutrients influence long chain polyunsaturated fatty acid metabolism and global methylation in rat placenta. We hypothesize that these changes are mediated through micronutrient dependent regulation of enzymes in one carbon cycle. Pregnant dams were assigned to six dietary groups with varying folic acid and vitamin B12 levels. Vitamin B12 deficient groups were supplemented with omega-3 fatty acid. Placental mRNA levels of enzymes, levels of phospholipids, and glutathione were determined. Results suggest that maternal micronutrient imbalance (excess folic acid with vitamin B12 deficiency) leads to lower mRNA levels of methylene tetrahydrofolate reductase (MTHFR) and methionine synthase , but higher cystathionine b-synthase (CBS) and Phosphatidylethanolamine-N-methyltransferase (PEMT) as compared to control. Omega-3 supplementation normalized CBS and MTHFR mRNA levels. Increased placental phosphatidylethanolamine (PE), phosphatidylcholine (PC), in the same group was also observed. Our data suggests that adverse effects of a maternal micronutrient imbalanced diet may be due to differential regulation of key genes encoding enzymes in one carbon cycle and omega-3 supplementation may ameliorate most of these changes. PMID:25003120

Khot, Vinita; Kale, Anvita; Joshi, Asmita; Chavan-Gautam, Preeti; Joshi, Sadhana



Determining the Effect of Gutkha on Serum Levels of Vitamin B12 and Folic Acid as Compared to Smoking among Chronic Periodontitis Subjects : A Cross-Sectional Study  

PubMed Central

Background: Periodontitis, being a common inflammatory disease has a multifactorial origin , with smoking and gutkha as few of the causative entities. The role of smoking as a risk factor for periodontitis is been well documented in literature. Cigarette smoke also affects vitamin B12 and folic acid mechanisms. Nutritionally derived vitamin B12 occurs mainly as either hydroxycobalamin or deoxyadenosycobalmin. Folic acid is also heat sensitive and water soluble, closely linked to vitamin B12 in its metabolism. However, effect of smokeless tobacco in form of gutkha on serum levels of vitamin B12 and folic acid is yet to be explored. Aims and Objectives: To estimate and correlate serum vitamin B12 (VB12) and folic acid (FA) levels among periodontally healthy subjects and Chronic Periodontitis (CP) subjects with habit of smoking and gutkha chewing. Materials and Methods: The study included 111 subjects ranging in age from 18 to 60 y. Participants were divided into four groups: 30 healthy subjects (Group I), 29 subjects with CP (Group II), 25 smokers with CP (Group III) and 27 gutkha chewers with CP (Group IV). Clinical parameters included pocket probing depth (PPD), clinical attachment level (CAL) & gingival index (GI) following which VB12 and FA levels were estimated through UV-spectrophotometry method and data was analysed using Statistical Package for Social Scientists software, Mann-Whitney U-test and Pearson correlation coefficient. p-values less than 0.05 were considered as significant. Results : Pairwise comparison by Mann-Whitney U-test showed an increase in the serum VB12 in Group IV when compared to Group I (p=0.01) and Group II (p=0.01). Although serum FA levels were found to be low in Group III (7.61 ug/ml) & Group IV (8.64 ug/ml), Group III was found to be statistically significant (P=0.046). The clinical parameters GI, PPD and CAL among the four groups of patients were also statistically significant (p < 0.05). Conclusion: The study results suggested that among the patients with periodontal disease, serum VB12 levels are directly related while serum FA levels are inversely related to inflammation and tissue destruction in periodontium as occurred in Group IV. PMID:25654040

Warad, Shivaraj; Kalburgi, Nagaraj B; Kalburgi, Veena C; Koregol, Arati C; Patanashetti, Jyoti; Rao, Subramaniam; Kokatnur, M. Vijayalaxmi



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



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


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



Combating Iron Deficiency Anemia among School Going Adolescent Girls in a Hilly State of North India: Effectiveness of Intermittent Versus Daily Administration of Iron Folic Acid Tablets  

PubMed Central

Background: National surveys in India have documented an increasing number of adolescent girls suffering from anemia. Efforts to build iron stores in adolescent girls will help them improve their prepregnancy hemoglobin level. To assess the effectiveness of school-based supervised weekly, bi–weekly, and daily regimen of iron folic tablets in the treatment of anemia among adolescent girls. Methods: This randomized clinical trial included 331 anemic school going adolescent girls of Shimla district of North India. Study subjects were randomized to once weekly, bi–weekly, and daily iron folic acid regimen group. An intent-to-treat approach was used to analyze the change in hemoglobin level and serum ferritin levels at the end of the trial period. Results: The rate of change of hemoglobin and serum ferritin levels from baseline to the end of the intervention was found to be similar in all the three groups (P = 0.64 and 0.98 for change in hemoglobin and serum ferritin). Bi-weekly treatment regimen results in comparatively more increase in hemoglobin levels (3.1 g/dl) as compared to once weekly (2.4 g/dl) and daily groups (2.3 g/dl) (ANOVA F statistics = 6.08, P = 0.003). Among the study subjects who reported side effects, more were from daily regimen group (55%) as compared to intermittent regimen group (25% in bi-weekly group; 18% in weekly group; P < 0.001). Conclusions: In Shimla hills of North India, school-based intermittent iron-folic acid therapy is a feasible and effective intervention for increasing hemoglobin and serum ferritin levels of anemic adolescent girls.

Gupta, Anmol; Parashar, Anupam; Thakur, Anita; Sharma, Deepak; Bhardwaj, Parveen; Jaswal, Saroj



Synthesis and biological evaluation of novel folic acid receptor-targeted, ?-cyclodextrin-based drug complexes for cancer treatment.  


Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily obtained by mixed solvent precipitation. The average size of FACD-Ada-Dox was 1.5-2.5 nm. The host-guest association constant K a was 1,639 M(-1) as determined by induced circular dichroism and the hydrophilicity of the FACDs was greatly enhanced compared to unmodified CD. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive tumor cells and a sustained drug release profile was seen in vitro. The delivery of Dox into FR(+) cancer cells via endocytosis was observed by confocal microscopy and drug uptake of the targeted nanoparticles was 8-fold greater than that of non-targeted drug complexes. Our docking results suggest that FA, FACD and FACD-Ada-Dox could bind human hedgehog interacting protein that contains a FR domain. Mouse cardiomyocytes as well as fibroblast treated with FACD-Ada-Dox had significantly lower levels of reactive oxygen species, with increased content of glutathione and glutathione peroxidase activity, indicating a reduced potential for Dox-induced cardiotoxicity. These results indicate that the targeted drug complex possesses high drug association and sustained drug release properties with good biocompatibility and physiological stability. The novel FA-conjugated ?-CD based drug complex might be promising as an anti-tumor treatment for FR(+) cancer. PMID:23658721

Yin, Juan-Juan; Sharma, Sonali; Shumyak, Stepan P; Wang, Zhi-Xin; Zhou, Zhi-Wei; Zhang, Yangde; Guo, Peixuan; Li, Chen-Zhong; Kanwar, Jagat R; Yang, Tianxin; Mohapatra, Shyam S; Liu, Wanqing; Duan, Wei; Wang, Jian-Cheng; Li, Qi; Zhang, Xueji; Tan, Jun; Jia, Lee; Liang, Jun; Wei, Ming Q; Li, Xiaotian; Zhou, Shu-Feng



Increasing Maternal or Post-Weaning Folic Acid Alters Gene Expression and Moderately Changes Behavior in the Offspring  

PubMed Central

Background Studies have indicated that altered maternal micronutrients and vitamins influence the development of newborns and altered nutrient exposure throughout the lifetime may have potential health effects and increased susceptibility to chronic diseases. In recent years, folic acid (FA) exposure has significantly increased as a result of mandatory FA fortification and supplementation during pregnancy. Since FA modulates DNA methylation and affects gene expression, we investigated whether the amount of FA ingested during gestation alters gene expression in the newborn cerebral hemisphere, and if the increased exposure to FA during gestation and throughout the lifetime alters behavior in C57BL/6J mice. Methods Dams were fed FA either at 0.4 mg or 4 mg/kg diet throughout the pregnancy and the resulting pups were maintained on the diet throughout experimentation. Newborn pups brain cerebral hemispheres were used for microarray analysis. To confirm alteration of several genes, quantitative RT-PCR (qRT-PCR) and Western blot analyses were performed. In addition, various behavior assessments were conducted on neonatal and adult offspring. Results Results from microarray analysis suggest that the higher dose of FA supplementation during gestation alters the expression of a number of genes in the newborns’ cerebral hemispheres, including many involved in development. QRT-PCR confirmed alterations of nine genes including down-regulation of Cpn2, Htr4, Zfp353, Vgll2 and up-regulation of Xist, Nkx6-3, Leprel1, Nfix, Slc17a7. The alterations in the expression of Slc17a7 and Vgll2 were confirmed at the protein level. Pups exposed to the higher dose of FA exhibited increased ultrasonic vocalizations, greater anxiety-like behavior and hyperactivity. These findings suggest that although FA plays a significant role in mammalian cellular machinery, there may be a loss of benefit from higher amounts of FA. Unregulated high FA supplementation during pregnancy and throughout the life course may have lasting effects, with alterations in brain development resulting in changes in behavior. PMID:25006883

Kuizon, Salomon; Buenaventura, Diego; Stapley, Nathan W.; Ruocco, Felicia; Begum, Umme; Guariglia, Sara R.; Brown, W. Ted; Junaid, Mohammed A.



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


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



Carboxymethyl chitosan-folic acid-conjugated Fe3O4@SiO2 as a safe and targeting antitumor nanovehicle in vitro  

PubMed Central

A synthetic method to prepare a core-shell-structured Fe3O4@SiO2 as a safe nanovehicle for tumor cell targeting has been developed. Superparamagnetic iron oxide is encapsulated inside nonporous silica as the core to provide magnetic targeting. Carboxymethyl chitosan-folic acid (OCMCS-FA) synthesized through coupling folic acid (FA) with OCMCS is then covalently linked to the silica shell and renders new and improved functions because of the original biocompatible properties of OCMCS and the targeting efficacy of FA. Cellular uptake of the nanovehicle was assayed by confocal laser scanning microscope using rhodamine B (RB) as a fluorescent marker in HeLa cells. The results show that the surface modification of the core-shell silica nanovehicle with OCMCS-FA enhances the internalization of nanovehicle to HeLa cells which over-express the folate receptor. The cell viability assay demonstrated that Fe3O4@SiO2-OCMCS-FA nanovehicle has low toxicity and can be used as an eligible candidate for drug delivery system. These unique advantages make the prepared core-shell nanovehicle promising for cancer-specific targeting and therapy. PMID:24667013



Folic Acid Quiz  


... of women with NTD-affected pregnancies have no personal or family history of NTDs. Close × Answer: ... product. While this level of fortification offers some protection against NTDs, most women will not get enough ...


Antagonists of retinoic acid receptors (RARs) are potent growth inhibitors of prostate carcinoma cells  

PubMed Central

Novel synthetic antagonists of retinoic acid receptors (RARs) have been developed. To avoid interference by serum retinoids when testing these compounds, we established serum-free grown sub-lines (>3 years) of the prostate carcinoma lines LNCaP, PC3 and DU145. A high affinity pan-RAR antagonist (AGN194310, Kd for binding to RARs = 2–5?nM) inhibited colony formation (by 50%) by all three lines at 16–34?nM, and led to a transient accumulation of flask-cultured cells in G1 followed by apoptosis. AGN194310 is 12–22 fold more potent than all-trans retinoic acid (ATRA) against cell lines and also more potent in inhibiting the growth of primary prostate carcinoma cells. PC3 and DU145 cells do not express RAR?, and an antagonist with predominant activity at RAR? and RAR? (AGN194431) inhibited colony formation at concentrations (?100?nM) commensurate with a Kd value of 70?nM at RAR?. An RAR? antagonist (AGN194301) was less potent (IC50 ?200?nM), but was more active than specific agonists of RAR? and of ??. A component(s) of serum and of LNCaP-conditioned medium diminishes the activity of antagonists: this factor is not the most likely candidates IGF-1 and EGF. In vitro studies of RAR antagonists together with data from RAR-null mice lead to the hypothesis that RAR?-regulated gene transcription is necessary for the survival and maintenance of prostate epithelium. The increased potencies of RAR antagonists, as compared with agonists, suggest that antagonists may be useful in the treatment of prostate carcinoma. © 2001 Cancer Research Campaign PMID:11487280

Hammond, L A; Krinks, C H Van; Durham, J; Tomkins, S E; Burnett, R D; Jones, E L; Chandraratna, R A S; Brown, G



Control of gastric acid with high dose H2-receptor antagonists after omeprazole failure: report of two cases.  


Successful omeprazole therapy in patients with symptomatic gastroesophageal reflux (GER) refractory to treatment with H2-receptor antagonists has often been reported. In contrast, successful treatment of GER by H2-receptor antagonists in patients resistant to the acid-suppressing effects of omeprazole is rarely reported. We describe two patients who demonstrated therapeutic responses to high dose H2-receptor antagonists after high dose omeprazole failed to suppress gastric acidity and GER. PMID:7572913

Leite, L P; Just, R J; Castell, D O; Lagerström, P O



Fabrication of reduced graphene oxide and sliver nanoparticle hybrids for Raman detection of absorbed folic acid: a potential cancer diagnostic probe.  


Reduced graphene oxide (RGO) and silver nanoparticle (AgNP) hybrids (RGO-AgNP) were prepared by a facile one-pot method using Poly (N-vinyl-2-pyrrolidone) as reductant and stabilizer. Folic acid (FA) molecules were attached to the RGO-AgNP by physisorption for targeting specific cancer cells with folate receptors (FRs) and using as Raman reporter molecules. The internalization of the FA loaded RGO-AgNP (RGO-AgNP-FA) inside the FRs-positive cancer cell was confirmed by confocal laser scanning and transmission electron microscopy. The Raman signals of the FA in live cancer cells were detected by confocal Raman spectroscope at 514 nm excitation, indicating that the RGO-AgNP-FA material has great potential as a Raman probe for cancer diagnosis in vitro. PMID:23629451

Hu, Chaofan; Liu, Yingliang; Qin, Jinlan; Nie, Guangting; Lei, Bingfu; Xiao, Yong; Zheng, Mingtao; Rong, Jianhua



Development, optimization and validation of a sub-minute analytical enantioselective high performance liquid chromatographic separation for a folic acid precursor in normal phase mode.  


A sub-minute enantioselective normal phase high performance liquid chromatographic (HPLC) method for the analysis of a chiral precursor molecule employed frequently in folic acid syntheses was developed, optimized and successfully validated according to ICH-guidelines. It could be shown that ultra-high performance chromatography (UHPLC) can give significant advantages compared to traditional HPLC not only in reversed phase HPLC, but also for enantioselective separations in normal phase mode. Novel 3 ?m-particle sizes allow developing analytical chromatographic methods completely resolving two enantiomers in the shortest time possible while preserving high efficiency and low detection limits. By offering increased resolution, sensitivity and speed, enantioselective UHPLC (eUHPLC) improves sample throughput, productivity and provides considerably faster access to information on enantiomeric purity also under non-aqueous conditions. PMID:23102632

Frühauf, Doris; Juza, Markus



Reduced-energy cranberry juice increases folic acid and adiponectin and reduces homocysteine and oxidative stress in patients with the metabolic syndrome.  


The metabolic syndrome (MetS) comprises pathological conditions that include insulin resistance, arterial hypertension, visceral adiposity and dyslipidaemia, which favour the development of CVD. Some reports have shown that cranberry ingestion reduces cardiovascular risk factors. However, few studies have evaluated the effect of this fruit in subjects with the MetS. The objective of the present study was to assess the effect of reduced-energy cranberry juice consumption on metabolic and inflammatory biomarkers in patients with the MetS, and to verify the effects of cranberry juice concomitantly on homocysteine and adiponectin levels in patients with the MetS. For this purpose, fifty-six individuals with the MetS were selected and divided into two groups: control group (n 36) and cranberry-treated group (n 20). After consuming reduced-energy cranberry juice (0·7 litres/d) containing 0·4mg folic acid for 60 d, the cranberry-treated group showed an increase in adiponectin (P=0·010) and folic acid (P=0·033) and a decrease in homocysteine (P<0·001) in relation to baseline values and also in comparison with the controls (P<0·05). There was no significant change in the pro-inflammatory cytokines TNF-a, IL-1 and IL-6. In relation to oxidative stress measurements, decreased (P<0·05) lipoperoxidation and protein oxidation levels assessed by advanced oxidation protein products were found in the cranberry-treated group when compared with the control group. In conclusion, the consumption of cranberry juice for 60 d was able to improve some cardiovascular risk factors. The present data reinforce the importance of the inverse association between homocysteine and adiponectin and the need for more specifically designed studies on MetS patients. PMID:23750500

Simão, Tathiana Name Colado; Lozovoy, Marcell Alysson Batisti; Simão, Andréa Name Colado; Oliveira, Sayonara Rangel; Venturini, Danielle; Morimoto, Helena Kaminami; Miglioranza, Lúcia Helena Silva; Dichi, Isaias



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



Discovery and evaluation of terephthalic acid derivatives as potent alpha4beta1 integrin antagonists.  


Terephthalic acid based derivatives containing beta- and gamma-amino acid residues were prepared as antagonists of the leukocyte cell adhesion process that is mediated through the interaction of the very late antigen 4 (VLA-4) and the vascular cell adhesion molecule 1 (VCAM-1). The compounds 2, 10-12, 14, and 16-17 inhibited the adhesion in a cell based assay in the low and sub micromolar range. PMID:14567545

Müller, Gerhard; Albers, Markus; Hessler, Gerhard; Lehmann, Thomas E; Okigami, Hiromi; Tajimi, Masaomi; Bacon, Kevin; Rölle, Thomas



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.  


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



Discovery of phenoxybutanoic acid derivatives as potent endothelin antagonists with antihypertensive activity.  


A series of phenoxybutanoic acid derivatives were synthesized and tested for their antagonistic activity on the contraction of the rat thoracic aortic ring induced by endothelin-1. Preliminary screening results showed that 6e and 6g with benzoheterocycles demonstrated significant antagonistic activities when compared to the reference compound BQ123. The results from additional assays for the binding affinity and selectivity for endothelin receptors showed that 6e was a selective ETA antagonist with a nanomolar IC50. Moreover, 6e was effective in relieving hypoxia-induced pulmonary arterial hypertension and right ventricular weight ratio. Therefore, 6e may have potential for further development as a therapeutic agent for the treatment of cardiovascular diseases. PMID:25614116

Cai, Jin; Liu, Ligang; Hong, Kwon Ho; Wang, Peng; Li, Lushen; Cao, Meng; Sun, Chunlong; Wu, Xiaoqing; Zong, Xi; Chen, Junqing; Ji, Min



Plasma reduced folates, reproductive performance, and conceptus development in sows in response to supplementation with oxidized and reduced sources of folic acid.  


The study was conducted to determine the response of sows to oxidized and reduced forms of supplemental folic acid in the diet. Gilts were mated and fed a standard corn-soybean meal diet with no supplemental folic acid. On d 105 of gestation, gilts were randomly assigned to one of four dietary treatments for the remainder of the study. Treatments were: 1) diet with no supplemental folate (control), 2) diet with 2.1 ppm (calculated) of added folate supplied by a synthetic pteroylmonoglutamate form (MG), 3) diet with 2.1 ppm (calculated) of added folate supplied by N5-formyl-5,6,7,8-tetrahydrofolic acid (THFA), or 4) a commercial bacterial cell powder source (Aj-PG) rich in reduced folates. Blood samples for high-performance liquid chromotography determination of reduced plasma folates were collected from gilts on d 105 of gestation, at weaning, at mating, and when the females were slaughtered on d 45 after mating for the second parity. There were 19, 18, 18, and 22 sows for the control, MG, THFA, and Aj-PG treatments, respectively. Supplementing folacin just before farrowing and during lactation had no effect on sow and litter performance during parity 1 (P > 0.10). Live fetuses at d 45 of gestation in Parity 2 were 10.06, 12.23, 10.87, and 11.07 for the control, MG, THFA, and Aj-PG treatments, respectively, and did not differ (P > 0.10). Fetal survival and placental size and protein content were generally unaffected by folate treatment. Concentration of reduced folates in sow plasma was 13.50, 13.58, 22.50, and 17.79 nM at weaning and 12.55, 19.29, 18.96, and 21.88 nM at mating for the control, MG, THFA, and Aj-PG treatments, respectively, with the THFA treatment elevated above the controls at weaning (P < 0.05) and the Aj-PG treatment greater than controls at mating (P < 0.05). At weaning, the reduced sources of supplemental folate (THFA and Aj-PG) were more effective in elevating plasma reduced folates than the oxidized folate supplement (MG; P < 0.05). Nonetheless, folate supplementation did not significantly improve sow reproductive performance in the subsequent parity, and there was no indication that reduced folate sources were superior to the oxidized pteroylmonoglutamate form as folate supplements for sows. PMID:12661654

Harper, A F; Knight, J W; Kokue, E; Usry, J L



Voluntary food fortification with folic acid in Spain: predicted contribution to children's dietary intakes as assessed with new food folate composition data.  


The Spanish market offers a significant number of folic acid (FA) voluntarily fortified foods. We analysed FA and (6S)-5-methyltetrahydrofolic acid ((6S)-5-CH3-H4PteGlu) content in ready-to-eat cereals (RTEC) (n=68) and cow's milk (n=25) by a previously validated affinity chromatography-HPLC method. Contribution to potential FA intakes for children aged 2-13years, was assessed using food consumption data from a representative nationwide study, folate Recommended Dietary Intakes (RDI), and Upper Levels (UL). Results showed that at all food fortification levels obtained, fortified products provided more than tenfold FA than (6S)-5-CH3-H4PteGlu. For RTEC, the high fortification level provided 6-21%, per serving, of RDI and ?32% of ULs at 90th percentile of RTEC consumption (P90). Milk products fortified at the higher level reached on average 54-136% of RDI per serving and only exceeded UL at P90 of milk consumption in children aged 2-5years. PMID:23601402

Samaniego-Vaesken, M L; Alonso-Aperte, E; Varela-Moreiras, G



Factors associated with prenatal folic acid and iron supplementation among 21,889 pregnant women in Northern Tanzania: A cross-sectional hospital-based study  

PubMed Central

Background Folate and iron deficiency during pregnancy are risk factors for anaemia, preterm delivery, and low birth weight, and may contribute to poor neonatal health and increased maternal mortality. The World Health Organization recommends supplementation of folic acid (FA) and iron for all pregnant women at risk of malnutrition to prevent anaemia. We assessed the use of prenatal folic acid and iron supplementation among women in a geographical area with a high prevalence of anaemia, in relation to socio-demographic, morbidity and health services utilization factors. Methods We analysed a cohort of 21,889 women who delivered at Kilimanjaro Christian Medical Centre (KCMC), Moshi, Tanzania, between 1999 and 2008. Logistic regression models were used to describe patterns of reported intake of prenatal FA and iron supplements. Results Prenatal intake of FA and iron supplements was reported by 17.2% and 22.3% of pregnant women, respectively. Sixteen percent of women reported intake of both FA and iron. Factors positively associated with FA supplementation were advanced maternal age (OR?=?1.17, 1.02-1.34), unknown HIV status (OR?=?1.54, 1.42-1.67), a diagnosis of anaemia during pregnancy (OR?=?12.03, 9.66-14.98) and indicators of lower socioeconomic status. Women were less likely to take these supplements if they reported having had a malaria episode before (OR?=?0.57, 0.53-0.62) or during pregnancy (OR?=?0.45, 0.41-0.51), reported having contracted other infectious diseases (OR?=?0.45, 0.42-0.49), were multiparous (OR?=?0.73, 0.66-0.80), had preeclampsia/eclampsia (OR?=?0.48, 0.38-0.61), or other diseases (OR?=?0.55, 0.44-0.69) during pregnancy. Similar patterns of association emerged when iron supplementation alone and supplementation with both iron and FA were evaluated. Conclusions FA and iron supplementation are low among pregnant women in Northern Tanzania, in particular among women with co-morbidities before or during pregnancy. Attempts should be made to increase supplementation both in general and among women with pregnancy complications. PMID:22734580



Microarray analysis reveals higher gestational folic Acid alters expression of genes in the cerebellum of mice offspring-a pilot study.  


Folate is a water-soluble vitamin that is critical for nucleotide synthesis and can modulate methylation of DNA by altering one-carbon metabolism. Previous studies have shown that folate status during pregnancy is associated with various congenital defects including the risk of aberrant neural tube closure. Maternal exposure to a methyl supplemented diet also can alter DNA methylation and gene expression, which may influence the phenotype of offspring. We investigated if higher gestational folic acid (FA) in the diet dysregulates the expression of genes in the cerebellum of offspring in C57BL/6 J mice. One week before gestation and throughout the pregnancy, groups of dams were supplemented with FA either at 2 mg/kg or 20 mg/kg of diet. Microarray analysis was used to investigate the genome wide gene expression profile in the cerebellum from day old pups. Our results revealed that exposure to the higher dose FA diet during gestation dysregulated expression of several genes in the cerebellum of both male and female pups. Several transcription factors, imprinted genes, neuro-developmental genes and genes associated with autism spectrum disorder exhibited altered expression levels. These findings suggest that higher gestational FA potentially dysregulates gene expression in the offspring brain and such changes may adversely alter fetal programming and overall brain development. PMID:25629700

Barua, Subit; Kuizon, Salomon; Chadman, Kathryn K; Brown, W Ted; Junaid, Mohammed A



Targeting delivery of etoposide to inhibit the growth of human glioblastoma multiforme using lactoferrin- and folic acid-grafted poly(lactide-co-glycolide) nanoparticles.  


Lactoferrin (Lf) and folic acid (FA) were crosslinked on poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) for transporting etoposide across the blood-brain barrier (BBB) and treating human brain malignant glioblastoma. Lf- and FA-grafted PLGA NPs (Lf/FA/PLGA NPs) were employed to permeate the monolayer of human brain-microvascular endothelial cells (HBMECs) regulated by human astrocytes and to inhibit the multiplication of U87MG cells. Lf/FA/PLGA NPs showed a satisfactory entrapment efficiency of etoposide and characteristics of sustained drug release. When compared with PLGA NPs, the permeability coefficient for etoposide across the BBB using Lf/FA/PLGA NPs increased about twofold. The antiproliferative efficacy against the growth of U87MG cells was in the following order: Lf/FA/PLGA NPs>FA/PLGA NPs>PLGA NPs>free etoposide solution. In addition, the targeting ability of Lf/FA/PLGA NPs was evidenced by immunostaining of Lf receptor on HBMECs and folate receptor on U87MG cells during endocytosis. Lf/FA/PLGA NPs with loaded etoposide can be a promising anticancer pharmacotherapy to enhance the delivery of etoposide to malignant brain tumors for preclinical trials. PMID:25560309

Kuo, Yung-Chih; Chen, Yu-Chun



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


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



Potential antagonistic effects of nine natural fatty acids against Meloidogyne incognita.  


Fatty acids, the essential components of life, were widely present in various seed cakes, gutter oil, and other resources. The objective of this study was to evaluate the potential antagonistic effects of nine fatty acids (FAs) against Meloidogyne incognita (root-knot nematodes). The results showed that butyric, caprylic, capric, lauric, myristic, palmitic, and oleic acids significantly reduced M. incognita reproduction, whereas cucumber (Cucumus sativus) biomass was not adversely affected by the tested FAs and was even significantly increased in several fatty acids treatments. All nine tested fatty acids showed apparent inhibitory effects on egg hatching on day 21, especially capric acid with which the hatching rate was reduced to 15.8% as compared to that using sterile distilled water. Caproic, caprylic, capric, lauric, myristic, and palmitic acids caused significantly higher mortality of the second-stage juvenile of M. incognita than the other three FAs, and both caprylic and capric acids resulted in approximately 50% mortality (2000 ?mol/L) after a 24 h exposure. In conclusion, fatty acids showed the nematicidal effect differently, among which capric acid showed a strong nematicidal effect and might be a powerful active substance for integrated M. incognita management. Given the general nematicidal properties of FAs, farmers might utilize waste resources, such as oil seed cake, gutter oil, etc., containing various FAs or use pure FAs for effective M. incognita management. PMID:23121218

Zhang, Wei-pu; Ruan, Wei-bin; Deng, Yun-ying; Gao, Yu-bao



Oral Administration of a Retinoic Acid Receptor Antagonist Reversibly Inhibits Spermatogenesis in Mice  

PubMed Central

Here we investigated a pharmacological approach to inhibit spermatogenesis in the mouse model by manipulating retinoid signaling using low doses of the pan-retinoic acid receptor (RAR) antagonist BMS-189453. Spermatogenesis was disrupted, with a failure of spermatid alignment and sperm release and loss of germ cells into lumen, abnormalities that resembled those in vitamin A-deficient and RAR?-knockout testes. Importantly, the induced sterility was reversible. Enhanced efficacy and a lengthened infertility period with full recovery of spermatogenesis were observed using systematically modified dosing regimens. Hematology, serum chemistry, and hormonal and pathological evaluations revealed no detectable abnormalities or adverse side effects except the distinct testicular pathology. Our results suggest that testes are exquisitely sensitive to disruption of retinoid signaling and that RAR antagonists may represent new lead molecules in developing nonsteroidal male contraceptives. PMID:21505053

Chung, Sanny S. W.; Wang, Xiangyuan; Roberts, Shelby S.; Griffey, Stephen M.; Reczek, Peter R.



PAF antagonistic activity of 2-hydroxy-3-methoxybenzoic acid glucose ester from Gentiana scabra.  


In order to find out anti-platelet activating factor (PAF) from natural resources, Korean medicinal plants used for the treatments of peripheral circulation disorders were tested for their possible protective effects on PAF-induced anaphylactic shock. From the above screening, the methanol extract of Gentiana scabra showed a potent antagonistic activity against PAF. Water suspension of the extract was partitioned with CH2Cl2 and EtOAc, successively. The EtOAc fraction which showed the highest activity was chromatographed on silica gel to yield 6 fractions. From the fraction which showed higher PAF-antagonistic activity than the other fractions, compound 1 was isolated by recrystallization. On the basis of spectral data, compound 1 was identified as 2-hydroxy-3-methoxybenzoic acid glucose ester. The compound prevented the mice from the PAF-induced death at a dose of 300 micrograms/mouse. PMID:9875472

Huh, H; Kim, H K; Lee, H K



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


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



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.  


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



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



Mechanistic Insights into Folic Acid-dependent Vascular Protection: Dihydrofolate reductase-mediated Reduction in Oxidant Stress in Endothelial Cells and Angiotensin II-Infused Mice  

PubMed Central

Background Folate supplementation improves endothelial function in patients with hyperhomocysteinemia. Mechanistic insights into potential benefits of folate on vascular function in general population however, remain mysterious. Methods and Results Expression of dihydrofolate reductase (DHFR) was markedly increased by folic acid (FA, 50 µmol/L, 24 hr) treatment in endothelial cells. Tetrahydrofolate (THF) is formed after incubation of purified DHFR or cellular extracts with 50 µmol/L of substrate dihydrofolic acid. THF could then be detected and quantified by high performance liquid chromatography (HPLC) with a fluorescent detector (295/365 nm). Using this novel and sensitive assay, we found that DHFR activity was significantly increased by FA. Furthermore, FA improved redox status of Ang II treated cells by increasing H4B and NO• bioavailability while decreasing superoxide (O2•?) production. It however failed to restore NO• levels in DHFR siRNA-transfected or methotrexate pre-treated cells, implicating a specific and intermediate role of DHFR. In mice orally administrated with FA (15 mg/kg/day, 16 days), endothelium upregulation of DHFR expression and activity occurred in correspondence to improved NO• and H4B bioavailability, and this was highly effective in reducing Ang II infusion (0.7 mg/kg/day, 14 days)-stimulated aortic O2•? production. 5’-methyltetrahydrofolate (5’-MTHF levels, GTPCH1 expression and activity remained unchanged in response to FA or Ang II treatment in vitro and in vivo. Conclusions FA supplementation improves endothelial NO• bioavailability via upregulation of DHFR expression and activity, and protects endothelial cells from Ang II-provoked oxidant stress both in vitro and in vivo. These observations likely represent a novel mechanism (intermediate role of DHFR) whereby FA induces vascular protection. PMID:19660467

Gao, Ling; Chalupsky, Karel; Stefani, Enrico; Cai, Hua



Determination of the binding mode and interacting amino-acids for dibasic H3 receptor antagonists.  


Due to its involvement in major CNS functions, the histamine H3 receptor (H3R) is the subject of intensive medicinal chemistry investigation, supported by the range of modern drug discovery tools, such as receptor modeling and ligand docking. Although the receptor models described to date share a majority of common traits, they display discrete alternatives in amino-acid conformation, rendering ligand binding modes quite different. Such variations impede structure-based drug design in the H3R field. In the present study, we used a combination of medicinal chemistry, receptor-guided and ligand-based methods to elucidate the binding mode of antagonists. The approaches converged towards a ligand orientation perpendicular to the membrane plane, bridging Glu206 of the transmembrane helix 5 to acidic amino acids of the extracellular loops. This consensus will help future structure-based drug design for H3R ligands. PMID:23787288

Levoin, Nicolas; Labeeuw, Olivier; Krief, Stéphane; Calmels, Thierry; Poupardin-Olivier, Olivia; Berrebi-Bertrand, Isabelle; Lecomte, Jeanne-Marie; Schwartz, Jean-Charles; Capet, Marc



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 Central

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?-(CF3)2-Bn], 20 [Ac-Aba-Gly-NMe-3?,5?-(CF3)2-Bn] and 23 [Ac-Tic-NMe-3?,5?-(CF3)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?-(CF3)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?-(CF3)2-Bn], which combines the N-terminus of the established Dmt1-DALDA agonist opioid pharmacophore (H-Dmt-D-Arg-Phe-Lys-NH2) and 20, the NK1R ligand. The opioid component of the chimeric compound 35, i.e. Dmt-D-Arg-Aba-Gly-NH2 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.; Broeck, Jozef Vanden; Tourwé, Dirk



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



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


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



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



Cardioprotective efficacy depends critically on pharmacological dose, duration of ischaemia, health status of animals and choice of anaesthetic regimen: a case study with folic acid.  


BackgroundAcute, high-dose folic acid (FA) administration has recently been shown to possess unprecedented effective cardioprotection against ischaemia/reperfusion (I/R) injury. Here we explore the translation potential of FA as treatment modality for cardiac I/R.MethodsDependency of FA protection on dose, ischaemia duration, and eNOS was examined in an isolated mouse heart I/R model, whereas dependency on animal health status and anaesthesia was examined in an in vivo rat model of regional cardiac I/R.Results50 ¿M FA provided maximal reduction (by 95%) of I/R-induced cell death following 25 min ischaemia in isolated wild-type hearts, with protection associated with increased coupled eNOS protein. No protection was observed with 35 min I or in eNOS¿/¿ hearts. Acute intravenous administration of FA during a 25 min ischaemic period reduced infarct size by 45% in in vivo pentobarbital-anaesthetised young, healthy rats. FA did not reduce infarct size in aged or pre-diabetic rats, although it did preserve hemodynamics in the pre-diabetic rats. Finally, using a clinically-relevant anaesthetic regimen of fentanyl-propofol anaesthesia, FA treatment was ineffective in young, aged and pre-diabetic animals.ConclusionsThe protective potential of an initially promising cardioprotective treatment of high dose FA against cardiac I/R infarction, is critically dependent on experimental conditions with relevance to the clinical condition. Our data indicates the necessity of expanded pre-clinical testing of cardioprotective interventions before embarking on clinical testing, in order to prevent too many ¿lost-in-translation¿ drugs and unnecessary clinical studies. PMID:25432364

Zuurbier, Coert J; Heinen, Andre; Koeman, Anneke; Stuifbergen, Roy; Hakvoort, Theodorus; Weber, Nina C; Hollmann, Markus W



Multifunctional core/shell nanoparticles cross-linked polyetherimide-folic acid as efficient Notch-1 siRNA carrier for targeted killing of breast cancer.  


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



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.



Antenatal iron/folic acid supplements, but not postnatal care, prevents neonatal deaths in Indonesia: analysis of Indonesia Demographic and Health Surveys 2002/2003–2007 (a retrospective cohort study)  

PubMed Central

Objective This study aimed to assess the contribution of postnatal services to the risk of neonatal mortality, and the relative contributions of antenatal iron/folic acid supplements and postnatal care in preventing neonatal mortality in Indonesia. Design Retrospective cohort study. Setting and participants Data used in this study were the 2002–2007 Indonesia Demographic and Health Surveys, nationally representative surveys. The pooled data provided survival information of 26?591 most recent live-born infants within the 5-years prior to each interview. Primary outcomes Primary outcomes were early neonatal mortality, that is, deaths in the first week, and all neonatal mortality, that is, deaths in the first month of life. Exposures were antenatal iron/folic acid supplementation and postnatal care from days 1 to 7. Potential confounders were community, socio-economic status and birthing characteristics and perinatal healthcare. Cox regression was used to assess the association between study factors and neonatal mortality. Results Postnatal care services were not associated with newborn survival. Postnatal care on days 1–7 after birth did not reduce neonatal death (HR=1.00, 95% CI 0.55 to 1.83, p=1.00) and early postnatal care on day 1 was associated with an increased risk of early neonatal death (HR=1.27, 95% CI 0.69 to 2.32, p=0.44) possibly reflecting referral of ill newborns. Early postnatal care on day 1 was not protective for neonatal deaths on days 2–7 whether provided by doctors (HR 3.61, 95% CI 1.54 to 8.45, p<0.01), or by midwives or nurses (HR 1.38, 95% CI 0.53 to 3.57, p=0.512). In mothers who took iron/folic acid supplements during pregnancy, the risk of early neonatal death was reduced by 51% (HR=0.49, 95% CI 0.30 to 0.79, p<0.01). Conclusions We found no protective effect of postnatal care against neonatal deaths in Indonesia. However, important reductions in the risk of neonatal death were found for women who reported use of antenatal iron/folic acid supplements during pregnancy. PMID:23117564

Titaley, Christiana Rialine; Dibley, Michael John



A Functionalized Congener Approach to Adenosine Receptor Antagonists: Amino Acid Conjugates of 1,3-Dipropylxanthine  

PubMed Central

SUMMARY 1,3-Dipropyl-8-phenylxanthine, a synthetic analog of theophylline and a potent antagonist of adenosine at A1 and A2-adenosine receptors, has been attached covalently through a functionalized chain to amino acids and oligopeptides. The xanthine conjugates have been studied as competitive inhibitors of the specific binding of [3H]N6-cyclohexyladenosine to A1-receptors of rat cerebral cortical membranes and for inhibition of cyclic AMP accumulation elicited by 2-chloroadenosine in guinea pig brain slices through A2-receptors. A free amino group on the extended chain generally resulted in high potency at A1-receptors. The potency (in some cases extending into the subnanomolar range) and selectivity for A1-receptors (up to 200-fold) suggest that this approach can yield a versatile class of “functionalized congeners” of adenosine receptor antagonists in which distal modifications of the attached moiety (“carrier”) can serve also to improve pharmacodynamic and pharmacokinetic parameters. The water solubility in many of the more potent analogs has been enhanced by two orders of magnitude over that of simple, uncharged 8-phenyl xanthine derivatives. Analogs in which the carrier contains d-tyrosine have potential for development of iodinated radioligands for adenosine receptors. The functionalized congener approach is potentially applicable to other drugs and for development of prodrugs. PMID:3005825




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

E-print Network

low, rang1ng from O-B~, with an average of 2~ 1n each group. fh 1 t r 1:t1 hf f tt, m1h ~mm. ~m:, 1, ~lt. e f*11. 1d 1. . t1 tr1&. te f t)e ~1 ht k. ". h* vita", in By; & was addod to the diet, the aver'. tge We1ght of the birds w, . s incre... acid (2 mg/kg) was added to the diets of the last four groups. At the end of the 10-week experimental period, 6 repre- sentative birds from each group were killed and the livers and kidneys removed for the purpose of running microbiological assays...

Welch, Billy E



Effect of the Folic Acid Analogue, Trimethoprim, on Growth, Macromolecular Synthesis, and Incorporation of Exogenous Thymine in Escherichia coli1  

PubMed Central

The effect of trimethoprim [2,4-diamino-5(2?,4?,5?trimethoxybenzyl)-pyrimidine] in the presence of thymine on Escherichia coli B temperature-sensitive and non-temperature-sensitive Thy? strains and a phosphodeoxyribomutase-negative mutant was studied. The inhibitory effect of 5 ?g of trimethoprim per ml on the growth of E. coli B was not overcome by thymine, thymidine, or thymidylate even in the presence of one-carbon metabolites and related metabolites. Deoxyribonucleic acid (DNA) and protein synthesis were more severely inhibited than ribonucleic acid (RNA) synthesis. The inhibition of DNA synthesis was partially reversed by addition of deoxyadenosine to increase the incorporation of exogenous thymine. By contrast, the inhibition of protein was not reversed even with one-carbon metabolites present, in keeping with the requirement for formylmethionyl-transfer RNAF for initiation. However, the inhibition of both DNA and protein synthesis in a phosphodeoxyribomutase-negative strain by 1 ?g of trimethoprim per ml with thymine present was partially reversed by deoxyadenosine and one-carbon metabolites, and nearly normal growth occurred. 5-Fluorodeoxyuridine added at the time of addition of trimethoprim prevented the inhibition. Sulfadiazine in the presence of thymine inhibited both Thy+ and Thy? strains whereas trimethoprim (with thymine) did not inhibit Thy? organisms. The effect of trimethoprim on the incorporation of labeled thymine into DNA was also studied. These experiments support the concept that trimethoprim in conjunction with the action of thymidylate synthetase inhibits the growth of Thy+ cells because of a depletion of tetrahydrofolate. DNA synthesis is inhibited initially by a limitation of thymine nucleotide precursor, resulting from the indirect inhibition of thymidylate synthetase and the poor incorporation of exogenous thymine. PMID:4260561

Dale, Beverly A.; Greenberg, G. Robert



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: [The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel)



Reversal of the action of amino acid antagonists by barbiturates and other hypnotic drugs  

PubMed Central

1 The effects of pentobarbitone (PB) and other sedative/hypnotic drugs have been examined in relation to ?-aminobutyric acid (GABA) in vitro on the superfused isolated superior cervical ganglion of the rat and in vivo on single units in the brain stem of the anaesthetized rat. 2 PB, and other barbiturates, depolarized the ganglion in a dose-dependent manner (threshold concentration 100-300 ?M, cf. GABA depolarization threshold 1 ?M). The depolarization was reduced in the presence of the selective GABA antagonist (+)-bicuculline methochloride (Bic). Other non-barbiturate sedatives e.g. chlordiazepoxide, amitriptyline, promethazine at concentrations up to 2mM produced no depolarization. 3 PB, tested at concentrations up to 80 ?M, produced variable effects on the dose-response curve to GABA. On most occasions a slight potentiation occurred in responses to low concentrations of GABA (below 10 ?M) coupled with a depression in the responses to concentrations of GABA greater than 10 ?M. 4 Superfusion with PB in the presence of Bic reversed the depression in the response to GABA produced by Bic. This reversal phenomenon occurred at concentrations of PB too low to depolarize the ganglion and was dependent not only on the concentration of PB but also on that of Bic. 5 The reversal potency within an homologous series of barbiturates increased with the size of the alkyl substituent (R2) at C5 on the barbiturate ring. The most potent occurred when the substituent contained 5 carbon atoms (pentobarbitone and amylobarbitone); above this, activity decreased. 6 PB reversed the effects of the other GABA antagonists, tetramethylenedisulphotetramine and isopropyl bicyclophosphate and also the non-selective antagonism produced by strychnine. A concomitant reduction by strychnine of responses to the cholinomimetic, carbachol, was not reversed by PB. 7 Non-barbiturate sedative/hypnotics also reversed the GABA antagonism produced by Bic. The benzodiazepines were effective at lower concentrations than PB (chlordiazepoxide threshold concentration 0.5 ?M, cf. PB 5 ?M), however, they only produced a partial reversal even at concentrations much higher than the maximally effective concentration of PB. 8 The Bic reversal effect of chloridazepoxide (and other benzodiazepines) lasted many hours after removal from the superfusion solution. By contrast the effect of PB lasted only 15-30 min after its removal. 9 Chlordiazepoxide (30 ?M) applied in the absence of Bic did not affect the response to GABA but did reduce the depression produced by the subsequent application of Bic even though the chlordiazepoxide had been removed 40 min earlier. 10 In the rat brain stem in vivo PB, applied iontophoretically in amounts which neither decreased the spontaneous neuronal firing rate nor affected the response to GABA or glycine, reversed the GABA antagonism induced by iontophoretic application of Bic (in all 23 neurones tested). PB also reversed the antagonism produced by strychnine of responses to glycine although this was less readily observed (5 out of 14 neurones tested). 11 Iontophoretic application of other barbiturates and chlordiazepoxide also reversed the effect of Bic. Chlordiazepoxide only produced a partial reversal, as in the isolated ganglion, and no reversal could be demonstrated with flurazepam. 12 Intravenous administration of thiopentone (1.3 mg/kg) pentobarbitone (0.4-5.5 mg/kg) hexobarbitone (0.4-0.8 mg/kg) and clonazepam (0.1-0.2 mg/kg) also reversed the effect of iontophoretically applied Bic. The reversal by clonazepam was of much longer duration than that produced by the barbiturates. 13 It is suggested that the reversal exhibited by PB and the other hypnotics may be explained by assuming that the amino acids and their antagonists bind to the membrane at separate sites. If the reversal agent has particular affinity only for the antagonist binding site then it may displace the antagonist without affecting the receptor. PMID:206305

Bowery, N. G.; Dray, A.



The utility of excitatory amino acid (EAA) antagonists as analgesic agents. I. Comparison of the antinociceptive activity of various classes of EAA antagonists in mechanical, thermal and chemical nociceptive tests.  


The present study was performed to assess the utility of excitatory amino acid (EAA) antagonists as analgesia agents. The antinociceptive activity of various classes of EAA antagonists was assessed in mechanical and thermal flexion reflexes tests, as well as in the formalin test. Additional testing assessed the motor dysfunction associated with antinociceptive dose levels of the agents used, by examining placing, grasping and righting reflexes, as well as occurrences of balance loss during locomotion. No antinociceptive activity was observed on any of the nociceptive measures for the non-NMDA receptor antagonists CNQX or L-AP-3. High doses of the non-competitive (PCP-site) NMDA receptor antagonist MK-801 and the allosteric-glycine receptor antagonist 7-CKA produced antinociception on both the mechanical and thermal flexion reflex measures, while a high dose of the competitive NMDA receptor antagonist CPP produced antinociception only on the thermal flexion reflex measure. Hyperalgesic effects on thermal flexion reflexes were obtained with all doses of the polyamine receptor antagonist ARCA, and with the highest dose of the allosteric-glycine receptor antagonist FICA. Formalin nociceptive behaviours were significantly reduced only by high doses of competitive (APV) and non-competitive (MK-801) NMDA receptor antagonists. The doses of EAA receptor antagonists which produced antinociceptive effects on any of the 3 nociceptive tests also produced evidence of motor dysfunction. Both competitive NMDA receptor antagonists (APV and CPP) produced disruptions of placing, grasping and righting reflexes, while 2 of the allosteric-glycine receptor antagonists (7-CKA and DCQX) significantly disrupted placing and righting reflexes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7708408

Coderre, T J; Van Empel, I



Proteome approach to characterize proteins induced by antagonist yeast and salicylic acid in peach fruit.  


Proteins induced by antagonist yeast Pichia membranefaciens and salicylic acid (SA) in peach fruit were determined using proteome analysis in this study. Both the yeast and SA enhanced the resistance of peach fruit and delayed the initiation infection of Penicillium expansum. When quadrupole time-of-flight tandem mass spectrometer was used, a total of 25 proteins could be identified as significantly up- or down-regulated in response to at least one activitor. According to the function, these proteins were attributed to protein metabolism, defense response, transcription, energy metabolism, and cell structure. Among them, 6 antioxidant and 3 pathogenesis-related (PR) proteins were induced by P. membranefaciens or SA treatments. The induction results of these proteins were related to treatment time. Six other proteins were identified as the enzymes which catalyze the reactions of glycolysis and tricarboxylic acid cycle. In addition, both the yeast and SA treatments enhanced the transcript and translation expression of the catalase gene. These results suggested that antioxidant and PR proteins, as well as enzymes associated with sugar metabolism, were involved in resistance of peach fruit induced by P. membranefaciens and SA. PMID:17381148

Chan, Zhulong; Qin, Guozheng; Xu, Xiangbin; Li, Boqiang; Tian, Shiping



An unblinded, randomised phase II study of platinum-based chemotherapy with vitamin B12 and folic acid supplementation in the treatment of lung cancer with plasma homocysteine blood levels as a biomarker of severe neutropenic toxicity  

PubMed Central

Background Vitamin B12 and folic acid (referred to as vitamin supplementation) improves the toxicity profile of pemetrexed containing regimens. Low baseline vitamin B12 and folate levels are reflected in a raised total homocysteine level (HC). Studies have suggested that pretreatment HC levels predict neutropenia toxicity. We have tested supplementation with vitamin B12 and folate in non-pemetrexed platinum-based regimens to decrease treatment-related toxicity and looked for a correlation between toxicity and change in homocysteine levels. Patient and method Eighty-three patients with advanced lung cancer and malignant mesothelioma were randomly assigned to receive platinum-based chemotherapy with (arm A) or without (arm B) vitamin B12 and folic acid supplementation. The primary end point was grade 3/4 neutropenia and death within 30?days of treatment. Secondary end points included quality of life, overall survival (OS) and the relationship between baseline and post supplementation HC levels and toxicity. Results In the intention-to-treat population, no significant difference was seen between the two groups with respect to chemotherapy-induced grade 3/4 neutropenia and death within 30?days of chemotherapy (36% vs 37%; p=0.966, emesis (2% vs 6%; p=0.9) or OS (12.3?months vs 7?months; p=0.41). There was no significant difference in survival rates by baseline HC level (p=0.9). Decrease in HC with vitamin supplementation was less frequent than expected. High baseline HC levels decreased with vitamin supplementation in only 9/36 (25%) patients (successful supplementation). Post hoc analysis showed that patients in arm A who were successfully supplemented (9/36=25%) had less neutropenic toxicity (0% vs 69%; p=0.02) compared to unsupplemented patients. Conclusions The addition of vitamin B12 and folic acid to platinum-containing regimens did not overall improve the toxicity, quality of life or OS. Rates of grade 3/4 neutropenia at 36/37% was as predicted. Further studies to increase the rate of successful supplementation and to further test the biomarker potential of post supplementation HC levels in predicting chemotherapy-induced neutropenia in platinum-based chemotherapy are warranted. Trial registration number: EudracCT 2005-002736-10 ISRCTN8734355. PMID:25553247

Minchom, A R; Saksornchai, K; Bhosle, J; Gunapala, R; Puglisi, M; Lu, S K; Nimako, K; Coward, J; Yu, K C; Bordi, P; Popat, S; O'Brien, M E R



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

Microsoft Academic Search

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

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


Characterisation and biological activity of Glu3 amino acid substituted GIP receptor antagonists.  


Glucose-dependent insulinotropic polypeptide (GIP) is an important gastrointestinal hormone, which regulates insulin release and glucose homeostasis, but is rapidly inactivated by enzymatic N-terminal truncation. Here we report the enzyme resistance and biological activity of several Glu(3)-substituted analogues of GIP namely; (Ala(3))GIP, (Lys(3))GIP, (Phe(3))GIP, (Trp(3))GIP and (Tyr(3))GIP. Only (Lys(3))GIP demonstrated moderately enhanced resistance to DPP-IV (p<0.05 to p<0.01) compared to native GIP. All analogues demonstrated a decreased potency in cAMP production (EC(50) 1.47 to 11.02 nM; p<0.01 to p<0.001) with (Lys(3))GIP and (Phe(3))GIP significantly inhibiting GIP-stimulated cAMP production (p<0.05). In BRIN-BD11 cells, (Lys(3))GIP, (Phe(3))GIP, (Trp(3))GIP and (Tyr(3))GIP did not stimulate insulin secretion with both (Lys(3))GIP and (Phe(3))GIP significantly inhibiting GIP-stimulated insulin secretion (p<0.05). Injection of each GIP analogue together with glucose in ob/ob mice significantly increased the glycaemic excursion compared to control (p<0.05 to p<0.001). This was associated with lack of significant insulin responses. (Ala(3))GIP, (Phe(3))GIP and (Tyr(3))GIP, when administered together with GIP, significantly reduced plasma insulin (p<0.05 to p<0.01) and impaired the glucose-lowering ability (p<0.05 to p<0.01) of the native peptide. The DPP-IV resistance and GIP antagonism observed were similar but less pronounced than (Pro(3))GIP. These data demonstrate that position 3 amino acid substitution of GIP with (Ala(3)), (Phe(3)), (Tyr(3)) or (Pro(3)) provides a new class of functional GIP receptor antagonists. PMID:17428436

Gault, Victor A; Hunter, Kerry; Irwin, Nigel; Green, Brian D; Greer, Brett; Harriott, Patrick; O'Harte, Finbarr P M; Flatt, Peter R



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.  


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 r (2) 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

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



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



Poly(l-lysine)-graft-folic acid-coupled poly(2-methyl-2-oxazoline) (PLL-g-PMOXA-c-FA): A Bioactive Copolymer for Specific Targeting to Folate Receptor-Positive Cancer Cells.  


In this study, we present the preparation, characterization and application of a novel bioactive copolymer poly(l-lysine)-graft-folic acid-coupled poly(2-methyl-2-oxazoline) (PLL-g-PMOXA-c-FA), which has a specific interaction with folate receptor (FR)-positive cancer cells. Glass surface immobilized with PLL-g-PMOXA-c-FA was demonstrated to be adhesive to FR-positive cancer cells (HeLa, JEG-3) while nonadhesive to FR-negative ones (MCF-7, HepG2) in 3 h. The specific interaction between conjugated FA on the substrate and FRs on the cells could hardly be inhibited unless a high concentration (5 mM) of free FA was used due to the multivalent nature of it. The FA functionality ratio of the copolymer on the substrate had a significant influence on the adhesion of HeLa cells, and our experiments revealed that the affinity of the substrate to the cells declined dramatically with the decrease of functionality ratio. This was believed to be caused by the polydispersity of PMOXA tethers, as supported by GPC and ToF-SIMS data. As a proof of concept in the application of our material, we demonstrated successful recovery of HeLa cells from mixture with MCF-7 (1:100) on the copolymer-coated glass, and our results showed that both high sensitivity (95.6 ± 13.3%) and specificity (24.3 ± 8.6%) were achieved. PMID:25581478

Chen, Yin; Cao, Wenbin; Zhou, Junli; Pidhatika, Bidhari; Xiong, Bin; Huang, Lu; Tian, Qian; Shu, Yiwei; Wen, Weijia; Hsing, I-Ming; Wu, Hongkai



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



Discovery of novel non-carboxylic acid 5-amino-4-cyanopyrazole derivatives as potent and highly selective LPA1R antagonists.  


High throughput screening (HTS) of our chemical library identified 3-alkylamino-2-aryl-5H-imidazo[1,2,b]pyrazol-7-carbonitrile 1 as a potent antagonist of the LPA1 receptor (LPA1R). Further evaluation of this class of compounds indicated that LPA1R antagonist activity originated from the degradation of the parent molecule in DMSO during the assay conditions. Here, we describe the isolation and characterization of the degradation products and their LPA1R antagonist activity. We further profiled these novel non-carboxylic acid LPA1R antagonists and demonstrated their inhibition of LPA-induced proliferation and contraction of normal human lung fibroblasts (NHLF). PMID:25155385

Sidduri, Achyutharao; Budd, David C; Fuentes, Maria E; Lambros, Ted; Ren, Yonglin; Roongta, Vikram; Schoenfeld, Ryan C; Gillespie, Paul; Stevenson, Christopher S; Truitt, Theresa; Qian, Yimin



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


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



Antagonistic Interaction between Systemic Acquired Resistance and the Abscisic Acid–Mediated Abiotic Stress Response in Arabidopsis[W  

PubMed Central

Systemic acquired resistance (SAR) is a potent innate immunity system in plants that is effective against a broad range of pathogens. SAR development in dicotyledonous plants, such as tobacco (Nicotiana tabacum) and Arabidopsis thaliana, is mediated by salicylic acid (SA). Here, using two types of SAR-inducing chemicals, 1,2-benzisothiazol-3(2H)-one1,1-dioxide and benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester, which act upstream and downstream of SA in the SAR signaling pathway, respectively, we show that treatment with abscisic acid (ABA) suppresses the induction of SAR in Arabidopsis. In an analysis using several mutants in combination with these chemicals, treatment with ABA suppressed SAR induction by inhibiting the pathway both upstream and downstream of SA, independently of the jasmonic acid/ethylene-mediated signaling pathway. Suppression of SAR induction by the NaCl-activated environmental stress response proved to be ABA dependent. Conversely, the activation of SAR suppressed the expression of ABA biosynthesis–related and ABA-responsive genes, in which the NPR1 protein or signaling downstream of NPR1 appears to contribute. Therefore, our data have revealed that antagonistic crosstalk occurs at multiple steps between the SA-mediated signaling of SAR induction and the ABA-mediated signaling of environmental stress responses. PMID:18586869

Yasuda, Michiko; Ishikawa, Atsushi; Jikumaru, Yusuke; Seki, Motoaki; Umezawa, Taishi; Asami, Tadao; Maruyama-Nakashita, Akiko; Kudo, Toshiaki; Shinozaki, Kazuo; Yoshida, Shigeo; Nakashita, Hideo



Dual effect of DL-homocysteine and S-adenosylhomocysteine on brain synthesis of the glutamate receptor antagonist, kynurenic acid.  


Increased serum level of homocysteine, a sulfur-containing amino acid, is considered a risk factor in vascular disorders and in dementias. The effect of homocysteine and metabolically related compounds on brain production of kynurenic acid (KYNA), an endogenous antagonist of glutamate ionotropic receptors, was studied. In rat cortical slices, DL-homocysteine enhanced (0.1-0.5 mM) or inhibited (concentration inducing 50% inhibition [IC50]=6.4 [5.5-7.5] mM) KYNA production. In vivo peripheral application of DL-homocysteine (1.3 mmol/kg intraperitoneally) increased KYNA content (pmol/g tissue) from 8.47 +/- 1.57 to 13.04 +/- 2.86 (P <0.01; 15 min) and 11.4 +/- 1.72 (P <0.01; 60 min) in cortex, and from 4.11 +/- 1.54 to 10.02 +/- 3.08 (P <0.01; 15 min) in rat hippocampus. High concentrations of DL-homocysteine (20 mM) applied via microdialysis probe decreased KYNA levels in rabbit hippocampus; this effect was antagonized partially by an antagonist of group I metabotropic glutamate receptors, LY367385. In vitro, S-adenosylhomocysteine acted similar to but more potently than DL-homocysteine, augmenting KYNA production at 0.03-0.08 mM and reducing it at > or =0.5 mM. The stimulatory effect of S-adenosylhomocysteine was abolished in the presence of the L-kynurenine uptake inhibitors L-leucine and L-phenyloalanine. Neither the N-methyl-D-aspartate (NMDA) antagonist CGS 19755 nor L-glycine influenced DL-homocysteine- and S-adenosylhomocysteine-induced changes of KYNA synthesis in vitro. DL-Homocysteine inhibited the activity of both KYNA biosynthetic enzymes, kynurenine aminotransferases (KATs) I and II, whereas S-adenosylhomocysteine reduced only the activity of KAT II. L-Methionine and L-cysteine, thiol-containing compounds metabolically related to homocysteine, acted only as weak inhibitors, reducing KYNA production in vitro and inhibiting the activity of KAT II (L-cysteine) or KAT I (L-methionine). The present data suggest that DL-homocysteine biphasically modulates KYNA synthesis. This seems to result from conversion of compound to S-adenosylhomocysteine, also acting dually on KYNA formation, and in part from the direct interaction of homocysteine with metabotropic glutamate receptors and KYNA biosynthetic enzymes. It seems probable that hyperhomocystemia-associated brain dysfunction is mediated partially by changes in brain KYNA level. PMID:15605380

Luchowska, E; Luchowski, P; Paczek, R; Ziembowicz, A; Kocki, T; Turski, W A; Wielosz, M; Lazarewicz, J; Urbanska, E M



Oxiracetam and d -pyroglutamic acid antagonize a disruption of passive avoidance behaviour induced by the N-methyl- d -aspartate receptor antagonist 2-amino-5-phosphonovalerate  

Microsoft Academic Search

Intracerebroventricular administration (6 µg\\/2 µl) ofd-2-amino-5-phosphonovalerate (AP-5), a specific antagonist of the NMDA receptors, prior to training impaired the passive avoidance\\u000a in a retention test in rat. Pretreatment with oxiracetam andd-pyroglutamic acid at doses ranging from 50 to 500 mg\\/kg SC dose-dependently prevented the disruptive effect of AP-5. This\\u000a finding indicates that an interaction with excitatory amino acid NMDA type

F. Paoli; G. Spignoli; G. Pepeu



Antagonistic Interaction between Systemic Acquired Resistance and the Abscisic Acid: Mediated Abiotic Stress Response in Arabidopsis  

Microsoft Academic Search

Systemic acquired resistance (SAR) is a potent innate immunity system in plants that is effective against a broad range of pathogens. SAR development in dicotyledonous plants, such as tobacco (Nicotiana tabacum) and Arabidopsis thaliana, is mediated by salicylic acid (SA). Here, using two types of SAR-inducing chemicals, 1,2-benzisothiazol-3(2H)-one1, 1-dioxide and benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester, which act upstream and downstrea of

Michiko Yasuda; Atsushi Ishikawa; Yusuke Jikumaru; Motoaki Seki; Taishi Umezawa; Tadao Asami; Akiko Maruyama-Nakashita; Toshiaki Kudo; Kazuo Shinozaki; Shigeo Yoshida; Hideo Nakashita



An arylaminopyridazine derivative of gamma-aminobutyric acid (GABA) is a selective and competitive antagonist at the GABAA receptor site.  

PubMed Central

In view of finding a new gamma-aminobutyric acid (GABA) receptor ligand we synthesized an arylaminopyridazine derivative of GABA, SR 95103 [2-(carboxy-3'-propyl)-3-amino-4-methyl-6-phenylpyridazinium chloride]. SR 95103 displaced [3H]GABA from rat brain membranes with an apparent Ki of 2.2 microM and a Hill number near 1.0. SR 95103 (1-100 microM) antagonized the GABA-mediated enhancement of [3H]diazepam binding in a concentration-dependent manner without affecting [3H]diazepam binding per se. SR 95103 competitively antagonized GABA-induced membrane depolarization in rat spinal ganglia. In all these experiments, the potency of SR 95103 was close to that of bicuculline. SR 95103 (100 microM) did not interact with a variety of central receptors--in particular the GABAB, the strychnine, and the glutamate receptors--did not inhibit Na+-dependent synaptosomal GABA uptake, and did not affect GABA-transaminase and glutamic acid decarboxylase activities. Intraperitoneally administered SR 95103 elicited clonicotonic seizures in mice (ED50 = 180 mg/kg). On the basis of these results it is postulated that St 95103 is a competitive antagonist of GABA at the GABAA receptor site. In addition to being an interesting lead structure for the search of GABA ligands, SR 95103 could also be a useful tool to investigate GABA receptor subtypes because it is freely soluble in water and chemically stable. Images PMID:2984669

Chambon, J P; Feltz, P; Heaulme, M; Restle, S; Schlichter, R; Biziere, K; Wermuth, C G



Mutations at amino-acid 482 in the ABCG2 gene affect substrate and antagonist specificity  

Microsoft Academic Search

Recent studies have shown that mutations at amino-acid 482 in the ABCG2 gene affect the substrate specificity of the protein. To delineate the effects of these mutations clearly, human embryonic kidney cells (HEK-293) were stably transfected with wild-type 482R or mutant 482G and 482T ABCG2. By flow cytometry, mitoxantrone, BODIPY-prazosin, and Hoechst 33342 were found to be substrates of all

R W Robey; Y Honjo; K Morisaki; T A Nadjem; S Runge; M Risbood; M S Poruchynsky; S E Bates



Impact on Inflammation and Recovery of Skin Barrier by Nordihydroguaiaretic Acid as a Protease-Activated Receptor 2 Antagonist  

PubMed Central

Atopic dermatitis is a chronic, inflammatory disease of the skin with increased transepidermal water loss. Both an abnormal inflammatory response and a defective skin barrier are known to be involved in the pathogenesis of atopic dermatitis. Protease activated receptor 2 (PAR2) belongs to a family of G-protein coupled receptors and is activated by both trypsin and a specific agonist peptide, SLIGKV-NH2. PAR2 is expressed in suprabasal layers of the epidermis and regulates inflammatory responses and barrier homeostasis. In this study, we show that nordihydroguaiaretic acid (NDGA) inhibits the PAR2-mediated signal pathway and plays a role in skin barrier recovery in atopic dermatitis. Specifically, NDGA reduces the mobilization of intracellular Ca2+ in HaCaT keratinocytes by down-regulating inflammatory mediators, such as interleukin-8, thymus and activation-regulated chemokine and intercellular cell adhesion molecule-1 in HaCaT keratinocytes. Also, NDGA decreases the protein expression of involucrin, a differentiation maker of keratinocyte, in both HaCaT keratinocytes and normal human epidermal keratinocytes. We examined NDGA-recovered skin barrier in atopic dermatitis by using an oxazolone-induced atopic dermatitis model in hairless mice. Topical application of NDGA produced an increase in transepidermal water loss recovery and a decrease in serum IgE level, without weight loss. Accordingly, we suggest that NDGA acts as a PAR2 antagonist and may be a possible therapeutic agent for atopic dermatitis. PMID:24009835

Kim, Hyo Young; Goo, Jung Hyun; Joo, Yeon Ah; Lee, Ha Yoen; Lee, Se Mi; Oh, Chang Taek; Ahn, Soo Mi; Kim, Nam-Hoon; Hwang, Jae Sung



Ultrastructural and biochemical studies on the neuroprotective effects of excitatory amino acid antagonists in the ischemic rat retina.  


The effects of glutamate receptor agonists were evaluated, by utilizing the electron microscope, in a photothrombotic occlusion model of rat retinal vessels in order to study the ischemic damage and its antagonism in each morphologically identified population of retinal neurons. Rats were systemically injected with rose bengal fluorescein dye and one of their eyes was then exposed to bright light. This treatment caused neuronal damage and reduced the activities of the neuronal marker enzymes, choline acetyltransferase and glutamate decarboxylase, by approximately 75%. A single intravitreal injection of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzoquinoxaline (NBQX, 10-50 nmol), an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, or of thiokynurenate (100-400 nmol), which also antagonizes N-methyl-D-aspartate (NMDA) receptors, performed immediately after the lesion, significantly reduced this loss. The electron microscope examination showed major damage in each type of retinal neuron, the pigment epithelium, and the microvessels. NBQX or thiokynurenic acid reduced, in a comparable manner, the effects of ischemia on the pigment epithelium, the photoreceptors, and the bipolar and the horizontal cells. NBQX was particularly efficient in reducing the damage to the amacrine cells located in the inner nuclear layer. The displaced amacrine and ganglion cells were not protected by NBQX but were almost completely spared in animals treated with thiokynurenate. These results show that antagonism of AMPA receptors is sufficient to reduce ischemic damage in a large number of retinal neurons, but that neuroprotection in the ganglion cell layer may be obtained only with agents which also antagonize NMDA receptors. PMID:9270053

Matini, P; Moroni, F; Lombardi, G; Faussone-Pellegrini, M S; Moroni, F



Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic.  


FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid 99 (GLPG0974), is able to inhibit acetate-induced neutrophil migration strongly in vitro and demonstrated ability to inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific epitope [AE], in a human whole blood assay. All together, these data supported the progression of 99 toward next phases, becoming the first FFA2 antagonist to reach the clinic. PMID:25380412

Pizzonero, Mathieu; Dupont, Sonia; Babel, Marielle; Beaumont, Stéphane; Bienvenu, Natacha; Blanqué, Roland; Cherel, Laëtitia; Christophe, Thierry; Crescenzi, Benedetta; De Lemos, Elsa; Delerive, Philippe; Deprez, Pierre; De Vos, Steve; Djata, Fatoumata; Fletcher, Stephen; Kopiejewski, Sabrina; L'Ebraly, Christelle; Lefrançois, Jean-Michel; Lavazais, Stéphanie; Manioc, Murielle; Nelles, Luc; Oste, Line; Polancec, Denis; Quénéhen, Vanessa; Soulas, Florilène; Triballeau, Nicolas; van der Aar, Ellen M; Vandeghinste, Nick; Wakselman, Emanuelle; Brys, Reginald; Saniere, Laurent



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.



Low-weight polyethylenimine cross-linked 2-hydroxypopyl-?-cyclodextrin and folic acid as an efficient and nontoxic siRNA carrier for gene silencing and tumor inhibition by VEGF siRNA  

PubMed Central

Background Targeted delivery of small interfering RNA (siRNA) has been regarded as one of the most important technologies for the development of siRNA therapeutics. However, the need for safe and efficient delivery systems is a barrier to further development of RNA interference therapeutics. In this work, a nontoxic and efficient siRNA carrier delivery system of low molecular weight polyethyleneimine (PEI-600 Da) cross-linked with 2-hydroxypopyl-?-cyclodextrin (HP-?-CD) and folic acid (FA) was synthesized for biomedical application. Methods The siRNA carrier was prepared using a simple method and characterized by nuclear magnetic resonance and Fourier transform infrared spectroscopy. The siRNA carrier nanoparticles were characterized in terms of morphology, size and zeta potential, stability, efficiency of delivery, and gene silencing efficiency in vitro and in vivo. Results The siRNA carrier was synthesized successfully. It showed good siRNA binding capacity and ability to protect siRNA. Further, the toxicity of the carrier measured in vitro and in vivo appeared to be negligible, probably because of degradation of the low molecular weight PEI and HP-?-CD in the cytosol. Flow cytometry and confocal microscopy confirmed that the FA receptor-mediated endocytosis of the FA-HP-?-CD-PEI/siRNA complexes was greater than that of the HP-?-CD-PEI/siRNA complexes in FA receptor-enriched HeLa cells. The FA-HP-?-CD-PEI/siRNA complexes also demonstrated excellent gene silencing efficiency in vitro (in the range of 90%), and reduced vascular endothelial growth factor (VEGF) protein expression in the presence of 20% serum. FA-HP-?-CD-PEI/siRNA complexes administered via tail vein injection resulted in marked inhibition of tumor growth and reduced VEGF protein expression in the tumors. Conclusion Our results suggest that the FA-HP-?-CD-PEI complex is a nontoxic and highly efficient gene carrier with the potential to deliver siRNA for cancer gene therapy effectively in vitro and in vivo. PMID:23766646

Li, Jin-Ming; Wang, Yuan-Yuan; Zhang, Wei; Su, Hua; Ji, Liang-Nian; Mao, Zong-Wan



Topographical amino acid substitution in position 10 of glucagon leads to antagonists/partial agonists with greater binding differences.  


The role of position 10 in the beta-turn region of glucagon was investigated by substituting chiral constrained amino acids and other modifications in the N-terminal region. A series of glucagon analogues have been designed and synthesized by incorporating beta-methylphenylalanine isomers (2S,3S, 2S,3R, 2R,3R, and 2R,3S) at position 10 in order to explore the structural and topographical requirements of the glucagon receptor, and, in addition, utilizing previous studies which indicated that antagonism could be enhanced by modifications (des-His1, Glu9) and a bulky group at position 5. The structures of the new analogues are as follows: [des-His1,-Tyr5,Glu9]glucagon-NH2 (II), [des-His1,Tyr5,Glu9,Phe10]glucagon-NH2 (III), [des-His1,Tyr5,Glu9,-Ala10]glucagon-NH2 (IV), [des-His1,Tyr5,Glu9,(2S,3R)-beta-MePhe10]glucagon-NH2 (V), [des-His1,-Tyr5,Glu9,(2S,3S)-beta-MePhe10]glucagon-NH2 (VI), [des-His1,Tyr5,Glu9,D-Tyr10]glucagon-NH2 (VII), [des-His1,Tyr5,Glu9,D-Phe10]glucagon-NH2 (VIII), [des-His1,Tyr5,Glu9,D-Ala10]glucagon-NH2 (IX), [des-His1,Tyr5,Glu9,(2R,3R)-beta-MePhe10]glucagon-NH2 (X), and [des-His1,Tyr5,Glu9,(2R,3S)-beta-MePhe10]glucagon-NH2 (XI). These analogues led to dramatically different changes in in vitro binding affinities for glucagon receptors. Their receptor binding potencies IC50 values (nM) are 2.3 (II), 4.1 (III), 395.0 (IV), 10.0 (V), 170.0 (VI), 74.0 (VII), 34.5 (VIII), 510.0 (IX), 120.0 (X), and 180.0 (XI). Analogues II, III, V, VI, and XI were found to be weak partial agonists/partial antagonists with maximum stimulation between 5%-9%, while the other compounds (IV and VII-X) were antagonists unable to activate the adenylate cyclase system even at concentrations as high as 10(-5) M. In competition experiments, all of the analogues caused a right shift of the glucagon-stimulated adenylate cyclase dose-response curve. The pA2 values were 6.60 (II), 6.85 (III), 6.20 (IV), 6.20 (V), 6.10 (VI), 6.50 (VII), 6.20 (VIII), 5.85 (IX), 6.20 (X), and 6.00 (XI). Putative topographical requirements of the glucagon receptor for the aromatic side chain conformation in position 10 of glucagon antagonists are discussed. PMID:8691441

Azizeh, B Y; Shenderovich, M D; Trivedi, D; Li, G; Sturm, N S; Hruby, V J



Antagonistic effects of humic acid and iron oxyhydroxide grain-coating on biochar nanoparticle transport in saturated sand.  


Biochar land application may result in multiple agronomic and environmental benefits (e.g., carbon sequestration, improving soil quality, and immobilizing environmental contaminants). However, our understanding of biochar particle transport is largely unknown in natural environments with significant heterogeneity in solid (e.g., patches of iron oxyhydroxide coating) and solution chemistry (e.g., the presence of natural organic matter), which represents a critical knowledge gap in assessing the environmental impact of biochar land application. Transport and retention kinetics of nanoparticles (NPs) from wheat straw biochars produced at two pyrolysis temperatures (i.e., 350 and 550 °C) were investigated in water-saturated sand columns at environmentally relevant concentrations of dissolved humic acid (HA, 0, 1, 5, and 10 mg L(-1)) and fractional surface coverage of iron oxyhydroxide coatings on sand grains (?, 0.16, 0.28, and 0.40). Transport of biochar NPs increased with increasing HA concentration, largely because of enhanced repulsive interaction energy between biochar NPs and sand grains. Conversely, transport of biochar NPs decreased significantly with increasing ? due to enhanced electrostatic attraction between negatively charged biochar NPs and positively charged iron oxyhydroxides. At a given ? of 0.28, biochar NPs were less retained with increasing HA concentration due to increased electrosteric repulsion between biochar NPs and sand grains. Experimental breakthrough curves and retention profiles were well described using a two-site kinetic retention model that accounted for Langmuirian blocking or random sequential adsorption at one site. Consistent with the blocking effect, the often observed flat retention profiles stemmed from decreased retention rate and/or maximum retention capacity at a higher HA concentration or smaller ?. The antagonistic effects of HA and iron oxyhydroxide grain-coating imparted on the mobility of biochar NPs suggest that biochar colloid transport potential will be dependent on competitive influences exerted by a number of environmental factors (e.g., natural organic matter and metal oxides). PMID:23614641

Wang, Dengjun; Zhang, Wei; Zhou, Dongmei



Effects of an H3R Antagonist on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid  

PubMed Central

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders primarily characterized by impaired social interaction and communication, and by restricted repetitive behaviors and interests. Ligands of histamine receptor 3 (H3R) are considered potential therapeutic agents for the treatment of different brain disorders and cognitive impairments. Considering this, the aim of the present study is to evaluate the actions of ciproxifan (CPX), an H3R antagonist, on the animal model of autism induced by prenatal exposure to valproic acid (VPA). Swiss mice were prenatally exposed to VPA on embryonic day 11 and assessed for social behavior, nociceptive threshold and repetitive behavior at 50 days of life. The treatment with CPX (3 mg/kg) or saline was administered 30 minutes before each behavioral test. The VPA group presented lower sociability index compared to VPA animals that were treated with CPX. Compared to the Control group, VPA animals presented a significantly higher nociceptive threshold, and treatment with CPX was not able to modify this parameter. In the marble burying test, the number of marbles buried by VPA animals was consistent with markedly repetitive behavior. VPA animals that received CPX buried a reduced amount of marbles. In summary, we report that an acute dose of CPX is able to attenuate sociability deficits and stereotypies present in the VPA model of autism. Our findings have the potential to help the investigations of both the molecular underpinnings of ASD and of possible treatments to ameliorate the ASD symptomatology, although more research is still necessary to corroborate and expand this initial data. PMID:25560049

Baronio, Diego; Castro, Kamila; Gonchoroski, Taylor; de Melo, Gabriela Mueller; Nunes, Gustavo Della Flora; Bambini-Junior, Victorio; Gottfried, Carmem; Riesgo, Rudimar



Effects of an H3R Antagonist on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid.  


Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders primarily characterized by impaired social interaction and communication, and by restricted repetitive behaviors and interests. Ligands of histamine receptor 3 (H3R) are considered potential therapeutic agents for the treatment of different brain disorders and cognitive impairments. Considering this, the aim of the present study is to evaluate the actions of ciproxifan (CPX), an H3R antagonist, on the animal model of autism induced by prenatal exposure to valproic acid (VPA). Swiss mice were prenatally exposed to VPA on embryonic day 11 and assessed for social behavior, nociceptive threshold and repetitive behavior at 50 days of life. The treatment with CPX (3 mg/kg) or saline was administered 30 minutes before each behavioral test. The VPA group presented lower sociability index compared to VPA animals that were treated with CPX. Compared to the Control group, VPA animals presented a significantly higher nociceptive threshold, and treatment with CPX was not able to modify this parameter. In the marble burying test, the number of marbles buried by VPA animals was consistent with markedly repetitive behavior. VPA animals that received CPX buried a reduced amount of marbles. In summary, we report that an acute dose of CPX is able to attenuate sociability deficits and stereotypies present in the VPA model of autism. Our findings have the potential to help the investigations of both the molecular underpinnings of ASD and of possible treatments to ameliorate the ASD symptomatology, although more research is still necessary to corroborate and expand this initial data. PMID:25560049

Baronio, Diego; Castro, Kamila; Gonchoroski, Taylor; de Melo, Gabriela Mueller; Nunes, Gustavo Della Flora; Bambini-Junior, Victorio; Gottfried, Carmem; Riesgo, Rudimar



Cyclic parathyroid hormone related protein antagonists: lysine 13 to aspartic acid 17 [i to (i + 4)] side chain to side chain lactamization.  


Cyclization of parathyroid hormone related protein (7-34)amide [PTHrP(7-34)NH2] via covalent bond formation between the epsilon-amino of Lys13 and the beta-carboxyl of Asp17 yielded a 20-membered ring lactam. This analogue, [Lys13,Asp17]PTHrP(7-34)NH2, was 5-10-fold more potent than the linear parent peptide (Kb = 15 and 18 nM in PTH receptor binding assays, and Ki = 130 and 17 nM in PTH-stimulated adenylate cyclase assays in bovine renal cortical membrane and in human bone derived B10 cells, respectively). In contrast, a linear analogue in which charges in positions 13 and 17 were eliminated and other stereoisomers of the above-mentioned lactam in which either Lys13 and/or Asp17 were replaced by the corresponding D-amino acids were much less potent with regard to antagonist bioactivity than the parent peptide. The rationale for the design of the lactam as well as the conformational implications for the PTHrP sequence in light of reported models suggested for the 1-34 peptide are described. The potential use of conformationally constrained analogues for elucidating the "bioactive conformation" of antagonists and for the design of substantially simplified molecular structures for antagonists is discussed. PMID:1646005

Chorev, M; Roubini, E; McKee, R L; Gibbons, S W; Goldman, M E; Caulfield, M P; Rosenblatt, M



Exploring a 2-Naphthoic Acid Template for the Structure-Based Design of P2Y14 Receptor Antagonist Molecular Probes.  


The P2Y14 receptor (P2Y14R), one of eight P2Y G protein-coupled receptors (GPCR), is involved in inflammatory, endocrine, and hypoxic processes and is an attractive pharmaceutical target. The goal of this research is to develop high-affinity P2Y14R fluorescent probes based on the potent and highly selective antagonist 4-(4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl)-2-naphthoic acid (6, PPTN). A model of hP2Y14R based on recent hP2Y12R X-ray structures together with simulated antagonist docking suggested that the piperidine ring is suitable for fluorophore conjugation while preserving affinity. Chain-elongated alkynyl or amino derivatives of 6 for click or amide coupling were synthesized, and their antagonist activities were measured in hP2Y14R-expressing CHO cells. Moreover, a new Alexa Fluor 488 (AF488) containing derivative 30 (MRS4174, Ki = 80 pM) exhibited exceptionally high affinity, as compared to 13 nM for the alkyne precursor 22. A flow cytometry assay employing 30 as a fluorescent probe was used to quantify specific binding to P2Y14R. Known P2Y receptor ligands inhibited binding of 30 with properties consistent with their previously established receptor selectivities and affinities. These results illustrate that potency in this series of 2-naphthoic acid derivatives can be preserved by chain functionalization, leading to highly potent fluorescent molecular probes for P2Y14R. Such conjugates will be useful tools in expanding the SAR of this receptor, which still lacks chemical diversity in its collective ligands. This approach demonstrates the predictive power of GPCR homology modeling and the relevance of newly determined X-ray structures to GPCR medicinal chemistry. PMID:25299434

Kiselev, Evgeny; Barrett, Matthew O; Katritch, Vsevolod; Paoletta, Silvia; Weitzer, Clarissa D; Brown, Kyle A; Hammes, Eva; Yin, Andrew L; Zhao, Qiang; Stevens, Raymond C; Harden, T Kendall; Jacobson, Kenneth A



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.



The anxiolytic-like activity of AIDA (1-aminoindan-1,5-dicarboxylic acid), an mGLu 1 receptor antagonist.  


In the present study we examined the effects of 1-aminoindan-1,5-dicarboxylic acid (AIDA), regarded as a selective and competitive mGluR1 antagonist, in animal models of anxiety. Diazepam (1-10 mg/kg) was used as a reference drug. After intraperitoneal administration, AIDA (0.5-2 mg/kg) produced anxiolytic-like effects in the conflict drinking test and the elevated plus-maze test in rats; however, in doses up to 8 mg/kg, it was inactive in the four-plate test in mice. AIDA tested at the effective doses in the conflict drinking test changed neither the treshold current nor water intake in rats compared to vehicle treatment. AIDA (in a dose of 4 mg/kg, but not lower) increased the exploratory locomotor activity of rats measured in the open-field test, but it did not disturb rat motor coordination in the rota-rod test. The above results indicate that selective mGluR1 antagonist AIDA induces antianxiety-like effects at a low risk of acute side effects characteristic of benzodiazepines. Further studies are required to identify the sites and the mechanism of action of AIDA. PMID:15082872

K?odzi?ska, A; Tatarczy?ska, E; Stachowicz, K; Chojnacka-Wójcik, E



Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules.  


1. Long chain fatty acids have recently been identified as agonists for the G protein-coupled receptors GPR40 and GPR120. Here, we present the first description of GW9508, a small-molecule agonist of the fatty acid receptors GPR40 and GPR120. In addition, we also describe the pharmacology of GW1100, a selective GPR40 antagonist. These molecules were used to further investigate the role of GPR40 in glucose-stimulated insulin secretion in the MIN6 mouse pancreatic beta-cell line. 2. GW9508 and linoleic acid both stimulated intracellular Ca2+ mobilization in human embryonic kidney (HEK)293 cells expressing GPR40 (pEC50 values of 7.32+/-0.03 and 5.65+/-0.06, respectively) or GPR120 (pEC50 values of 5.46+/-0.09 and 5.89+/-0.04, respectively), but not in the parent HEK-293 cell line. 3. GW1100 dose dependently inhibited GPR40-mediated Ca2+ elevations stimulated by GW9508 and linoleic acid (pIC50 values of 5.99+/-0.03 and 5.99+/-0.06, respectively). GW1100 had no effect on the GPR120-mediated stimulation of intracellular Ca2+ release produced by either GW9508 or linoleic acid. 4. GW9508 dose dependently potentiated glucose-stimulated insulin secretion in MIN6 cells, but not in primary rat or mouse islets. Furthermore, GW9508 was able to potentiate the KCl-mediated increase in insulin secretion in MIN6 cells. The effects of GW9508 on insulin secretion were reversed by GW1100, while linoleic acid-stimulated insulin secretion was partially attenuated by GW1100. 5. These results add further evidence to a link between GPR40 and the ability of fatty acids to acutely potentiate insulin secretion and demonstrate that small-molecule GPR40 agonists are glucose-sensitive insulin secretagogues. PMID:16702987

Briscoe, Celia P; Peat, Andrew J; McKeown, Stephen C; Corbett, David F; Goetz, Aaron S; Littleton, Thomas R; McCoy, David C; Kenakin, Terry P; Andrews, John L; Ammala, Carina; Fornwald, James A; Ignar, Diane M; Jenkinson, Stephen



Discovery of isoquinolinone indole acetic acids as antagonists of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2) for the treatment of allergic inflammatory diseases.  


Previously we reported the discovery of CRA-898 (1), a diazine indole acetic acid containing CRTH2 antagonist. This compound had good in vitro and in vivo potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. However, it showed low oral exposure in nonrodent safety species (dogs and monkeys). In the current paper, we wish to report our efforts to understand and improve the poor PK in nonrodents and development of a new isoquinolinone subseries that led to identification of a new development candidate, CRA-680 (44). This compound was efficacious in both a house dust mouse model of allergic lung inflammation (40 mg/kg qd) as well as a guinea pig allergen challenge model of lung inflammation (20 mg/kg bid). PMID:24512187

Kaila, Neelu; Follows, Bruce; Leung, Louis; Thomason, Jennifer; Huang, Adrian; Moretto, Alessandro; Janz, Kristin; Lowe, Michael; Mansour, Tarek S; Hubeau, Cedric; Page, Karen; Morgan, Paul; Fish, Susan; Xu, Xin; Williams, Cara; Saiah, Eddine



FOLICation: engineering approved drugs as potential p53-MDM2 interaction inhibitors for cancer therapy.  


Cancer is characterized by uncontrolled growth of abnormal cells leading to the formation of tumors. Normally, the pro-apoptotic p53 protein plays a central role in protecting cells against carcinogenesis. In almost 50% human tumor cells, however, the p53 protein is dysregulated by direct interaction with its negative regulator, the Murine Double Minute 2 (MDM2) protein. Therefore, blocking the p53-binding pocket on MDM2, leading to the activation of tumor suppressor p53 presents a novel therapeutic strategy against several types of cancers. The published crystal structure of MDM2 bound with the p53 binding domain has revealed that three key hydrophobic residues of p53 are buried deep into the binding cavity of MDM2 and thus are central to p53-MDM2 binding. Accordingly, several low-molecular-weight compounds have been developed that mimic these three hydrophobic residues and thus bind to the MDM2 pocket, leading in turn to inhibition of the deleterious p53-MDM2 interaction. It is noteworthy that these inhibitors also possess an additional hydrophilic group that is shown to be necessary as a "cover" protecting the hydrophobic interaction surface between inhibitor and MDM2 from surrounding solvent. In comparison, several FDA-approved drugs possess the three key hydrophobic features necessary for binding to MDM2, but lack the fourth hydrophilic moiety, thus possibly hindering their ability as potential p53-MDM2 interaction inhibitors. Therefore, we hypothesize that conjugation of hydrophilic vitamin folic acid or its analogs to these drugs (termed "FOLICation") may provide them with the much-needed hydrophilic cover and make them suitable for investigation as potentially novel p53-MDM2 inhibitors. We also anticipate that FOLICation of these drugs may further lead to their enhanced and selective uptake by cancer cells, owing to the significantly higher expression of folic acid receptors on cancer cells compared to normal cells. PMID:24210632

Patil, Sachin P



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.



Conversion of a scorpion toxin agonist into an antagonist highlights an acidic residue involved in voltage sensor trapping during activation of neuronal Na+ channels.  


Gating modifiers constitute a large group of polypeptide toxins that interact with the voltage-sensing module of ion channels. Among them, scorpion beta-toxins induce a negative shift in the voltage dependence of sodium channel activation. To explain their effect, a "voltage sensor trapping" model has been proposed in which the voltage sensor of domain-II (DIIS4) is trapped in an outward, activated position by a prebound beta-toxin upon membrane depolarization. Whereas toxin effect on channel activation was enhanced upon neutralization of the two outermost arginines in DIIS4, toxin residues involved in sensor trapping have not been identified. Using the scorpion excitatory beta-toxin, Bj-xtrIT, we found two conserved acidic residues, Glu15 and Glu30, mandatory for toxin action. Whereas mutagenesis of Glu30 affected both toxicity and binding affinity, substitutions E15A/F abolished activity but had minor effects on binding. Complete uncoupling of activity from binding was obtained with mutant E15R, acting as an efficient antagonist of Bj-xtrIT. On the basis of the voltage sensor trapping model and our results, we propose that Glu15 interacts with the emerging gating charges of DIIS4 upon membrane depolarization. Conserved acidic residues found in a variety of gating modifiers from scorpions and spiders may interact similarly with the voltage sensor. PMID:15054090

Karbat, Izhar; Cohen, Lior; Gilles, Nicholas; Gordon, Dalia; Gurevitz, Michael; Izhar, Karbat; Lior, Cohen; Nicholas, Gilles; Dalia, Gordon; Michael, Gurevitz



A novel modified carbon paste electrode based on NiO/CNTs nanocomposite and (9, 10-dihydro-9, 10-ethanoanthracene-11, 12-dicarboximido)-4-ethylbenzene-1, 2-diol as a mediator for simultaneous determination of cysteamine, nicotinamide adenine dinucleotide and folic acid.  


A carbon paste electrode (CPE) modified with (9, 10-dihydro-9, 10-ethanoanthracene-11, 12-dicarboximido)-4-ethylbenzene-1, 2-diol (DEDE) and NiO/CNTs nanocomposite was used for the sensitive voltammetric determination of cysteamine (CA), nicotinamide adenine dinucleotide (NADH) and folic acid (FA) for the first time. The synthesized materials were characterized with different methods such as XRD, cyclic voltammetry, electrochemical impedance spectroscopy (EIS) and square wave voltammetry (SWV). The modified electrode exhibited a potent and persistent electron mediating behavior followed by well-separated oxidation peaks of CA, NADH and FA. The peak currents were linearly dependent on CA, NADH and FA concentrations using square wave voltammetry (SWV) method in the ranges of 0.01-250, 1.0-500, and 3.0-550 µmol L?¹, with detection limits of 0.007, 0.6, and 0.9 µmol L?¹, respectively. The modified electrode was used for the determination of CA, NADH and FA in biological and pharmaceutical samples. PMID:23707873

Karimi-Maleh, Hassan; Biparva, Pourya; Hatami, Mehdi





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



Identification of Endogenous Gibberellins in Petunia Flowers (Induction of Anthocyanin Biosynthetic Gene Expression and the Antagonistic Effect of Abscisic Acid).  

PubMed Central

The elongation and pigmentation of corollas of Petunia hybrida requires the presence of anthers. The ability of exogenous gibberellic acid (GA3) to substitute for the anthers suggests a role for endogenous GAs. Here we report the identification of endogenous GAs in corollas and in anthers and show that both tissues contain detectable levels of GA1, GA4, and GA9, of which GA4 is the most abundant. These GAs stimulate corolla pigmentation, chalcone synthase (chs) mRNA accumulation, and chs transcription in an in vitro flower bud culture system. Methyl ester derivatives of GA3 and GA4 were not active but did not inhibit the bioactive GAs. Even though it is unknown whether abscisic acid (ABA) is involved in corolla maturation, ABA inhibited pigmentation of intact flowers, overruling the effect of the anthers. In detached flower buds it was shown that ABA prevented activation of the chs promoter by GA3. The synthesis of anthocyanin pigments requires the coordinate expression of at least 15 structural genes. Expression of early biosynthetic genes and of late biosynthetic genes are regulated by different transcriptional activators. GA induces both classes of genes with similar kinetics, indicating that GA acts relatively early in the signaling pathway. PMID:12228393

Weiss, D.; Van Der Luit, A.; Knegt, E.; Vermeer, E.; Mol, JNM.; Kooter, J. M.



Zhankuic acid A isolated from Taiwanofungus camphoratus is a novel selective TLR4/MD-2 antagonist with anti-inflammatory properties.  


TLR4, a membrane receptor that functions in complex with its accessory protein myeloid differentiation factor-2 (MD-2), is a therapeutic target for bacterial infections. Taiwanofungus camphoratus is highly valued as a medicinal mushroom for cancer, hypertension, and inflammation in traditional medicine. Zhankuic acid A (ZAA) is the major pharmacologically active compound of T. camphoratus. The mechanism of action of T. camphoratus or ZAA has not been fully elucidated. We analyzed the structure of human TLR4/MD-2 complex with ZAA by X-score and HotLig modeling approaches. Two Abs against MD-2 were used to verify the MD-2/ZAA interaction. The inflammation and survival of the mice pretreated with ZAA and injected with LPS were monitored. The modeling structure shows that ZAA binds the MD-2 hydrophobic pocket exclusively via specific molecular recognition; the contact interface is dominated by hydrophobic interactions. Binding of ZAA to MD-2 reduced Ab recognition to native MD-2, similar to the effect of LPS binding. Furthermore, ZAA significantly ameliorated LPS-induced endotoxemia and Salmonella-induced diarrhea in mice. Our results suggest that ZAA, which can compete with LPS for binding to MD-2 as a TLR4/MD-2 antagonist, may be a potential therapeutic agent for gram-negative bacterial infections. PMID:24532584

Chen, Yu-Fon; Shiau, Ai-Li; Wang, Sheng-Hung; Yang, Jai-Sing; Chang, Sue-Joan; Wu, Chao-Liang; Wu, Tian-Shung



Quantitative determination of the NMDA antagonist cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) in human plasma using capillary gas chromatography/mass spectrometry.  


An analytical method has been developed and validated for the quantitative determination of the N-methyl-D-aspartate (NMDA) antagonist cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) in human plasma. It is a member of a new class of compounds with the potential to be neuroprotective and attenuate neuronal damage resulting from brain trauma caused by stroke and head trauma. The method is based on gas chromatography/mass spectrometry and uses stable-isotope labeled CGS 19755 as the internal standard. Samples (1 ml) were first acidified (pH 2), then extracted using a solid-phase aminopropyl ion exchange column. The drug was eluted with NH4OH and evaporated until dry. Extracts were derivatized with a mixture of pentafluoropropionic anhydride and pentafluoropropanol, and analyzed by gas chromatography/mass spectrometry. Separation was accomplished on a DB-225 capillary column (15 m x 0.32 mm) with a 0.25 micron film thickness. Mass spectrometry was carried out under negative ion ammonia chemical ionization conditions with selected ion monitoring at m/z 760 and 764 for derivatized CGS 19755 and the internal standard, respectively. Specificity was shown by the lack of interfering peaks at the retention time of CGS 19755 and internal standard. Recovery and reproducibility assessments show good accuracy, precision and linearity over the validated concentration range of 2-5000 ng ml-1. PMID:7948048

Hayes, M J; Khemani, L; Powell, M L



Antagonistic roles of abscisic acid and cytokinin during response to nitrogen depletion in oleaginous microalga Nannochloropsis oceanica expand the evolutionary breadth of phytohormone function.  


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



Antagonistic lactic acid bacteria isolated from goat milk and identification of a novel nisin variant Lactococcus lactis  

PubMed Central

Background The raw goat milk microbiota is considered a good source of novel bacteriocinogenic lactic acid bacteria (LAB) strains that can be exploited as an alternative for use as biopreservatives in foods. The constant demand for such alternative tools justifies studies that investigate the antimicrobial potential of such strains. Results The obtained data identified a predominance of Lactococcus and Enterococcus strains in raw goat milk microbiota with antimicrobial activity against Listeria monocytogenes ATCC 7644. Enzymatic assays confirmed the bacteriocinogenic nature of the antimicrobial substances produced by the isolated strains, and PCR reactions detected a variety of bacteriocin-related genes in their genomes. Rep-PCR identified broad genetic variability among the Enterococcus isolates, and close relations between the Lactococcus strains. The sequencing of PCR products from nis-positive Lactococcus allowed the identification of a predicted nisin variant not previously described and possessing a wide inhibitory spectrum. Conclusions Raw goat milk was confirmed as a good source of novel bacteriocinogenic LAB strains, having identified Lactococcus isolates possessing variations in their genomes that suggest the production of a nisin variant not yet described and with potential for use as biopreservatives in food due to its broad spectrum of action. PMID:24521354



The effect of delayed administration of folinic acid on immunological inhibition by methotrexate  

PubMed Central

Administration of folinic acid to mice 8 hours after various doses of methotrexate gave considerable protection against mortality and weight-loss. The immune response to T.A.B. vaccine, however, which was inhibited by methotrexate, was negligibly affected in these circumstances, there being little difference between the degrees of inhibition found in protected and unprotected mice. The action of methotrexate on the immune apparatus required for completion some 6–8 hours after its administration, and administration of folinic acid at earlier times resulted in partial or complete reversal of inhibition. It is suggested that, during the early stages of the immune response, antigenically stimulated cells may be irreparably damaged by only a few hours exposure to folic acid antagonists. PMID:14315108

Berenbaum, M. C.; Brown, I. N.



Ureas with histamine H3-antagonist receptor activity--a new scaffold discovered by lead-hopping from cinnamic acid amides.  


A group of tri and tetrasubstituted urea derivatives have been found to be hH(3)-antagonists. The most potent compounds were found in the class of (piperazine-1-yl)-(piperidine-1-yl)-methanones which in addition showed negligible hERG inhibition. PMID:16908150

Lau, Jesper F; Jeppesen, Claus Bekker; Rimvall, Karin; Hohlweg, Rolf



Synthesis and separation of the enantiomers of the Neuropeptide S receptor antagonist (9R/S)-3-Oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68)  

PubMed Central

This study reports the synthesis, chromatographic separation and pharmacological evaluation of the two enantiors of the neuropeptide S receptor (NPSR) antagonist (9R/S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68). The (9R)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (compound 10) and (9S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (compound 10a) were synthesized and their purity assessed by chiral chromatography. The absolute configuration of the enantiomer 10 has been assigned from the crystal structure of the corresponding (S)-phenyl ethyl amine derivative 8. Calcium mobilization studies performed on cells expressing the recombinant NPSR demonstrated that compound 10 is the active enantiomer while the contribution of 10a to the NPSR antagonist properties of the racemic mixture is negligible. PMID:21466221

Trapella, Claudio; Pela', Michela; Zoppo, Luisa Del; Calo', Girolamo; Camarda, Valeria; Ruzza, Chiara; Cavazzini, Alberto; Costa, Valentina; Bertolasi, Valerio; Reinscheid, Rainer K.; Salvadori, Severo; Guerrini, Remo



Synthesis and separation of the enantiomers of the neuropeptide S receptor antagonist (9R/S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68).  


This study reports the synthesis, chromatographic separation, and pharmacological evaluation of the two enantiomers of the neuropeptide S receptor (NPSR) antagonist (9R/S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68). The (9R)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (compound 10) and (9S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (compound 10a) were synthesized and their purity assessed by chiral chromatography. The absolute configuration of the enantiomer 10 has been assigned from the crystal structure of the corresponding (S)-phenyl ethyl amine derivative 8. Calcium mobilization studies performed on cells expressing the recombinant NPSR demonstrated that compound 10 is the active enantiomer while the contribution of 10a to the NPSR antagonist properties of the racemic mixture is negligible. PMID:21466221

Trapella, Claudio; Pela, Michela; Del Zoppo, Luisa; Calo, Girolamo; Camarda, Valeria; Ruzza, Chiara; Cavazzini, Alberto; Costa, Valentina; Bertolasi, Valerio; Reinscheid, Rainer K; Salvadori, Severo; Guerrini, Remo



Pharmacological profile of novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methyl cyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526).  


The pharmacological profiles of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526) were investigated in terms of hog gastric H+,K+-ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in comparison with other proton pump inhibitors (PPIs). CS-526 inhibited H+,K+-ATPase activity in a concentration-dependent manner, with an IC50 value of 61 nM. The inhibitory effect of CS-526 on H+,K+-ATPase activity was more potent than that of any of the other PPIs examined. The inhibitory mechanism of CS-526 on H+,K+-ATPase was a competitive antagonism to the K+ binding site of H+,K+-ATPase, and it was also a reversible inhibition. In pylorus-ligated rats, intraduodenal or oral administration of CS-526 inhibited gastric acid secretion in a dose-dependent manner, and the ID50 values were 2.8 or 0.7 mg/kg, respectively. In Heidenhain pouch dogs, intrapouch administration of CS-526 inhibited histamine-stimulated gastric acid secretion in a dose- and retention time-dependent manner. In a reflux esophagitis model, intraduodenal and oral administration of CS-526 prevented esophageal lesions with ID50 values of 5.4 and 1.9 mg/kg, respectively. Lansoprazole prevented esophagitis only by intraduodenal administration (ID50 = 2.2 mg/kg). Furthermore, CS-526 inhibited acute gastric mucosal lesions. These data demonstrate that the novel acid pump antagonist CS-526 has potent antisecretory and antiulcer effects. These findings indicate that CS-526 would have a curative effect on gastroesophageal reflux disease via its potent antisecretory and antiulcer actions. PMID:17630360

Ito, Keiichi; Kinoshita, Kazuya; Tomizawa, Atsuyuki; Inaba, Fumi; Morikawa-Inomata, Yuka; Makino, Mitsuko; Tabata, Keiichi; Shibakawa, Nobuhiko



21 CFR 862.1295 - Folic acid test system.  

Code of Federal Regulations, 2014 CFR

...diagnosis and treatment of megaloblastic anemia, which is characterized by the presence of megaloblasts (an abnormal red blood cell series) in the bone marrow. (b) Classification. Class II. [52 FR 16122, May 1, 1987; 53 FR 11645,...



21 CFR 862.1295 - Folic acid test system.  

Code of Federal Regulations, 2012 CFR

...diagnosis and treatment of megaloblastic anemia, which is characterized by the presence of megaloblasts (an abnormal red blood cell series) in the bone marrow. (b) Classification. Class II. [52 FR 16122, May 1, 1987; 53 FR 11645,...



21 CFR 172.345 - Folic acid (folacin).  

Code of Federal Regulations, 2010 CFR

21 Food and Drugs 3 2010-04-01 2009-04-01...accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available from the National...section 5(b)(3) of the Orphan Drug Act (21 U.S.C. 360ee(b)(3)), at...



Uracil misincorporation into DNA and folic acid supplementation  

Technology Transfer Automated Retrieval System (TEKTRAN)

BACKGROUND: Folate deficiency decreases thymidylate synthesis from deoxyuridylate, which results in an imbalance of deoxyribonucleotide that may lead to excessive uracil misincorporation (UrMis) into DNA during replication and repair. OBJECTIVE: We evaluated the relation between UrMis in different ...


Folic acid, homocysteine and cardiovascular disease: Are the dots connecting?  

Technology Transfer Automated Retrieval System (TEKTRAN)

For many decades, atherosclerosis research has been dominated by the lipid hypothesis. Even when new concepts were brought to the table (i.e., oxidation hypothesis); efforts were made to fit them into the lipid context (i.e., oxidized LDL). This dominance provided the right environment for the devel...


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.



A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel and selective transient receptor potential type V1 receptor antagonist, blocks channel activation by vanilloids, heat, and acid.  


The vanilloid receptor transient receptor potential type V1 (TRPV1) integrates responses to multiple stimuli, such as capsaicin, acid, heat, and endovanilloids and plays an important role in the transmission of inflammatory pain. Here, we report the identification and in vitro characterization of A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel, potent, and selective TRPV1 antagonist. A-425619 was found to potently block capsaicin-evoked increases in intracellular calcium concentrations in HEK293 cells expressing recombinant human TRPV1 receptors (IC50 = 5 nM). A-425619 showed similar potency (IC50 = 3-4 nM) to block TRPV1 receptor activation by anandamide and N-arachidonoyl-dopamine. Electrophysiological experiments showed that A-425619 also potently blocked the activation of native TRPV1 channels in rat dorsal root ganglion neurons (IC50 = 9 nM). When compared with other known TRPV1 antagonists, A-425619 exhibited superior potency in blocking both naive and phorbol ester-sensitized TRPV1 receptors. Like capsazepine, A-425619 demonstrated competitive antagonism (pA2 = 2.5 nM) of capsaicin-evoked calcium flux. Moreover, A-425619 was 25- to 50-fold more potent than capsazepine in blocking TRPV1 activation. A-425619 showed no significant interaction with a wide range of receptors, enzymes, and ion channels, indicating a high degree of selectivity for TRPV1 receptors. These data show that A-425619 is a structurally novel, potent, and selective TRPV1 antagonist. PMID:15837819

El Kouhen, Rachid; Surowy, Carol S; Bianchi, Bruce R; Neelands, Torben R; McDonald, Heath A; Niforatos, Wende; Gomtsyan, Arthur; Lee, Chih-Hung; Honore, Prisca; Sullivan, James P; Jarvis, Michael F; Faltynek, Connie R



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.  


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



Occurrence and fate of the angiotensin II receptor antagonist transformation product valsartan acid in the water cycle--a comparative study with selected ?-blockers and the persistent anthropogenic wastewater indicators carbamazepine and acesulfame.  


The substantial transformation of the angiotensin II receptor antagonist valsartan to the transformation product 2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-carboxylic acid (referred to as valsartan acid) during the activated sludge process was demonstrated in the literature and confirmed in the here presented study. However, there was a severe lack of knowledge regarding the occurrence and fate of this compound in surface water and its behavior during drinking water treatment. In this work a comparative study on the occurrence and persistency of valsartan acid, three frequently used ?-blockers (metoprolol, atenolol, and sotalol), atenolol acid (one significant transformation product of atenolol and metoprolol), and the two widely distributed persistent anthropogenic wastewater indicators carbamazepine and acesulfame in raw sewage, treated wastewater, surface water, groundwater, and tap water is presented. Median concentrations of valsartan acid in the analyzed matrices were 101, 1,310, 69, <1.0, and 65 ng L(-1), respectively. Treated effluents from wastewater treatment plants were confirmed as significant source. Regarding concentration levels of pharmaceutical residues in surface waters valsartan acid was found just as relevant as the analyzed ?-blockers and the anticonvulsant carbamazepine. Regarding its persistency in surface waters it was comparable to carbamazepine and acesulfame. Furthermore, removal of valsartan acid during bank filtration was poor, which demonstrated the relevance of this compound for drinking water suppliers. Regarding drinking water treatment (Muelheim Process) the compound was resistant to ozonation but effectively eliminated (?90%) by subsequent activated carbon filtration. However, without applying activated carbon filtration the compound may enter the drinking water distribution system as it was demonstrated for Berlin tap water. PMID:24070867

Nödler, Karsten; Hillebrand, Olav; Idzik, Krzysztof; Strathmann, Martin; Schiperski, Ferry; Zirlewagen, Johannes; Licha, Tobias



[Synthesis of potential CCK antagonist quinazolone derivatives].  


An original route has been found for the synthesis of [1,4]diazepino-quinazolones, a new ring system of heterocondensed quinazolones. These anthranilicacid-alanin-beta-alanin cyclopeptide derivatives constitute a structural moiety of asperlicin, the first natural cholecystokinin antagonist alkaloid. These compounds are therefore potential CCK antagonists. The new compounds were prepared via condensation of 2-amino-alkyl-quinazolones, obtained from 2-alkyl-quinazolones by side-chain substitution, with 1,3-bifunctional-reagents. We studied the cyclisation process under basic, acidic and phase-transfer catalyzed conditions. The structures of the synthesized compounds were characterized by IR, UV and NMR spectroscopy. PMID:7572196

Szabó, M; Kökösi, J; Orfi, L



Optimization of alkylidene hydrazide based human glucagon receptor antagonists. Discovery of the highly potent and orally available 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide.  


Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-cyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure-metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC(50) = 2.3 nM, K(B) = 760 pM) and of the isolated rat receptor (IC(50) = 430 pM, K(B) = 380 pM). Glucagon-stimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (K(i) = 14 nM). This compound was orally available in dogs (F(po) = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia. PMID:12477359

Madsen, Peter; Ling, Anthony; Plewe, Michael; Sams, Christian K; Knudsen, Lotte B; Sidelmann, Ulla G; Ynddal, Lars; Brand, Christian L; Andersen, Birgitte; Murphy, Douglas; Teng, Min; Truesdale, Larry; Kiel, Dan; May, John; Kuki, Atsuo; Shi, Shenghua; Johnson, Michael D; Teston, Kimberly Ann; Feng, Jun; Lakis, James; Anderes, Kenna; Gregor, Vlad; Lau, Jesper



Vasopressin receptor antagonists.  


Arginine vasopressin (AVP) is the principal hormone involved in regulating the tonicity of body fluids. Less appreciated is the role that AVP plays in a variety of other physiologic functions including glucose metabolism, cardiovascular homeostasis, bone metabolism, and cognitive behavior. AVP receptor antagonists are now available and currently approved to treat hyponatremia. There is a great deal of interest in exploring the potential benefits that these drugs may play in blocking AVP-mediated effects in other organ systems. The purpose of this report is to provide an update on the expanding role of AVP receptor antagonists and what disease states these drugs may eventually be used for. PMID:25604388

Palmer, Biff F



Perampanel, an antagonist of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, for the treatment of epilepsy: studies in human epileptic brain and nonepileptic brain and in rodent models.  


Perampanel [Fycompa, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate 4:3; Eisai Inc., Woodcliff Lake, NJ] is an AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both the cerebral cortex and hippocampus associated with antiepileptic efficacy and also in the cerebellum associated with motor side effects in rodent and human brains. We also asked whether epileptic or nonepileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, we found that perampanel inhibited AMPA receptors from hippocampal tissue that had been removed from a patient who underwent surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 ?M). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array, and 10 ?M perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter, demonstrating the effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients. PMID:25027316

Zwart, R; Sher, E; Ping, X; Jin, X; Sims, J R; Chappell, A S; Gleason, S D; Hahn, P J; Gardinier, K; Gernert, D L; Hobbs, J; Smith, J L; Valli, S N; Witkin, J M



Effects of the new H2-receptor antagonist 3-amino-4-[4- [4- (1-piperidinomethyl)-2-pyridyloxy]-cis-2-butenylamino]-3-cyclobutene-1, 2- dione hydrochloride on gastric acid secretion and ulceration.  


The effect of 3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis- 2-butenylamino]-3-cyclobutene-1,2-dione hydrochloride (IT-066), a new H2-receptor antagonist, on gastric acid secretion and on various experimental ulcers was investigated. IT-066 showed very potent and long lasting antisecretory action in pylorus ligated rats. The inhibitory potency of IT-066 given subcutaneously for gastric acid secretion was 1285 and 44 times higher than for cimetidine and famotidine, respectively. The duration of the inhibitory action of IT-066 was significantly longer than that of famotidine and cimetidine. In pylorus ligated rats, IT-066 showed almost 20 times higher potency than omeprazole with intraduodenal administration, and almost the same duration of action as omeprazole with one tenth the dose in oral administration. IT-066 showed a powerful protective effect on various experimental ulcer models. The potency of IT-066 administered subcutaneously was significantly higher compared with that of cimetidine, famotidine and omeprazole. IT-066 given orally also showed a more powerful antiulcer effect than cimetidine and omeprazole, and was comparable with that of famotidine in restraint and water immersion stress and cold-stress plus indometacin induced ulcer models in rats. These results suggest that IT-066 has powerful and long lasting antisecretory and antiulcer effects and is a useful antisecretory drug for treatment of peptic ulcer diseases. PMID:1971169

Muramatsu, M; Isobe, Y; Arai, I; Hirose-Kijima, H; Usuki-Ito, C; Nagai, H; Aihara, H; Otomo, S



N-(2-hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), a novel, potent, and selective acid pump antagonist for the treatment of gastroesophageal reflux disease.  


Inhibition of H(+),K(+)-ATPase is accepted as the most effective way of controlling gastric acid secretion. However, current acid suppressant therapy for gastroesophageal reflux disease, using histamine H(2) receptor antagonists and proton pump inhibitors, does not fully meet the needs of all patients because of their mechanism of action. This study sought to characterize the in vitro and in vivo pharmacology of a novel acid pump antagonist, N-(2-Hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), and to compare it with other acid suppressants. Porcine, canine, and human recombinant gastric H(+),K(+)-ATPase activities were measured by ion-leaky and ion-tight assay. The affinities for a range of receptors, ion channels, and enzymes were determined to analyze selectivity profile. Acid secretion in Ghosh-Schild rats and Heidenhain pouch dogs were measured by titrating perfusate and gastric juice samples. PF-03716556 demonstrated 3-fold greater inhibitory activity than 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine (revaprazan), the only acid pump antagonist that has been available on the market, in ion-tight assay. The compound did not display any species differences, exhibiting highly selective profile including the canine kidney Na(+),K(+)-ATPase. Kinetics experiments revealed that PF-03716556 has a competitive and reversible mode of action. More rapid onset of action than 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-sulfinyl}-benzimidazole (omeprazole) and 3-fold greater potency than revaprazan were observed in Ghosh-Schild rats and Heidenhain pouch dogs. PF-03716556, a novel acid pump antagonist, could improve upon or even replace current pharmacological treatment for gastroesophageal reflux disease. PMID:18981288

Mori, Hiroki; Tonai-Kachi, Hiroko; Ochi, Yasuo; Taniguchi, Yasuhito; Ohshiro, Hiroyuki; Takahashi, Nobuyuki; Aihara, Takeshi; Hirao, Akiko; Kato, Teruhisa; Sakakibara, Minoru; Kurebayashi, Yoichi



Combined treatment of ascorbic acid or alpha-tocopherol with dopamine receptor antagonist or nitric oxide synthase inhibitor potentiates cataleptic effect in mice  

Microsoft Academic Search

Rationale  Drugs like haloperidol (Hal) that decrease dopamine (DA) neurotransmission in the striatum induce catalepsy in rodents and\\u000a Parkinson disease-like symptoms in humans. Nitric oxide synthase (NOS) inhibitors interfere with motor activity, disrupting\\u000a rodent exploratory behavior and inducing catalepsy. Catalepsy induced by NOS inhibitors probably involves striatal DA-mediated\\u000a neurotransmission. Antioxidants such as ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) have

M. Lazzarini; C. Salum; E. A. Del Bel



A Quantitative Structure-Activity Relationship and Molecular Modeling Study on a Series of Heteroaryl- and Heterocyclyl-Substituted Imidazo[1,2-a]Pyridine Derivatives Acting as Acid Pump Antagonists  

PubMed Central

A quantitative structure-activity relationship (QSAR) and molecular docking study has been performed on a series of heteroaryl- and heterocyclyl-substituted imidazo[1,2-a]pyridine derivatives acting as acid pump antagonists in order to have a better understanding of the mechanism of H+/K+-ATPase inhibition. The QSAR study shows a significant correlation of activity with Global Topological Charge Indices (GTCI) of the compounds and the hydrophobic constant ? of some substituents, indicating that the charge transfer within the molecule and the hydrophobic property of some substituents will be the controlling factor of the activity of these compounds and that there can be dispersion interaction between the molecules and the receptor, where some substituents may have hydrophobic interaction, too. Based on this correlation some new compounds with higher potency have been predicted and their docking study has been performed to see if they can have better interaction with the receptor. The ADME properties of these predicted compounds have also been reported that follow Lipinski's rule of five. PMID:24089639

Agarwal, Neeraj; Bajpai, Anubha; Gupta, Satya P.



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.



Plasma glucose, insulin, free fatty acids, lactate and cortisol concentrations in dexmedetomidine-sedated dogs with or without MK-467: a peripheral ?-2 adrenoceptor antagonist.  


Six healthy laboratory Beagles were treated IV with 10 ?g/kg dexmedetomidine (DEX) or 10 ?g/kg dexmedetomidine combined with 500 ?g/kg MK-467 in the same syringe (DMK) in a randomised cross-over design with a 14 day washout. Blood was collected immediately before treatment and 35, 60 and 120 min post-injection through a central venous catheter. The plasma concentrations of glucose, insulin, non-esterified free fatty acids (NEFAs), lactate and cortisol were determined. A repeated-measures ANOVA test was used to compare treatments and effects for each sample time point. Significant differences between treatments were found for plasma glucose (P=0.037) and insulin (P=0.009). DEX significantly increased plasma glucose at 120 min, but reduced plasma insulin at 35 and 60 min. NEFA decreased for both treatments at 35 min. This reduction was transient for DMK, whereas it persisted during the follow up period for DEX. Plasma lactate concentrations increased at 35 and 60 min with DEX. Neither treatment altered plasma cortisol concentrations. The addition of MK-467 to dexmedetomidine prevented or abolished most metabolic changes in healthy Beagles. PMID:22277719

Restitutti, F; Raekallio, M; Vainionpää, M; Kuusela, E; Vainio, O



Fosinopril H(2)-receptor antagonists interaction studies by derivative spectroscopy.  


Fosinopril sodium, a phosphinic acid derivative is an angiotensin converting enzyme (ACE) inhibitor, which had been employed for the treatment of hypertension and congestive heart failure; long tem use of ACE inhibitor often result in stress ulcers due to which H(2) receptor antagonists are also concurrently prescribed. The later compete with histamine for H(2) receptors and block gastric acid secretion and some cardiovascular effects of histamine. Our studies are focused on the in vitro availability of fosinopril in presence of commonly used H(2) receptor antagonists. Derivative spectroscopy has been employed for the quantitation of fosinopril and H(2) receptor antagonists followed by linear regression analysis. These studies were carried out in buffers of pH 7.4 and 9 at 37, 48 and 60( masculine)C. Stability constant and thermodynamic function had also been calculated in order to evaluate the reaction mechanism. Commonly prescribed H(2) receptor antagonists like cimetidine, ranitidine and famotidine were used in these studies. Present study clearly indicated that most of the H(2) receptor antagonists studied decreased the availability of fosinopril which conclude that availability of fosinopril can be affected by the concurrent administration of H(2) receptor antagonists. PMID:17337423

Sultana, Najma; Arayne, M Saeed; Sana, Aisha



Naloxone: actions of an antagonist  

Microsoft Academic Search

The opioid antagonist naloxone has a special place in pharmacology – it has no intrinsic\\u000aaction of its own, but it is able to save lives in the case of life threatening side-effects caused by other drugs. Naloxone is an antagonist for all opioid receptors, but most specifically for the ?-opioid receptor, which is the receptor through which opioids such

Eveline Louise Arianna van Dorp



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



Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature.  


The transient receptor potential vanilloid-1 (TRPV1) channel is involved in the development and maintenance of pain and participates in the regulation of temperature. The channel is activated by diverse agents, including capsaicin, noxious heat (? 43°C), acidic pH (< 6), and endogenous lipids including N-arachidonoyl dopamine (NADA). Antagonists that block all modes of TRPV1 activation elicit hyperthermia. To identify efficacious TRPV1 antagonists that do not affect temperature antagonists representing multiple TRPV1 pharmacophores were evaluated at recombinant rat and human TRPV1 channels with Ca(2+) flux assays, and two classes of antagonists were identified based on their differential ability to inhibit acid activation. Although both classes of antagonists completely blocked capsaicin- and NADA-induced activation of TRPV1, select compounds only partially inhibited activation of the channel by protons. Electrophysiology and calcitonin gene-related peptide release studies confirmed the differential pharmacology of these antagonists at native TRPV1 channels in the rat. Comparison of the in vitro pharmacological properties of these TRPV1 antagonists with their in vivo effects on core body temperature confirms and expands earlier observations that acid-sparing TRPV1 antagonists do not significantly increase core body temperature. Although both classes of compounds elicit equivalent analgesia in a rat model of knee joint pain, the acid-sparing antagonist tested is not effective in a mouse model of bone cancer pain. PMID:22570364

Reilly, Regina M; McDonald, Heath A; Puttfarcken, Pamela S; Joshi, Shailen K; Lewis, LaGeisha; Pai, Madhavi; Franklin, Pamela H; Segreti, Jason A; Neelands, Torben R; Han, Ping; Chen, Jun; Mantyh, Patrick W; Ghilardi, Joseph R; Turner, Teresa M; Voight, Eric A; Daanen, Jerome F; Schmidt, Robert G; Gomtsyan, Arthur; Kort, Michael E; Faltynek, Connie R; Kym, Philip R



In vitro interactions of captopril with H2-receptor antagonists.  


Captopril is effective in the treatment of hypertension of all grades of severity. H2-receptors antagonists block gastric acid secretion and some cardiovascular effects of histamine. In view of the fact that, simultaneous administration of both drugs may alter the antihypertensive effect of captopril, present paper deals with the in vitro availability studies of captopril in presence of commonly used H2-receptor antagonists like cimetidine, ranitidine and famotidine. In order to simulate various pH levels in GI tract and to find out the kinetics and energetics of captopril-H2-receptor antagonist interactions, these studies were carried out in buffers of pH 4, 7.4 and 9 at 37 degrees C and at elevated temperatures. These studies clearly indicate that most of the H2-receptor antagonists bind to captopril, forming charge-transfer complexes. As a result, the availability of captopril was affected by the concurrent administration of H2-receptor antagonists. Accordingly coadministration of both the drugs should be avoided. PMID:17416569

Sultana, Najma; Arayne, M Saeed; Quraish, Reeshanul



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



Pharmacological differences between calcium antagonists.  


The calcium channel antagonists are not an homogeneous group. From both pharmacological and clinical points of view, they can be divided into those of the dihydropyridine family like nifedipine, and those of the non-dihydropyridine family like verapamil and diltiazem. These families bind at different sites to the calcium channel, which may explain some of the clinical differences. The dihydropyridines are more vascular selective and the non-dihydropyridines are more myocardial selective and tend to reduce the heart rate. Further important differences are between short- and long-acting forms of the calcium channel antagonists. From the clinical point of view, these agents are most used in angina pectoris and hypertension. Emerging studies suggest that in angina of effort these agents have a safety record somewhat similar to that of beta-blockers. In congestive heart failure, these agents, as a group, are contraindicated. PMID:9049541

Opie, L H



Further studies at neuropeptide S position 5: discovery of novel neuropeptide S receptor antagonists  

PubMed Central

Neuropeptide S (NPS) regulates various biological functions by activating the NPS receptor (NPSR). Previous studies demonstrated that the substitution of Gly5 with D-amino acids generates NPSR antagonists. Eleven [D-Xaa5]NPS derivatives were synthesized and pharmacologically tested measuring [Ca2+]i in HEK293mNPSR cells. The present results confirmed that the [D-Xaa5] substitution promotes antagonist activity with potency inversely related to the side chain size and allowed to identify the novel potent NPSR peptide antagonist [tBu-D-Gly5]NPS. PMID:19473027

Guerrini, Remo; Camarda, Valeria; Trapella, Claudio; Calo’, Girolamo; Rizzi, Anna; Ruzza, Chiara; Fiorini, Stella; Marzola, Erika; Reinscheid, Rainer K.; Regoli, Domenico; Salvadori, Severo



Discovery of furan-2-carbohydrazides as orally active glucagon receptor antagonists.  


Furan-2-carbohydrazides were found as orally active glucagon receptor antagonists. Starting from the hit compound 5, we successfully determined the structure activity relationships of a series of derivatives obtained by modifying the acidity of the phenol. We identified the ortho-nitrophenol as a good scaffold for glucagon receptor inhibitory activity. Our efforts have led to the discovery of compound 7l as a potent glucagon receptor antagonist with good bioavailability and satisfactory long half-life. PMID:25127101

Hasegawa, Futoshi; Niidome, Kazumi; Migihashi, Chiaki; Murata, Makoto; Negoro, Toshiyuki; Matsumoto, Takafumi; Kato, Kaori; Fujii, Akihito



Non-NMDA receptor antagonist-induced drinking in rat  

NASA Technical Reports Server (NTRS)

Glutamate has been implicated in the central control of mechanisms that maintain body fluid homeostasis. The present studies demonstrate that intracerebroventricular (i.c.v.) injections of the non-N-methyl-d-aspartate (NMDA) receptor antagonists 6, 7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX) induce drinking in rats. The dipsogenic effect of i.c.v. DNQX was antagonized by the non-NMDA receptor agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). The water intake induced by DNQX was also blocked by pretreatment with a NMDA receptor antagonist, MK-801, but not by angiotensin type 1 (AT1) or acetylcholine muscarinic receptor antagonists (losartan and atropine). The results indicate that non-NMDA receptors may exert a tonic inhibitory effect within brain circuits that control dipsogenic activity and that functional integrity of NMDA receptors may be required for the non-NMDA receptor antagonists to induce water intake. Copyright 1998 Published by Elsevier Science B.V.

Xu, Z.; Johnson, A. K.



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



Antagonistic action of siderophores from Rhodotorula glutinis upon the postharvest pathogen Penicillium expansum  

Microsoft Academic Search

Rhodotorulic acid produced by Rhodotorula glutinis strains improved the biological control of blue rot caused by Penicillium expansum in harvested apples. The production of the siderophore was closely associated with the iron concentration in the medium. Thus, very low additions of the metal reduced the siderophore production considerably. The antagonistic effect of R. glutinis and rhodotorulic acid was studied by

V Calvente; D Benuzzi; M. I. S de Tosetti



NMDA receptor antagonists reduce medial, but not lateral, perforant path-evoked EPSPs in dentate gyrus of rat hippocampal slice  

Microsoft Academic Search

NMDA receptor antagonists produced differential effects on medial and lateral perforant path-evoked excitatory postsynaptic potentials (EPSPs) recorded in the dentate gyrus molecular layer of hippocampal slices. D-(-)-2-amino-5-phosphonovaleric acid (D(-)APV) and 3-[(±)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP) significantly reduced the peak amplitude and total area, but not the initial negative slope, of the medial perforant path-evoked EPSP. Neither antagonist affected any component of the

D. Dahl; E. C. Burgard; J. M. Sarvey



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.



Sensitive and rapid behavioral differentiation of N-methyl-D-aspartate receptor antagonists.  


Behavioral effects of PCP-type noncompetitive antagonists of N-methyl-D-aspartate (NMDA) receptors overlap with those of a host of other centrally acting compounds. In the present experiment, locomotor activity and performance on an inverted screen test in untrained mice were used to differentiate PCP-type non-competitive NMDA antagonists from other drug classes. These uncompetitive NMDA antagonists [PCP, dizocilpine, (-)-MK-801, TCP, (+)-SKF 10,047, dextrorphan, ketamine] produced dose-related increases in locomotor activity and the percentage of mice falling off an inverted, elevated wire mesh screen. Both effects demonstrated stereoselectivity, occurred at comparable dose levels, and were within the range of doses producing other biological effects (e.g., anticonvulsant). The potencies of these drugs for producing behavioral effects were positively correlated with affinities for PCP ([3H]MK-801) but not sigma([3H]SKF 10,047) receptors. Although muscarinic antagonists (benactyzine, atropine) produced effects in the same direction, locomotor stimulation was small and occurred at lower doses than those inducing screen failures. Competitive NMDA antagonists (LY 274614, LY 233536, CPP, NPC 12626), sigma receptor ligands (DTG, dextromethorphan), postsynaptic dopamine agonists (quinpirole, SKF 38393) and antagonists (haloperidol, SCH 39166), and some depressant compounds (morphine, diazepam) increased failures on the screen test but decreased locomotor activity. Ligands of the polyamine regulatory site of the NMDA receptor (ifenprodil, SL 82.0715-10) and the AMPA receptor antagonist NBQX decreased locomotor activity without increasing screen failures. An antagonist of the strychnine-insensitive glycine receptor (7-chlorokynurenic acid) did not affect performance on either test. Psychomotor stimulants (cocaine and methamphetamine) stimulated locomotor activity without affecting screen performance. The only false positives occurred with barbiturates (pentobarbital, phenobarbital). Nonetheless, the present procedure demonstrates excellent sensitivity and power for rapid discrimination of uncompetitive NMDA antagonists. PMID:7855218

Ginski, M J; Witkin, J M



Neurotoxic study of H2 antagonists using Xenopus oocytes injected with mouse-brain mRNA.  


To clarify the dominant mechanism for the convulsant activity of H2 antagonists, the effects of an H2 antagonist, cimetidine, on membrane currents induced by various agonists were investigated. In Xenopus oocytes injected with mouse-brain mRNA, acetylcholine (ACh), serotonin (5-HT), gamma-aminobutyric acid (GABA), glycine (Gly), glutamic acid (Glu), kainic acid (KA), quisqualic acid (QA) and N-methyl-D-aspartic acid (NMDA)-induced current responses were recorded under a voltage-clamp condition. Cimetidine inhibited GABA-induced currents in a concentration-dependent manner; however, the current responses induced by the other agonists were not modified. The IC50 of various H2 antagonists, famotidine, nizatidine, cimetidine and ranitidine, for GABA (10 microM)-induced current response were 66, 260, 450 and 980 microM, respectively. However, these values of cimetidine and ranitidine were 40-400 times higher than the reported brain and cerebrospinal fluid (CSF) concentration of H2 antagonists at the occurrence of a clonic convulsion in vivo. In conclusion, we observed an inhibitory effect of H2 antagonists on the GABA response; however, this inhibition of GABA-mediated neurotransmission may not be the dominant mechanism for H2 antagonist-induced clonic convulsion in vivo. PMID:9331993

Kawakami, J; Yamamoto, K; Shimokawa, M; Sawada, Y; Asanuma, A; Yanagisawa, K; Iga, T



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



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...


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



Aspirin and Folic Acid for the Prevention of Recurrent Colorectal Adenomas  

Microsoft Academic Search

Background & Aims: Although observational studies have found regular aspirin use to be associated with a reduced risk of colorectal neoplasia, results from ran- domized trials using aspirin have been inconsistent. Dietary folate intake also has been found to be asso- ciated with a reduced risk of colorectal neoplasms in observational studies. Methods: A multicenter, ran- domized, double-blind trial of



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



Antianginal Actions of Beta-Adrenoceptor Antagonists  

PubMed Central

Angina pectoris is usually the first clinical sign of underlying myocardial ischemia, which results from an imbalance between oxygen supply and oxygen demand in the heart. This report describes the pharmacology of ?-adrenoceptor antagonists as it relates to the treatment of angina. The ?-adrenoceptor antagonists are widely used in long-term maintenance therapy to prevent acute ischemic episodes in patients with chronic stable angina. Beta-adrenoceptor antagonists competitively inhibit the binding of endogenous catecholamines to ?1-adrenoceptors in the heart. Their anti-ischemic effects are due primarily to a reduction in myocardial oxygen demand. By decreasing heart rate, myocardial contractility and afterload, ?-adrenoceptor antagonists reduce myocardial workload and oxygen consumption at rest as well as during periods of exertion or stress. Predictable adverse effects include bradycardia and cardiac depression, both of which are a direct result of the blockade of cardiac ?1-adrenoceptors, but adverse effects related to the central nervous system (eg, lethargy, sleep disturbances, and depression) may also be bothersome to some patients. Beta-adrenoceptor antagonists must be used cautiously in patients with diabetes mellitus, peripheral vascular disease, heart failure, and asthma or other obstructive airway diseases. Beta-adrenoceptor antagonists may be used in combination with nitrates or calcium channel blockers, which takes advantage of the diverse mechanisms of action of drugs from each pharmacologic category. Moreover, concurrent use of ?-adrenoceptor antagonists may alleviate the reflex tachycardia that sometimes occurs with other antianginal agents. PMID:17998992



Intraseptal infusion of selective and competitive glutamate receptor agonist NMDA and antagonist d-2-amino-5-phosphonopentanoic acid spectral implications for the physostigmine-induced hippocampal theta rhythm in urethane-anesthetized rats  

Microsoft Academic Search

Theta (?) rhythm may be mediated, at least in part, by a glutamate neurotransmitter. Thus, in the present study, it was hypothesized that the septum glutamatergic NMDA receptor subtype may be involved in the modulation of physostigmine-induced ? rhythm. To test this hypothesis, we analyzed, in the urethane-anesthetized rat, the effects of septum application of NMDA and d-2-amino-5-phosphonopentanoic acid (AP5),

C. Puma; V. Monmaur; A. Sharif; P. Monmaur



?N-dependent control of acid resistance and the locus of enterocyte effacement in enterohemorrhagic Escherichia coli is activated by acetyl phosphate in a manner requiring flagellar regulator FlhDC and the ?S antagonist FliZ  

PubMed Central

In enterohemorrhagic Escherichia coli (EHEC), sigma factor N (?N) regulates glutamate-dependent acid resistance (GDAR) and the locus of enterocyte effacement (LEE); discrete genetic systems that are required for transmission and virulence of this intestinal pathogen. Regulation of these systems requires nitrogen regulatory protein C, NtrC, and is a consequence of NtrC-?N-dependent reduction in the activity of sigma factor S (?S). This study elucidates pathway components and stimuli for ?N-directed regulation of GDAR and the LEE in EHEC. Deletion of fliZ, the product of which reduces ?S activity, phenocopied rpoN (?N) and ntrC null strains for GDAR and LEE control, acid resistance, and adherence. Upregulation of fliZ by NtrC-?N was shown to be indirect and required an intact flagellar regulator flhDC. Activation of flhDC by NtrC-?N and FlhDC-dependent regulation of GDAR and the LEE was dependent on ?N-promoter flhDP2, and a newly described NtrC upstream activator sequence. Addition of ammonium chloride significantly altered expression of GDAR and LEE, acid resistance, and adherence, independently of rpoN, ntrC, and the NtrC sensor kinase, ntrB. Altering the availability of NtrC phosphodonor acetyl phosphate by growth without glucose, with acetate addition, or by deletion of acetate kinase ackA, abrogated NtrC-?N-dependent control of flhDC, fliZ, GDAR, and the LEE. PMID:24931910

Mitra, Avishek; Fay, Pamela A; Vendura, Khoury W; Alla, Zimrisha; Carroll, Ronan K; Shaw, Lindsey N; Riordan, James T



Endothelin1 Receptor Antagonist (LU135252) Improves the Microcirculation and Course of TNBS Colitis in Rats  

Microsoft Academic Search

The role of microcirculation in the pathogenesis and course of chronic inflammatory bowel disease is still unclear. The aim of this study was the evaluation of the role of microcirculation in colitis activity in the rat TNBS (trinitrobenzenesulfonic acid) colitis model using endothelin-1 and a selective endothelin-1 receptor antagonist (LU-135252). Target parameters were capillary blood flow, functional capillary density, vascular

Martin Kruschewski; Tanja Anderson; Christoph Loddenkemper; Heinz J. Buhr



[Fermentation of Bacillus subtilis ge25 strain and preliminary study on its antagonistic substances].  


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



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


Androgen receptor antagonists for prostate cancer therapy.  


Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach. PMID:24639562

Helsen, Christine; Van den Broeck, Thomas; Voet, Arnout; Prekovic, Stefan; Van Poppel, Hendrik; Joniau, Steven; Claessens, Frank



The Importance of Hydrogen Bonding and Aromatic Stacking to the Affinity and Efficacy of Cannabinoid Receptor CB2 Antagonist, 5-(4-Chloro-3-methyl-phenyl)-1-(4-methyl-benzyl)-1H-pyrazole-3-carboxylic acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide (SR144528)  

PubMed Central

Despite the therapeutic promise of the sub-nanomolar affinity cannabinoid CB2 antagonist, N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan2-yl]-5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-1H-pyrazole-3-carboxamide (SR144528, 1), little is known about its binding site interactions and no primary interaction site for 1 at CB2 has been identified. We report here the results of Glide docking studies in our cannabinoid CB2 inactive state model that were then tested via compound synthesis, binding and functional assays. Our results show that the amide functional group of 1 is critical to its CB2 affinity and efficacy and that aromatic stacking interactions in the TMH5/6 aromatic cluster of CB2 are also important. Molecular modifications that increased the positive electrostatic potential in the region between the fenchyl and aromatic rings led to more efficacious compounds. This result is consistent with the EC-3 loop negatively charged amino acid, D275 (identified via Glide docking studies) acting as the primary interaction site for 1 and its analogs. PMID:23855811

Kotsikorou, Evangelia; Navas, Frank; Roche, Michael J.; Gilliam, Anne F.; Thomas, Brian; Seltzman, Herbert H.; Kumar, Pritesh; Song, Zhao-Hui; Hurst, Dow P.; Lynch, Diane L.; Reggio, Patricia H.



Synthesis of leukotriene B4 antagonists labeled with In111 or Tc99m to image infectious and inflammatory foci  

Microsoft Academic Search

In previous studies we demonstrated that lipophilic (99m)Tc-labeled LTB4 antagonist 1 (RP517) accumulated in infectious foci in rabbits, but hepatobiliary clearance hampered imaging of abdominal lesions. We now report the use of cysteic acid as a pharmacokinetic modifier to improve the water solubility and renal clearance of three hydrophilic analogues of 1. Divalent LTB4 antagonist 17 (DPC11870-11) is a DTPA

Matthias Broekema; Julliëtte J. E. M. van Eerd; Wim J. G. Oyen; Frans H. M. Corstens; Rob M. J. Liskamp; Otto C. Boerman; Thomas D. Harris



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.  


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



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



Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate  

Technology Transfer Automated Retrieval System (TEKTRAN)

Background: An analysis of data from the National Health and Nutrition Examination Survey indicated that in older adults exposed to folic acid fortification, the combination of low serum vitamin B-12 and elevated folate is associated with higher concentrations of homocysteine and methylmalonic acid ...


FK520 interacts with the discrete intrahelical amino acids of multidrug transporter Cdr1 protein and acts as antagonist to selectively chemosensitize azole-resistant clinical isolates of Candida albicans.  


FK520, a homolog of antifungal FK506, displays fungicidal synergism with azoles in Candida albicans and inhibits drug efflux mediated by ABC multidrug transporter. This study establishes the molecular basis of interaction of FK520 with Cdr1 protein, which is one of the major ABC multidrug transporters of C. albicans. For this, we have exploited an in-house library of Cdr1 protein consisting of 252 mutant variants where the entire primary structure of the two transmembrane domains comprising of 12 transmembrane helices was subjected to alanine scanning. With these mutant variants of Cdr1 protein, we could identify the critical amino acids of the transporter protein, which if replaced with alanine, not only abrogated FK520-dependent competitive inhibition of drug efflux but simultaneously decreased susceptibility to azoles. Notably, the replacement of most of the residues with alanine was inconsequential; however, there were close to 13% mutant variants, which showed abrogation of drug efflux and reversal of fungicidal synergy with azoles. Of note, all the intrahelical residues of Cdr1 protein, which abrogated inhibitor's ability to block the efflux and reversed fungicidal synergy, were common. Taken together, our results provide evidence of cross-talk of FK520 with Cdr1 by interacting with the select intrahelical residues of the protein to chemosensitize isolates of Candida. PMID:24628911

Nim, Shweta; Rawal, Manpreet K; Prasad, Rajendra



Quantification of Thiazolidine-4-carboxylic Acid in Toxicant-Exposed Cells by Isotope-Dilution Liquid Chromatography-Mass Spectrometry Reveals an Intrinsic Antagonistic Response to Oxidative Stress-Induced Toxicity.  


Carcinogenic formaldehyde is produced by endogenous protein oxidation and various exogenous sources. With formaldehyde being both ubiquitous in the ambient environment and one of the most common reactive carbonyls produced from endogenous metabolism, quantifying formaldehyde exposure is an essential step in risk assessments. We present in this study an approach to assess the risk of exposure to oxidative stress by quantifying thiazolidine-4-carboxylic acid (TA), a cysteine-conjugated metabolite of formaldehyde in toxicant-exposed Escherichia coli. The method entails TA derivatization with ethyl chloroformate, addition of isotope-labeled TA derivatives as internal standards, solid-phase extraction of the derivatives, and quantification by liquid chromatography-mass spectrometry (LC-MS). After validating for accuracy and precision, the developed method was used to detect TA in oxidizing agent-exposed E. coli samples. Dose-dependent TA formation was observed in E. coli exposed to hydroxyl radical mediators Fe(2+)-EDTA, H2O2, and NaOCl, indicating the potential use of TA as a biomarker of exposure to oxidative stress and disease risk. PMID:25325739

Liu, Jingjing; Chan, Wan



The structure–activity relationship of the series of non-peptide small antagonists for p56lck SH2 domain  

Microsoft Academic Search

The antagonists for the SH2 domain are regarded as novel therapeutic candidates for cancer, autoimmune disease, and chronic inflammatory disease. Previously, we identified rosmarinic acid (?-o-caffeoyl-3,4-dihydroxyphenyl-lactic acid; RosA) from Prunella vulgaris as an antagonist for the p56lck SH2 domain by screening natural products. RosA not containing phosphotyrosine surrogate had a considerable inhibitory activity for T-cell antigen receptor (TCR)-induced interleukin (IL)-2

See-Hyoung Park; Hyun-Sik Oh; Mi-Ae Kang; Hyeongjin Cho; Joshi Bishnu Prasad; Jonghwa Won; Keun-Hyeung Lee



CCKB/gastrin receptor antagonists: recent advances and potential uses in gastric secretory disorders.  

PubMed Central

Cholecystokinin (CCK) and the structurally related peptide, gastrin, have numerous effects on tissues in the central nervous system and gastrointestinal tract. Recent studies show these effect are mediated by a CCKA and CCKB receptor. Knowledge of the physiological role and role of CCKB receptors in pathologic processes has been particularly limited by the availability of selective, potent receptor antagonists. Recently, new members of five different classes of non-peptide CCKB receptor antagonists are reported and are reviewed briefly. these include compounds isolated from Streptomyces (tetronothiodin, virginiamycin analogues), ureido-acetamide analogues (RP 69758, RP 72540, RP 73870), newer benzodiazepine analogues (L-368,935, L-740,093, YM022), pyrazolidimine analogues (LY 262,691) and glutamic acid analogues (CR2194). Many of these compounds have greater than 1000-fold selectivity for the CCKB over the CCKA receptor and some have greater than 10,000-fold selectivity. The pharmacology and effects of CCKB receptor antagonists on gastric acid secretion is briefly reviewed. Furthermore, the possible clinical usefulness of CCKB receptor antagonists in treating disorders of gastric acid secretion, in inhibiting the trophic effects of gastrin and in other clinical conditions is briefly discussed. PMID:9165693

Jensen, R. T.



Hypaphorine, an indole-3-acetic acid antagonist delivered by the ectomycorrhizal fungus Pisolithus tinctorius, induces reorganisation of actin and the microtubule cytoskeleton in Eucalyptus globulus ssp bicostata root hairs.  


Hypaphorine, an indole alkaloid from the ectomycorrhizal fungus Pisolithus tinctorius Coker & Couch., counteracts indole-3-acetic acid (IAA) activity and controls the rate of root hair elongation in Eucalyptus globulus ssp. bicostata. The present investigation shows that hypaphorine changes cytoskeletal organisation in elongating root hairs of the host. The actin cytoskeleton was investigated by two different fixation and labelling procedures, which gave similar results. In control root hairs, actin organisation was characterised by (i) an actin cap at the very tip region, (ii) a subapical region with reduced labelling and containing fine actin filaments, and (iii) axial bundles of actin filaments running from the subapical part to the base of the root hair. In the hypaphorine-treated root hairs no actin cap was distinguished. The fine actin filaments occurring in the subapical region were replaced by a few thick actin filament bundles that extended from the subapical region toward the root hair tip. In the hypaphorine-treated hairs the total number of actin filament bundles along most of the root hair length was significantly reduced, presumably due to aggregation of pre-existing actin filaments. The first signs of alteration to the cytoskeleton could be detected as soon as 15 min after hypaphorine treatment. In hypaphorine-treated, but not in control root hairs, a patch of aggregated microtubules regularly occurred at a distance of approximately 10 microm from the tip, possibly as a consequence of changes induced by hypaphorine in the actin cytoskeleton. The hypaphorine-induced aggregations in the actin and microtubule cytoskeletons could stabilise the structure of cytoskeletal elements, which in turn could hinder the vesicle delivery at the tip necessary for elongation. Such cytoskeletal alterations may be a consequence of the antagonism between IAA and hypaphorine. The latter view was supported by restoration of the actin cytoskeleton in hypaphorine-treated root hairs by IAA application. PMID:14504925

Ditengou, Franck Anicet; Raudaskoski, Marjatta; Lapeyrie, Frédéric



Biologically active lipid A antagonist embedded in a multilayered polyelectrolyte architecture.  


Recently [Jessel N, Schwinte P, Donohue R, Lavalle P, Boulmedais F, Darcy R, et al. Pyridylamino-beta-cyclodextrin as a molecular chaperone for lipopolysaccharide embedded in a multilayered polyelectrolyte architecture. Adv Funct Mater 2004;14:963-9], we demonstrated the biological activity of a lipopolysaccharide from Escherichia coli incorporated into layer-by-layer films made of poly (l-lysine) and poly (l-glutamic acid) and containing a polycationic beta-cyclodextrin (CD) with chaperone properties. Here we develop innovative architectures containing a complex made of a charged beta-cyclodextrin and a lipid A antagonist (LAA) as potential systems for local endotoxin antagonistic activity. We examine the biological activity of these architectures. The CD-LAA complex adsorbed on top, or embedded into the polyelectrolyte films keeps its LPS antagonistic activity on both murine and human macrophages for at least 24h. PMID:16243394

Gangloff, Sophie C; Ladam, Guy; Dupray, Valérie; Fukase, Kochi; Brandenburg, Klaus; Guenounou, Moncef; Schaaf, Pierre; Voegel, Jean-Claude; Jessel, Nadia



Anxiolytic-like effect of group III mGlu receptor antagonist is serotonin-dependent.  


Literature data have provided evidence that antagonists of group I metabotropic glutamate receptors (mGluRs) and agonists of group II/III mGluRs show anxiolytic-like properties in preclinical studies. However data reporting anxiolytic-like action of group III mGlu receptor antagonists were also published. In the present paper we investigated the anxiolytic-like activity of the group III mGlu receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). To examine its anxiolytic-like effects, the basolateral amygdala was chosen as an injection site, as this brain region is involved in the regulation of anxiety-related behavior. To detect anxiolytic-like activity, the Vogel conflict-drinking test in rats was used. Intra-amygdalar injections of CPPG exhibited dose-dependent, potent anxiolytic-like action at a dose of 75 nmol, which was blocked by a concomitant administration of the group III mGlu receptor agonist CI (S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) at a dose of 7.5 nmol. The benzodiazepine receptor antagonist flumazenil (given intraperitoneally, 10 mg/kg) did not change the anxiolytic-like effect of CPPG, but that effect was abolished by the non-selective antagonist of 5-HT receptors metergoline and the antagonist of 5-HT2A/C receptors ritanserin (both given intraperitoneally at doses of 2 and 0.5 mg/kg, respectively). These findings suggest that the blockade of group III mGlu receptors in the amygdala is responsible for anxiolysis and that serotonergic, but not the benzodiazepine recognition site of the GABA-ergic system are involved in the anxiolytic-like response induced by group III mGlu antagonist. PMID:17020774

Stachowicz, K; Chojnacka-Wójcik, E; K?ak, K; Pilc, A



TXA2-antagonistic properties of agents affecting prostaglandin synthesis or the cyclic nucleotide system in human platelets.  


Prostaglandins (PG) E1 and E2 as well as 3-isobutyl-1-methylxanthine, nitroprusside, dibutyryl cyclic AMP and N-0164 inhibited platelet aggregation induced by the thromboxane (TX) A2-mimetic prostaglandin endoperoxide analogue U46619. Non-steroidal anti-inflammatory agents - acetylsalicylic acid, indomethacin, tolfenamic acid, flumizole, nictindole and proquazone - did not demonstrate any antagonistic actions on U46619-induced aggregation at concentrations causing inhibition of prostaglandin/thromboxane synthesis-dependent forms of platelet aggregation. Comparing with the effects of the different test substances on ADP-or arachidonic acid-induced platelet aggregation, it can be suggested that PGE2 as well as 3-isobutyl-1-methylxanthine, nitroprusside, and dibutyryl cyclic AMP are functional antagonists and N-0164 is a receptor level antagonist of TXA2 in platelets. PMID:6624480

Kangasaho, M; Vapaatalo, H



Polish Academy of Sciences Bismuth increases hydroxyl radical-scavenging activity of histamine H2-receptor antagonists  

E-print Network

The effects of histamine H2-receptor antagonists, alone or in a combination with bismuth, on • OH-provoked degradation of deoxyribose were studied. The histamine H2-receptor antagonists (cimetidine, ranitidine and roxatidine), themselves decreased the deoxyribose damage in Fenton-type systems. In combinations with bismuth, their inhibitory effect in Fenton system (Fe(III)/ascorbic acid + H2O2) was stronger. Moreover, unlike Fe(III) and Cu(II), which in the presence of ascorbic acid + H2O2led to an increase in the • OH formation (deoxyribose damage), Bi(III) showed an opposite effect. The present results are interpreted in view of a better • OH scavenging activity of bismuth complexes of histamine H2-receptor antagonists as compared to that of the corresponding drugs. These findings might be one more explanation why bismuth salts, in combination with acid-reducing agents, are more effective anti-ulcer agents. Key words:

Margarita Kirkova; Albena Alex; Neli Yordanova



A Lepidopteran ortholog of reaper reveals functional conservation and evolution of IAP antagonists  

PubMed Central

Genetic studies in Drosophila melanogaster have revealed that IAP (Inhibitor of Apoptosis) proteins and IAP antagonists such as reaper play a pivotal role in controlling cell death in insects. Interestingly, while the sequences and structures of IAPs are highly conserved, the sequence of IAP antagonists diverged very rapidly during evolution, making their identification difficult. Using a customized bioinformatics approach, we identified an IAP antagonist, Ibm1, from the genome of the silkworm Bombyx mori. This is the first reaper/grim ortholog identified in a non-Dipteran insect. Previous analysis indicated that both Reaper and Grim induce cell death through their N-terminal IAP-binding motif (IBM) as well as the Grim_helix3 (GH3) domain. Functional studies indicated that Ibm1 binds to an IAP protein from Bombyx mori, BmIAP1, and induces apoptosis in insect cells via the IAP-binding motif, a 7 amino acid sequence that is highly conserved in all IAP antagonists. Interestingly, Ibm1 also contains a region that is a statistically significant match to the GH3 domain. Mutational analysis indicated that the GH3-like motif in Ibm1 has an important supportive role in IAP-antagonist function and can trigger cell death under certain conditions. PMID:19523066

Bryant, Bart; Zhang, Yanping; Zhang, Can; Santos, Carl P.; Clem, Rollie J.; Zhou, Lei



beta-Adrenoceptor blockade enhances the anticonvulsant effect of glutamate receptor antagonists against maximal electroshock.  


In this study, we evaluated whether beta-adrenoceptor antagonists may modify the protective efficacy of dizocilpine (MK-801), a NMDA receptor antagonist, and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), a non-NMDA (AMPA/kainate) receptor antagonist, against maximal electroshock-induced seizures in mice. Propranolol, acebutolol, metoprolol and atenolol were used in doses that did not alter the electroconvulsive threshold. Propranolol potentiated the anticonvulsant activity of MK-801 and GYKI 52466, significantly lowering their ED(50) values from 0.38 and 15.0 to 0.15 (P<0.001) and 8.4 mg/kg (P<0.001), respectively. Similarly, metoprolol lowered the ED(50) of MK-801 and GYKI 52466 from 0.38 and 15.0 to 0.17 (P<0.05) and 11.2 mg/kg (P<0.05). Acebutolol enhanced the protective action of GYKI 52466, lowering its ED(50) value from 15.0 to 12.2 mg/kg (P<0.05), but not that of MK-801. Atenolol, not penetrating the blood-brain barrier, did not affect the anticonvulsive efficacy of MK-801 and GYKI 52466. In conclusion, beta-adrenoceptor antagonists may act synergistically with excitatory amino acid receptor antagonists to inhibit generalised tonic-clonic seizures. PMID:11728427

Luchowska, E; Luchowski, P; Wielosz, M; Kleinrok, Z; Urbanska, E M



Effects of hydrophobic substitutions at position 18 on the potency of parathyroid hormone antagonists.  


Position 18 in a parathyroid hormone (PTH) antagonist, [Nle8,18,Tyr34]bPTH(7-34)NH2 (ii), was shown to tolerate substitutions by a range of amino acids with retention of inhibitory activity. The effects of hydrophobic substitutions at this position as a means of enhancing binding interactions with the receptor were evaluated. Substitution of Nle at position 18 with either D-Ala, D-Trp, or L-Trp in analog ii or with Trp (D or L) in the recently reported, highly potent antagonist, [Nle8,18,D-Trp12,Tyr34]bPTH(7-34)NH2 (in vitro activities; Kb = 15 nM and Ki = 125 nM), was performed. In terms of activity on renal receptors, one antagonist, [Nle8,D-Trp12,18,Tyr34]bPTH(7-34)NH2, is the most active in vitro PTH antagonist yet reported (Kb = 4 nM; Ki = 30 nM). The rationale for design of this antagonist and the conclusions regarding PTH-receptor interactions are discussed. PMID:2177456

Chorev, M; Roubini, E; Goldman, M E; McKee, R L; Gibbons, S W; Reagan, J E; Caulfield, M P; Rosenblatt, M



Anti-platelet therapy: ADP receptor antagonists  

PubMed Central

The P2Y12 receptor on platelets with which ADP interacts has an important role in promoting platelet function and thereby platelet involvement in both haemostasis and thrombosis. Agents that act as antagonists at this receptor are thus likely to provide effective antithrombotic therapy, provided that there are no adverse effects on haemostasis. Here we describe the ADP receptor antagonists that are available and in development. We also consider their mode of action and ask whether there are additional mechanisms through which they exert their inhibitory effects on platelet function. PMID:21518389

Wijeyeratne, Yanushi Dullewe; Heptinstall, Stan



Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia.  


Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated ion channel that functions as an integrator of multiple pain stimuli including heat, acid, capsaicin and a variety of putative endogenous lipid ligands. TRPV1 antagonists have been shown to decrease inflammatory pain in animal models and to produce limited hyperthermia at analgesic doses. Here, we report that ABT-102, which is a potent and selective TRPV1 antagonist, is effective in blocking nociception in rodent models of inflammatory, post-operative, osteoarthritic, and bone cancer pain. ABT-102 decreased both spontaneous pain behaviors and those evoked by thermal and mechanical stimuli in these models. Moreover, we have found that repeated administration of ABT-102 for 5-12 days increased its analgesic activity in models of post-operative, osteoarthritic, and bone cancer pain without an associated accumulation of ABT-102 concentration in plasma or brain. Similar effects were also observed with a structurally distinct TRPV1 antagonist, A-993610. Although a single dose of ABT-102 produced a self-limiting increase in core body temperature that remained in the normal range, the hyperthermic effects of ABT-102 effectively tolerated following twice-daily dosing for 2 days. Therefore, the present data demonstrate that, following repeated administration, the analgesic activity of TRPV1 receptor antagonists is enhanced, while the associated hyperthermic effects are attenuated. The analgesic efficacy of ABT-102 supports its advancement into clinical studies. PMID:19135797

Honore, Prisca; Chandran, Prasant; Hernandez, Gricelda; Gauvin, Donna M; Mikusa, Joseph P; Zhong, Chengmin; Joshi, Shailen K; Ghilardi, Joseph R; Sevcik, Molly A; Fryer, Ryan M; Segreti, Jason A; Banfor, Patricia N; Marsh, Kennan; Neelands, Torben; Bayburt, Erol; Daanen, Jerome F; Gomtsyan, Arthur; Lee, Chih-Hung; Kort, Michael E; Reilly, Regina M; Surowy, Carol S; Kym, Philip R; Mantyh, Patrick W; Sullivan, James P; Jarvis, Michael F; Faltynek, Connie R



Development and Validation of a High-Throughput Based on Liquid Chromatography with UV/MS Detection Method for Quantitation of Cichoric Acid in Echinacea purpurea Aerial-Based Dietary Supplements  

Technology Transfer Automated Retrieval System (TEKTRAN)

A method using LC/UV in combination with LC/MS/MS for quantification of seven B-complex vitamins (B1 - thiamine, B6 - pyridoxine, B3 - nicotinamide, pantothenic acid, B9 - folic acid, B2 - riboflavin, and biotin) in multi-vitamin daily supplements has been described. It involves the use of a Phenom...


Antagonistic peptide technology for functional dissection of CLV3/ESR genes in Arabidopsis.  


In recent years, peptide hormones have been recognized as important signal molecules in plants. Genetic characterization of such peptides is challenging since they are usually encoded by small genes. As a proof of concept, we used the well-characterized stem cell-restricting CLAVATA3 (CLV3) to develop an antagonistic peptide technology by transformations of wild-type Arabidopsis (Arabidopsis thaliana) with constructs carrying the full-length CLV3 with every residue in the peptide-coding region replaced, one at a time, by alanine. Analyses of transgenic plants allowed us to identify one line exhibiting a dominant-negative clv3-like phenotype, with enlarged shoot apical meristems and increased numbers of floral organs. We then performed second dimensional amino acid substitutions to replace the glycine residue individually with the other 18 possible proteinaceous amino acids. Examination of transgenic plants showed that a glycine-to-threonine substitution gave the strongest antagonistic effect in the wild type, in which over 70% of transgenic lines showed the clv3-like phenotype. Among these substitutions, a negative correlation was observed between the antagonistic effects in the wild type and the complementation efficiencies in clv3. We also demonstrated that such an antagonistic peptide technology is applicable to other CLV3/EMBRYO SURROUNDING REGION (CLE) genes, CLE8 and CLE22, as well as in vitro treatments. We believe this technology provides a powerful tool for functional dissection of widely occurring CLE genes in plants. PMID:23321419

Song, Xiu-Fen; Guo, Peng; Ren, Shi-Chao; Xu, Ting-Ting; Liu, Chun-Ming



Reviewing and identifying amino acids of human, murine, canine and equine TLR4 / MD-2 receptor complexes conferring endotoxic innate immunity activation by LPS/lipid A, or antagonistic effects by Eritoran, in contrast to species-dependent modulation by lipid IVa  

PubMed Central

There is literature evidence gathered throughout the last two decades reflecting unexpected species differences concerning the immune response to lipid IVa which provides the opportunity to gain more detailed insight by the molecular modeling approach described in this study. Lipid IVa is a tetra-acylated precursor of lipid A in the biosynthesis of lipopolysaccharide (LPS) in Gram-negative bacteria. Lipid A of the prototypic E. coli-type is a hexa-acylated structure that acts as an agonist in all tested mammalian species by innate immunorecognition via the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) receptor complex. In contrast, lipid IVa is proinflammatory in mouse cells (agonism) but it remains inactive to human macrophages and even antagonizes the action of potent agonists like E. coli-type lipid A. This particular ambivalent activity profile of lipid IVa has been confirmed in other mammalian species: in equine cells Lipid IVa also acts in a weak agonistic manner, whereas being inactive and antagonizing the lipid A-induced activation of canine TLR4/MD-2. Intriguingly, the respective TLR4 amino acid sequences of the latter species are more identical to the human (67%, 68%) than to the murine (62%, 58%) ortholog. In order to address the unpaired activity-sequence dualism for human, murine, canine and equine species regarding the activity of lipid IVa as compared to LPS and lipid A and, we review the literature and computationally pinpoint the differential biological effects of lipid IVa versus LPS and lipid A to specific amino acid residues. In contrast to lipid IVa the structurally related synthetic compound Eritoran (E5564) acts consistently in an antagonistic manner in these mammalian species and serves as a reference ligand for molecular modeling in this study. The combined evaluation of data sets provided by prior studies and in silico homology mapping of differential residues of TLR4/MD-2 complexes lends detailed insight into the driving forces of the characteristic binding modes of the lipid A domain in LPS and the precursor structure lipid IVa to the receptor complex in individual mammalian species. PMID:24688705

Scior, Thomas; Alexander, Christian; Zaehringer, Ulrich



Preconceptional omega-3 fatty acid supplementation on a micronutrient-deficient diet improves the reproductive cycle in Wistar rats.  


Folic acid and vitamin B12 deficiencies are associated with high reproductive risks ranging from infertility to fetal structural defects. The aim of the present study was to examine the effects of preconceptional omega-3 fatty acid supplementation (eicosapentaenoic acid and docosahexaenoic acid) to a micronutrient-deficient diet on the reproductive cycle in Wistar rats. Female rats were divided into five groups from birth and throughout pregnancy: a control group, a folic acid-deficient (FD) group, a vitamin B12-deficient (BD) group, a folic acid-deficient + omega-3 fatty acid-supplemented (FDO) group and a vitamin B12 deficient + omega-3 fatty acid-supplemented (BDO) group. Dams were killed on gestation Day 20 and their ovaries and mammary glands were dissected out and subjected to histological examination. Maternal micronutrient deficiency (FD and BD groups) resulted in an abnormal oestrous cycle (P<0.001), whereas omega-3 fatty acid supplementation (FDO and BDO groups) restored the oestrous cycle to normal. There were fewer corpora lutea in the ovaries of FD rats compared with controls. In addition, rats in both the FD and BD groups exhibited an absence of lactating ducts in their mammary glands compared with controls. The findings of the present study indicate, for the first time, that maternal micronutrient deficiency affects the oestrous cycle and morphology of the ovary and mammary glands. Omega-3 fatty acid supplementation ameliorated these effects. This may have implications for infertility and pregnancy outcomes. PMID:23137932

Meher, Akshaya P; Joshi, Asmita A; Joshi, Sadhana R



Antagonistic Interactions among Marine Pelagic Bacteria  

PubMed Central

Recent studies suggest that bacterial abundance and species diversity in the ocean's water column are variable at the millimeter scale, apparently in response to the small-scale heterogeneity in the distribution of organic matter. We hypothesized that bacterium-bacterium antagonistic interactions may contribute to variations in community structure at the microscale. We examined each of the 86 isolates for their inhibition of growth of the remaining 85 isolates by the Burkholder agar diffusion assay. More than one-half of the isolates expressed antagonistic activity, and this trait was more common with particle-associated bacteria than with free-living bacteria. This was exemplified by members of the ? subclass of the class Proteobacteria (?-proteobacteria), in which production of antagonistic molecules was dominated by attached bacteria. We found that ?-proteobacteria (members of the orders Alteromonadales and Vibrionales) are the most prolific producers of inhibitory materials and also the most resilient to them, while members of the Bacteriodetes were the organisms that were least productive and most sensitive to antagonistic interactions. Widespread interspecies growth inhibition is consistent with the role of this phenomenon in structuring bacterial communities at the microscale. Furthermore, our results suggest that bacteria from pelagic marine particles may be an underutilized source of novel antibiotics. PMID:11679315

Long, Richard A.; Azam, Farooq



Narcotic antagonists in the benzomorphan series  

Microsoft Academic Search

The behavioral, respiratory and cardiovascular effects of four analgesic antagonists derived from the benzomorphan nucleus have been described. In addition, the ability of these agents to reverse the respiratory, cardiovascular and behavioral depression produced by morphine and meperidine has been reported.

Louis S. Harris



Antagonist-elicited cannabis withdrawal in humans.  


Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral ??-tetrahydrocannabinol (THC) dosages (40-120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0-8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses. PMID:21869692

Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; McMahon, Robert P; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A



Identification of the essential and free amino acids of the freshwater shrimp, Macrobrachium ohione  

E-print Network

supplement, folic acid, biotin, niacin, thiamine, riboflavin supplement, pyridoxine hydrochloride, menadione sodium bisulfite (source of vitamin K activity), iron oxide, manganous oxide, copper oxide, cobalt carbonate, and zinc oxide. Ralston Purina...). Fractions of the column effluent were collected at 1 min intervals with n fraction collector. Aliqunts of each fraction were ninhydrin analyzed using a Technicon analytical system to determine the location of each amino acid peak. Fractions cor...

Miyajima, Lester Shigemi



Suppression of Niacin-induced Vasodilation with an Antagonist to Prostaglandin D2 Receptor Subtype 1  

Microsoft Academic Search

Niacin (nicotinic acid) reduces cardiovascular events in patients with dyslipidemia. However, symptoms associated with niacin-induced vasodilation (e.g., flushing) have limited its use. Laropiprant is a selective antagonist of the prostaglandin D2 receptor subtype 1 (DP1), which may mediate niacin-induced vasodilation. The aim of this proof-of-concept study was to evaluate the effects of laropiprant (vs placebo) on niacin-induced cutaneous vasodilation. Coadministration

E Lai; I De Lepeleire; T M Crumley; F Liu; L A Wenning; N Michiels; E Vets; G O'Neill; J A Wagner; K Gottesdiener



N-methyl-D-aspartate receptor antagonist APV blocks acquisition but not expression of fear conditioning  

Microsoft Academic Search

The role of N-methyl-o-aspartate (NMDA) receptors in Pavlovian fear conditioning was ex- amined using the NMDA antagonist DL-2-amino-5-phosphonovaleric acid (APV). Either APV (5 #g\\/rat) or saline was administered before the training phase, the testing phase, or both. APV completely blocked acquisition but not expression of fear conditioning. The L enantiomer of APV did not affect the acquisition of conditional fear.

Jeansok J. Kim; Joseph P. DeCola; Jesus Landeira-Fernandez; Michael S. Fanselow



Anxiolytic effect of glycine antagonists microinjected into the dorsal periaqueductal grey  

Microsoft Academic Search

To investigate if blockade of the modulatory glycine site of NMDA receptors in the dorsal periaqueductal grey (DPAG) would produce anxiolytic effects, groups of 9–14 rats received microinjections into this structure of 7-chloro-kynurenic acid (7-Cl-KY, 4 and 8 nmol) or 3-amino-1-hydroxypyrrolid-2-one (HA-966, 30 or 100 nmol), two selective antagonists at the strychnine-insensitive glycine modulatory site, and were submitted to the

M. G. Matheus; R. L. Nogueira; A. P. Carobrez; F. G. Graeff; F. S. Guimarfies



On-line visualization of the competitive behavior of antagonistic bacteria.  

PubMed Central

To study the interaction between cocultured Listeria monocytogenes and an antagonistic Leuconostoc strain producing an anti-Listeria bacteriocin, flow cytometry, a technique allowing on-line and real-time analysis, was used along with classical microbiological methods. Culture methods and flow cytometric measurements of the mixed culture over time point to a bactericidal action of the lactic acid-producing bacterial strain against L. monocytogenes cells. Images PMID:1482199

Héchard, Y; Jayat, C; Letellier, F; Julien, R; Cenatiempo, Y; Ratinaud, M H



Efficacy of H2 receptor antagonists in the treatment of gastroesophageal reflux disease and its symptoms.  


Gastroesophageal reflux disease (GERD) is caused by prolonged esophageal mucosal exposure to acid gastric refluxate due to failure of the normal antireflux mechanisms of the lower esophageal sphincter. Gastroesophageal reflux can be controlled by suppression of acid secretion or by improvement of gastric emptying and esophageal clearance. H2 receptor antagonists are the most commonly used antisecretory drugs, and in the past 20 years have constituted the cornerstone of therapy for the treatment of reflux disease. They have been shown to be effective in the symptomatic treatment of intermittent or mild nonerosive GERD (greater than 70%). When used at the usual recommended dose, all four H2 receptor antagonists (cimetidine, ranitidine, famotidine and nizatidine) are equally effective and are found to be generally very safe; interactions with other drugs metabolized through the cytochrome p450 notwithstanding. However, their efficacy is limited in more severe forms of GERD such as erosive esophagitis (symptomatic improvement 40% to 60%, endoscopic healing 40% to 50%) in which the superior efficacy and more rapid symptomatic relief provided by proton pump inhibitors is clearly demonstrated. The availability of H2 receptor antagonists for over-the-counter use will increase their use for mild and intermittent disease but is unlikely to alter the need for more potent acid suppression in aggressive reflux disease. PMID:9347179

Tougas, G; Armstrong, D



Development of Kappa Opioid Receptor Antagonists  

PubMed Central

Kappa opioid receptors (KORs) belong to the G-protein coupled class of receptors (GPCRs). They are activated by the endogenous opioid peptide dynorphin (DYN) and expressed at particularly high levels within brain areas implicated in modulation of motivation, emotion, and cognitive function. Chronic activation of KORs in animal models has maladaptive effects including increases in behaviors that reflect depression, the propensity to engage in drug-seeking behavior, and drug craving. The fact that KOR activation has such a profound influence on behaviors often triggered by stress has led to interest in selective KOR antagonists as potential therapeutic agents. This perspective provides a description of preclinical research conducted in the development of several different classes of selective KOR antagonists, a summary of the clinical studies conducted thus far, and recommendations for the type of work needed in the future to determine if these agents would be useful as pharmacotherapies for neuropsychiatric illness. PMID:23360448

Carroll, F. Ivy; Carlezon, William A.



TRPV1 antagonists as potential antitussive agents.  


Cough is an important defensive pulmonary reflex that removes irritants, fluids, or foreign materials from the airways. However, when cough is exceptionally intense or when it is chronic and/or nonproductive it may require pharmacologic suppression. For many patients, antitussive therapies consist of OTC products with inconsequential efficacies. On the other hand, the prescription antitussive market is dominated by older opioid drugs such as codeine. Unfortunately, "codeine-like" drugs suppress cough at equivalent doses that also often produce significant ancillary liabilities such as GI constipation, sedation, and respiratory depression. Thus, the discovery of a novel and effective antitussive drug with an improved side effect profile relative to codeine would fulfill an unmet clinical need in the treatment of cough. Afferent pulmonary nerves are endowed with a multitude of potential receptor targets, including TRPV1, that could act to attenuate cough. The evidence linking TRPV1 to cough is convincing. TRPV1 receptors are found on sensory respiratory nerves that are important in the generation of the cough reflex. Isolated pulmonary vagal afferent nerves are responsive to TRPV1 stimulation. In vivo, TRPV1 agonists such as capsaicin elicit cough when aerosolized and delivered to the lungs. Pertinent to the debate on the potential use of TRPV1 antagonist as antitussive agents are the observations that airway afferent nerves become hypersensitive in diseased and inflamed lungs. For example, the sensitivity of capsaicin-induced cough responses following upper respiratory tract infection and in airway inflammatory diseases such as asthma and COPD is increased relative to that of control responses. Indeed, we have demonstrated that TRPV1 antagonism can attenuate antigen-induced cough in the allergic guinea pig. However, it remains to be determined if the emerging pharmacologic profile of TRPV1 antagonists will translate into a novel human antitussive drug. Current efforts in clinical validation of TRPV1 antagonists revolve around various pain indications; therefore, clinical evaluation of TRPV1 antagonists as antitussive agents will have to await those outcomes. PMID:17926096

McLeod, Robbie L; Correll, Craig C; Jia, Yanlin; Anthes, John C



Angiogenin antagonists prevent tumor growth in vivo.  

PubMed Central

A noncytotoxic neutralizing monoclonal antibody (mAb), 26-2F, to human angiogenin (Ang), a potent inducer of neovascularization, has been reported to prevent or delay the establishment of HT-29 human tumor xenografts in athymic mice. In the present study the tumor model was modified to increase sensitivity to Ang antagonists to facilitate further investigations and comparisons of their capacity to inhibit tumor growth. An increase in the percentage of tumor-free mice from 10-25% to 65% is observed in this modified model after treatment with mAb 26-2F. An additional neutralizing mAb, 36u, that interacts with a different epitope on Ang similarly prevents the appearance of tumors, both alone and in combination with mAb 26-2F. In those tumors that develop in mice treated with these agents, the number of vascular elements is reduced. Actin, an Ang antagonist that unlike the mAbs binds both human and mouse Ang, also prevents the establishment of tumors while exhibiting no toxic effects at daily doses > 50 times the molar amount of circulating mouse Ang. Ang antagonists also inhibit the appearance of tumors derived from two other Ang-secreting human tumor cell lines--i.e., A549 lung adenocarcinoma and HT-1080 fibrosarcoma. These results demonstrate that inhibition of the action of Ang is an effective therapeutic approach for the treatment of malignant disease. Images Fig. 2 PMID:7831307

Olson, K A; Fett, J W; French, T C; Key, M E; Vallee, B L



Homology modeling and antagonist binding site study of the human histamine H2 receptor.  


On the basis of the high resolution crystal structures of bovine rhodopsin, human beta2-adrenergic receptor and human A(2a) adenosine receptor, three-dimensional structure of the human histamine H2 receptor (HHR2) was developed by homology modeling. Results of the evaluations suggest that a high quality homology model for HHR2 has been obtained. Three antagonists, cimetidine, ranitidine and nizatidine, were applied to binding site study with this model through molecular docking, molecular dynamics simulations and the molecular mechanics-Poisson-Boltzmann surface area calculations. One aspartic acid, Asp98 in transmembrane domain 7 (TM3), has been identified as major contributors to ligand binding by H-bond interactions. Asn159 in TM4 and Asp186 in TM5 are of great importance in stabilizing HHR2- antagonist complexes. Two hydrophobic sites especially two residues, Val99 in TM3 and Phe254 in TM6, were identified to be essential for their strong hydrophobic interactions with antagonists. The findings reported here are in agreement with available experimental mutagenesis data. This study should be very helpful for a better understanding of the action mode of the antagonist and for guiding further drug design and mutagenesis studies. PMID:22779803

Zhang, Jing; Qi, Tao; Wei, Jing



Antagonistic regulation of Arabidopsis growth by brassinosteroids and abiotic stresses.  


To withstand ever-changing environmental stresses, plants are equipped with phytohormone-mediated stress resistance mechanisms. Salt stress triggers abscisic acid (ABA) signaling, which enhances stress tolerance at the expense of growth. ABA is thought to inhibit the action of growth-promoting hormones, including brassinosteroids (BRs). However, the regulatory mechanisms that coordinate ABA and BR activity remain to be discovered. We noticed that ABA-treated seedlings exhibited small, round leaves and short roots, a phenotype that is characteristic of the BR signaling mutant, brassinosteroid insensitive1-9 (bri1-9). To identify genes that are antagonistically regulated by ABA and BRs, we examined published Arabidopsis microarray data sets. Of the list of genes identified, those upregulated by ABA but downregulated by BRs were enriched with a BRRE motif in their promoter sequences. After validating the microarray data using quantitative RT-PCR, we focused on RD26, which is induced by salt stress. Histochemical analysis of transgenic Arabidopsis plants expressing RD26pro:GUS revealed that the induction of GUS expression after NaCl treatment was suppressed by co-treatment with BRs, but enhanced by co-treatment with propiconazole, a BR biosynthetic inhibitor. Similarly, treatment with bikinin, an inhibitor of BIN2 kinase, not only inhibited RD26 expression, but also reduced the survival rate of the plant following exposure to salt stress. Our results suggest that ABA and BRs act antagonistically on their target genes at or after the BIN2 step in BR signaling pathways, and suggest a mechanism by which plants fine-tune their growth, particularly when stress responses and growth compete for resources. PMID:25377253

Chung, Yuhee; Kwon, Soon Il; Choe, Sunghwa



Antagonistic functional duality of cancer genes.  


Cancer evolution is a stochastic process both at the genome and gene levels. Most of tumors contain multiple genetic subclones, evolving in either succession or in parallel, either in a linear or branching manner, with heterogeneous genome and gene alterations, extensively rewired signaling networks, and addicted to multiple oncogenes easily switching with each other during cancer progression and medical intervention. Hundreds of discovered cancer genes are classified according to whether they function in a dominant (oncogenes) or recessive (tumor suppressor genes) manner in a cancer cell. However, there are many cancer "gene-chameleons", which behave distinctly in opposite way in the different experimental settings showing antagonistic duality. In contrast to the widely accepted view that mutant NADP(+)-dependent isocitrate dehydrogenases 1/2 (IDH1/2) and associated metabolite 2-hydroxyglutarate (R)-enantiomer are intrinsically "the drivers" of tumourigenesis, mutant IDH1/2 inhibited, promoted or had no effect on cell proliferation, growth and tumorigenicity in diverse experiments. Similar behavior was evidenced for dozens of cancer genes. Gene function is dependent on genetic network, which is defined by the genome context. The overall changes in karyotype can result in alterations of the role and function of the same genes and pathways. The diverse cell lines and tumor samples have been used in experiments for proving gene tumor promoting/suppressive activity. They all display heterogeneous individual karyotypes and disturbed signaling networks. Consequently, the effect and function of gene under investigation can be opposite and versatile in cells with different genomes that may explain antagonistic duality of cancer genes and the cell type- or the cellular genetic/context-dependent response to the same protein. Antagonistic duality of cancer genes might contribute to failure of chemotherapy. Instructive examples of unexpected activity of cancer genes and "paradoxical" effects of different anticancer drugs depending on the cellular genetic context/signaling network are discussed. PMID:23933273

Stepanenko, A A; Vassetzky, Y S; Kavsan, V M



Plant growth-promoting rhizobacteria (PGPR): Their potential as antagonists and biocontrol agents  

PubMed Central

Bacteria that colonize plant roots and promote plant growth are referred to as plant growth-promoting rhizobacteria (PGPR). PGPR are highly diverse and in this review we focus on rhizobacteria as biocontrol agents. Their effects can occur via local antagonism to soil-borne pathogens or by induction of systemic resistance against pathogens throughout the entire plant. Several substances produced by antagonistic rhizobacteria have been related to pathogen control and indirect promotion of growth in many plants, such as siderophores and antibiotics. Induced systemic resistance (ISR) in plants resembles pathogen-induced systemic acquired resistance (SAR) under conditions where the inducing bacteria and the challenging pathogen remain spatially separated. Both types of induced resistance render uninfected plant parts more resistant to pathogens in several plant species. Rhizobacteria induce resistance through the salicylic acid-dependent SAR pathway, or require jasmonic acid and ethylene perception from the plant for ISR. Rhizobacteria belonging to the genera Pseudomonas and Bacillus are well known for their antagonistic effects and their ability to trigger ISR. Resistance-inducing and antagonistic rhizobacteria might be useful in formulating new inoculants with combinations of different mechanisms of action, leading to a more efficient use for biocontrol strategies to improve cropping systems. PMID:23411488

Beneduzi, Anelise; Ambrosini, Adriana; Passaglia, Luciane M.P.



Enhancement of the inhibitory effect of an IL-15 antagonist peptide by alanine scanning.  


IL-15 is a proinflammatory cytokine that acts early in the inflammatory response and has been associated with several autoimmune diseases including rheumatoid arthritis, where it had been proposed as a therapeutic target. We recently reported an IL-15 antagonist peptide corresponding to sequence 36-45 of IL-15 (KVTAMKCFLL) named P8, which specifically binds to IL-15R? and inhibits IL-15 biological activity with a half maximal inhibitory concentration (IC50) of 130?µ m in CTLL-2 proliferation assay. In order to improve binding of peptide P8 to the receptor IL-15R?, we used an Ala scan strategy to study contribution of each individual amino acid to the peptide's antagonist effect. Here, we found that Phe and Cys are important for peptide binding to IL-15R?. We also investigated other single site mutations and replaced the second Lys in the sequence by the polar non-charged amino acid threonine. The resulting peptide [K6T]P8 exhibited a higher activity than P8 with an IC50 of 24?µm. We also found that this peptide was more active than peptide P8 in the inhibition of TNF? secretion by synovial cells from rheumatoid arthritis patients. The peptide [K6T]P8 described in this work is a new type of IL-15 antagonist and constitutes a potential therapeutic agent for rheumatoid arthritis. PMID:22052738

Savio, Alicia Santos; Acosta, Osvaldo Reyes; Pérez, Haydee Gerónimo; Alvarez, Yunier Rodríguez; Chico, Araceli; Pérez, Hilda Garay; Ojeda, Miriam Ojeda; Aguero, Celia Aurora Arrieta; Estévez, Miguel; Nieto, Gerardo Guillen



Diphenyl purine derivatives as peripherally selective cannabinoid receptor 1 antagonists.  


Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorders. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are our efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS. PMID:23098108

Fulp, Alan; Bortoff, Katherine; Zhang, Yanan; Seltzman, Herbert; Mathews, James; Snyder, Rodney; Fennell, Tim; Maitra, Rangan



Agonists and antagonists for P2 receptors  

PubMed Central

Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X2/3/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X2/3/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4 nM at the P2Y1 receptor, with >10 000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. PMID:16805423

Jacobson, Kenneth A.; Costanzi, Stefano; Joshi, Bhalchandra V.; Besada, Pedro; Shin, Dae Hong; Ko, Hyojin; Ivanov, Andrei A.; Mamedova, Liaman



Quinoxalinediones: Potent Competitive Non-NMDA Glutamate Receptor Antagonists  

Microsoft Academic Search

The N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors has been well described as a result of the early appearance of NMDA antagonists, but no potent antagonist for the ``non-NMDA'' glutamate receptors has been available. Quinoxalinediones have now been found to be potent and competitive antagonists at non-NMDA glutamate receptors. These compounds will be useful in the determination of the structure-activity relations of

Tage Honore; Steve N. Davies; Jorgen Drejer; Elizabeth J. Fletcher; Poul Jacobsen; David Lodge; Flemming E. Nielsen



Discovery of MK-3697: a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia.  


Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species. PMID:25248679

Roecker, Anthony J; Reger, Thomas S; Mattern, M Christa; Mercer, Swati P; Bergman, Jeffrey M; Schreier, John D; Cube, Rowena V; Cox, Christopher D; Li, Dansu; Lemaire, Wei; Bruno, Joseph G; Harrell, C Meacham; Garson, Susan L; Gotter, Anthony L; Fox, Steven V; Stevens, Joanne; Tannenbaum, Pamela L; Prueksaritanont, Thomayant; Cabalu, Tamara D; Cui, Donghui; Stellabott, Joyce; Hartman, George D; Young, Steven D; Winrow, Christopher J; Renger, John J; Coleman, Paul J



Dihydropyrrolo[2,3-d]pyrimidines: Selective Toll-Like Receptor 9 Antagonists from Scaffold Morphing Efforts.  


Toll-like receptors (TLRs) play important roles in the innate immune system. In fact, recognition of endogenous immune complexes containing self-nucleic acids as pathogen- or damage-associated molecular patterns contributes to certain autoimmune diseases, and inhibition of these recognition signals is expected to have therapeutic value. We identified dihydropyrrolo[2,3-d]pyrimidines as novel selective TLR9 antagonists with high aqueous solubility. A structure-activity relationship study of a known TLR9 antagonist led to the promising compound 18, which showed potent TLR9 antagonistic activity, sufficient aqueous solubility for parenteral formulation, and druggable properties. Compound 18 suppressed the production of the proinflammatory cytokine IL-6 in CpG-induced mouse model. It is therefore believed that compound 18 has great potential in the treatment of TLR9-mediated systemic uncontrollable inflammatory response like sepsis. PMID:25408837

Watanabe, Manabu; Kasai, Mai; Tomizawa, Hideyuki; Aoki, Masamitsu; Eiho, Kazuo; Isobe, Yoshiaki; Asano, Shigehiro



Modified 2'-ribose small RNAs function as Toll-like receptor-7/8 antagonists.  


A subset of Toll-like receptors (TLRs) senses microbial nucleic acids in endosomal compartments. Furthermore, under certain conditions TLRs can recognize self-RNAs leading to the induction and/or perpetuation of inflammatory diseases. Recent studies have shown that the incorporation of modified nucleotides into small interfering RNA suppressed unwanted immunostimulation. Interestingly, RNA harboring 2'-ribose modifications, particularly 2'-O-methyl not only evaded immune activation but also suppressed TLR signaling triggered in-trans by immunostimulatory RNAs. This new generation of TLR antagonists may have utility as inhibitors of pathogenic inflammatory reactions mediated by TLR activation. Beyond their structural role, natural modifications in native eukaryotic RNAs may function as endogenous TLR antagonists as well. This chapter describes the characterization of short synthetic small RNAs that suppress immunostimulatory activity in-trans. PMID:25319669

Sioud, Mouldy



Recent advances in non-steroidal FXR antagonists development for therapeutic applications.  


Farnesoid X receptor (FXR, NR1H4), a nuclear receptor (NR) highly expressed in the liver, intestine, kidney, adrenal glands and other cholesterol-rich tissues, functions as the master regulator for bile acid homeostasis. FXR, which regulates the expression of genes encoding proteins involved in cholesterol homeostasis, plays an essential role in regulating cholesterol, lipid, and glucose metabolism. Recently, some FXR agonists are reported to have low selectivity on NRs, which forces the researchers to move their eyes onto the development of FXR antagonists with high selectivity. The development of non-steroidal FXR antagonists with different scaffolds including AGN34, tuberatolides, atractylenolides, andrographolides, GW4064 derivatives and 1,3,4-trisubstitutedpyrazolones, provides us a prospect for the therapy of in ammation, metabolic syndrome, diabetes, cholesterol gallstones, and cancer. PMID:25388534

Huang, Huang; Xu, Yong; Zhu, Jin; Li, Jian



Evaluation in vitro of the antagonistic substances produced by Lactobacillus spp. isolated from chickens  

PubMed Central

To determine the inhibitory capacity of lactic acid bacteria due to the action of antagonistic substances, we tested 474 isolates of Lactobacillus from the crop and cecum of chickens against gram-positive and gram-negative indicator microorganisms by the spot-on-the-lawn and well-diffusion antagonism methods. Of the 474 isolates, 265 demonstrated antimicrobial activity against the indicator microorganisms. Isolates identified as L. reuteri, L. salivarius, or Lactobacillus spp. inhibited Enterococcus faecalis, E. faecium, Listeria monocytogenes, and Salmonella spp. but not L. casei, L. delbrueckii, L. fermentum, or L. helveticus by the well-diffusion simultaneous antagonism method under anaerobic incubation conditions. The antagonistic substances produced by some of the Lactobacillus isolates were inactivated after treatment by proteolytic enzymes, which suggested that the substances could be antimicrobial peptides or bacteriocins. PMID:17479773

Lima, Edna T.; Andreatti Filho, Raphael L.; Okamoto, Adriano S.; Noujaim, José C.; Barros, Mércia R.; Crocci, Adalberto J.



Interaction of Wheat Germ Ca2+-Dependent Protein Kinases with Calmodulin Antagonists and Polyamines 1  

PubMed Central

The two soluble Ca2+-dependent protein kinases resolved from wheat (Triticum aestivum) embryo (protein kinases I and II) are inhibited by the phenothiazine-derived calmodulin antagonists trifluoperazine fluphenazine, and chlorpromazine. Protein kinases I and II are also inhibited by a variety of other calmodulin antagonists (including calmidazolium, amitriptyline, and iprindole), phosphodiesterase inhibitors (including flufenamic acid and papavarine) and by lanthanides. A number of compounds that inhibit mammalian Ca2+ - and phospholipid-activated protein kinase (protein kinase C) including quercetin, polymixin B sulfate, and polyamines (as well as phenothiazine derivatives) also inhibit protein kinases I and II. Poly-l-lysine and poly-l-ornithine activate both plant Ca2+-dependent protein kinases. PMID:16664554

Polya, Gideon M.; Micucci, Vito



Microbial antagonists of Escherichia coli O157:H7 on fresh-cut lettuce and spinach.  


Fresh-cut lettuce and spinach can become contaminated with pathogens at numerous points from the field to the retail market. Natural microflora present on fresh produce may help reduce the pathogen load. The objective of this study was to isolate natural microflora from fresh-cut iceberg lettuce and baby spinach and to determine whether these bacteria were antagonistic toward Escherichia coli O157:H7. Samples were collected under conditions that mimicked actual practices between production and retail sale. Evidence of naturally occurring microorganisms on fresh lettuce (295